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Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients’ primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158F/V variants. Using MM patients’ primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.

Monoclonal antibodies such as daratumumab that target antigens that are also expressed on red blood cells impede blood group typing. The preferred approach to potential transfusion is to do prior extensive antigen typing of patients' red cells; however, this is not always possible. Ehrend et al describe a technique for absorbing the antibodies from serum to allow accurate red cell typing for transfusion.

The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase. The ongoing randomized phase has met its prespecified primary end point of an improved stringent complete response (sCR) rate after consolidation for D-RVd (reported elsewhere). Final analysis of the safety run-in cohort is reported herein and provides longer follow-up (median, 40.8 months) encompassing daratumumab plus lenalidomide (D-R) maintenance therapy. Patients in the safety run-in cohort (N = 16) received 4 induction cycles (D-RVd), high-dose melphalan supported by autologous stem cell transplant, 2 consolidation cycles (D-RVd), and 24 months of maintenance (D-R). By the end of consolidation, all patients had responded, with a best response of sCR in 9 (56.3%) patients; 8 (50.0%) patients were minimal residual disease (MRD) negative (10‒5 threshold). After maintenance, 15 (93.8%) patients had achieved a best response of sCR, and 13 (81.3%) patients were MRD (10‒5) negative. Estimated 36-month progression-free and overall survival rates were 78.1% and 93.8%, respectively. One death from progressive disease occurred in the patient who did not achieve sCR. Observed safety profiles were consistent with daratumumab and RVd. With >3 years of median follow-up, D-RVd achieved durable responses that deepened with D-R maintenance. This study was registered at www.clinicaltrials.gov as #NCT02874742.

CD38 antibodies were first evaluated in extensively pretreated patients with multiple myeloma (MM). Currently, there are 3 CD38 antibody–based regimens approved for the treatment of both transplant-eligible (daratumumab plus bortezomib-thalidomide-dexamethasone [D-VTd]) and transplant-ineligible (daratumumab plus lenalidomide-dexamethasone [D-Rd] or daratumumab plus bortezomib-melphalan-prednisone [D-VMP]) patients with newly diagnosed MM (NDMM). The phase 3 studies that evaluated these regimens uniformly showed that the addition of daratumumab to backbone regimens improved the depth of response, which translated into improved progression-free survival and also overall survival in 2 of the studies. Importantly, elderly patients age 75 years or older benefit from these regimens, indicating that these regimens have an acceptable safety profile. Although the number of patients with high-risk cytogenetics was relatively small, these patients also experienced benefit from the addition of daratumumab to standard-of-care regimens, but poor risk conferred by the cytogenetic aberrations is not completely abrogated. Altogether, daratumumab-based regimens have high anti-MM activity and a favorable toxicity profile and therefore represent new standards of care for patients with NDMM.

Background: Systemic AL amyloidosis is a rare disease characterized by amyloid fibril deposits, most commonly in the heart and kidneys; there are currently no health authority-approved treatments. Therapies for the treatment of multiple myeloma (MM), including bortezomib, cyclophosphamide, and dexamethasone (VCd), have been shown to improve outcomes in AL amyloidosis, but more effective therapies are needed to achieve deep and rapid hematologic responses, reverse amyloid-mediated organ dysfunction, and improve overall survival. Daratumumab is an anti-CD38 monoclonal antibody approved as monotherapy or in combination with other agents for the treatment of MM. ANDROMEDA (NCT03201965) is a randomized, open-label, active-controlled phase 3 trial of VCd ± daratumumab subcutaneous (DARA SC) in patients with newly-diagnosed AL amyloidosis. After a median follow-up of 11.4 months, the complete hematologic response rate was 53% for DARA SC + VCd (DARA-VCd) and 18% for VCd (odds ratio, 5.1; 95% CI, 3.2-8.2; P Methods: Patients with newly-diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage (Mayo 2004) I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic MM were randomized 1:1 to DARA-VCd or VCd and treated for six 28-day cycles; thereafter, patients in the DARA-VCd group received DARA SC alone every 4 weeks for up to 24 cycles. PROs were assessed on Day 1 of Cycles 1-6 for both treatment groups and every 8 weeks thereafter in the DARA-VCd group. PRO assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30), the EuroQol 5-dimensional descriptive system (EQ-5D-5L), and Short Form-36 (SF-36). Improvements in EORTC QLQ-C30 global health status (GHS) and fatigue scale scores and SF-36 mental component summary (MCS) score were secondary endpoints. Assessment of physical functioning, symptom improvement, functional improvement, and health utility as measured by the SF-36, EORTC QLQ-C30 with supplemental symptom items, and the EQ-5D-5L were exploratory outcomes. Patients completed PRO questionnaires prior to study assessments or study drug administration. Analyses of PROs were performed on the intent-to-treat analysis set; patients without a baseline or post-baseline assessment were censored at date of randomization. Compliance with PRO assessments was calculated as the number of assessments received divided by the number of assessments expected at each time point. Descriptive statistics are provided for all PRO endpoints at each time point by treatment group. A distribution-based method was used to define worsening/improvement in scores. Time to worsening/improvement, hazard ratios, and associated 95% confidence intervals were estimated using Kaplan Meier methods and Cox proportional hazards regression. Change from baseline at each time point up to Cycle 6 (Week 24) was calculated using a mixed effects model with repeated measures with patients as a random effect and baseline value, treatment group, time (weeks), treatment-by-time interaction, and stratification factors as fixed effects. Results: A total of 388 patients were randomized (DARA-VCd, n=195; VCd, n=193). Compliance rates for all PRO questionnaires were >90% at baseline and >83% through Cycle 6. Median time to improvement was shorter and median time to worsening was longer in the DARA-VCd group than in the VCd group for EORTC QLQ-C30 GHS and fatigue scales and EQ-5D-5L visual analog scale (VAS) (Table 1). Least squares mean scores for EORTC QLQ-C30 GHS and fatigue, EQ-5D-5L VAS, and SF-36 MCS remained stable in the DARA-VCd group but worsened compared with baseline in the VCd group; between-group differences are shown in Table 2. The greatest between-group differences in PRO score changes from baseline were observed at Week 16 (Cycle 4). After Cycle 6, patients in the DARA-VCd group reported improvements in mean GHS and fatigue scores that continued while on treatment (Figure). Conclusions: Patients with AL amyloidosis treated with DARA-VCd experienced clinical improvements without any decrement in health-related quality of life over 6 cycles. Following Cycle 6, improvements in GHS and fatigue were reported in patients in the DARA-VCd group. These findings further support the value of DARA-VCd in patients with AL amyloidosis. Disclosures Sanchorawala: UpToDate: Patents & Royalties; Abbvie: Other: advisory board; Proclara: Other: advisory board; Caleum: Other: advisory board; Regeneron: Other: advisory board; Oncopeptide: Research Funding; Caelum: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Minnema:Servier: Consultancy; Amgen: Consultancy; Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding. Jaccard:Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding; Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding. Lee:Janssen: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Regeneron: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding. Gibbs:Janssen, BMS/Celgene, Amgen, Takeda, Pfizer, Caelum, Abbvie and Eidos: Membership on an entity's Board of Directors or advisory committees. Mollee:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. Schönland:Janssen: Honoraria, Other: travel support to meetings, Research Funding; Prothena: Honoraria, Other: travel support to meetings, Research Funding; Takeda: Honoraria, Other: travel support to meetings, Research Funding. Suzuki:Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Kim:BMS, Takeda, Amgen, Celgene, Janssen: Consultancy, Honoraria, Research Funding. Cibeira:Janssen, Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene, Amgen: Honoraria, Other: Educational lectures. Beksac:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Valent:Celgene: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Amgen Inc.: Other: Teaching, Speakers Bureau. Wong:GSK: Research Funding; Roche: Research Funding; Janssen: Research Funding; Bristol Myers Squibb: Research Funding; Fortis: Research Funding; Amgen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig:Janssen: Speakers Bureau. Bumma:Amgen: Speakers Bureau; Sanofi: Speakers Bureau. Gries:Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau:Janssen: Current Employment, Current equity holder in publicly-traded company. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Comenzo:Caleum: Consultancy; Amgen: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Unum: Consultancy; Karyopharm: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria. Wechalekar:Takeda: Honoraria, Other: Travel; Celgene: Honoraria; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory.

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In phase 3 clinical studies, the addition of daratumumab to standard-of-care regimens consistently demonstrated a significant progression-free survival (PFS) benefit and improved depth of response, including minimal residual disease-negativity, in patients (pts) with newly diagnosed MM or RRMM. In the primary analysis of the phase 3 CASTOR study (median follow-up: 7.4 mo), D-Vd reduced the risk of disease progression or death by 61% (median PFS, not reached [NR] vs 7.2 mo; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.28-0.53; P Methods: Eligible pts in LEPUS and CASTOR received ≥1 prior line of therapy and were randomized 2:1 in LEPUS and 1:1 in CASTOR to 8, 21-day cycles of V (1.3 mg/m2 SC) on Days 1, 4, 8, and 11, and d (20 mg, PO or IV) on Days 1, 2, 4, 5, 8, 9, 11, and 12 ± D (16 mg/kg IV) given QW for Cycles 1-3, Q3W for Cycles 4-8, and Q4W thereafter. The primary endpoint for both studies was PFS. Results: A total of 211 (D-Vd, n=141; Vd, n=70) pts in LEPUS and 498 (D-Vd, n=251; Vd, n=247) pts in CASTOR were randomized. The median (range) age was 61 (28-82) years for Chinese and 64 (30-88) years for global pts. In general, baseline characteristics were similar between Chinese and global pts and balanced between treatment arms, with the exception of median body weight (LEPUS: 67 kg; CASTOR: 76 kg). Chinese and global pts both received a median of 2 prior lines of therapy; 79% and 66% received prior V, 27% and 28% were refractory to lenalidomide, and 64% and 32% were refractory to their last prior line of therapy, respectively. After a median follow up of 8.2 months in LEPUS and 7.4 months in CASTOR, a consistent PFS benefit of D-Vd vs Vd was demonstrated in the pooled analysis set across age (60 mL/min) subgroups (Table 1). Median time to progression was also consistently prolonged with D-Vd vs Vd across pooled pt subgroups. Among response evaluable pts, D-Vd improved overall response rate, rate of very good partial response or better, and rate of complete response or better (Table 2) and prolonged median duration of response vs Vd in all pt subgroups. Additional data, including PFS2, from the pooled subgroups analysis will be presented at the meeting. The safety profile of D-Vd was generally consistent across pts in LEPUS and CASTOR. Grade 3/4 treatment-emergent adverse events (TEAEs; D-Vd/Vd) occurring at a ≥5% frequency with D-Vd vs Vd in both Chinese and global pts included thrombocytopenia (51%/37%; 45%/33%), lymphopenia (44%/29%; 10%/3%), neutropenia (16%/6%; 13%/4%), and hypertension (12%/3%; 7%/1%). 49%/38% of Chinese and 42%/34% of global pts had ≥1 serious TEAEs. TEAEs leading to treatment discontinuation occurred in 4%/3% of Chinese and 7%/9% of global pts, and TEAEs leading to death occurred in 4%/10% of Chinese and 5%/6% of global pts. Rates of infusion-related reactions (IRRs) were similar for D-Vd across studies (LEPUS: 38%; CASTOR: 45%); most occurred during the first infusion and the majority were grade 1/2. Conclusions: D-Vd demonstrated a clinical benefit, including significantly improved PFS, in pooled Chinese and global pts with RRMM who received ≥1 prior line of therapy, regardless of age, cytogenetic risk status, or renal function. The safety profile of D-Vd was consistent across all pts, and no new safety concerns were identified. These results support the use of D-Vd in Chinese pts with RRMM. Disclosures Jin: The First Affiliated Hospital of Zhejiang University: Current Employment. Spencer:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Cilag GmbH: Consultancy, Honoraria, Research Funding, Speakers Bureau. Weisel:Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; GlaxoSmithKline: Honoraria. Mateos:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nooka:Adaptive Technologies: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding. Qi:Janssen: Current Employment, Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company. Sun:Janssen: Current Employment, Current equity holder in publicly-traded company. Gai:Janssen: Current Employment, Current equity holder in publicly-traded company. Liu:Janssen: Current Employment, Current equity holder in publicly-traded company. Yang:Janssen: Current Employment, Current equity holder in publicly-traded company.

Although no therapies are approved for light chain (AL) amyloidosis, cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is considered standard of care. Based on outcomes of daratumumab in multiple myeloma (MM), the phase 3 ANDROMEDA study (NCT03201965) is evaluating daratumumab-CyBorD vs CyBorD in newly diagnosed AL amyloidosis. We report results of the 28-patient safety run-in. Patients received subcutaneous daratumumab (DARA SC) weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 2 years. CyBorD was given weekly for 6 cycles. Patients had a median of 2 involved organs (kidney, 68%; cardiac, 61%). Patients received a median of 16 (range, 1-23) treatment cycles. Treatment-emergent adverse events were consistent with DARA SC in MM and CyBorD. Infusion-related reactions occurred in 1 patient (grade 1). No grade 5 treatment-emergent adverse events occurred; 5 patients died, including 3 after transplant. Overall hematologic response rate was 96%, with a complete hematologic response in 15 (54%) patients; at least partial response occurred in 20, 22, and 17 patients at 1, 3, and 6 months, respectively. Renal response occurred in 6 of 16, 7 of 15, and 10 of 15 patients, and cardiac response occurred in 6 of 16, 6 of 13, and 8 of 13 patients at 3, 6, and 12 months, respectively. Hepatic response occurred in 2 of 3 patients at 12 months. Daratumumab-CyBorD was well tolerated, with no new safety concerns versus the intravenous formulation, and demonstrated robust hematologic and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT03201965.

Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light-chain amyloidosis (AL). We report the results of a prospective multicenter phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) >50 mg/L were included in 15 centers between September of 2016 and April of 2018. Patients received 6 28-day cycles of IV daratumumab, every week for cycles 1 and 2 and every 2 weeks for cycles 3 through 6. Median age was 69 years (range, 45-83). Twenty-six patients had ≥2 organs involved, with heart in 24 and kidney in 26. Median time from diagnosis to enrollment was 23 months (interquartile range, 4-122), with a median of 3 prior therapies (range, 1-5). At data cutoff (September of 2019), all patients discontinued therapy; 33 received the planned 6 cycles. Overall, 22 patients had hematological response, and 19 patients (47.5%) achieved very good partial response (dFLC

Daratumumab has shown promising first results in systemic amyloid light-chain (AL) amyloidosis. We analyzed a consecutive series of 168 patients with advanced AL receiving either daratumumab/dexamethasone (DD, n = 106) or daratumumab/bortezomib/dexamethasone (DVD, n = 62). DD achieved a remission rate (RR) of 64% and a very good hematologic remission (VGHR) rate of 48% after 3 months. Median hematologic event-free survival (hemEFS) was 11.8 months and median overall survival (OS) was 25.6 months. DVD achieved a 66% RR and a 55% VGHR rate. Median hemEFS was 19.1 months and median OS had not been reached. Cardiac organ responses were noted in 22% with DD and 26% with DVD after 6 months. Infectious complications were common (Common Terminology Criteria [CTC] grade 3/4: DD 16%, DVD 18%) and likely related to a high rate of lymphocytopenia (CTC grade 3/4: DD 20%, DVD 17%). On univariable analysis, hyperdiploidy and gain 1q21 conferred an adverse factor for OS and hemEFS with DD, whereas translocation t(11;14) was associated with a better hemEFS. N-terminal prohormone of brain natriuretic peptide >8500 ng/L could not be overcome for survival with each regimen. Multivariable Cox regression analysis revealed plasma cell dyscrasia (difference between serum free light chains [dFLC]) >180 mg/L as an overall strong negative prognostic factor. Additionally, nephrotic-range albuminuria with an albumin-to-creatinine-ratio (ACR) >220 mg/mmol was a significantly adverse factor for hemEFS (hazard ratio, 2.1 and 3.1) with DD and DVD. Daratumumab salvage therapy produced good results and remission rates challenging any therapy in advanced AL. Outcome is adversely influenced by the activity of the underlying plasma cell dyscrasia (dFLC) and nephrotic-range albuminuria (ACR).

Daratumumab, a monoclonal CD38 antibody, is approved in the treatment of myeloma, but its efficacy and safety in light-chain (AL) amyloidosis has not been formally studied. This prospective phase 2 trial of daratumumab monotherapy for the treatment of AL amyloidosis was designed to determine the safety, tolerability, and hematologic and clinical response. Daratumumab 16 mg/kg was administered by IV infusion once weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, and every 4 weeks thereafter until progression or unacceptable toxicity, for up to 24 months. Twenty-two patients with previously treated AL amyloidosis were enrolled. The majority of the patients had received high-dose melphalan and stem cell transplantation and/or treatment with a proteasome inhibitor. The median time between prior therapy and trial enrollment was 9 months (range, 1-180 months). No grade 3-4 infusion-related reactions occurred. The most common grade ≥3 adverse events included respiratory infections (n = 4; 18%) and atrial fibrillation (n = 4, 18%). Hematologic complete and very-good-partial response occurred in 86% of patients. The median time to first and best hematologic response was 4 weeks and 3 months, respectively. Renal response occurred in 10 of 15 patients (67%) with renal involvement and cardiac response occurred in 7 of 14 patients (50%) with cardiac involvement. In summary, daratumumab is well tolerated in patients with relapsed AL amyloidosis and leads to rapid and deep hematologic responses and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT02841033.

Key PointsDaratumumab is effective in treated light chain deposition disease. Daratumumab can prevent progression of renal failure in these patients.

Key Points A source of treatment refractoriness in immune cytopenias appears to be residual CD138/38-positive lymphocyte populations. A short course of daratumumab is a novel treatment of refractory thrombocytopenia after failure of standard treatment options.

Immunoglobulin light chain amyloidosis (AL amyloidosis) involves deposition of abnormally folded light chains into a wide range of tissues causing organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously treated disease. However, data on survival outcomes and organ responses to daratumumab are lacking. Seventy-two patients with previously treated AL amyloidosis who received daratumumab monotherapy with dexamethasone were retrospectively evaluated. With a median follow-up of 27 months, 2-year overall survival (OS) was 86.9% (median OS, not reached) and 2-year time-to-next treatment or death (TTNT)–free survival was 62% (median TTNT, not reached). Forty of 52 evaluable patients achieved a hematologic response (77%), with >60% of patients achieving a very good partial response or better; median time-to-hematologic response was 1 month. Fifty-seven patients (79%) had cardiac involvement, and 55% of evaluable patients achieved a cardiac response, with a median response time of 3.2 months among responders. Cardiac responses were associated with an improvement in OS, with landmark analysis for cardiac responses at 3 months trending toward statistical significance (100% vs 55% at 30 months, P = .051). Forty-seven patients (65%) had renal involvement, and 52% of evaluable patients achieved a renal response, with a median response time of 6 months among responders; there was no significant difference in OS between renal responders and nonresponders. This study demonstrates that daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve deep hematologic responses, as well as improvements in organ function.

Introduction: Daratumumab (DARA) is a human, CD38-targeting, IgG1κ monoclonal antibody approved as monotherapy in relapsed/refractory multiple myeloma (RRMM) and in combination with standard of care for RRMM and NDMM. The addition of DARA to standard-of-care regimens in phase 3 studies has consistently improved progression-free survival (PFS) and led to deep and durable responses, including higher rates of minimal residual disease (MRD) negativity compared with standard of care. In the primary analysis of the phase 3 MAIA study (median follow-up, 28.0 mo), D-Rd vs Rd significantly improved PFS and MRD-negativity rates in transplant-ineligible NDMM (Facon T, N Engl J Med 2019). With longer follow-up (36.4 mo), D-Rd maintained a PFS benefit and deeper and more durable responses vs Rd alone (Bahlis N, Blood 2019. 134[Suppl 1]:1875). Here, we report updated efficacy and safety findings from MAIA after approximately 4 years of follow-up. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 years or comorbidities were randomly assigned (1:1) to receive Rd ± DARA. Stratification factors included International Staging System stage (ISS [I vs II vs III]), region (North America vs other), and age ( Results: A total of 737 patients were randomized (D-Rd, n = 368; Rd, n = 369). Patient baseline characteristics were well balanced between the two treatment arms. Median (range) age was 73 (45-90) years, with 44% of patients ≥75 years of age. 27%, 43%, and 29% of all patients were ISS stage I, II, and III, respectively. Among 642 patients evaluable for FISH/karyotyping analysis, 86% had standard and 14% had high cytogenetic risk. After a median follow-up of 47.9 months, 176 (48%) and 273 (75%) patients discontinued study treatment in the D-Rd vs Rd groups, respectively, with 85 (23%) and 113 (31%) patients discontinuing treatment due to progressive disease. PFS remained improved for D-Rd vs Rd (median, not reached [NR] vs 34 mo; HR, 0.54; 95% CI, 0.43-0.67; P Grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) occurring in ≥10% of patients were neutropenia (53%/37%), pneumonia (18%/11%), anemia (16%/21%), lymphopenia (16%/11%), hypokalemia (12%/10%), leukopenia (11%/6%), and cataract (11%/10%); grade 3/4 infection rates were 40%/29%. The most common serious TEAE was pneumonia (17%/11%). 11% of patients in the D-Rd arm and 22% in the Rd arm discontinued treatment due to an adverse event. The complete updated data set will be presented at the meeting with additional efficacy endpoints, including MRD-negativity rate. Conclusion : After 48 months follow up, the addition of DARA to Rd continues to demonstrate a superior PFS benefit. More patients continued to have deeper and more durable responses with D-Rd vs Rd alone. No new safety concerns were observed with longer follow-up. These results continue to support the use of D-Rd in the first line of treatment for patients with transplant-ineligible NDMM. Disclosures Kumar: Sanofi: Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; MedImmune: Research Funding; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Adaptive Biotechnologies: Consultancy. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Usmani:Abbvie: Consultancy; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Other; GSK: Consultancy, Research Funding; Merck: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding. Plesner:Janssen: Consultancy. Orlowski:Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Goldschmidt:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Incyte: Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Mundipharma GmbH: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Molecular Partners: Research Funding; Merck Sharp and Dohme (MSD): Research Funding. O'Dwyer:Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Research Funding; Carrick Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy; ONK Therapeutics: Consultancy, Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Weisel:Adaptive: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Karlin:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Preis:Janssen: Other: for factor XI inhibitor. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Krevvata:Janssen: Current Employment. Wang:Janssen: Current Employment. Van Rampelbergh:Janssen: Current Employment. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Uhlar:Janssen: Current Employment, Current equity holder in publicly-traded company. Kobos:Janssen: Current Employment, Current equity holder in publicly-traded company. Perrot:Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding.

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, and has been approved across lines of therapy for the treatment of multiple myeloma. The addition of DARA to standard-of-care (SoC) regimens, lenalidomide and dexamethasone (D-Rd) and bortezomib, melphalan, and prednisone (D-VMP), in the phase 3 MAIA and ALCYONE clinical studies reduced the risk of disease progression or death by ≥44%, nearly doubled the rate of complete response (CR) or better, and induced a >3-fold increase in MRD-negativity rates (10-5 sensitivity threshold) vs SoC alone in pts with TIE NDMM. In both MAIA and ALCYONE, MRD negativity was associated with longer progression-free survival (PFS), irrespective of trial treatments. MRD negativity provides an index of deep clinical response and may be a more robust evaluation of disease control if sustained over time. Here, we evaluate MRD negativity, including sustained MRD negativity, in pts with TIE NDMM from MAIA and ALCYONE and its association with PFS with longer follow-up. Methods: Pts with NDMM ineligible for high-dose chemotherapy with stem cell transplantation due to age (≥65 years) or unacceptable coexisting conditions in MAIA and ALCYONE were randomized (1:1) to SoC ± DARA. Pts in MAIA received 28-day cycles of Rd (R: 25 mg PO on Days 1-21; d: 40 mg PO QW) ± DARA (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter). ALCYONE pts received up to nine 6-week cycles of VMP (V: 1.3 mg/m2 SC twice weekly during Weeks 1, 2, 4, and 5 of Cycle 1 and QW during Weeks 1, 2, 4, and 5 of Cycles 2-9; M: 9 mg/m2 PO on Days 1-4 of Cycles 1-9; and P: 60 mg/m2 PO on Days 1-4 of Cycles 1-9) ± DARA (16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+). Study treatments continued until progressive disease or unacceptable toxicity. MRD was assessed in MAIA and ALCYONE in all pts who achieved a CR or stringent CR. For ≥CR pts, additional MRD assessments occurred at 12, 18, 24, and 30 months after the first dose in ALCYONE and at 12, 18, 24, 30, 36, 48, and 60 months in MAIA. MRD was assessed via next-generation sequencing using the clonoSEQ® assay (v.2.0; Adaptive Biotechnologies, Seattle, WA) at the 10-5 sensitivity threshold. Sustained MRD negativity was defined as the maintenance of MRD negativity confirmed ≥6 or ≥12 months apart with no MRD positive test in between and was evaluated in the intention-to-treat (ITT) population. Results: A total of 737 (D-Rd, n=368; Rd, n=369) pts in MAIA and 706 (D-VMP, n=350; VMP, n=356) pts in ALCYONE were randomized; median duration of follow-up was 36.4 months in MAIA and 40.1 months in ALCYONE. In both studies, DARA-based therapy improved MRD negativity vs SoC in the ITT population (D-Rd, 28.8% vs Rd, 9.2%, P In general, baseline characteristics were comparable among pts in DARA and control treatment groups with sustained MRD negativity. A higher proportion of pts in the ITT populations of MAIA (D-Rd, n=368; Rd, n=369) and ALCYONE (D-VMP, n=350; VMP, n=356) achieved sustained MRD negativity with DARA-based therapy vs SoC for ≥6-months (D-Rd, 14.9% vs Rd, 4.3%, P Conclusions: DARA-based combination regimens induce higher rates of MRD-negativity and sustained MRD negativity in pts with TIE NDMM, which are associated with deep responses and improved PFS. Disclosures San-Miguel: Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:Celgene and Janssen: Research Funding; Celgene, Amgen, Bristol-Myers Squibb, Sanofi, and Janssen;: Honoraria, Speakers Bureau. Paiva:Takeda: Consultancy, Honoraria, Research Funding; SkylineDx: Consultancy; Kite: Consultancy; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Honoraria; Adaptive: Honoraria; Roche: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding. Kumar:Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy, Research Funding; MedImmune: Research Funding; Sanofi: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Carsgen: Other, Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Tenebio: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria. Dimopoulos:Beigene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mateos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Pharmamar: Consultancy; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EDOMundipharma: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Touzeau:Sanofi: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Usmani:Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; GSK: Consultancy, Research Funding; Array Biopharma: Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Incyte: Research Funding; SkylineDX: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding. Cook:Karyopharm: Honoraria; Celgene, Janssen, Takeda: Research Funding; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, Sanofi: Honoraria. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Quach:GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Ramaswami:Janssen: Current equity holder in publicly-traded company. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Sun:Janssen: Current Employment, Current equity holder in publicly-traded company. Wang:Janssen: Current Employment. Krevvata:Janssen: Current Employment. DeAngelis:Janssen: Current Employment, Current equity holder in publicly-traded company. Heuck:Christoph Heuck: Current Employment, Current equity holder in publicly-traded company. Van Rampelbergh:Janssen: Current Employment. Kudva:Janssen: Current Employment, Current equity holder in publicly-traded company; Memorial Sloan Kettering Cancer Center: Other: non-paid consultancy. Kobos:Janssen: Current Employment, Current equity holder in publicly-traded company. Qi:Janssen: Current Employment, Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company. Bahlis:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria.

Background: Systemic AL amyloidosis is characterized by the deposition of insoluble amyloid fibrils produced by light chains synthesized by clonal CD38+ plasma cells. Combining daratumumab (DARA) with bortezomib, cyclophosphamide, and dexamethasone (VCd) has demonstrated significantly improved outcomes in patients with AL amyloidosis. The classification of hematologic complete response (CR) in this disease is evolving, and the absolute reduction of the involved free light chain (iFLC) and the difference between iFLC and uninvolved free light chain (dFLC) are being recognized as very meaningful endpoints. Here, we present results from the ANDROMEDA study (NCT03201965) to demonstrate the impact of achieving deep reductions of iFLC and dFLC on major organ deterioration progression-free survival (MOD-PFS), a novel, key secondary endpoint in this study. Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease (serum monoclonal protein ≥0.5 g/dL by protein electrophoresis or serum free light chain ≥5.0 mg/dL with an abnormal kappa:lambda ratio or dFLC ≥50 mg/L), ≥1 involved organ, cardiac stage I-IIIA, eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 subcutaneous [SC] weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every other week in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic CR rate, defined here as normalization of FLC levels and ratio (FLCr) and negative serum and urine immunofixation, confirmed at a subsequent visit; normalization of uninvolved FLC level and FLCr were not required if iFLC Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and 65% of patients had ≥2 organs involved. The proportions of patients with heart and kidney involvement were 71% and 59%, respectively, and the proportions of patients with cardiac stage I, II, and IIIA were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). The rates of deep hematological responses by all criteria strongly favored the DARA-VCd treatment arm (Table). MOD-PFS was longer in patients achieving deep hematological responses by all criteria (Figure). In addition, the corresponding MOD-PFS was similar regardless of the hematological response criteria used. Conclusions: Regardless of the criteria used, the addition of DARA to VCd increased the rates of deep hematologic responses in patients with newly diagnosed AL amyloidosis, which, in turn, was associated with prolonged MOD-PFS. These results support the benefit of DARA in this patient population. References 1. Comenzo RL, et al. Leukemia. 2012;26(11):2317-25 2. Sidana S, et al. Leukemia. 2019;34(5):1472-75 3. Muchtar E, et al. Leukemia. 2019;33(3):790-94 4. Manwani R, et al. Blood. 2019;134(25):2271-2280 Disclosures Comenzo: Amgen: Consultancy; Sanofi: Consultancy; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Unum: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Caleum: Consultancy. Kastritis:Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Palladini:Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Minnema:Celgene: Other: travel support, Research Funding; Kite, a Gilead Company: Speakers Bureau; Amgen: Consultancy; Servier: Consultancy. Wechalekar:Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel; Celgene: Honoraria. Jaccard:Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding; Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding. Sanchorawala:Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Regeneron: Other: advisory board; Caleum: Other: advisory board; Janssen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Prothena: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding. Lee:Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Gibbs:Janssen, BMS/Celgene, Amgen, Takeda, Pfizer, Caelum, Abbvie and Eidos: Membership on an entity's Board of Directors or advisory committees. Mollee:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Suzuki:Takeda, Amgen, Janssen and Celgene: Consultancy; Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Kim:Amgen, BMS, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Cibeira:Janssen, Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene, Amgen: Honoraria, Other: Educational lectures. Beksac:Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Valent:Amgen Inc.: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau. Wong:Fortis: Research Funding; GSK: Research Funding; Amgen: Consultancy; Janssen: Research Funding; Roche: Research Funding; Bristol Myers Squibb: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig:Janssen: Speakers Bureau. Bumma:Sanofi: Speakers Bureau; Amgen: Speakers Bureau. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company.

Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) plays an important role in the treatment of transplant-eligible multiple myeloma (MM) patients and yields deep responses, prolongs progression-free survival (PFS) and overall survival (OS). Daratumumab (Dara), a humanized monoclonal antibody that binds to CD38+ on the surface of myeloma cells and is increasingly used upfront to treat MM. Up to 75% of mobilized CD34+ hematopoietic progenitors also express CD38 and, hence exposure to Dara may potentially impact stem cell mobilization, and, given the extended half-life of Dara, also impair engraftment. The Cassiopeia trial (Moreau, P. 2019) showed the utility of Dara in combination with bortezomib and thalidomide as upfront treatment for MM without a negative impact on stem cell collection yield. Similarly, the Griffin trial (Voorhees, PM, 2020) demonstrated the safety of upfront Dara when combined with bortezomib and lenalidomide also with no impact on stem cell collection or engraftment. However, others(Al Saleh, A. 2019) reported delayed neutrophil engraftment in patients treated with Dara. Given the conflicting findings of these studies and scarcity of data on the direct impact of Dara on erythroid and myeloid progenitors, we investigated the effect of Dara on stem cell collection yield, graft composition and time to engraftment among patients who underwent ASCT. Methods We evaluated all patients with MM who underwent ASCT at our institute between 2017-2020 and excluded patients undergoing 2nd transplant or tandem ASCT. Disease risk stratification was assessed as per International Staging System (ISS) for MM. Treatment response prior to transplant was assessed as per response criteria definitions by International Myeloma Working Group (IMWG). Stem cells were collected according to institutional protocol and prior to cryopreservation, 1x105 peripheral blood cells are plated in duplicate in semi-solid media- MethoCult™ H4434 (Stem Cell Technologies, Vancouver, BC) and cultured in 37°C, 5% CO2 following which CFU-GM (colony forming unit- granulocyte macrophage) and BFU-E (burst forming units- erythroid) colonies are scored on day 14 based on morphological recognition, and reported as 104 colonies per kg of recipient weight. CFU-C (colony forming unit combined) is calculated by combining BFU-E and CFU-GM. Results Patients (N=108) that underwent ASCT between 2017-2020 were identified and demographic data are summarized (Table 1). Sixteen patients received Dara as part of upfront treatment prior to stem cell collection. Median age was 62 years old for the entire group with no significant age difference between patients who received Dara vs. those who did not receive. Similarly, there was no difference in race, ISS stage, pre-transplant response, plerixafor or lenalidomide use between the groups. Pts who received Dara were more likely to have received more than one chemotherapy regimen prior to transplant (62.5% vs. 30%, p-value=0.014). Although, total and day 1 collection of CD34+ stem cells was lower in the Dara treated group (7.18 x 106/kg) compared to Dara untreated (8.78 x 106/kg), the difference was not statistically significant. (p-value=0.151). Stem cell product composition based on measurement of BFU-E, CFU-GM and CFU-C colonies were similar independent of Dara use. Prior exposure to Dara was also not predictive of day 1 stem cell collection failure (defined as < 5x106 CD34+ cells/kg) as determined by multivariate analysis. Median time to absolute neutrophil count (ANC) recovery (defined as ANC >1500) was 12 days in both groups (p-value=0.09). Median time to platelet recovery (defined as platelet count >20k) was 12 days in the Darauntreated group vs. 13 days Dara treated group (p-value=0.06). Discussion In this single institute experience, there was a trend towards lower CD34+ collection as well as lower progenitor scoring with Dara use but was not statistically significant and also there was no difference in time to ANC or platelet recovery. The majority of patients in this study received plerixafor for mobilization, which might abrogate the effect of Dara and lenalidomide on the graft and stem cell collection. Further studies to investigate the impact of Dara on CD38+ mobilized hematopoietic cells is warranted. Disclosures Manjappa: Pfizer: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau.

Introduction: DARA is a human IgGκ monoclonal antibody targeting CD38 and is approved for intravenous (IV) infusion across lines of therapy for MM. In phase 3 clinical studies, DARA IV plus Rd for RRMM (POLLUX) and DARA IV plus VMP for transplant-ineligible (TIE) NDMM (ALCYONE) led to deep and durable responses and reduced the risk of disease progression or death by ≥56% (Kaufman J, Blood 2019. 134[Suppl 1]:1866; Mateos M, Lancet 2020). In the phase 1b MMY1001 study of DARA IV plus carfilzomib/dexamethasone (Kd) in RRMM, DARA IV plus Kd was well tolerated and demonstrated deep responses, regardless of prior lenalidomide treatment (Chari A, Blood 2019.134[Suppl 1]:1876). In the phase 3 CANDOR study, DARA IV plus Kd reduced the risk of disease progression or death by 37% in pts with RRMM (Dimopoulos M, Lancet 2020). A formulation of DARA for subcutaneous administration (DARA SC) was developed (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.). Advantages of DARA SC include reduced administration time (3-5 minutes) and lower rates of infusion-related reactions (IRRs). The phase 2 PLEIADES study is evaluating the safety and efficacy of DARA SC combined with SoC for MM, including D-Kd for RRMM, D-Rd for RRMM, and D-VMP for TIE NDMM. In the primary analysis of the D-Rd and D-VMP cohorts in PLEIADES, D-Rd and D-VMP demonstrated clinical activity and safety comparable to corresponding DARA IV regimens, with low rates of IRRs, leading to approval in the United States (Chari A, Clin Lymphoma Myeloma Leuk 2019.19[10]:e16-e17). Here, we present the primary analysis of the D-Kd cohort and updated data for the D-Rd and D-VMP cohorts of PLEIADES. Methods: RRMM pts with 1 prior line of therapy (including 2 consecutive cycles of lenalidomide therapy) received 28-day cycles of Kd (K: 20 mg/m2 IV Cycle 1 Day 1, escalated to 70 mg/m2 on Cycle 1 Days 8 and 15, then 70 mg/m2 on Days 1, 8 and 15 of each cycle thereafter; d: 40 mg IV or PO QW) with DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). RRMM pts with ≥1 prior line received 28-day cycles of Rd (R: 25 mg PO Days 1-21; d: 40 mg IV or PO QW for each cycle) with DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). TIE NDMM pts received 9, 6-week cycles of VMP (V: 1.3 mg/m2 SC twice weekly in Cycle 1 and QW in Cycles 2-9; M [9 mg/m2] and P [60 mg/m2] PO on Days 1-4 of Cycles 1-9) with DARA SC (QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ in 28-day cycles). All pts were treated until disease progression/unacceptable toxicity. Overall response rate (ORR) was the primary endpoint for each cohort. Additional outcomes were VGPR or better rate, CR or better rate, duration of response, minimal residual disease (MRD)-negativity rate, DARA serum concentrations, and safety. Results: At the time of the clinical cutoff for the D-Kd cohort, 66 pts were treated and the median duration of follow-up was 8.7 months. The ORR for D-Kd was 84.8% (90% CI, 75.7-91.5; Table) and response rates were consistent with DARA IV plus Kd in CANDOR (Dimopoulos M, Lancet 2020). For the updated analysis of the D-Rd cohort (n=65), median follow-up was 23.1 months, and the ORR was 93.8% (90% CI, 86.5-97.9; Table). Response rates for D-Rd were consistent with DARA IV plus Rd in POLLUX (Kaufman J, Blood 2019. 134[Suppl 1]:1866). For the updated analysis of the D-VMP cohort (n=67), median follow-up was 22.6 months. The ORR for D-VMP was 89.6% (90% CI, 81.3-95.0; Table), and response rates were consistent with DARA IV plus VMP in ALCYONE (Mateos M, Lancet 2020). The median duration of DARA SC administration was 5 minutes for all D-Kd injections. The safety profile of D-Kd was consistent with DARA IV as combination therapy with SoC regimens. The rates of IRRs and injection-site reactions were comparable to those observed with DARA SC monotherapy in the COLUMBA study (Mateos M, Lancet Haematol 2020). Additional data will be presented including MRD-negativity rates for all cohorts and updated safety data for the D-Rd and D-VMP cohorts. Conclusions: The primary analysis of the D-Kd cohort demonstrated comparable clinical activity and safety to DARA IV plus Kd. With extended follow-up in the D-Rd and D-VMP cohorts, clinical activity was comparable to corresponding DARA IV-containing regimens (DARA IV plus Rd [POLLUX]; DARA IV plus VMP [ALCYONE]). A low incidence of IRRs and a short duration of administration were reported in the D-Kd cohort in PLEIADES. Table 1 Disclosures Moreau: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Chari:Janssen, Celgene, Novartis, Amgen, Pharmacyclics, Seattle Genetics, Millennium/Takeda: Research Funding; Janssen, Celgene, Novartis, Amgen, Bristol-Myers Squibb, Karyopharm, Sanofi, Genzyme, Seattle Genetics, Oncopeptides, Millennium/Takeda, Antengene, Glaxo Smith Kline, Secura Bio: Consultancy. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rodriguez-Otero:Abbvie: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; Kite: Consultancy, Honoraria. McCarthy:Janssen: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Suzuki:Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Sureda Balari:BMS: Speakers Bureau; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Magen:AbbVie: Research Funding; Merck Sharpe and Dohme: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sano: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding. Iida:Bristol-Myers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Merck Sharpe Dohme: Research Funding; AbbVie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Honoraria, Research Funding. Maisnar:Janssen, Amgen, Takeda, Celgene/Bristol-Myers Squibb, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Sanofi: Honoraria; Celgene: Other: Personal fees. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Yang:Janssen: Current Employment. Kosh:Janssen: Current Employment. Delioukina:Maria Delioukina: Current Employment. Heuck:Christoph Heuck: Current Employment, Current equity holder in publicly-traded company. Goldschmidt:GlaxoSmithKline (GSK): Honoraria; Merck Sharp and Dohme (MSD): Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Incyte: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Molecular Partners: Research Funding. OffLabel Disclosure: This abstract includes discussion of a combination therapy with subcutaneous daratumumab plus carfilzomib and dexamethasone, which is currently under investigation in clinical trials, but has not yet been approved. Subcutaneous daratumumab is approved as monotherapy and in combination with other standard-of-care regimens for the treatment of multiple myeloma.

With the advent new proteasome inhibitors (carfilzomib, ixazomib), new immune-modulatory drugs (pomalidomide), and new monoclonal antibodies (elotuzimab, daratumumab) as approved treatments for myeloma, the therapeutic landscape for this disease has changed. In this chapter, using a case-based approach, I will provide a personal guide of how I approach myeloma therapy in a transplant eligible patient in 2018.

TO THE EDITOR: Treatment of proteasome inhibitor (PI)–refractory multiple myeloma (MM) is challenging, with response rates of only 15% to 35% being achieved with next-generation drugs such as pomalidomide, carfilzomib, and daratumumab, alone or in combination.[1][1][⇓][2]-[3][3] The oral HIV

TO THE EDITOR: The survival of myeloma patients has doubled in the past decade, but patients refractory to both proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) still have poor prognosis.[1][1] Immunotherapy with monoclonal antibodies targeting cell-surface antigens is a promising new

CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, and also functions as a receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune-effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38+ immune-suppressor cells. CD38-targeting antibodies are generally well tolerated and induce partial response or better in ∼30% of heavily pretreated MM patients as monotherapy. Based on their distinct mechanisms of action, favorable toxicity profile, and single-agent activity, CD38 antibodies are attractive partners in combination regimens. Indeed, deep responses and prolonged progression-free survival can be achieved in relapsed/refractory MM patients when CD38 antibodies are combined with immunomodulatory agents or proteasome inhibitors. Infusion-related reactions, which typically occur during the first infusion, are the most frequent adverse events. Attention should also be paid to the interference of CD38 antibodies with certain laboratory assays, which may complicate response evaluation and blood compatibility testing. Several studies are currently examining the role of CD38-based therapies in newly diagnosed and high-risk smoldering MM. Furthermore, CD38 antibodies are currently also under investigation in other hematologic malignancies, including acute lymphoblastic leukemia, natural killer/T-cell lymphoma, and acute myeloid leukemia, as well as in solid tumors.

Introduction: The phase 3 APOLLO study demonstrated significantly better progression-free survival (PFS) and clinical responses with daratumumab, pomalidomide, and dexamethasone (D-Pd) vs pomalidomide and dexamethasone (Pd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Based on these results, D-Pd became 1 of many treatment regimens approved in this patient population. In the absence of head-to-head data, indirect comparisons can provide important information to help optimize treatment for patients with RRMM. However, indirect comparisons of aggregated clinical trial data can be subject to selection and confounding bias, thus limiting the conclusions that can be drawn from the comparison. Several statistical methodologies are available that can be used to control for baseline differences and estimate the relative treatment effect of different treatment regimens. Here, we report the results of indirect comparisons that used patient-level data to compare improvement in PFS with D-Pd vs daratumumab, bortezomib, and dexamethasone (D-Vd) and D-Pd vs Vd in patients with RRMM with prior immunomodulatory drug (IMiD) and proteasome inhibitor (PI) exposure. Methods: Data for the D-Pd cohort came from the APOLLO (NCT03180736) and EQUULEUS (NCT01998971) studies. APOLLO is a randomized, open-label, phase 3 trial in which patients with RRMM and ≥1 prior line of therapy (LOT) including lenalidomide and a PI were randomized to D-Pd (N=151) or Pd (N=153). EQULEUUS was a nonrandomized, open-label, phase 1b trial that evaluated D-Pd in 103 patients with RRMM and ≥1 prior LOT, including lenalidomide and a PI. Data for the D-Vd and Vd cohorts came from CASTOR (NCT02136134), a randomized, open-label, phase 3 trial comparing D-Vd (N=251) vs Vd (N=247) in patients with RRMM and ≥1 prior LOT. Harmonized eligibility criteria (≥1 prior LOT including an IMiD and a PI; no prior pomalidomide) were applied prior to weighting/matching. Stabilized inverse probability of treatment weighting (sIPTW), propensity score matching (PSM), and cardinality matching (CM) were explored to adjust for imbalances in patient characteristics at baseline. Propensity scores were estimated using logistic regression for sIPTW and PSM. CM is an optimization-based method to find the mathematically-guaranteed largest matched sample meeting prespecified maximum standardized mean difference criteria for matching covariates, thereby overcoming limitations of PSM associated with limited covariate overlap, which was identified in this sample. Age, sex, cytogenetic risk (high/standard/missing), Eastern Cooperative Oncology Group performance status (0, 1, or 2), International Staging System (ISS) stage (I, II, III, or missing), MM type (IgG/non-IgG/missing), prior autologous stem cell transplant (yes/no), number of prior LOT (1, 2-3, or ≥4), refractory to lenalidomide status (yes/no/not received), refractory to IMiD/PI status (IMiD only, PI only, both, neither), and years since diagnosis were considered for adjustment. The analysis focused on PFS; overall survival was not analyzed as these data are immature. Results: After harmonized eligibility criteria were applied, 253, 104, and 122 patients from the D-Pd, D-Vd, and Vd cohorts, respectively, were included for comparison. A naïve comparison of baseline characteristics identified differences between D-Pd and D-Vd/Vd cohorts. After sIPTW, PSM, and CM adjusting, some imbalances between the D-Pd and D-Vd/Vd cohorts remained. ISS stage and MM type could not be adjusted for due to the amount of missing data in EQUULEUS. The CM method yielded better balance than sIPTW. The effective sample sizes (ESS) for each method are shown in the Table. The ESS for PSM was too low for comparison of PFS. PFS hazard ratios favored D-Pd over D-Vd and Vd and were statistically significant for sIPTW and CM (Figure). Conclusions: This indirect treatment comparison showed a PFS benefit for D-Pd compared with well-established SOC regimens D-Vd and Vd in patients with RRMM with previous exposure to an IMiD and a PI. Although the low ESS of sIPTW and PSM is a limitation, these findings provide support in favor of using D-Pd in a population of patients with difficult-to-treat MM. Figure 1 Figure 1. Disclosures He: Janssen: Current Employment, Current equity holder in publicly-traded company. Heeg: Janssen: Research Funding. Kampfenkel: Janssen: Current Employment. Dwarakanathan: Janssen: Other: Data related vendor services. Johnston: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Mendes: Janssen-Cilag Farmacêutica: Current Employment. Lam: Janssen: Current Employment, Current equity holder in publicly-traded company. Bathija: Janssen: Current Employment; Parexel International: Ended employment in the past 24 months.

Background: Treatment of multiple myeloma (MM) has significantly evolved in the last decade leading to significant improvements in survival. Still, cure remains elusive and new combinations incorporating drugs with novel mechanism of action are needed to rescue patients becoming resistant to standard of care. Selinexor is an exportin-1 (XPO1) inhibitor approved in combination with dexamethasone for the treatment of penta-exposed relapsed-refractory MM (RRMM) and showing superior PFS and ORR combination with weekly Vd versus standard twice weekly Vd in RRMM after 1-3 prior lines (PL). Dara-Vd is also a combination approved in RRMM after 1-3 PL. Here we report the initial results of a phase 2, multicenter, open label study (GEM-SELIBORDARA trial) (NCT03589222), based on the combination of Selinexor with D-Vd (SELIBORDARA) for the treatment of RRMM. Patients and methods: Between July 2018 and March 2021, 57 patients were included. The study had two different parts. In part 1 patients with ≥ 3 PL, previously treated with proteasome inhibitor (PI) and immunomodulatory drugs and refractory to the last line or double refractory were included. In part 2, patients in relapse or with progressive disease after ≥ 1 PL were included. Patients received intravenous daratumumab (Dara, 16mg/kg) at the approved schedule, plus bortezomib (1.3 mg/m 2 on days 1, 8, 15 and 22 in cycle (C) 1-8 and days 1 and 15 from C9-onwards) and dexamethasone (40mg days 1, 8, 15, 22), in combination with Selinexor days 1, 8, 15 and 22 (100mg in Part 1 and 60mg in Part 2). Cycles were of 4 weeks duration in part 1 and 5-weeks duration in part 2. Treatment was continued until disease progression or unacceptable toxicity. Study was conducted following Declaration of Helsinki and ICHGCP guidelines. Primary endpoint was complete response (CR) rate. Key secondary endpoints were ORR and safety profile. Cut-off date: 1 June 2021. Results: Patients included in part 1 (n=24) had a median age of 65.5 years. Median number of PL was 3 (range 2-3). 96% and 71% of patients had MM refractory to lenalidomide (Len-Refr) and PI. 71% had double refractory and 96% had MM refractory to last line. 21% had high-risk cytogenetics (HR-CA) and 12.5% had R-ISS 3. Part 1 ORR was 50% with 3 patients (12%) achieving CR/sCR. After a median f/u of 28.3 months, 18 patients have discontinued treatment, 14/18 due to disease progression. Median PFS and OS were 7.1 (95% CI 3.4 - 20.0) and 27.5 months (95% CI 10.6 - NE), respectively. In part 2 (n=33) median age was 69 years. Median PL was 1, 61% with 1 PL. Forty-five percent of patients were Len-refractory and 12% were double refractory. 36% were refractory to the last line. 5 patients had HR-CA and 3 patients had R-ISS 3. After a median f/u of 9.8 months, 8/33 patients have discontinued treatment, 5/8 due to disease progression. ORR was 82% with 8 patients (24%) achieving CR/sCR. Median PFS is not yet reached (95% CI 12.1 - NE). Median PFS in Len-Refr patients included in part 2 (n=15) was 12.1 months. Median OS is NR (95% CI NE-NE). Adverse events (AEs) were manageable. Recommended supportive care to prevent Selinexor associated nausea (± anorexia) included ondansetron for 2 days and daily olanzapine. Hematological adverse events (AEs) were registered in 77% of the patients. Thrombocytopenia was the most frequent (68.4%; grade 3-4 in 34%). Neutropenia was reported in 33% (grade 3-4 in 25%). Non-hematological adverse events (AEs) were registered in 75% of the patients. GI-Tox was reported in 22 patients (38%), with nausea as the most frequent GI event (16/22, only 2 grade 3-4). Overall, 35 patients (61.4%) required dose modifications. Selinexor was the drug most frequently modified, and was reduced in 24 (15 in part 1 and 14 in part 2) and discontinued in 5 patients (4 in part 1 and 1 in part 2), respectively. Only 1 patient discontinued the trial due to AEs. Conclusion: In this phase 2 single arm, open label study, the combination of Selinexor plus DVd showed encouraging efficacy and manageable safety profile both in the setting of late and particularly early relapse MM, although data in this second cohort is still immature and requires longer follow-up. Disclosures Rodríguez-Otero: Regeneron: Honoraria; Celgene-BMS, Janssen, Amgen, Sanofi, GSK, Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gonzalez De La Calle: Celgene-BMS, Janssen, Amgen: Honoraria. Sureda: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; MSD: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. De Arriba: Amgen: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS-Celgene: Consultancy, Honoraria, Speakers Bureau. Oriol: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Sirvent: Sanofi: Honoraria; Celgene-BMS: Honoraria. Bladé Creixenti: Janssen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Lahuerta: Celgene: Other: Travel accomodations and expenses; Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy. San-Miguel: Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, GSK, Karyopharm, Abbvie, SecuraBio and Regeneron: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mateos: Oncopeptides: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria.

Background: Outcomes for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with primary plasma cell leukemia (pPCL) remain unsatisfactory with current standard therapies. Traditional comparative trials randomising against a standard of care control arm are thus challenging for patients with UHiR NDMM or pPCL, and novel approaches to address their high unmet need are required. OPTIMUM/MUKnine (NCT03188172) is a 'digital comparator arm' trial for UHiR NDMM and pPCL patients with protocol defined outcome comparison against fully molecularly matched UHiR patients from the near-concurrent NCRI Myeloma XI/XI+ trial, the 'MyXI prior'. We report final analysis of the primary endpoint progression free survival (PFS) at 18 months for patients treated in OPTIMUM with Dara-CVRd induction, V-augmented ASCT and Dara-VRd consolidation, compared to the MyXI prior. Methods: Between Sep 2017 and Jul 2019, 472 patients from 39 UK hospitals with suspected NDMM or pPCL were screened. 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with pPCL (circulating plasmablasts >20%) were identified and recruited to OPTIMUM. Patients received up to 6 cycles of Dara-CVRd induction, V-ASCT, followed by Dara-VRd consolidation 1 for 6 cycles (Cons1), Dara-VR consolidation 2 for 12 cycles and monthly Dara-R maintenance until progression. This is the final analysis of the primary trial endpoint progression-free survival (PFS) at 18 months comparing OPTIMUM with the MyXI prior of patients treated with CRd or carfilzomib-CRd (KCRd) induction, ASCT and R maintenance or observation, using a Bayesian framework. Secondary endpoints include PFS, OS, safety and quality of life. Results: At median follow-up of 27.1 months (95% CI 25.1-29.3), median PFS was not reached for OPTIMUM patients. PFS was superior at the pre-specified time point of 18 months for OPTIMUM patients with an estimate of 81.7% (95% CI: 74.2-89.1) versus 65.9% (95% CI: 57.3-74.4) for the MyXI prior (Figure 1). PFS at 18 months was consistently shorter for both CRd (64.5%; 95% CI: 53.8-75.3) and KCRd (68.3%; 95% CI: 54.0-82.5) treated patients compared with OPTIMUM. There was a 99.5% chance of superior PFS outcome with OPTIMUM therapy compared to the MyXI prior within the Bayesian framework; easily surpassing the 85% pre-specified threshold of sufficient evidence of activity. The difference between trial treatments increased over time: 6 month estimates were similar across all treatment arms with OPTIMUM 95.3% (95% CI: 91.3-99.3), MyXI KCRd 95.1% (95% CI: 88.5-100.0), MyXI CRd 93.5% (95% CI: 88.0-99.0), while 12 month estimates were similar for OPTIMUM with 87.5% (95% CI: 81.2-93.9) and MyXI KCRd 87.8% (77.8-97.8), but lower in CRd 81.7% (95% CI: 73.0-90.3). The majority (94%) of patients who started OPTIMUM Cons1 completed all 6 cycles of therapy. Most frequent grade 3/4 adverse events (AEs) during Cons1 included thrombocytopenia (27.9%), neutropenia (21%) and infection (19.8%), however, grade 4 events were rare ( Conclusions: OPTIMUM demonstrated a clear PFS benefit at 18 months for intensified Dara combination therapy pre- and post-ASCT for UHiR NDMM and pPCL over the MyXI prior. Improvement of comparative benefit over time suggests particular efficacy of Dara-VRd in maintaining responses post ASCT, a key challenge in UHiR MM. This is, to our knowledge, the first prospective digital comparator trial for MM; central screening of an all-comer population combined with robust, detailed molecular matching maintained reliability and limited biases. These results demonstrate a novel framework for accelerated comparative evidence generation for patients with high unmet clinical need. Figure 1 Figure 1. Disclosures Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy. Hall: Janssen: Research Funding; BMS/Celgene: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Cook: BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. Pratt: Binding Site: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy.

Introduction: Novel agents are needed for multiple myeloma (MM), which remains incurable with most patients (pts) relapsing or becoming refractory to standard therapies. Talquetamab (Tal) is a bispecific antibody that binds to G protein-coupled receptor family C group 5 member D (GPRC5D), a receptor highly expressed on plasma cells with limited expression in healthy tissue, and CD3 to redirect T cells to GPRC5D-expressing MM cells. Tal monotherapy at the recommended phase 2 dose (RP2D) was well tolerated and yielded an overall response rate of 70% after 6.3 months of follow-up in pts with relapsed/refractory MM (RRMM) in the phase 1 MonumenTAL-1 study; responses were durable and continued to deepen over time. Daratumumab (Dara) is a monoclonal antibody approved for MM treatment that targets CD38 on MM cells, resulting in direct cytotoxicity of MM cells. Dara also impacts immune cell populations, ie, increasing helper and cytotoxic T cells and decreasing suppressive CD38+ immunoregulatory cells. Preclinical studies showed addition of Dara enhanced Tal-mediated lysis of MM cells, suggesting the combination may also increase clinical activity in pts with RRMM. We report initial findings for pts with RRMM who received Tal + Dara in a phase 1b multicohort study (TRIMM-2; NCT04108195). Methods: Eligible pts (aged ≥18 years) were diagnosed with MM and had received ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and an IMiD. Pts were excluded if they had received an anti-CD38 therapy ≤90 days. Subcutaneous (SC) Tal and Dara were administered in 28-day cycles in different dosing cohorts (with step-up dosing for Tal). The primary objectives were to identify the RP2D of Tal in combination with Dara and to characterize the safety of Tal + Dara at the RP2D. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] graded per ASTCT guidelines). Results: As of Jul 23, 2021, 23 pts were administered SC Tal + Dara in separate cohorts: Dara 1800 mg + Tal 400 µg/kg weekly (n=8), + Tal 400 µg/kg biweekly (n=5), and + Tal 800 µg/kg biweekly (n=10). Median follow-up across the Tal + Dara cohorts was 2.9 months (range 0.3-11.2). Median age of pts treated with Tal + Dara was 68 years (range 44-81), and 52.2% were male. Pts had received a median of 6 prior lines of therapy (range 3-18); 82.6% were triple-class exposed (82.6% received prior Dara and 8.7% received prior isatuximab) and 73.9% were penta-drug exposed. Any grade AEs were reported in 95.7% of pts and grade 3/4 AEs in 78.3%. The most frequently reported AEs (≥30% across Tal + Dara cohorts) were dysgeusia (52.2%; all grade 1/2), neutropenia (39.1%; grade 3/4 30.4%), thrombocytopenia (39.1%; grade 3/4 21.7%), anemia (34.8%; grade 3/4 21.7%), CRS (34.8%; all grade 1/2), and skin exfoliation (30.4%; all grade 1/2). The median time to CRS onset was 2.5 days (range 2-4), and the median duration was 2 days (range 1-3). Infections occurred in 34.8% of pts (grade 3/4 17.4%). Skin disorders were reported in 65.2% of pts (grade 3/4 13.0%), including nail disorders in 17.4% (all grade 1/2); these events were manageable and did not lead to treatment discontinuation. Two events of ICANS were reported (a grade 1 event [concurrent with CRS] and a grade 3 event), both of which resolved and did not recur. One pt in the Dara 1800 mg + Tal 400 μg/kg biweekly cohort died due to disease progression. Responses in different dosing cohorts are shown in the Table. The median time to first response across Tal + Dara cohorts was 1.0 month (range 0.9-2.4), and median duration of response was not reached. The pharmacokinetic profile of Tal was similar to that observed in the phase 1 monotherapy study. Tal + Dara treatment resulted in proinflammatory cytokine production and T-cell activation, evidenced by interferon-γ and tumor necrosis factor-α induction and PD-1 and CD38 upregulation on peripheral T cells, respectively. Updated data with longer follow-up will be presented at the congress. Conclusions: Tal in combination with Dara was well tolerated, with a safety profile comparable to the monotherapies, and showed promising efficacy in pts with RRMM. These findings support further clinical development of Tal + Dara combination therapy. Figure 1 Figure 1. Disclosures Chari: BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hari: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Bahlis: Janssen: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Mateos: Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. van de Donk: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding. Dholaria: Janssen: Research Funding; Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau; Pfizer: Research Funding. Garfall: Janssen: Honoraria, Research Funding; GSK: Honoraria; Novartis: Research Funding; Tmunity Therapeutics: Research Funding; Amgen: Honoraria. Goldschmidt: Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Molecular Partners: Research Funding; Johns Hopkins University: Other: Grant; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. Krishnan: City of Hope Cancer Center: Current Employment; JANSSEN: Consultancy, Research Funding; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; MAGENTA: Consultancy; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau. Martin: Janssen: Research Funding; Amgen: Research Funding; Oncopeptides: Consultancy; Sanofi: Research Funding; GlaxoSmithKline: Consultancy. Morillo Giles: Janssen: Honoraria; Takeda: Honoraria; Abbvie: Honoraria. Oriol: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Reece: BMS: Honoraria, Research Funding; GSK: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Millennium: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria. Rodriguez: Takeda: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; BMS: Consultancy, Speakers Bureau. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board. Usmani: Array BioPharma: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; Merck: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding. Verona: Janssen: Current Employment. Wang Lin: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Prior: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Wade: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Weiss: Janssen: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Askari: Janssen: Research Funding.

Introduction:Plasmablastic lymphoma (PBL) is a rare and aggressive lymphoma most commonly seen in the setting of chronic immunosuppression, such as HIV infection and organ transplantation, or in patients with pre-existing lymphoproliferative or autoimmune disorders. PBL commonly presents at extranodal sites and carries a poor prognosis with a global overall survival of 9-15 months after initial diagnosis. Despite poor prognosis for patients with PBL, therapeutic strategies to target this disease are limited, as CHOP-like regimens have failed to produce durable remission, and no standard of care has been established. The cell of origin for PBL is believed to be the plasmablast, as PBL cells possess immunoblastic morphology and contain an immunohistochemical profile positive for plasmablast markers, such as CD38, CD138, and MUM1/IRF4, and negative for B cell markers, such as CD20, CD19, and PAX5. The similarities between PBL cells and multiple myeloma (MM) cells, a plasma cell neoplasm, have led to investigations of the efficacy of MM therapeutics for the treatment of PBL. Daratumumab is a first-in-class monoclonal antibody directed against CD38 that has shown efficacy in treating relapsed/refractory and newly diagnosed MM. Here, we describe the treatment of four patients with advanced-stage PBL in the context of varying degrees of immunosuppression using combination treatment with daratumumab and EPOCH. Methods:Four consecutive patients were treated with daratumumab plus chemotherapy. Three of the four patients were treated in the frontline setting and received low-dose EPOCH (vincristine, doxorubicin, etoposide daily for 4 days; cyclophosphamide day 5) with 16mg/kg daratumumab dosed on days 1 and 8 for 6 cycles. Patient #4 showed partial CD20 positivity, prompting Rituximab co-administration (R-EPOCH). Patient #3 was treated in the relapsed setting with 16mg/kg daratumumab in combination with lenalidomide, dexamethasone, and doxorubicin. She was treated for 12 months. Responses were followed by PET/CT imaging. Results:The four consecutive patients (2 female, 2 male) ranged in age from 26-88 and all had advanced-stage PBL (Table 1). Three of the four patients had some degree of immunosuppression (Patient #1- post-transplantation lymphoproliferative disorder (PTLD), Patient #2- HIV/AIDS, Patient #3- Chron's disease, Patient #4- no history of immunosuppression). All patients had a Ki67 proliferation index over 70% and demonstrated extranodal involvement of disease (bone n=3, intestine n=2, liver n=2; kidney n=1; adrenal n=1). The three patients that received daratumumab in combination with EPOCH demonstrated a complete response at their first disease assessment by PET/CT scan after cycle 2 (Patient #1) or cycle 4 (Patients #2,4) (Fig1). Patient #3, who demonstrated a mixed response to previous therapy, achieved a complete response 5 months after starting treatment with daratumumab in combination with chemotherapy. As of July 2021, three of the four patients continued to have no evidence of disease for a median of 17 months (range 15-19 months). Patient #4 relapsed in July 2021, 3 months after demonstrating a complete response. Adverse events that required hospitalization were rarely noted following daratumumab treatment but included neutropenic fever (n=2, one event following treatment cycle 4 and the other event 2 months after completion of daratumumab administration), COVID-19 infection (n=1), and a PICC line-associated thrombus (n=1). Minor events were also noted and included self-limiting bradycardia (n=1), neuropathy (n=1), and rigor (n=1). Conclusions:We describe four patients with varying degrees of immunosuppression and HIV-status with aggressive-stage PBL that achieved complete response following treatment with daratumumab in combination with low-dose EPOCH or other chemotherapy. Three of four patients obtained durable responses. At the time of this writing, three additional HIV +patients have initiated treatment with daratumumab but have not yet reached their first disease assessment. Disease progression for these patients will be monitored and presented as part of this study. Our findings suggest a potential efficacy and warrant further investigation of using daratumumab for the treatment of HIV +and HIV - PBLs. Figure 1 Figure 1. Disclosures Amengual: Epizyme, Inc.: Speakers Bureau; Appia Pharmaceuticals: Research Funding; Daiichi Sankyo, Inc: Consultancy; Seagen: Consultancy. OffLabel Disclosure: our work uses daratumumab, a first-in-class monoclonal antibody against CD38 for the treatment of plasmablastic lymphoma

Background and Scientific Rationale Lenalidomide maintenance after autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM) patients has demonstrated an improved progression free survival (PFS) and overall survival (OS) when compared to placebo or observation in a meta-analysis (McCarthy et al. JCO 2017). Despite these improvements, patients on maintenance had higher rates of second primary malignancy and discontinuation due to treatment-emergent adverse events which may lead to decreased quality of life (QoL). Most MM patients are treated with lenalidomide maintenance in the absence of great alternatives. Thus, there is an unmet clinical need to develop alternative maintenance strategies. Daratumumab is well tolerated and effective in MM, with many studies continuing daratumumab as maintenance until disease progression. The proposed study seeks to further investigate and directly compare patient reported QoL between maintenance lenalidomide and daratumumab. Study Design and Methods This is an open-label single-center randomized pilot study of daratumumab versus lenalidomide maintenance in 100 newly diagnosed MM patients (Figure). Clinical trial registry number : NCT04497961, actively recruiting. Study population A total of 100 patients will be enrolled, randomized 1:1 to each arm (50 patients per arm). Randomization for enrollment will be stratified by patient age ( Inclusion criteria Newly diagnosed MM treated with combination therapy with or without ASCT Documentation of a very good partial response or better.Enrollment within 6 months of completing initial combination therapy.Enrollment following minimum 100-day washout per standard guidelines in ASCT recipients.ECOG performance status ≤ 2. Exclusion criteria Progressive or refractory MM.History of disease refractory to lenalidomide or daratumumab.History of prior anti-myeloma therapy for smoldering MM.Currently receiving other investigational agents to treat MM. Study treatment The length of therapy on both arms is 36 cycles of 28 days (~3 years), or until disease progression or unacceptable toxicity. Subjects under the lenalidomide arm will be treated with a maintenance dose of lenalidomide 10mg per day on days 1 to 21 of each cycle. Subjects under the daratumumab arm will be treated with a standard subcutaneous dose of 1800mg weekly in cycles 1 & 2, followed by every 2 weeks in cycles 3-6 and every 4 weeks cycles 7-36. Study assessments Subjects will complete three validated questionnaires - EORTC QLQ-C30 (general QOL in cancer patients), EORTC QLQ-MY20 (QOL in MM patients) and PRO-CTCAE (adverse events). These will be collected at baseline, day 1 of cycle 2, every cycle day 1 thereafter, at study/therapy discontinuation, and at 1-month post therapy follow-up. The GHS score will be calculated based on questions from the EORTC QLQ-C30. Endpoints Primary To compare differences in GHS scores between patients receiving lenalidomide versus daratumumab maintenance Secondary To explore differences in EORTC QLQ-C30, EORTC QLQ-MY20 and PRO-CTCAE scoresTo compare CTCAE adverse eventsTo evaluate differences in PFS and OSTo estimate differences in minimal residual disease statusTo explore the association between minimal residual disease status and clinical outcomes Exploratory To compare minimal residual disease techniques of multi-parametric flow with next-generation sequencing and mass spectrometryTo assess differences in T cell, NKT, NK cell subtypesTo explore associations between disease biology and clinical outcomes using genomic sequencing.To assess changes in the stool microbiome Statistical methods This protocol is a randomized pilot study to estimate the difference in the global health status for patients receiving lenalidomide maintenance to patients receiving daratumumab maintenance. The primary endpoint is the GHS from EORTC QLQ-C30. The primary analysis will be performed using a linear mixed effects model. The randomization stratification factors will be included as covariates in the regression model. The primary endpoint evaluation will use all GHS available up until the final evaluation at 36 cycles. Figure 1 Figure 1. Disclosures Shah: Celgene/BMS: Research Funding; Janssen: Research Funding. Mailankody: Bristol Myers Squibb/Juno: Research Funding; Fate Therapeutics: Research Funding; Physician Education Resource: Honoraria; Evicore: Consultancy; Legend Biotech: Consultancy; Plexus Communications: Honoraria; Jansen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Takeda Oncology: Research Funding. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Hultcrantz: Intellisphere LLC: Consultancy; Daiichi Sankyo: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy. Hassoun: Celgene, Takeda, Janssen: Research Funding. Scordo: Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; McKinsey & Company: Consultancy. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Lahoud: MorphoSys: Membership on an entity's Board of Directors or advisory committees. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Shah: Janssen: Research Funding; Amgen: Research Funding. Giralt: Actinnum: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees. Lesokhin: Behringer Ingelheim: Honoraria; bristol myers squibb: Research Funding; pfizer: Consultancy, Research Funding; Serametrix, Inc: Patents & Royalties; Trillium Therapeutics: Consultancy; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding. Landgren: Amgen: Honoraria; Janssen: Other: IDMC; Amgen: Research Funding; Janssen: Research Funding; Janssen: Honoraria; Celgene: Research Funding; Takeda: Other: IDMC; GSK: Honoraria.

Background: Clinical data support the combination of an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). The combination of lenalidomide, bortezomib, and low-dose dexamethasone is a very active, well-tolerated standard of care in the transplant-ineligible NDMM population. Ixazomib, an oral proteasome inhibitor is approved by the US Food and Drug Administration in combination with lenalidomide and dexamethasone for the treatment of relapsed MM. Given that ixazomib has improved binding kinetics and pharmacologic profile compared with bortezomib, it is expected that these differences will translate into similar, if not improved, efficacy and safety profiles in the upfront setting. A phase l/ll study of lenalidomide, ixazomib, and dexamethasone in previously untreated patients with MM demonstrated that this combination was well-tolerated and active (NCT01217957). More recently, the GRIFFIN study evaluated the addition of the anti-CD38 monoclonal antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated the ability of daratumumab to improve efficacy of the three-drug combination with an acceptable safety profile. Building upon these data, our study evaluates the addition of daratumumab to the all-oral regimen of lenalidomide, ixazomib, and dexamethasone in transplant-ineligible NDMM. The combination proposed in this study has been evaluated in NDMM irrespective of transplant eligibility and has demonstrated excellent efficacy and tolerability. Responses were rapid with 88% achieving a partial response (PR) or better after 2 cycles (33% very good partial response (VGPR) and 52% VGPR for 29 patients who had completed 4 cycles) with an overall response rate of 95%. 1 In our study, transplant-ineligible NDMM patients will be randomized to receive 12 cycles of induction with lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide alone versus lenalidomide, ixazomib, and daratumumab. Study Design and Methods: A randomized, phase II clinical trial (NCT04009109) is being conducted to assess the impact on progression-free survival (PFS) of the addition of ixazomib and daratumumab to lenalidomide as maintenance treatment following induction with lenalidomide, ixazomib, dexamethasone, and daratumumab. In this ongoing trial, eligible patients are randomized 1:1 to Arm A (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide until disease progression or unacceptable toxicity or a maximum of 2 years of maintenance therapy) vs. Arm B (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab, followed by lenalidomide, ixazomib, and daratumumab until disease progression or unacceptable toxicity or a maximum of 2 years maintenance therapy). Eligible patients have NDMM requiring treatment, are ≥18 years, have ECOG PS of 0-2, and must have been deemed ineligible for stem cell transplantation. The primary endpoint is PFS. With a sample size of 188 patients (94 patients per arm) enrolled over a 36-month period and followed for a minimum of 24 months after the close of enrollment, a one-sided alpha=0.10 log rank test will have an 85% chance of detecting an increase in median PFS time from 30 months to 48 months (a hazard ratio of 0.625) with the addition of ixazomib and daratumumab to lenalidomide as a maintenance treatment following induction with ixazomib, lenalidomide, dexamethasone, and daratumumab. Secondary outcomes of interest include minimal residual disease, overall survival, changes in body composition, quality of life, psychosocial measures of functional status including social activity and support, psychological state, and nutrition using a geriatric assessment tool, and the association of these psychosocial measures with therapy-associated toxicities. 1Kapoor et al. Blood (2019) 134 (Supplement_1): 864. Support: Alliance Foundation Trials; Janssen, Takeda, Celgene; https://acknowledgments.alliancefound.org Figure 1 Figure 1. Disclosures O'Donnell: Bristol Myer Squibb: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopeptide: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Bristol Myer Squibb: Consultancy. Dinner: Kite/Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Yee: Takeda: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Adaptive: Consultancy; GSK: Consultancy. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy. Tuchman: Karyopharm: Research Funding; Shattuck Labs: Consultancy; Sanofi / Genzyme: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Oncopeptides: Consultancy. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; Protocol Intelligence: Consultancy; Karyopharm: Consultancy, Research Funding; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

Introduction Non-transplant eligible newly diagnosed multiple myeloma (NTE-NDMM) patients have a heterogeneous clinical outcome, which can be partly explained by differences in frailty level. Accordingly, intermediate-fit patients, according to the IMWG frailty index, have an inferior survival and higher rates of treatment discontinuation as compared to fit NTE-NDMM patients. The aim of this study was to prospectively investigate the efficacy and tolerability of the novel regimen ixazomib-daratumumab-low dose dexamethasone in intermediate-fit NTE-NDMM patients. This trail is registered at www.trialregister.nl as NTR6297. Methods In the phase II HOVON 143 study, intermediate-fit NTE-NDMM patients were treated with nine 28-day induction cycles, consisting of ixazomib 4mg (day 1, 8, 15), daratumumab 16mg/kg (cycle 1-2 on day 1, 8, 15, 22; cycle 3-6 on day 1, 15; cycle 7-9 on day 1) and dexamethasone (on days of daratumumab; cycle 1-2 20mg, subsequent cycles 10mg), followed by maintenance therapy of 8-week cycles with ixazomib (days 1, 8, 15, 29, 36, 43), and daratumumab (day 1), of maximum 2 years or until earlier progression. Inclusion criteria were NTE-NDMM patients who were intermediate-fit according to the IMWG frailty index. Main exclusion criteria were severe cardiac dysfunction, chronic obstructive pulmonary disease with an FEV1 The primary endpoint was overall response rate (ORR) after nine induction cycles, defined by having at least a partial response (≥PR). Secondary endpoints were PFS, OS, event free survival (EFS, defined as either treatment discontinuation, progressive disease (PD), death, hematological adverse events (AE) grade 4 or non-hematological AE grade 3/4), and health-related quality of life (using the EORTC-QLQ C30 and -MY20). Results Sixty-five NTE-NDMM patients were included in the study of whom the demographics are described in Table 1. Median age was 76 years (range 65-80), 14% had a WHO≥2, 18% had ISS3 and 14% had high-risk cytogenetic abnormalities. The ORR was 71% (95% CI 63-73), including 23 (35%) patients with a very good partial response and 1 (2%) with a complete response. After a median follow-up time of 18.1 months (range 9.5-27.8), the median PFS was 17.4 months (95% CI 10.4-22.6), the median OS was not reached and 12-month OS was 92% (95% CI 82-97)(Figure 1). Eight patients died, 3/65 (5%) due to relapse and 5/65 (8%) due to other reasons, including one early death (≤60 days from registration). The median EFS was 5.3 months (95% CI 2.8-8.3). EFS defining events were non-hematological AEs grade 3/4 in 31 (48%), PD in 15 (23%), hematological AEs grade 4 in 2 (3%), treatment discontinuation in 2 (3%) and death in 1 (2%) patients (Figure 1). Thirty/65 (46%) patients did not proceed to maintenance therapy, due to PD (19/65 (29%)), toxicity (4/65 (6%)), incompliance (3/65 (5%)), sudden death (1/65 (2%)) or other reasons (3/65 (5%)). In addition, 7/65 (11%) patients had to discontinue ixazomib-only, all 7 due to PNP. Cumulative grade 3 or higher hematological AEs occurred in 8/65 (12%), mainly neutropenia (6%), whereas grade ≥3 non-hematological AEs were reported in 33/65 (51%) patients. Most common non-hematological grade ≥3 AEs were gastro-intestinal (14%), central nervous system AEs (11%) or infections (9%). Of 27/65 (42%) patients experiencing PNP, 4 (8%) had PNP grade 3. During induction, patients experienced a statistically and clinically (reaching minimal important difference thresholds) significant improvement in GHS/QoL, role functioning, and future perspective. In contrast, PNP worsened over time. Conclusion In intermediate-fit patients, ixazomib, daratumumab and dexamethasone is an effective and feasible regime, which improves QoL. However, treatment discontinuation due to toxicity (either the whole regimen (6%), but especially ixazomib only (11%)) or incompliance, which negatively affects PFS, remains a concern. This underscores the need to investigate novel monoclonal antibody-based treatment combinations with a higher efficacy to tolerability balance for intermediate-fit patients with NDMM. Figure 1 Figure 1. Disclosures Vekemans: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. van de Donk: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Timmers: Gilead Sciences: Other: Travel, Accommodations, Expenses; Daiichi Sankyo Ned: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. van der Spek: Amgen: Other. De Waal: Celgene: Speakers Bureau; Roche: Other: Travel, Accommodations, Expenses. Nijhof: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction: In systemic light chain (AL) amyloidosis free light chains produced by clonal plasma cells form amyloid fibrils that are deposited in tissues and organs resulting in organ dysfunction. Cardiac involvement by AL amyloidosis is frequent and the most critical prognostic factor. Prognostic evaluation in AL is based on cardiac biomarkers and patients with very high levels of both NTproBNP (≥8500 pg/ml) and cardiac Troponins (Mayo stage 3B) are at high-risk of early death and have a median survival of just 3-6 months in most series. The outcome of stage 3B patients has not improved despite the introduction of bortezomib-based therapies and there is an urgent need for new non-toxic treatments which can also lead to rapid and deep hematologic responses. Daratumumab, an IgGκ monoclonal antibody targeting CD38, has proved highly effective either alone or in combination with bortezomib, cyclophosphamide and dexamethasone and with good tolerability in AL amyloidosis patients. Methods: EMN22 is a phase 2, open-label, multicenter study planning to enroll 40 newly diagnosed patients with stage 3B AL amyloidosis from 5 sites in Greece, the Netherlands, Italy and France. Eligible patients should have high-sensitivity troponin T (hsTnT) >54 pg/mL and NT-proBNP ≥8500 pg/mL. Primary treatment consists of daratumumab monotherapy, initially administered intravenously at 16 mg/mL, and since February 2020 administered subcutaneously at a fixed dose of 1800 mg; weekly during Cycles 1-2, every 2 weeks for Cycles 3-6 and every 4 weeks thereafter. Patients who do not achieve a hematologic VGPR or better by Cycle 4 may also receive at investigator's discretion weekly bortezomib and low dose dexamethasone. Treatment continues until disease progression according to major organ deterioration progression-free survival criteria, start of new therapy, or for a maximum of 2 years. The current analysis includes patients who started treatment at least 3 months prior to the cut-off date (16 June 2021). Results: Among 17 patients included in this analysis, 9 (53%) are still on treatment and 8 (47%) have discontinued, either due to an adverse event (n=5, 29%), or due to disease progression (n=3, 18%). Most patients were males (n=12, 71%) and median age was 65 years (range 45-84). Eastern Cooperative Oncology Group performance status was 1 for 5 (29%), 2 for 11 patients (65%), and 3 for one patient (6%). Eight (47%) patients had New York Heart Association (NYHA) class II symptoms, and 9 (53%) NYHA class IIIA. At screening, median NT-proBNP was 13,994 pg/mL (range 8,816-40,428), median hsTnT 119.1 pg/mL (range 59.8-692) and median difference of involved to uninvolved free light chains (dFLC) was 553 mg/L (range 49-2823). Apart from the heart, the median number of other organs involved was 1 (range 0-5), with nervous system (n=8, 47%) and kidneys (n=7, 41%) most commonly affected. The median number of daratumumab infusions was 13 and the median duration of therapy with daratumumab therapy was 3.7 months. Overall, 5 patients (29%) started additional treatment with bortezomib after completion of 3 cycles of daratumumab monotherapy. All 17 patients had at least one treatment-emergent adverse event. Eleven patients (65%) had a serious adverse event (SAE); 9 (53%) had at least one cardiac-related serious adverse event, and one SAE (fatigue) was related to bortezomib. Six patients (35%) suffered a fatal SAE: sepsis (n=1), sudden death (n=3), and cardiac failure (n=2). Most common grade 3 or 4 non-serious AEs were peripheral edema (n=4, 24%), dyspnea (n=3, 18%), and atrial fibrillation (n=2, 12%), and only one non-serious neutropenia grade 3 was related to daratumumab. The overall response rate was 71%, with 3 patients (18%) achieving CR, 6 (35%) VGPR, and 3 (18%) a PR, with a combined CR+VGPR rate of 53% (9/17). One-, two-, and three-month overall response rates were 65% (n=11), 71% (n=12), and 71% (n=12), and the median time to first response was 7 days while the median time to at least VGPR was 14 days. The 6-month and 12-month OS rate were 70% and 53% respectively (median OS has not been reached). Conclusions: In this prospective phase 2 study, in patients with high-risk AL amyloidosis (stage 3B), daratumumab monotherapy shows a favorable safety profile and induced very rapid and deep hematologic responses with a median time to first response of 7 days, with 53% of the patients achieving VGPR or better and a 6-month OS of 70%. Figure 1 Figure 1. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria. Minnema: Jansen-Cilag: Consultancy; Kite/Gilead: Consultancy; Alnylam: Consultancy; Celgene: Other: Hospitality; BMS: Honoraria. Dimopoulos: Amgen: Honoraria; Beigene: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Huart: Janssen: Honoraria. Leonidakis: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Sonneveld: Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Palladini: Pfizer: Honoraria; Siemens: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees.

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. DARA is approved as monotherapy or in combination with standard-of-care regimens for the treatment of relapsed or refractory multiple myeloma (RRMM). In the primary analysis (median follow-up, 16.9 months) of the phase 3 APOLLO study (NCT03180736), the addition of DARA to pomalidomide and dexamethasone (D-Pd) showed a significant progression-free survival (PFS) improvement over pomalidomide and dexamethasone (Pd) alone in patients (pts) with RRMM (Dimopoulos MA, et al. Lancet Oncol. 2021;22[6]:801-812). Here, we report results from the APOLLO study, including outcomes of pts refractory to lenalidomide based on the last dose of lenalidomide received. Methods: Eligible pts were ≥18 years of age, had RRMM, had received ≥1 prior line of therapy (including both a proteosome inhibitor and lenalidomide), and had responded to prior treatment; pts with only 1 prior line of therapy were required to be refractory to lenalidomide. Pts were randomized 1:1 to Pd ± DARA, stratified via International Staging System disease stage (I vs II vs III) and number of lines of prior therapy (1 vs 2-3 vs ≥4). All pts received 28-day cycles of pomalidomide (4 mg PO daily on Days 1-21) and dexamethasone (40 mg [20 mg for pts ≥75 years of age], PO daily on Days 1, 8, 15, and 22). Pts in the D-Pd group received DARA subcutaneously (DARA SC; 1,800 mg; co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; ENHANZE ® drug delivery technology, Halozyme, Inc.]) or, prior to a protocol amendment, intravenously (DARA IV; 16 mg/kg; n=7) weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter. Pts receiving DARA IV were allowed to switch to DARA SC starting on Day 1 of Cycle 3 or later. All pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. Results: In total, 304 pts were randomized (D-Pd, n=151; Pd, n=153). At the time of randomization, 120 (79.5%) pts in the D-Pd group and 122 (79.7%) pts in the Pd group were refractory to lenalidomide. Among pts refractory to lenalidomide, the last dose of lenalidomide received was 5-10 mg in 30 (25.0%) pts in the D-Pd group and 31 (25.4%) pts in the Pd group and was 15-25 mg in 86 (71.7%) pts in the D-Pd group and 89 (73.0%) pts in the Pd group. With a median follow-up of 16.9 months, the median PFS in the overall population was 12.4 months in the D-Pd group versus 6.9 months in the Pd group (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.85; P=0.0018); the estimated 18-month PFS rate was 42.1% for the D-Pd group and 25.5% for the Pd group. Among pts refractory to lenalidomide, the median PFS was 9.9 months in the D-Pd group and 6.5 months in the Pd group (HR, 0.66; 95% CI, 0.49-0.90). For lenalidomide-refractory pts who last received a dose of 5-10 mg lenalidomide, the median PFS was 10.3 months for the D-Pd group and 8.5 months for the Pd group (HR, 0.75; 95% CI, 0.41-1.36); for lenalidomide-refractory pts who last received a dose of 15-25 mg lenalidomide, the median PFS was 10.7 months for the D-Pd group and 6.1 months for the Pd group (HR, 0.61; 95% CI, 0.42-0.88) (Figure). Grade 3/4 treatment-emergent adverse events occurred in 130 (87.3%) pts in the D-Pd group and 123 (82.0%) pts in the Pd group; the most frequently reported (≥15% in both groups) were neutropenia (67.8% vs 50.7%), thrombocytopenia (17.5% vs 18.0%), and anemia (16.8% vs 21.3%). Grade 3/4 pneumonia occurred in 20 (13.4%) pts in the D-Pd group and 10 (6.7%) of pts in the Pd group. Serious adverse events occurred in 75 (50.3%) pts in the D-Pd group and 59 (39.3%) pts in the Pd group. Conclusion: The addition of DARA to Pd provided a PFS benefit in the overall pt population and among pts refractory to lenalidomide. The safety profile observed in the APOLLO trial was consistent with previous reports for DARA SC and Pd. Additional analyses for lenalidomide-refractory pts, as well as efficacy and safety data for the overall population at longer follow up, will be presented. Figure 1 Figure 1. Disclosures Sonneveld: Celgene/BMS: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Terpos: Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Boccadoro: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding. Delimpasi: Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Beksac: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Symeonidis: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Demo: Research Funding; WinMedica: Research Funding; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bila: Janssen, Takeda, AMGEN: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mateos: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Orfanidis: Health Data Specialists: Current holder of individual stocks in a privately-held company. Kampfenkel: Janssen: Current Employment. Qiu: Janssen: Current Employment. Amin: Janssen: Current Employment, Current equity holder in publicly-traded company. Kosh: Janssen: Current Employment. Tran: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Dimopoulos: Beigene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; BMS: Honoraria. OffLabel Disclosure: The regimen is approved for patients who have received at least two prior therapies, whereas the APOLLO study included patients who have received at least 1 prior therapy.

Introduction: Daratumumab, a CD38 monoclonal antibody, was approved for the treatment of heavily pretreated relapsed or refractory multiple myeloma (MM) in 2015 and for newly diagnosed MM (NDMM) in 2018. The phase 3 MAIA study demonstrated that daratumumab plus lenalidomide/dexamethasone (D-Rd) improved clinical outcomes, including overall survival, versus lenalidomide/dexamethasone (Rd) in transplant-ineligible NDMM (Facon T, et al. EHA Library. 2021). However, limited real-world data are available regarding patients with MM treated with daratumumab in the US. We evaluated patient characteristics and treatment outcomes among transplant-ineligible NDMM patients who received D-Rd as first-line therapy in US oncology practices. Methods: This retrospective, observational cohort study evaluated patients from the Flatiron MM Core Registry who received first-line D-Rd between November 1, 2015 and February 28, 2021. The Flatiron Health electronic health record (EHR)-derived deidentified database has longitudinal patient-level records for patients treated at community oncology practices and academic medical centers across the US. The index date was the date of the first observed record of the D-Rd regimen. Patients aged Results: From November 1, 2015 to February 28, 2021, 1,721 patients were identified from the Flatiron MM Core Registry as patients treated with a daratumumab-based regimen; 120 (7.0%) of the 1,721 patients were treated with a daratumumab-based regimen as first-line therapy, and 35 (29.2%) of the 120 patients were identified as eligible patients treated with D-Rd as first-line therapy. For patients treated with first-line D-Rd (n=35), the mean age as of the index date was 73.5 years (SD: 7.9). Most patients were White (72.4%), had an ECOG PS score of 1 (51.9%), and had an ISS stage of II (38.1%) or III (42.9%). Of these patients, 15 (42.9%) patients were ≥75 years of age, 4 (11.4%) were Black or African American, 4 (11.4%) had high-risk cytogenetics, 21 (60.0%) were frail, 6 (17.1%) had diabetes, and 6 (17.1%) had acute renal impairment. The median time from the initial diagnosis date to the index date was 1.2 months and the median follow-up was 8.0 months. The median PFS was not reached in this study. The estimated 6-month PFS rate was 91.6%, 9-month PFS rate was 81.0%, and 12-month PFS rate was 73.6% (Figure). After 15 months of follow-up, an estimated 80.5% of patients had not received their next treatment. Conclusions: The real-world population of patients who received D-Rd as first-line therapy is similar to the population studied in MAIA. The early trend of PFS is also similar to that in MAIA, with the majority of patients progression free at 6, 9, and 12 months. Greater understanding of long-term outcomes among transplant-ineligible NDMM patients who received D-Rd as first-line therapy at US oncology practices is needed to further facilitate the safe and effective use of daratumumab. Figure 1 Figure 1. Disclosures Tai: Janssen Scientific Affairs, LLC: Current Employment. Cai: Janssen: Current Employment. Fu: Janssen: Current Employment. Khare: Janssen: Current Employment. Kaila: Janssen Scientific Affairs, LLC: Current Employment.

Introduction: The 2-part phase 3 CASSIOPEIA study (NCT02541383) investigated the combination of DARA with VTd (D-VTd) in transplant-eligible NDMM pts. D-VTd induction/consolidation (ind/cons) led to increased rates of MRD negativity and prolonged progression-free survival (PFS) compared with VTd (Moreau P, et al. Lancet. 2019;394(10192):29-38). In Part 2, DARA as post-autologous stem cell therapy (ASCT) maintenance significantly improved PFS in pts who received VTd ind/cons. Most common (≥2.5%) grade 3/4 adverse events included pneumonia (DARA: 2.5%; observation [OBS]: 1.4%), lymphopenia (3.6%; 1.8%), and hypertension (3.0%; 1.6%; Moreau P, et al. J Clin Oncol. 2021;39(no. 15_suppl):8004). Here, we present results from a detailed analysis of MRD negativity. Methods: Eligible pts were 18-65 years of age, had NDMM and were ASCT eligible. Pts were randomized 1:1 to 4 (28-day) cycles of pre-ASCT induction and 2 (28-day) cycles of post-ASCT consolidation with D-VTd or VTd (bortezomib, 1.3 mg/m 2 SC on Days 1, 4, 8, 11; thalidomide, 100 mg PO daily; dexamethasone, 20-40 mg IV/PO; ± DARA, 16 mg/kg IV weekly (QW) in Cycles 1-2, Q2W in Cycles 3-6). Pts who completed consolidation and achieved partial response or better were re-randomized 1:1 to maintenance DARA at reduced intensity (DARA, 16 mg/kg Q8W) for a maximum of 2 years, or OBS. Samples were collected for MRD analysis at predefined timepoints from all pts regardless of response to ind/cons and in pts with very good partial response or better during maintenance. The primary MRD assessment methodology was multiparametric flow cytometry during ind/cons and next-generation sequencing during maintenance, each at the 10 -5 threshold. MRD negativity is reported here for pts who achieved complete response or better. Results: 1,085 pts were randomized to ind/cons (D-VTd, n=543 or VTd, n=542) and 886 pts were re-randomized for post-ASCT maintenance (DARA, n=442 or OBS, n=444). The rate of MRD negativity was higher with D-VTd than with VTd following induction (9.2% vs 5.4%; odds ratio [OR], 1.79; P=0.0150) and consolidation (33.7% vs 19.9%; OR, 2.06; P During maintenance, the rate of MRD negativity significantly favored DARA over OBS (58.6% vs 47.1%; OR, 1.80; P=0.0001). In pts who received D-VTd ind/cons, the MRD-negativity rates with DARA and OBS were 64.2% and 57.6% respectively (OR, 1.43; P=0.1037). In contrast, pts who had received VTd ind/cons showed significantly higher MRD-negativity rates during DARA maintenance vs OBS (52.6% vs 35.8%; OR, 2.26; P=0.0002). The rates of sustained MRD negativity in the D-VTd group were not significantly different with DARA vs OBS (1yr sustained: 48.5% vs 41.0%; OR, 1.41; P=0.0885; 2yr sustained: 28.8% vs 21.8%; OR, 1.47; P=0.0789). In the VTd group, the 1-year sustained MRD-negativity rate was significantly higher with DARA vs OBS (35.7% vs 21.4%; OR, 2.22; P=0.0006) but no difference was observed in the 2-year sustained MRD rate (11.3% vs 13.0%; OR, 0.83; P=0.5481). Conclusion: In CASSIOPEIA, the highest and most durable rates of MRD negativity were achieved after D-VTd ind/ASCT/cons and DARA maintenance. Reduced intensity (Q8W) DARA maintenance did not significantly improve MRD negativity compared to OBS in patients treated with D-VTd. In patients treated with VTd, DARA maintenance did improve MRD negativity, but this effect was not long lasting. Longer follow-up is required to assess the potential long-term benefits of sustained MRD negativity for DARA vs OBS after D-VTd. Figure 1 Figure 1. Disclosures Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Moreau: Amgen: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. van der Velden: Janssen: Other: Service Level Agreement; BD Biosciences: Other: Service Level Agreement; Navigate: Other: Service Level Agreement; Agilent: Research Funding; EuroFlow: Other: Service Level Agreement, Patents & Royalties: for network, not personally. Hulin: abbvie: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Arnulf: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria. Karlin: Janssen: Honoraria, Other: member of advisory board, travel support; Abbvie: Honoraria; Amgen: Honoraria, Other: travel support and advisory board ; Sanofi: Honoraria; Takeda: Honoraria, Other: member of advisory board; Celgene-BMS: Honoraria, Other: member of advisory board; GSK: Honoraria, Other: member of advisory board; oncopeptide: Honoraria. Macro: Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Celgen/BMS: Honoraria. Perrot: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van De Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy. Krevvata: Janssen: Current Employment. Rigat: Janssen: Current Employment, Current equity holder in publicly-traded company. Yang: Janssen: Current Employment. Vanquickelberghe: Janssen: Current Employment. de Boer: Janssen: Current Employment. Kampfenkel: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Broyl: Celgene: Honoraria; Janssen Pharmaceuticals: Honoraria; Sanofi: Honoraria; Bristol-Meyer Squibb: Honoraria; Amgen: Honoraria. OffLabel Disclosure: The specific regimen combination is not yet approved in the maintenance setting.

Purpose: Frail patients with multiple myeloma have an inferior outcome, especially in the relapse setting. This adverse prognosis is mainly related to a high discontinuation rate due to treatment related adverse events. The aim of this phase 2 study is to evaluate efficacy and tolerability of Ixazomib-Daratumumab (I-Dara) without Dexamethasone in elderly frail patients with relapsed myeloma (NCT03757221). Methods: Fifty Ixa-Dara naïve RRMM patients (1-2 prior therapy) were planned to receive oral Ixa (4 mg: days 1, 8, 15), IV Dara (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Dara (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled if frailty score was ≥2 by IMWG score and FIRST proxy score (Facon T et al, Leukemia, 2020). The primary endpoint was ≥very good partial response rate at one year. Secondary endpoints included ORR, PFS, OS & toxicity according to NCI-CTCAE version 5.0. Results: Among 52 patients screened during this ongoing trial, 44 were included between 03/2018 and 05/2021. Patient were at first (n=28) or second relapse (n=16). Thirty -eight patients (86%) were previously exposed to bortezomib and 8 (18%) were previously refractory to lenalidomide. Median age was 82 (80-84). All patients had a frailty score ≥2. In 22 patients ISS was stage I (n=5), II (n=10) or III (n=7). Eleven (32%) patients harbored high-risk cytogenetic, including t(4;14) (n=3) or del17p (n=8). The median duration of Tx among 23 pts with ongoing Tx was 6 months [0-27] at data cutoff (July 19)]. The median duration of Tx among 21 pts who stopped Tx was 7 months [0-21]: 13 had progressive disease. Six patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2); progressive disease (C2 & C4), sepsis (C1 & C2). Regarding toxicity, 28 ≥grade 3 AE occurred amongst 24 pts (54%). The most common grade 3-4 toxicities were thrombocytopenia (n=5), other cytopenias (n=4), infection (n=4) and gastrointestinal disorders (n=2). Fourteen out of 28 were SAE including 1 bronchospasm, 1 acute respiratory failure and 2 ixazomib overdoses. Overall response rate, including minimal response, was 86 % in pts with ongoing treatment and 71% in pts who stopped Tx; ≥VGPR rate was 33% and 6% respectively. Conclusions: These preliminary results show a favorable safety profile of ixazomib and daratumumab combination, without dexamethasone, in this specific population of very elderly frail patients with RRMM and high risk cytogenetic for almost one third of them. Efficacy results will be analyzed when the 50 patients will be enrolled in the study and evaluable for the primary endpoint. Disclosures Macro: GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Takeda: Honoraria, Other: Travel accomodation, Research Funding. Manier: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vincent: Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. OffLabel Disclosure: Ixazomib and Daratumumab association is not approved in NDMM or in RRMM

Introduction: Daratumumab (DARA) is a human IgGk monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Since its approval for relapsed or refractory multiple myeloma (MM) in 2015 and newly diagnosed MM (NDMM) in 2018, DARA has become the foundation of treatment for MM. However, there is limited real-world evidence describing patients (pts) with MM treated with DARA-containing regimens in the US, especially for NDMM pts. Thus, using a large US claims database, we evaluated pt and treatment characteristics among MM pts who received DARA-containing regimens as first-line (1L) or second-line (2L) therapy, and separately for the subset who received DARA plus lenalidomide/dexamethasone (D-Rd) given its more recent approval in NDMM. Methods: This retrospective, observational cohort study evaluated pts aged ≥18 years at the index date (first observed treatment date with ≥1 medical or pharmacy claim for DARA) from the Optum Clinformatics Data Mart database between January 1, 2013 and December 31, 2020, with ≥1 diagnosis code for MM before the index date, and who were continuously enrolled in a medical benefit plan and pharmacy plan from ≥6 months before the initial MM diagnosis date to the index date. Pts with a hematopoietic stem cell transplant from 6 months before the observed initial MM diagnosis date to the index date were excluded. Eligible pts were categorized into 4 cohorts: pts with (1) a DARA-containing regimen as 1L (1L DARA-based cohort), (2) a DARA-containing regimen as 2L (2L DARA-based cohort), (3) D-Rd as 1L (1L D-Rd cohort), and (4) D-Rd as 2L (2L D-Rd cohort) after the observed initial MM diagnosis. Demographics were assessed on the index date; clinical characteristics, all-cause healthcare resource utilization (HCRU), and total all-cause healthcare costs (medical + pharmacy costs) were measured during the 6-month baseline period before the index date. Results: Among the 1L DARA-based cohort (n=235), 48 (20.4%) pts received D-Rd (1L D-Rd cohort). Overall, the most common 1L DARA-based regimens (with or without dexamethasone or prednisone) were D-R (28.5%), DARA plus bortezomib (V)/R (D-VR; 23.8%), D-V (18.7%), and D (14.9%). Among the 2L DARA-based cohort (n=310), 44 (14.2%) pts received D-Rd (2L D-Rd cohort). In the 1L DARA-based and 1L D-Rd cohorts, the mean (SD) age on the index date was 72.4 (9.0) and 76.1 (7.9) years, respectively. In the 2L DARA-based and 2L D-Rd cohorts, the mean (SD) age on the index date was 72.7 (9.3) and 70.5 (11.5) years, respectively. Mean baseline Quan-Charlson Comorbidity index was higher in the 2L cohorts versus 1L cohorts (1L DARA-based: 3.1; 1L D-Rd: 2.8; 2L DARA-based: 3.5; 2L D-Rd: 3.6). Hypercalcemia, renal impairment, anemia, and/or bone lesions (CRAB symptoms) were identified in about 50% of pts in all cohorts. Renal impairment was identified in 32.3%, 22.9%, 32.9%, and 34.1% of pts in the 1L DARA-based, 1L D-Rd, 2L DARA-based, and 2L D-Rd cohorts, respectively. Cardiovascular conditions (myocardial infarction, angina, peripheral vascular disease, and/or congestive heart failure) were found in 26.4% of pts in the 1L DARA-based cohort, 29.2% in the 1L D-Rd cohort, 34.5% in the 2L DARA-based cohort, and 47.7% in the 2L D-Rd cohort. The most common (>5% of pts) 1L regimens for pts in the 2L D-Rd cohort were VRd (17 [38.6%] pts), Vd (6 [13.6%]), V/cyclophosphamide (C)/d (4 [9.1%]), Rd (4 [9.1%]), and VC (3 [6.8%]). In the 1L DARA-based, 1L D-Rd, 2L DARA-based, and 2L D-Rd cohorts, 47.7%, 41.7%, 47.7%, and 54.5% of pts, respectively, had ≥1 hospitalization, and mean numbers of outpatient encounters were 26.4, 25.1, 50.6, and 52.8 within the 6-month baseline period. Mean 6-month baseline total healthcare cost (in 2020 USD) was $53,874 (medical: $51,837; pharmacy: $2,038) in the 1L DARA-based cohort, $39,695 ($35,896; $3,799) in the 1L D-Rd cohort, $131,832 ($96,737; $35,095) in the 2L DARA-based cohort, and $136,218 ($97,380; $38,838) in the 2L D-Rd cohort. Conclusions: In this real-world assessment using claims data, pts with MM receiving DARA-based therapy in 1L or 2L had median age ≥70 years, with high clinical burden as observed by their comorbidities, HCRU, and costs. Understanding the characteristics of real-world pts with MM treated with DARA-based therapy can further aid in the understanding of effective use of DARA in the real world. Disclosures Feng: Janssen: Current Employment. Fu: Janssen: Current Employment. Khare: Janssen: Current Employment. Ogbonnaya: Janssen: Current Employment. Kaila: Janssen Scientific Affairs, LLC: Current Employment.

Introduction : Daratumumab (Dara) is an anti-CD38 monoclonal antibody that is approved for use in patients with newly diagnosed and relapsed multiple myeloma (MM). We hypothesized that early therapeutic intervention with Dara in patients with high-risk MGUS (HR-MGUS) or low-risk SMM (LR-SMM) would lead to eradication of the tumor clone by achieving deep responses, resulting in prevention of progression to MM. We present results of our phase II, single arm study of Dara in HR-MGUS and LR-SMM. Methods : Patients enrolled on this study met eligibility for either HR-MGUS or LR-SMM. HR-MGUS is defined as 1.65, M protein ≥ 1.5g/dL or non-IgG M protein. LR-SMM is defined by one of the following 3 criteria: M protein ≥3g/dL, ≥10% bone marrow plasma cells, SFLC ratio 8. Dara (16mg/kg) was administered intravenously on a weekly schedule for cycles 1-2, every other week cycles 3-6, and monthly during cycles 7-20. The primary objective of this study was to determine the proportion of patients who achieve very good partial response (VGPR) or greater after 20 cycles of Dara. Secondary objectives included duration of response, safety, and rates of minimal residual disease (MRD)-negativity in VGPR or greater patients. Correlative studies included assessing changes in immune microenvironment, evaluating clonal heterogeneity using deep sequencing, and determining association of genomic aberrations correlating with either response to therapy or progression of disease. Results : At the time of data cutoff, a total of 42 patients were enrolled on this study from 2018 to 2020 with participation of 5 sites. The median age for all patients at enrolment was 60 years (range 38 to 76), with 22 males (52.4%) and 20 females (47.6%). Majority of patients enrolled were classified as LR-SMM (n = 37, 88.1%) and the remaining 5 patients had HR-MGUS (11.9%). 41 patients have started treatment and are included in toxicity assessment, and 40 patients have at least completed 16 cycles (range 6-20). Grade 3 toxicities were rare and only experienced in 5/41 patients including diarrhea (n =1/41; 2%), flu like symptoms (n = 1/41; 2%), headache (n=1/41; 2%), and hypertension (n=2/41; 5%). Most common toxicities of any grade included fatigue (n = 24/41, 51%), cough (n = 19/41, 46%), nasal congestion (n = 18/41, 44%), headache (n = 14/41, 34%), hypertension (n = 11/41, 27%), nausea (n = 13/41, 32%), and leukopenia (n = 13/41, 32%). No patients have discontinued therapy due to toxicity. Minimal response or better was observed in 82.9% of patients (34/41) and PR or better was observed in 51.2% of patients (21/41). This included overall CR (n = 4, 9.8%), VGPR (n = 1, 2.4%), PR (n = 16, 39.0%), MR (n = 13, 31.7%), and SD (n = 7, 17.1%). In the 40 patients who completed at least 16 cycles, response rates were as follows: MR or better 85% (34/40), PR or better 52.5% (21/40) and VGPR or better 12.5% (5/40). Median time to VGPR was 7 months. Median overall survival and progression-free survival have not been reached and no patients have progressed to overt multiple myeloma while on study. Conclusion : Dara is very well tolerated among patients with HR-MGUS and LR-SMM with minimal toxicities. Responses are seen in majority of patients. Early therapeutic intervention in this precursor patient population appears promising but longer follow up is required to define the role of single agent Dara in preventing progression to MM, therefore avoiding more toxic interventions in this low-risk patient population. Disclosures Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Yee: GSK: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Zonder: Caelum Biosciences: Consultancy; Amgen: Consultancy; BMS: Consultancy, Research Funding; Intellia: Consultancy; Alnylam: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy. Rosenblatt: Attivare Therapeutics: Consultancy; Imaging Endpoints: Consultancy; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Wolters Kluwer Health: Consultancy, Patents & Royalties. Mo: AbbVIE: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sperling: Adaptive: Consultancy. Richardson: Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein 2weeks) (RR: 1.0, P=0.97), treatment duration ( Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Despite significant improvements in myeloma (MM) therapies, patients (pts) refractory to immunomodulatory agents (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (mAbs) have poor prognosis and limited treatment options. Daratumumab (DARA), an anti-CD38 mAb, is active in pts with relapsed/refractory MM through mechanisms that include complement-dependent and antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis and immunomodulation. DARA + IMiDs have substantial efficacy, probably through the combination of their immune and microenvironmental effects. The mechanisms of resistance are not fully elucidated but resistance to DARA may be reversed by addition of IMiDs and vice versa, as previously shown (Gavriatopoulou Blood 2019, Nooka Cancer 2019). We prospectively evaluated the combination of DARA + IMiD following refractoriness to both agents, to assess clinical activity but also to longitudinally assess immune cell populations in the peripheral blood (PB) in order to understand the resulting immunomodulation. Consecutive PB samples from 35 pts refractory to an IMiD (LEN or POM) and progressing on DARA monotherapy were analyzed. The last IMiD on which each patient was refractory was added without modulating DARA backbone (RESET). In consenting pts, PB samples were collected at the time of DARA initiation, at progression to DARA monotherapy and IMiD addition, at response and at progression to DARA-IMiD. Samples were viably frozen and analyzed using specific two 8-color panels. Panel 1: CD38-FITC, Granzyme B-PE, CD127-PeCy7, CD25-APC, CD4-APCCy7, CD3-BV510, Lag-3-BV421 and 7-AAD as viability dye; panel 2: CD14-FITC, CD56-PE, CD66-b-PeCy7, CD80-APC, CD45-APCCy7, CD3/CD19-BV510, CD16-BV421 and 7-AAD as viability dye. Pts' median age was 73 years (range 52-86; 66% male); median prior treatment lines were 3 (range 1-16); all had prior exposure and refractoriness to at least one PI; all were refractory to LEN and 51% to POM, 40% had prior ASCT. The IMiD added was the last used prior to DARA, i.e., LEN in 49% (17/35) and POM in 51% (18/35). Median duration of DARA monotherapy prior to RESET was 7.9 months (range 1-38) and 64% responded (≥PR) before progression. Median duration of RESET therapy was 5.5 months (range 0.46 to 23.86) and 43% had ≥PR (≥MR: 60%) [including VGPR: 8.6% (n=3), PR: 34.3% (n=12), MR: 17.1% (n=6), SD/NR: 28.6% (n=10), PD: 11.4% (n=4)]. Median PFS was 5 months (95% CI 1.5-8.4) and median OS was 19 months (95% CI 13.5-24.5). Based on response at 3-month landmark, PFS was 9 months for pts who achieved ≥ PR vs 4 months for < PR (p=0.031). PFS and response to RESET were independent of type or dose of IMiD, prior response to DARA monotherapy or IMiD, number of prior treatments, ISS at diagnosis or at time of RESET. Multivariate flow cytometry analysis showed significant heterogeneity between pts (n=20). After DARA monotherapy there was an increase in CD8+ T cells compared to baseline which persisted throughout DARA-containing therapy with CD4+ T remaining at similar levels at all time-points. Total Tregs reduced after DARA start; however, within Tregs the relative proportion of Lag3+ Tregs tended to increase during DARA monotherapy. NK cell levels were significantly reduced after DARA and remained low throughout DARA therapy, with no recovery after IMiD addition; within NKs, we noticed an increase of CD16-/CD56+ immunomodulatory/cytokine producing and, to a lesser extent, of CD56-/CD16+ cytotoxic subsets compared to mature CD56+/CD16+ NK cells which tended to decrease, especially during DARA monotherapy. Although the samples at response to DARA/IMiD combination are few (n=10), CD56-CD16+ NK cell percentages at the time of progression to DARA were associated with response to DARA/IMiD. Finally, there was a noticeable increase in M1- and a decrease in M2-type macrophage subsets at response to DARA/IMiD. In conclusion, retaining DARA backbone therapy may be associated with clinically relevant activity (ORR 43%, 5 months median PFS) among pts refractory toDARA and IMiD, when these drugs are combined. Longitudinal evaluation of PB immune cell composition showed DARA-specific immunomodulation, which was not altered after addition of IMiDs, but may be related to restoration of sensitivity to the DARA/IMiD combination. Further investigation is in progress to reveal potential immune signatures of clinical relevance. Disclosures Krevvata: Janssen: Current Employment. Gavriatopoulou: Genesis: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Terpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria. Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria.

Introduction: Daratumumab is approved across lines of therapy for multiple myeloma (MM) by subcutaneous administration (DARA SC) or by intravenous administration (DARA IV). In clinical studies, the administration time ranges from 3-5 minutes for DARA SC versus 3-7 hours for DARA IV, and DARA SC is associated with reduced rates of administration-related reactions (ARRs). These characteristics of DARA SC are associated with benefits for clinics in terms of safety and clinic time. We previously reported DARA administration characteristics at Mayo Clinic infusion centers: DARA SC had shorter total clinic and total chair times compared with DARA IV, and DARA SC was associated with very low rates of ARR-related events (Soefje S, et al. EHA Library. 2021). Based upon this analysis, the treatment plan was modified to reduce the mandated observation time for DARA SC to improve clinic efficiency. Here, we describe updated clinical administration characteristics for DARA SC at Mayo Clinic infusion centers before and after the reduction in procedure-mandated observation time, versus DARA IV, using a novel empirical data extraction approach from Electronic Health Records (EHR). Methods: Patients ≥18 years of age with an ICD-9/10 diagnosis code of MM and a first DARA treatment between April 5, 2017 and June 22, 2021 were identified in Mayo Clinic's EHR database. Data were extracted using a scheduling and pharmacy software that tracked patient movement through appointments at a Mayo Clinic infusion center. On May 3, 2021, the Mayo treatment plan was amended to shorten the mandated post-administration observation time for DARA SC from 4 to 2 hours for Dose 1 and from 1 hour to 30 minutes for Doses 2 and 3, with no mandated observation time for Doses 4+. In this analysis, data were captured for patients initiating DARA IV throughout the defined treatment window. For DARA SC, data were captured for patients starting DARA SC therapy on the initial treatment plan (before May 3, 2021; DARA SC initial) and after the change to shorten the mandated post-administration observation time for DARA SC (after May 3, 2021; DARA SC shortened). Time-based measures included: total clinic time (check-in time through patient check-out); total chair time (time from infusion room entry to infusion room exit or check-out time, including order review, pharmacy preparation time, and post-administration observation time); and observation time (time from the end of medication administration to infusion room exit or patient check-out). The medication administration time documented for DARA SC was 0 minutes due to the default duration for SC injections in the EHR. Results: In total, 755 (DARA IV, n=586; DARA SC initial, n=145; DARA SC shortened, n=24) patients received DARA treatment for MM. For all doses combined, the median total clinic time was 2.9 hours shorter for DARA SC compared with DARA IV (DARA IV, 4.9 hrs; DARA SC initial, 2.0 hrs). The median total clinic time for DARA SC and DARA IV was highest at Dose 1 (DARA IV, 9.5 hrs; DARA SC initial, 6.1 hrs; DARA SC shortened, 4.4 hrs) and lower for subsequent doses (Dose 4+: DARA IV, 4.6 hrs; DARA SC initial, 1.7 hrs; DARA SC shortened, 1.6 hrs; Figure). Similarly, the median total chair time was 2.7 hours shorter in the DARA SC group compared with the DARA IV group for all doses combined (DARA IV, 4.1 hrs; DARA SC initial, 1.4 hrs). The median total chair time for DARA SC and DARA IV was highest at Dose 1 (DARA IV, 8.8 hrs; DARA SC initial, 5.6 hrs; DARA SC shortened, 3.9) and lower for subsequent doses (Dose 4+: DARA IV, 3.7 hrs; DARA SC initial, 1.1 hrs; DARA SC shortened, 1.1 hrs). Conclusion: Marked reductions in the amount of time spent both in clinic and in chair were observed with DARA SC compared with DARA IV, with additional time savings observed following the Mayo procedure change to reduce the DARA SC mandated observation time. These favorable DARA SC administration characteristics may indicate a reduction in the burden on both clinical resources and patients in Mayo Clinic infusion centers. These results add to the growing body of evidence supporting the use of DARA SC as an efficient and convenient treatment administration option for patients with MM. Figure 1 Figure 1. Disclosures Soefje: Beigene: Consultancy; Pfizer: Speakers Bureau; Janssen: Consultancy, Research Funding. Carpenter: nference Inc.: Current Employment; Janssen: Consultancy. Carlson: nference Inc.: Current Employment; Janssen: Consultancy. Awasthi: nference Inc.: Current Employment, Current holder of individual stocks in a privately-held company; Janssen: Consultancy. Lin: Janssen: Current Employment. Kaila: Janssen Scientific Affairs, LLC: Current Employment. Kayal: nference Inc.: Current Employment; Janssen: Consultancy. Kirkup: nference Inc.: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months; Path AI: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Wagner: nference Inc.: Current Employment; Janssen: Consultancy. Gray: Janssen Scientific Affairs, LLC: Current Employment, Current holder of individual stocks in a privately-held company. Kumar: Oncopeptides: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Bluebird Bio: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; Roche-Genentech: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Background: Newly drugs access for MM treatment still a challenge in some countries. One of the most available inductions for TE NDMM patients (pts) worldwide is cyclophosphamide (C), thalidomide (T) and dexamethasone (d)-(CTd). Dara the first anti- CD38, had been combined with VCd, VTd and VRd and markedly increased the depth and duration of the response. We hypothesized that Dara and CTd combination could be safe and allow deeper activity as an alternative protocol. Aims: The aims of this analysis were to evaluate Progression Free Survival (PFS) of Dara-CTd treatment and minimal residual disease (MRD) after one year of Dara maintenance. Primary endpoint of the study was to evaluate the VGPR after two consolidation cycles post-autologous stem cell transplantation (ASCT). Methods: This is a phase II, open-label single-center clinical trial. The main inclusion criteria were: TE NDMM, creatinine clearance > 30 ml/min, normal cardiac, renal and liver function and the Easter Cooperative Oncology Group (ECOG) performance status = 0 - 2. The protocol was Dara-CTd for up to four 28-day induction cycles: C-500mg oral (PO) on days 1,8 and 15, T at 100-200mg PO on days 1 to 28, (d) at 40mg PO on days 1,8,15 and 22 and Dara at 16mg/Kg/dose intravenous (IV) on days 1,8,15 and 22 during cycles 1 - 2 and every other week in cycles 3 - 4, followed by ASCT. All pts received up to four 28-day consolidation cycles that was started at D+30 after ASCT: Dara at 16mg/Kg and (d) at 40mg every other week, associated with T at 100mg PO on days 1 - 28. Dara at 16mg/Kg was used monthly as maintenance until progression or limiting toxicity. G-CSF was used for stem cell (SC) mobilization and plerixafor had been allowed whenever the pts need. The MRD was evaluated by next-generation flow (NGF) based and PET-CT was performed when the patient obtained NGF negativity or finished consolidation. PFS outcome was estimated using Kaplan-Meier method. All pts received antiviral, anti-pneumocystis and anti-thrombotic prophylaxis. Data cut-off was June 15, 2021. Results: The first pts was enrolled in November 2018. A total of 24 pts were included, the median age being 60 (range 37- 67 years), 23 (92%) were non-white, 5 (21%) had an R-ISS = 1, 12 (54%) had an R-ISS = 2 and 4 (16%), an R-ISS = 3. Six (25%) pts had high-risk chromosomal abnormalities [del17p, t(4;14) or t(14;16)]. To date, all pts have completed induction, 20 have received transplant and 17 have completed D+90 post-transplant assessment. No SC mobilization failure was observed, and six (30%) pts needed plerixafor use. By ITT analysis after a median follow up of 20 months the PFS at 12 and 18 months was 86%. No PFS difference was observed between different subgroups. Regarding response rates, after the end of induction (cycle 4), 19 (90%) of the pts obtained > PR and 8 (38%) obtained >VGPR, including three MRD negativity by NGF. 17 pts have completed two consolidation cycles after transplant and 94% obtained > VGPR as best response, 13 (76%) obtained MRD negativity by NGF and 10 (58%) had negative PET-CT. Seven (41%) pts had both flow and PET-CT negativity. Six pts completed one year of maintenance and five of them (83%) still MRD negativity by NGF. Four pts died from infection, two of them related with covid infection (one before transplant and one during maintenance). Another case post-transplant, considered not related to the investigational agent and one after consolidation, related to the investigational agent. Two pts have discontinued treatment due to progression - 1 before ASCT e 1 during maintenance. The most common adverse events (AEs) grades 3 and 4 were neutropenia (n = 12), infusion reaction (n = 7), neuropathy (n = 6), lymphopenia (n = 4), infection (n = 3), hypertension (n = 1) and rash (n = 1). Summary/Conclusion: The Daratumumab - CTd protocol is an active regimen capable of producing deep and sustainable responses and improve the PFS of NDMM TE pts with a favorable safety profile. Clinical trial information: NCT03792620. Disclosures De Queiroz Crusoe: Janssen: Research Funding. Hungria: Sanofi: Honoraria, Other: Support for attending meetings/travel ; Takeda: Honoraria; Abbvie: Honoraria; Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel .

Introduction The use of lenalidomide in frontline therapy for patients (pts) with newly diagnosed multiple myeloma (NDMM) has increased the number of pts who become refractory to lenalidomide at second line. Thus, there is an ongoing need for new treatment options for lenalidomide refractory patients at first relapse. Daratumumab, an anti-CD38 monoclonal antibody, has shown significant activity and acceptable safety in pts with relapsed/refractory multiple myeloma (RRMM) as monotherapy or in combination with other agents. Ixazomib, the first oral proteasome inhibitor, in combination with lenalidomide and dexamethasone also improves key survival endpoints in RRMM. This study assessed the efficacy of daratumumab in combination with ixazomib and dexamethasone (Dara-Ixa-dex) as second-line therapy in pts with RRMM who have been previously treated with a lenalidomide-based regimen. Methods DARIA is an ongoing, prospective, open-label, multicenter, phase 2 study. Eligible adult pts with RRMM had measurable disease after one prior line with a lenalidomide-based regimen and a Karnofsky Performance Status (KPS) score of ≥70. Exclusion criteria included previous anti-CD38 or ixazomib treatment, treatment with CYP3A inducers or use of St. John's wort within 14 days before C1D1, anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment prior to C1D1 and allogenic or autologous stem cell transplantation (ASCT) within 12 weeks before C1D1. Treatment with Dara-Ixa-dex comprises an induction phase of nine 28-days cycles and a maintenance phase. In induction, pts received DARA 16mg/kg (weekly for cycles 1-2, bi-weekly for cycles 3-6, and every 4 weeks thereafter) administered intravenously until November 2020 and subcutaneously at a fixed dose of 1800 mg thereafter; 4mg oral ixazomib (days 1, 8, and 15 of each cycle); and 40mg oral dexamethasone (weekly, each cycle). In maintenance, Dara-Ixa were administered every 4 weeks until disease progression or unacceptable toxicity, with dexamethasone being discontinued. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), the toxicity profile of Dara-Ixa-dex, and the effects of the combination on serum bone metabolism markers (C-terminal telopeptide of type 1 collagen [CTX], tartrate-resistant acid phosphatase isoform 5b [TRACP-5b], bone-specific alkaline phosphatase [bALP], and osteocalcin [OC]) from baseline until disease progression. Results The study has completed accrual and 50 pts have been enrolled (mean [range] age: 69.0 (50.0-89.0) years; female: 28 [56.0%]). At screening, 24 (48.0%) pts had a KPS score ≥90, and most pts were at stage ≤II by the International Staging System (ISS; 42, 84.0%) or by the revised ISS (47, 94.0%). Thirty-two (64.0%) pts were refractory to lenalidomide, and 15 (37.5%) had prior ASCT. The median (range) number of study treatment cycles was 9 (1-26). ORR was 50.0% (25 pts); one (2.0%) pt had a complete response, 13 (26.0%) a very good partial response (VGPR), and 11 (22.0%) pts had a PR. The median (range) time from first Dara-Ixa-dex dose until first response (≥PR) is 1.0 (0.9-3.7) month. The median PFS was 8.1 months (95% CI: 5.8-15.6) (Figure). After a median (range) follow-up of 12.4 (0.9-28.4) months, 14 (28.0%) pts are still on treatment; reasons for treatment discontinuation were progressive disease (28 pts, 77.8%), physician's decision and fatal serious adverse event [SAE] (3 pts, 8.3% each), and adverse event [AE] (2pts, 5.6%). Following 15 months of treatment, the median change from baseline for CTX, TRACP-5b, bALP and OC were significant (p Overall, 20 (40.0%) pts have ≥1 grade 3/4 AE, the most common being thrombocytopenia (10 pts, 20.0%), and 14 (28.0%) pts have ≥1 SAE, the most common being acute kidney injury and pneumonia (2 pts [4.0%] each condition). Four fatal SAEs were reported (pneumonia, infection, urinary tract infection, and lower respiratory tract infection). Conclusions Second-line treatment with Dara-Ixa-dex in pts with RRMM who were pre-treated with a lenalidomide-based regimen resulted in rapid ( Figure 1 Figure 1. Disclosures Terpos: Genesis: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Sanofi: Honoraria; Genesis: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Hatjiharissi: Gilead: Honoraria; Genesis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Verrou: Karyopharm: Research Funding; Takeda: Honoraria; Genesis: Honoraria; Abbvie: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria; Amgen: Honoraria. Leonidakis: Health Data Specialists: Current Employment. Delimpasi: Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Symeonidis: MSD: Consultancy, Research Funding; GSK: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Demo: Research Funding; WinMedica: Research Funding. Dimopoulos: Amgen: Honoraria; Janssen: Honoraria; BMS: Honoraria; Beigene: Honoraria; Takeda: Honoraria.

Introduction: Daratumumab (Dara) is an anti-CD38 monoclonal antibody representing a novel treatment agent for multiple myeloma (MM). Nonetheless, several studies have reported a Dara-related impairment of CD34+ hematopoietic stem cell (HSC) mobilization and post-autologous stem cell transplantation (ASCT) complications, including low yields of mobilized HSCs and delayed neutrophil engraftment. Impact of Dara on the mobilization process and HSCs remains poorly understood even though sufficient yields of CD34+ cells are necessary for a successful ASCT and subsequent patient recovery. Aims: To compare the effect of the Dara-containing (Dara-Bortezomib-Dexamethasone [D-VCd]) and conventional (Bortezomib-Thalidomide-Dexamethasone [VTd]) therapy on CD34+ HSCs. Methods: Transplant eligible MM patients were treated with D-VCd or VTd induction regimen followed by a cyclophosphamide + G-CSF mobilization and a high-dose melphalan D -1 before ASCT. Flow cytometry (FCM) screening of CD34+ subsets was performed in the bone marrow (BM) or apheresis product (AP) at three consecutive time points: 1) diagnostic BM (DG), 2) mobilization AP (MOB), 3) a day prior ASCT BM (D-1). Furthermore, RNA sequencing (RNAseq) of sorted CD34+ cells was performed on total RNA with ribo-depletion protocol in AP after the induction. D-VCd samples had lower RNA yields thus the D-VCd or VTd groups were processed as independent batches. Results: Clinical data revealed no significant differences in mobilization (p >0.050) likely due to a small cohort sizes (D-VCd n=5 vs VTd n=9), though a trend towards worse performance in D-VCd was observed. Median CD34+ cell yield was 3.08 vs 10.56 x 10 6/kg. Platelet recovery of >20x10 9/L was D+14 vs D+12 (range: 11-18 vs 10-16). Neutrophil recovery of >0.5x10 9/L was D+12 in both groups (range: 11-17 vs 11-12). In FCM analysis, DG (n=14), MOB D-VCd (n=5) vs VTd (n=9), D-1 D-VCd (n=7) vs VTd (n=15) were compared. CD34+ frequency (Fig. 1A) difference in MOB D-VCd vs VTd was insignificant (median: 1.15% vs 1.89%), whereas CD34+ fraction dropped in D-1 D-VCd (median: 0.52% vs 0.72%, p=0.027), albeit there was no significant reduction in D-1 D-VCd vs initial DG (median: 0.52% vs 0.45%). Differences in the distribution of certain HSC subsets were detected in the CD34+ pool (Fig. 1B-E). Frequency of multipotent progenitors (MPPs) (Fig. 1B) was increased in MOB D-VCd (median: 82.1% vs 66.2%, p=0.004). Frequency of lympho-myeloid-primed progenitor + granulocyte-monocyte progenitor (LMPP+GMP) (Fig. 1C) subset was reduced in D-VCd in both MOB (median: 1.7% vs 16.9%, p=0.042) and D-1 (median: 5.3% vs 14.0%; p=0.026). Erythro-myeloid progenitors (EMPs) (Fig. 1D) were reduced in MOB D-VCd (median: 10.7% vs 19.5%, p=0.042), while the frequency of EMPs increased in D-1 D-VCd (median: 20.8% vs 12.4%, p=0.045). No considerable differences were found in the expression of adhesion molecules CD44/HCAM or CD184/CXCR4. CD38 was strongly diminished in the whole D-VCd CD34+ fraction of MOB and D-1. To understand whether the differences in the mobilization efficacy after D-VCd induction were reflected in the expression profile of mobilized CD34+ cells, differential expression analysis was performed. Overall 133 significantly deregulated genes (p(-)1) between cohorts (D-VCd n=5 vs VTd n=5) were revealed (Fig. 2). Pathway analysis showed cellular response and localization as the most deregulated categories. The list of deregulated genes contained 25% of non-coding RNAs, some of which were linked to a protein localization in the cell (RN7SL1/2). The expression of adhesion molecules was inspected independently. Out of 59 HSC hallmark genes, only 8 were significantly altered in D-VCd. Interestingly, the main homing molecule CXCR4 seemed to be downregulated in D-VCd, while integrins A3 and B4 were upregulated. Conclusions: Despite the limited cohort sizes, a prospective trend of delayed neutrophil and platelet recovery was observed after D-VCd therapy. FCM analysis revealed a significant reduction of CD34+ subsets responsible, among others, for a reconstitution of neutrophils and megakaryocytes. A strong signal in transcriptome data which would potentially explain differential mobilization in D-VCd cohort was not detected, nevertheless, several genes with adhesive/homing and stem cell differentiation function were indeed altered. The results warrant further investigation. Figure 1 Figure 1. Disclosures Hajek: BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Peripheral blood stem cell (PBSC) mobilisation in multiple myeloma (MM) patients after exposure to daratumumab (D), a CD38 targeting monoclonal antibody, produces a lower stem cell yield possibly due to an effect on CD34+ stem cells (Hulin et al., 2021). Similarly, the GRIFFIN study reported greater plerixafor usage to facilitate PBSC mobilisation in patients randomised to DARA-Velcade, Lenalidomide and Dexamethasone (D-VRd) when compared to VRd (Voorhees et al., 2020). In addition, R use has previously been shown to impact adversely on PBSC yields (Kumar et al., 2007) with a recommendation to use cyclophosphamide (cyclo) assisted mobilisation for this group of patients (Mazumder et al., 2008). In this context there remains uncertainty about the role of plerixafor, compared to chemotherapy assisted mobilisation. Aim: To investigate the effect of DRd on PBSC mobilisation and to determine the outcomes of G-CSF (G) + cyclo and G +/-plerixafor mobilisation for patients with prior DRd exposure and to compare PBSC yields to patients mobilised after Velcade, Cyclophosphamide, Dexamethasone (VCD) based induction therapy Methods: The ALLG MM21 study (ACTRN12618001490268) is a multicentre study of transplant eligible refractory and/or relapsed MM patients. Patients were eligible if they had progressive disease or less than a partial response to prior VCD induction therapy. D at 16mg/m2 and d at 40mg was administered on Day 1,8,15 and 22 in combination with R 25mg D1-21 for the first 2 induction cycles. From cycle 3, D was administered fortnightly with R 10mg D1-28 and d 40mg weekly. PBSC mobilisation was undertaken after 2-3 cycles of DRd with a minimum of 14 days off R and D prior to proceeding. The PBSC mobilisation approach and the need plerixafor were based on institutional practice. Results: Fifty patients were enrolled on trial. Three patients experienced progressive disease and 3 patients died prior to mobilisation. A total of 44 patients underwent PBSC mobilisation,11 (25%) of these post-VCD but prior to starting DRd received G-only (Group A); 22/44 (50%) post-DRd received G + cyclo (Group B); and 11/44 (25%) post-DRd received G-only (Group C) (Figure 1). Based on low day 1 CD34+ counts 13/33 (33%) patients required plerixafor post-DRd and 2/11 (18%) post-VCD. Post-DRd 7/33 (21%) patients failed to collect more than 2 million cells/kg and 4 then failed a second attempt at mobilisation. All patients post-VCD/pre-DRd were successfully mobilised. Total PBSC yields were comparable between Groups A and B but significantly lower for Group C versus Group A (Table 1). Group B patients were then compared to a contemporaneous group of non-trial VCD treated and G only mobilised patients (n = 32) and found to have significantly inferior day 1 median peripheral blood (PB) CD34+ cell counts (Table 2, Figure 1). Seven patients (21%) who received G + cyclo experienced grade 3/4 infections with 5 of the 7 demonstrating day 1 PB CD34+ cell counts of Conclusions: PBSC collection after DRd salvage was characterised by lower CD34+ cell mobilisation and lower overall PB CD34+ yields when compared to patients mobilised after receiving VCD. Cyclo assisted mobilisation but not G + plerixafor abrogated this effect. Further evaluation of strategies to mitigate against the impact of DR containing induction are required. Figure 1 Figure 1. Disclosures Indran: Jansse-Cilag Pty Ltd.: Other: Registration costs , Patents & Royalties. Quach: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Janowski: BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Estell: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Spencer: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. OffLabel Disclosure: The combination of Daratumumab, Lenalidomide and Dexamethasone therapy is not approved on the Pharmaceutical Benefits Scheme in Australia.

Introduction: In 2015, U.S. Food and Drug Administration granted daratumumab approval, based on two phase II studies, as monotherapy (16 mg/kg in heavily treated patients) for MM patients who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or patient's double refractory to these agents [1]. Daratumumab is a human IgG1 monoclonal antibody targeting CD38, expressed at high levels on malignant cells in multiple myeloma (MM) [2]. METHODS AND METHODOLOGY: This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per PRISMA guidelines and its summary is given in Figure 1. Two authors (AA and MZ) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane library using the medical search terms: "daratumumab, refractory, relapsed, multiple myeloma". Three of the totals of 679 articles reviewed were selected as having identical primary and secondary outcomes Results: A total of 3 studies including 1533 patients (849 in Daratumumab treatment group while 684 patients in control group) were included in the study (Figure I). Mean age was 65 years in both groups. 54.4% had a progression free survival in daratumumab group as compared to 8% in control. Overall response rate, very good partial response, and complete response favors treatment group while minimal and partial response outcome favored control group. Adverse effects were more common in treatment group as compared to treatment group. Discussion: In ELOQUENT-3 trial, role of Elotuzumab was studied in RRMM patients which showed ORR of 53% in treatment group in comparison to our study which showed ORR of 85.2% with significant p-value of References: 1. Overdijk MB, Jansen JH, Nederend M, Lammerts van Bueren JJ, Groen RW, Parren PW. The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcγ Receptor-Mediated Cross-Linking. 2016;197(3):807-13. 2. Dima D, Dower J, Comenzo RL, Varga C. Evaluating Daratumumab in the Treatment of Multiple Myeloma: Safety, Efficacy and Place in Therapy. Cancer management and research. 2020;12:7891-903. 3. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. N Engl J Med. 2018 Nov 8;379(19):1811-1822. 4. Zhang T, Wang S, Lin T, Xie J, Zhao L, Liang Z, et al. Systematic review and meta-analysis of the efficacy and safety of novel monoclonal antibodies for treatment of relapsed/refractory multiple myeloma. Oncotarget. 2017;8(20):34001-17. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Despite recent treatment (tx) advances that have improved overall survival (OS), multiple myeloma (MM) remains a mostly incurable malignancy. Txs become less effective with each successive line of therapy (LOT). The rapidly evolving tx landscape has raised questions about the optimal tx sequence; recent trial data may be useful to develop and test hypotheses about tx sequencing. However, real-world (RW) data have shown that while most patients (pts) with newly diagnosed MM (NDMM) receive first-line (1L) tx, attrition rates are high in later LOT, with up to 50% of transplant ineligible (TIE) pts receiving no tx beyond 1L. As many pts will not have an opportunity to be salvaged with later LOT, achieving the longest possible progression-free survival (PFS) upfront is critical. In the MAIA trial, daratumumab (DARA), lenalidomide, and dexamethasone (D-Rd) demonstrated significant PFS (hazard ratio [HR]=0.53, P Methods: We examined 3 potential clinical tx sequences using a lifetime three-health state clinical simulation to estimate survival outcomes in pts with TIE NDMM. The 3 health states were: 1L (time on tx + any subsequent tx-free interval), 2L (time on 2L + any subsequent LOT), and death. Tx sequences were reflective of clinical guidelines: D-Rd in 1L followed by pomalidomide (POM)- or carfilzomib (CAR)-based regimens in 2L and VRd or Rd in 1L followed by DARA-based regimens in 2L (Figure). Pt characteristics were assumed to be similar to those of pts in MAIA. Time spent in the 1L health state with D-Rd and Rd was based on time to next tx or death (TTNT) curves derived from MAIA; TTNT curves with VRd were derived by applying PFS HRs estimated in the PEGASUS study. The attrition rate for the base case analysis (58.8%) was based on MAIA data. Although similar to published studies, it includes pts who were lost to follow-up and may be an overestimate. A sensitivity analysis evaluated a more conservative estimate (27.2%) excluding censored pts. Attrition rates were assumed to be the same across tx arms. Time spent in the 2L health state with DARA-based and POM- or CAR-based regimens was based on RW OS curves derived from the nationwide EHR-derived deidentified Flatiron Health database. RW data were used as pts in published 2L trials are younger than in MAIA and many have had prior ASCT. We evaluated median OS and 5- and 10-year survival rates. Results: Using D-Rd in 1L improved median OS by 2.5 or 3.5 years compared with delaying DARA-based regimens until 2L after VRd or Rd, respectively (Table). The probability of being alive at 5 and 10 years was higher with D-Rd than with VRd or Rd as initial therapy (Table). Changes in attrition rates impacted the expected median OS, but the absolute difference in median OS was maintained, with an incremental OS benefit consistently >2 years. Conclusions: Unlike previous attempts to examine outcomes with different tx sequences, we incorporated clinically representative sequences for pts with NDMM, included attrition rates, and explored their impact on OS with different tx sequences. Our approach shows that achieving the longest possible PFS in 1L drives OS outcomes. Saving agents until later LOT does not take into account that many pts do not reach 2L, as evidenced by published data on attrition rates in MM. Our findings show that in pts with TIE NDMM, starting with D-Rd may provide up to 3.5 years of additional OS gain with the currently available 2L tx. This gain could increase with new 2L agents currently in development, reinforcing the importance of using the best agents first, to increase the probability of pts benefitting from tx currently in development. Figure 1 Figure 1. Disclosures Fonseca: Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Janssen: Consultancy; GSK: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aduro: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; AbbVie: Consultancy; Mayo Clinic in Arizona: Current Employment; BMS: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Juno: Consultancy; Takeda: Consultancy; Merck: Consultancy. Hashim: Johnson and Johnson: Current Employment. Nair: Janssen Research & Development: Current Employment. He: Janssen: Current Employment, Current equity holder in publicly-traded company. Ammann: Janssen: Current Employment, Current equity holder in publicly-traded company. Lam: Janssen: Current Employment, Current equity holder in publicly-traded company. Wildgust: Janssen: Current Employment, Current equity holder in publicly-traded company. Kumar: Beigene: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Consultancy; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

A phase 2 clinical trial has demonstrated that daratumumab monotherapy was safe and well tolerated in relapsed/refractory Natural Killer/T-Cell Lymphoma (NKTL). However, no patients achieved complete response, and duration of response was short. Similarly, in Multiple Myeloma (MM), while daratumumab based combinations are approved for front line treatment, responses are heterogeneous and development of treatment resistance inevitable. Therefore, elucidation of mechanisms which can overcome daratumumab resistance is essential for the optimization of therapeutic response in patients. To this end, 2 pairs of isogenic daratumumab resistant and sensitive models of NKTL were developed in vitro via sequential exposure of cell lines to increasing concentrations of daratumumab in the presence of complement serum. A 3rd model was also studied in vivo whereby long-term administration of daratumumab in mice identified a sub-group of tumors which stopped responding to treatment and began to rapidly enlarge ('Resistant') as compared to others which remained similar to or smaller ('Sensitive') than the tumour volume at the initiation of treatment. RNA sequencing was performed on these models and genes commonly upregulated or downregulated analyzed. Differential gene expression analysis highlighted an enrichment for the upregulation of genes involved in exosome biogenesis and secretion in both cell line and mouse-derived daratumumab resistant NKTL models. An additional daratumumab resistant model was developed in an MM cell line to further validate these findings and extend the study in an MM model. Immunoblotting of the 3 pairs of isogenic sensitive and resistant cell line models demonstrate that there is indeed an upregulation of proteins regulating exosomal biogenesis and secretion; Alix, TSG101 and Rab27b in the daratumumab resistant phenotype. This is associated with a concomitant increase in secreted exosomes levels in the tumour microenvironment. The size and quantification of extracellular vesicles (EV) secreted in the media were studied by nanoparticle tracking analysis. Extracellular vesicles ranged in the size of 70-150nM corroborating with the size of exosomes and nanoparticle quantification revealed a higher concentration of exosomes present in the tumour microenvironment of resistant cells as compared to sensitive cells. Subsequently, exosomes were purified via ultracentrifugation and protein expression analysis confirmed elevation of exosome markers CD63 and CD81. To study the role of exosomal-mediated mechanisms in the survival of daratumumab resistant cells, we treated isogenic models with neticonazole and ketoconazole (azoles) which have been identified as selective inhibitors of exosomal biogenesis in a drug repurposing study for advanced cancers. Interestingly, azole treatment demonstrated a selective and more effective suppression of tumour cell viability in daratumumab resistant than sensitive cell lines. Immunoblot analysis showed that azole treatment at identical concentrations resulted in a more extensive downregulation of Alix, Rab27b and CD81 protein expression in resistant than sensitive cells. Additionally, depletion of Alix and Rab27b protein expression via siRNA knockdown induced cell death confirming that daratumumab-resistant cell lines are dependent on exosomal-mediated pathways for survival. Current research is focused mainly on intrinsic or immune cell-mediated mechanisms of daratumumab resistance, but little is known regarding the effect of extrinsic components in the tumour microenvironment. We demonstrate that daratumumab resistant models exhibit a distinct upregulation of proteins mediating exosome biogenesis resulting in enhanced exosome secretion. Daratumumab resistant cells are targeted more efficaciously with exosome biogenesis inhibitors than sensitive counterparts thereby suggesting an addiction to exosome-mediated mechanisms of survival. This is further supported by gene silencing studies. In future, we aim to perform miRNA profiling of exosomes purified from the tumour microenvironment of isogenic daratumumab-resistant and sensitive cell line models as well as from bone marrow plasma of daratumumab treated patients. miRNA which are enriched in the exosomes of resistant phenotypes will be characterized, unique biomarkers of response identified and in depth mechanisms of resistance studied. Disclosures No relevant conflicts of interest to declare.