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In the phase 3 MAIA study of patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab plus lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd). We present a subgroup analysis of MAIA by frailty status. Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit, intermediate, non-frail (fit + intermediate), or frail. Of the randomized patients (D-Rd, n = 368; Rd, n = 369), 396 patients were non-frail (D-Rd, 196 [53.3%]; Rd, 200 [54.2%]) and 341 patients were frail (172 [46.7%]; 169 [45.8%]). After a 36.4-month median follow-up, non-frail patients had longer PFS than frail patients, but the PFS benefit of D-Rd versus Rd was maintained across subgroups: non-frail (median, not reached [NR] vs 41.7 months; hazard ratio [HR], 0.48; P P = 0.003). Improved rates of complete response or better and minimal residual disease (10–5) negativity were observed for D-Rd across subgroups. The most common grade 3/4 treatment-emergent adverse event in non-frail and frail patients was neutropenia (non-frail, 45.4% [D-Rd] and 37.2% [Rd]; frail, 57.7% and 33.1%). These findings support the clinical benefit of D-Rd in transplant-ineligible NDMM patients enrolled in MAIA, regardless of frailty status.

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.

This study aimed to predict long-term progression-free survival (PFS) using early M-protein dynamic measurements in patients with relapsed/refractory multiple myeloma (MM). The PFS was modeled based on dynamic M-protein data from two phase III studies, POLLUX and CASTOR, which included 569 and 498 patients with relapsed/refractory MM, respectively. Both studies compared active controls (lenalidomide and dexamethasone, and bortezomib and dexamethasone, respectively) alone vs. in combination with daratumumab. Three M-protein dynamic features from the longitudinal M-protein data were evaluated up to different time cutoffs (1, 2, 3, and 6 months). The abilities of early M-protein dynamic measurements to predict the PFS were evaluated using Cox proportional hazards survival models. Both univariate and multivariable analyses suggest that maximum reduction of M-protein (i.e., depth of response) was the most predictive of PFS. Despite the statistical significance, the baseline covariates provided very limited predictive value regarding the treatment effect of daratumumab. However, M-protein dynamic features obtained within the first 2 months reasonably predicted PFS and the associated treatment effect of daratumumab. Specifically, the areas under the time-varying receiver operating characteristic curves for the model with the first 2 months of M-protein dynamic data were ~ 0.8 and 0.85 for POLLUX and CASTOR, respectively. Early M-protein data within the first 2 months can provide a prospective and reasonable prediction of future long-term clinical benefit for patients with MM.

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10−5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172., The studies were supported by Janssen Research & Development, LLC.

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.

In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1–21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35–0.55; P P P –5; 30.4 vs 5.3%; P P P

In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed.Eligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/mOf 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)-negativity rates (10After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates.

Introduction Daratumumab is a human IgGκ monoclonal antibody targeting CD38. Despite the demonstrated benefit of daratumumab in multiple myeloma, not all patients have access to commercially available daratumumab. Here we report a pooled analysis of patients from the UK, Spain, Italy, and Russia enrolled in an open-label, early access treatment protocol (EAP) that provided daratumumab (16 mg/kg) monotherapy to patients with heavily pre-treated relapsed or refractory multiple myeloma (RRMM). Methods Intravenous daratumumab 16 mg/kg was administered to patients who had received ≥ 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or who were double refractory to both a PI and an IMiD. Safety and patient-reported outcomes data were collected. Results A total of 293 patients received ≥ 1 dose of daratumumab. The median duration of daratumumab exposure was 4.2 (range 0.03–24.1) months, with a median number of 13 (range 1–37) infusions. The overall response rate was 33.1%, and the median progression-free survival was 4.63 months. Grade 3/4 treatment-emergent adverse events occurred in 60.1% of patients, of which the most common were thrombocytopenia (18.8%), anemia (11.9%), and neutropenia (11.6%). The most common serious adverse events were pneumonia (4.4%) and pyrexia (4.1%). Infusion-related reactions occurred in 45.1% of patients. The median change from baseline in all domains of patient-reported outcome instruments (European Quality of Life Five Dimensions Questionnaire [EQ-5D–5L], European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ-C30], and EORTC Multiple Myeloma Module [QLQ-MY20]) was generally 0 or close to 0. Conclusion These EAP results are consistent with those from previous trials of daratumumab monotherapy and confirm its safety in patients from Europe and Russia with heavily pre-treated RRMM. Trial Registration ClinicalTrials.gov identifier, NCT02477891. Supplementary Information The online version contains supplementary material available at 10.1007/s40487-020-00137-x.

PURPOSE In relapsed and/or refractory multiple myeloma, daratumumab reduced the risk of progression or death by > 60% in POLLUX (daratumumab/lenalidomide/dexamethasone [D-Rd]) and CASTOR (daratumumab/bortezomib/dexamethasone [D-Vd]). Minimal residual disease (MRD) is a sensitive measure of disease control. Sustained MRD negativity and outcomes were evaluated in these studies. METHODS MRD was assessed via next-generation sequencing (10−5) at suspected complete response (CR), 3 and 6 months following confirmed CR (POLLUX), 6 and 12 months following the first dose (CASTOR), and every 12 months post-CR in both studies. Sustained MRD negativity (≥ 6 or ≥ 12 months) was evaluated in the intention-to-treat (ITT) and ≥ CR populations. RESULTS The median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the ITT population, MRD-negativity rates were 32.5% versus 6.7% for D-Rd versus lenalidomide and dexamethasone (Rd) and 15.1% versus 1.6% for D-Vd versus bortezomib and dexamethasone (Vd; both P < .0001). Higher MRD negativity rates were achieved in ≥ CR patients in POLLUX (D-Rd, 57.4%; Rd, 29.2%; P = .0001) and CASTOR (D-Vd, 52.8%; Vd, 17.4%; P = .0035). More patients in the ITT population achieved sustained MRD negativity ≥ 6 months with D-Rd versus Rd (20.3% v 2.1%; P < .0001) and D-Vd versus Vd (10.4% v 1.2%; P < .0001), and ≥ 12 months with D-Rd versus Rd (16.1% v 1.4%; P < .0001) and D-Vd versus Vd (6.8% v 0%). Similar results for sustained MRD negativity were observed among ≥ CR patients. More patients in the daratumumab-containing arms achieved MRD negativity and sustained MRD negativity, which were associated with prolonged progression-free survival. CONCLUSION Daratumumab-based combinations induce higher rates of sustained MRD negativity versus standard of care, which are associated with durable remissions and prolonged clinical outcomes.

[Background]: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status., [Patients and Methods]: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients., [Results]: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%)., [Conclusion]: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status., This study was sponsored by Janssen Research & Development, LLC.

Background: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. Methods: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0–2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1–21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. Findings: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60–72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4–20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3–19·3] vs 6·9 months [5·5–9·3]; hazard ratio 0·63 [95% CI 0·47–0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. Interpretation: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. Funding: European Myeloma Network and Janssen Research and Development., European Myeloma Network and Janssen Research and Development.

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10−5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE)., The studies were supported by Janssen Research & Development, LLC.

© The Author(s) 2020., Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable., The data collection study was conducted by the International Myeloma Foundation as an International Myeloma Working Group project supported in part by a grant funded by Janssen.

Summary This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D‐VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4–8 induction cycles of bortezomib 1·5 mg/m2, cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split‐first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty‐six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after 4 induction cycles were 44% (primary endpoint) and 79%, respectively, and 56% and 81% at end of induction. The 12‐month progression‐free survival (PFS) rate was 87%. Efficacy was also observed in RMM patients. Fatigue (59%) and neutropenia (13%) were the most frequent treatment‐emergent adverse event (TEAE) and grade 3/4 TEAE, respectively. Infusion reactions occurred in 54% of patients, primarily during the first dose, and were mild (2% grade 3). The first 2 daratumumab infusions were 4·5 and 3·8 h (median). Overall, D‐VCd was well tolerated, split‐first daratumumab dosing was feasible, the ≥VGPR rate after 4 cycles was 44% and the 1‐year PFS rate was 87%.

The prognostic value of minimal residual disease (MRD) for progression-free survival (PFS) and overall survival (OS) was evaluated in a large cohort of patients with multiple myeloma (MM) using a systematic literature review and meta-analysis. Medline and EMBASE databases were searched for articles published up to 8 June 2019, with no date limit on the indexed database. Clinical end points stratified by MRD status (positive or negative) were extracted, including hazard ratios (HRs) on PFS and OS, P values, and confidence intervals (CIs). HRs were estimated based on reconstructed patient-level data from published Kaplan-Meier curves. Forty-four eligible studies with PFS data from 8098 patients, and 23 studies with OS data from 4297 patients were identified to assess the association between MRD status and survival outcomes. Compared with MRD positivity, achieving MRD negativity improved PFS (HR, 0.33; 95% CI, 0.29-0.37; P < .001) and OS (HR, 0.45; 95% CI, 0.39-0.51; P < .001). MRD negativity was associated with significantly improved survival outcomes regardless of disease setting (newly diagnosed or relapsed/refractory MM), MRD sensitivity thresholds, cytogenetic risk, method of MRD assessment, depth of clinical response at the time of MRD measurement, and MRD assessment premaintenance and 12 months after start of maintenance therapy. The strong prognostic value of MRD negativity and its association with favorable outcomes in various disease and treatment settings sets the stage to adopt MRD as a treatment end point, including development of therapeutic strategies. This large meta-analysis confirms the utility of MRD as a relevant surrogate for PFS and OS in MM.

Background Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM). Methods A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment-emergent grade ≥3 adverse events (AEs), serious AEs, and AEs of special interest were collected. Results Three hundred forty-eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03-6.0 months). Fifty-two percent of patients transitioned to commercially-available daratumumab and 37% discontinued because of progressive disease. Grade ≥3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug-related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast. Conclusions The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000-000.

Introduction Immunomodulatory drug (IMiD)-based regimens are a standard of care (SOC) for RRMM. Daratumumab (DARA) is a CD38-targeted mAb approved for treatment of pts with RRMM. The subcutaneous (SC) formulation of DARA has a similar safety profile as intravenous DARA, with a statistically significant reduction in infusion-related reaction (IRR) rates and a considerably shorter administration duration of 5 mins. DARA SC is approved for use in the US, EU, Canada, and Korea. In the phase 1b study of DARA plus the IMiD pomalidomide, D-Pd induced deep responses and was well tolerated in pts with heavily pretreated RRMM, including those with prior lenalidomide (len) treatment. D-Pd is approved in the US for RRMM pts with ≥2 prior lines of therapy, including len and a proteasome inhibitor (PI). APOLLO (NCT03180736) is a phase 3 study conducted in collaboration between European Myeloma Network investigators and Janssen to evaluate DARA SC plus Pd vs Pd alone in RRMM pts who had received ≥1 prior line of therapy including len and a PI. We report the primary analysis of APOLLO. Methods In this open-label, multicenter study, eligible pts had RRMM and received ≥1 prior line of therapy including len and a PI, had responded to prior treatment and progressed on or after their last regimen; pts with only 1 prior line of therapy (1PL) were required to be refractory to len. Prior anti-CD38 or pomalidomide was not permitted. Pts were randomized 1:1 to Pd ± DARA SC. Stratification was based on International Staging System (ISS) disease stage (I, II, III) and number of lines of prior therapy (1, 2-3, ≥4). All pts received 28-day treatment cycles (C). P: 4 mg (PO) QD on Days 1-21; d: 40 mg (PO) on Days 1, 8, 15 and 22 (20 mg for pts ≥75 years of age). For D-Pd pts, DARA was given QW for C 1-2, Q2W for C 3-6, and Q4W thereafter. Prior to protocol amendment, pts received DARA IV 16 mg/kg (n=7); after protocol amendment, all pts received DARA SC 1,800 mg co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.). All pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. Major secondary endpoints included overall response rate, rates of very good partial response or better and complete response or better, MRD-negativity rate, overall survival (OS), and safety. Results A total of 304 pts from 12 European countries were randomized (151 D-Pd; 153 Pd). The median (range) age was 67 (35-90) years, and 45%/33%/22% pts were ISS stage I/II/III. 35% had high cytogenetic risk (presence of del17p, t[14;16], or t[4;14]). 11% of pts had received 1PL (median [range] prior lines of therapy = 2 [1-5]). 82% of pts were refractory to len, 68% of pts were refractory to a PI, and 63% of pts were refractory to both. Median duration of treatment was 11.5 months with D-Pd vs 6.6 months with Pd. The primary analysis was performed after 190 PFS events. The study met its primary endpoint of improved PFS; the hazard ratio (HR) was 0.63 (95% CI, 0.47-0.85; P=0.0018), representing a 37% reduction in the risk of progression or death in pts treated with D-Pd. The median PFS for the D-Pd vs Pd arms was 12.4 vs 6.9 months, respectively. With a median follow-up of 16.9 months, 99 pts (33%) have died; the HR for OS was 0.91 (95% CI, 0.61-1.35); survival data are immature and follow-up is ongoing. ≥CR rates for D-Pd vs Pd were 24.5% vs 3.9%; ≥VGPR rates were 51.0% vs 19.6%. The most common grade 3/4 adverse events with a >5% difference between D-Pd vs Pd were neutropenia (68% vs 51%), leukopenia (17% vs 5%), lymphopenia (12% vs 3%), febrile neutropenia (9% vs 3%), and pneumonia (13% vs 7%). The rate of IRRs with DARA SC was low (6%, all grade 1/2), and 2% of pts had local injection-site reactions (all grade 1). Median duration of injection was 5 mins. Rates of study treatment discontinuation due to TEAEs were similar for D-Pd vs Pd (2% vs 3%). The safety profile of D-Pd is consistent with known profiles of DARA SC and Pd. Conclusion In this phase 3 study evaluating DARA SC plus Pd, D-Pd significantly reduced the risk of progression or death by 37% in pts with RRMM who had received ≥1 prior line of therapy vs Pd alone. No new safety concerns were observed. The IRR rate was very low and administration duration short, thus increasing convenience for pts and decreasing treatment burden. Collectively, these data show that D-Pd is an effective and convenient treatment for pts with RRMM who received ≥1 prior therapy, including len and a PI. Disclosures Dimopoulos: Beigene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Terpos:Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Beksac:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; Janssen: 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. Katodritou:Theagenion Cancer Hospital: Current Employment; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Other: Expenses, Research Funding; Genesis Pharma: Honoraria, Other: Expenses, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Symeonidis:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Celgene/Bristol-Myers Squibb: 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; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Mateos:Adaptive Biotechnologies: Consultancy, 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; PharmaMar-Zeltia: Consultancy; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Seattle Genetics: 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; Roche: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: 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. Einsele:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Orfanidis:Health Data Specialists: Current Employment, Current equity holder in private company. Ahmadi:Genmab: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Kampfenkel:Janssen: Current Employment. Schecter:Janssen: Current Employment, Current equity holder in publicly-traded company. Qiu:Janssen: Current Employment. Amin:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Sonneveld:Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding.

Introduction: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for relapsed/refractory multiple myeloma and NDMM. In the primary analysis of the phase 2 GRIFFIN study (NCT02874742) in patients with transplant-eligible NDMM, DARA plus RVd (D-RVd) significantly improved rates of stringent complete response (sCR) by the end of post-transplant consolidation therapy versus RVd (Voorhees P, Blood 2020). Here, we present updated efficacy and safety results following 12 months of maintenance therapy with lenalidomide (R) or DARA plus R (D-R). Methods: Patients with NDMM eligible for high-dose therapy (HDT) and autologous stem cell transplant (ASCT) were randomized 1:1 to RVd ± DARA, stratified by ISS stage and creatinine clearance rate. Patients received 4 induction cycles, HDT, ASCT, 2 consolidation cycles, and maintenance with R ± DARA for 24 months. During induction and consolidation, patients received R 25 mg PO on Days 1-14; V 1.3 mg/m2 SC on Days 1, 4, 8, and 11; and d 40 mg QW every 21 days. DARA 16 mg/kg IV was given on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of Cycles 5-6. During maintenance (Cycles 7-32), patients received R 10 mg (15 mg in Cycles 10+ if tolerated) on Days 1-21 every 28 days ± DARA 16 mg/kg IV Q8W (or Q4W per patient decision after Amendment 2). The primary endpoint was rate of sCR at the end of post-ASCT consolidation per IMWG criteria, evaluated by a validated computer algorithm. Key secondary endpoints included progression-free survival (PFS) and rate of minimal residual disease (MRD) negativity (10-5 threshold per IMWG criteria) assessed by next-generation sequencing (clonoSEQ; Adaptive Biotechnologies). The primary hypothesis was tested at a 1-sided alpha of 0.10. All secondary analyses were evaluated using a 2-sided P value (alpha 0.05) and were not adjusted for multiplicity. Results: In total, 207 patients were randomized (D-RVd, n=104; RVd, n=103). Baseline demographics and disease characteristics were well balanced between arms. At the end of post-transplant consolidation (median follow-up, 13.5 months) in the response-evaluable population, the sCR rate favored D-RVd versus RVd (42.4% [42/99] vs 32.0% [31/97]; 1-sided P=0.0680). With additional D-R or R maintenance therapy, responses continued to deepen and remained higher for the D-RVd group versus the RVd group. At the 12-months-of-maintenance therapy data cut (median follow-up, 26.7 months), the sCR rate still favored D-RVd versus RVd (63.6% [63/99] vs 47.4% [46/97], 2-sided P=0.0253; Figure). MRD-negativity (10‒5) rates in the ITT population favored D-RVd versus RVd (62.5% [65/104] vs 27.2% [28/103], P Conclusions: After 26.7 months of median follow-up, the addition of DARA to RVd induction and consolidation, followed by D-R maintenance in patients with transplant-eligible NDMM continued to demonstrate deep and improved responses, including higher sCR and MRD negativity rates, compared with lenalidomide alone. Maintenance therapy increased sCR and MRD negativity rates, compared to post-consolidation rates. No new safety concerns were observed with longer follow-up. Support: Alliance Foundation Trials; https://acknowledgments.alliancefound.org; Janssen Oncology Disclosures Kaufman: Tecnopharma: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Sanofi/Genyzme: Consultancy, Honoraria; AbbVie: Consultancy; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Sborov:University of Utah: Current Employment; Celgene, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Reeves:Incyte: Honoraria; Takeda: Honoraria; Bristol Myers Squibb: Speakers Bureau. Rodriguez:BMS, Takeda, Amgen: Consultancy, Speakers Bureau. Chari:Janssen, Celgene, Novartis, Amgen, Bristol-Myers Squibb, Karyopharm, Sanofi, Genzyme, Seattle Genetics, Oncopeptides, Millennium/Takeda, Antengene, Glaxo Smith Kline, Secura Bio: Consultancy; Janssen, Celgene, Novartis, Amgen, Pharmacyclics, Seattle Genetics, Millennium/Takeda: Research Funding. Silbermann:Karyopharm: Consultancy; Janssen: Consultancy; Sanofi-Aventis: Consultancy, Research Funding. Costa:AbbVie: Consultancy; Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genentech: Consultancy; BMS: Consultancy, Honoraria. Anderson:Amgen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Efebera:Pharmacyclics: Research Funding; Ohio State University: Current Employment; Celgene: Research Funding; Takeda: Honoraria, Speakers Bureau. Holstein:Sorrento: Consultancy; Adaptive Biotechnologies: Consultancy; Takeda: Consultancy; GSK: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding. Costello:Takeda, Celgene: Consultancy, Honoraria. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wildes:Seattle Genetics: Consultancy; Carevive Systems: Consultancy; Janssen: Research Funding. 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; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; 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. Shain:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; AbbVie: Research Funding; GlaxoSmithKline: Speakers Bureau; Adaptive: Consultancy, Honoraria; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Cowan:Nektar: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Bristol-Myer Squibb: Research Funding; Celgene: Consultancy, Research Funding; Cellectar: Consultancy; Sanofi-Aventis: Consultancy. Lutska:Janssen: Current Employment. Bobba:Janssen: Current Employment. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Lin:Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Voorhees:TeneoBio: Other: Advisory Board; Oncopeptides: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Other: Advisory Board; GSK: Honoraria; BMS: Other: Advisory Board; Adaptive Biotechnologies: Other: Advisory Board. OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are.

Introduction: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with bortezomib, thalidomide and dexamethasone for transplant-eligible NDMM; however, RVd is the standard of care in the US for transplant-eligible NDMM. The phase 2 GRIFFIN study (NCT02874742) of DARA plus RVd (D-RVd) for transplant-eligible NDMM in the US included a safety run-in phase followed by a randomized phase. In the 16-patient safety run-in, no dose limiting toxicities (DLTs) occurred and no new safety concerns were identified for D-RVd (Voorhees P, Blood 2018 132 [Suppl 1]:151). The randomized phase of GRIFFIN met its prespecified primary endpoint with improved rate of stringent complete response (sCR) by the end of consolidation (D-RVd, 42.4% vs RVd, 32.0%; 1-sided P=0.068) (Voorhees P, Blood 2020); however, median follow-up was limited (13.5 months). Therefore, we conducted an updated analysis of efficacy and safety for the safety run-in cohort to examine longer follow-up data for D-RVd and evaluate the role of DARA plus lenalidomide (D-R) maintenance therapy. Methods: Patients with NDMM eligible for high-dose therapy (HDT) and autologous stem cell transplant (ASCT) were enrolled. Patients in the safety run-in cohort received 4 induction cycles of D-RVd, HDT, ASCT, 2 consolidation cycles of D-RVd, and 24 months of maintenance with D-R. During induction and consolidation, patients received R 25 mg PO on Days 1-14; V 1.3 mg/m2 SC on Days 1, 4, 8, and 11; and d 40 mg QW every 21 days. DARA 16 mg/kg IV was given on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of Cycles 5-6. During maintenance (Cycles 7-32), patients received R 10 mg (15 mg in Cycles 10+ if tolerated) on Days 1-21 every 28 days plus DARA 16 mg/kg IV Q8W (or Q4W per patient decision after protocol Amendment 2). The primary objective of the safety run-in phase was to assess DLTs. Additional endpoints included safety, sCR rate by the end of consolidation and end of maintenance per IMWG criteria by computer algorithm, progression-free survival (PFS), and minimal residual disease (MRD) negativity (10-5 and 10-6 threshold) assessed by next-generation sequencing (clonoSEQ; Adaptive Biotechnologies). Results: Sixteen patients enrolled in the safety run-in and received D-RVd. Median age was 62.5 years, 8 (50%) patients were male, 4 (25%) were International Staging System stage II or III, and 4 (25%) had high cytogenetic risk based on fluorescence in situ hybridization. Thirteen (81%) patients completed study therapy, and 3 (19%) patients discontinued due to progressive disease (n=2) or adverse event (n=1). With continued therapy, responses further deepened for D-RVd (Figure). By the end of D-RVd consolidation, all patients responded, with a best response of sCR for 9 (56%) patients. By the end of D-R maintenance therapy, 15 (94%) patients achieved a best response of sCR. MRD negativity (10‒5) at the end of consolidation occurred in 8 patients (50%); no patient was MRD negative at 10-6. By the end of maintenance, 13 (81%) patients were MRD negative at 10‒5, and 5 (31%) were MRD negative at 10‒6. At a median follow-up of 39.0 months, 3 of 16 patients have progressed, with estimated 24-month and 36-month PFS rates of 94% and 78%, respectively. One death occurred, due to progressive disease in the patient who failed to achieve sCR. With longer follow-up, no new safety concerns were identified. Grade 3-4 treatment emergent adverse events (TEAEs) occurred in 14 (88%) patients, with the most common being neutropenia (44%; n=7), pneumonia (31%; n=5), lymphopenia (25%; n=4), and thrombocytopenia (25%; n=4). One patient had TEAEs leading to discontinuation of study treatment. No grade 5 TEAEs occurred. Infusion-related reactions occurred in 4 (25%) patients (all grade 1-2), mainly during the first cycle. Conclusions: With >3 years of follow-up in the safety run-in cohort of GRIFFIN, D-RVd induction, ASCT, and consolidation led to durable responses that deepened with 2 years of D-R maintenance. There were no new safety concerns. These emerging data suggest that the deep responses seen in the randomized phase of GRIFFIN are durable and will continue to improve over time, and that D-RVd may be a potential new standard of care for transplant-eligible NDMM. Support: Alliance Foundation Trials; https://acknowledgments.alliancefound.org; Janssen Oncology Disclosures Voorhees: Janssen: Other: Advisory Board; Novartis: Consultancy; Oncopeptides: Consultancy, Honoraria; TeneoBio: Other: Advisory Board; Adaptive Biotechnologies: Other: Advisory Board; BMS: Other: Advisory Board; GSK: Honoraria. Rodriguez:BMS, Takeda, Amgen: Consultancy, Speakers Bureau. Reeves:Bristol Myers Squibb: Speakers Bureau; Incyte: Honoraria; Takeda: Honoraria. Costa:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Genentech: Consultancy; Celgene: Consultancy, Honoraria; AbbVie: Consultancy; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Lutska:Janssen: Current Employment. Bobba:Janssen: Current Employment. Hoehn:Merck (current), Janssen (within 24 months): Current Employment, Ended employment in the past 24 months. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Ukropec: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. Lin:Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are.

Introduction: DARA is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the phase 3 ALCYONE study (median follow-up of 40.1 months), DARA in combination with VMP (D-VMP) reduced the risk of disease progression or death by 58% versus VMP alone (median 36.4 vs 19.3 months; HR, 0.42; 95% CI, 0.34-0.51; P Methods: Pts with TIE NDMM were randomized 1:1 to receive up to nine 6-week cycles of VMP (V 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 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 intravenously once weekly (QW) for Cycle 1 and Q3W for Cycles 2-9). Pts in the D-VMP group received DARA as maintenance therapy Q4W for Cycles 10+ until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included overall response rate (ORR), rate of ≥CR, rate of ≥very good partial response (VGPR), MRD-negativity rate (10-5), OS, and HRQoL. Outcomes were also examined at the time of best response at the beginning of DARA monotherapy (Cycle 10+) and 1 and 2 years after beginning DARA monotherapy. Results: A total of 706 (D-VMP, n=350; VMP, n=356) pts were randomized. Baseline characteristics were well balanced between groups. After a median follow-up of 40.1 months, D-VMP increased the ORR (90.9% vs 73.9%) and the rates of ≥CR (46% vs 25%), ≥VGPR (73% vs 50%), MRD-negativity (28% vs 7%; all P For patients in the D-VMP group who received DARA monotherapy in Cycle 10+, responses continued to deepen: rates of ≥CR improved from 44% at the beginning of maintenance to 64% and 68% at 1 and 2 years, respectively, after the start of DARA maintenance therapy. As in the full study population, improved PFS and OS were observed with deepening responses. Conclusions: D-VMP induced deep responses in TIE NDMM pts and improved PFS, regardless of response status. Depth of response improved PFS, OS, and time to subsequent therapy and responses continued to deepen for patients receiving DARA maintenance therapy. HRQoL was improved in both treatment groups over the course of the study as clinical response deepened. These findings suggest that the addition of DARA to VMP achieves and maintains deep responses for TIE NDMM pts, leading to better outcomes and HRQoL. Disclosures Rodriguez-Otero: Janssen, BMS: Other: Travel, accommodations, expenses; Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria; BMS, Janssen, Amgen: Honoraria; Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding. Boccadoro:Mundipharma: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Martinez-Lopez:Novartis: Consultancy; Incyte: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding. Lucio:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Nagy:MorphoSys AG: Patents & Royalties. Liberati:Onconova: Research Funding; Takeda: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Pfizer: Research Funding; Abbvie: Honoraria, Research Funding; Morphosys: Research Funding; Novartis: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Karyopharm: Research Funding; Verastem: Research Funding; Janssen: Honoraria, Research Funding. Takamatsu:Adaptive Biotechnologies: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; Janssen Pharmaceutical: Consultancy, Honoraria, Research Funding; SRL: Consultancy, Research Funding. Romejko-Jarosinska:Janssen: Honoraria; Celgene: Honoraria; Gilead: Honoraria, Other: travel expences ; Servier: Honoraria; Sanofi: Honoraria; Roche: Honoraria, Other: travel expences ; Macopharma: Other: travel expences ; Servier: Other: travel expences . Knop:Celgene; Bristol Myers Squibb; Sanofi; Janssen: Honoraria. Forsyth:Amgen: Consultancy; Janssen Pharmaceuticals Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gries:Janssen: Current Employment, Current equity holder in publicly-traded company. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Kudva:Memorial Sloan Kettering Cancer Center: Other: non-paid consultancy; Janssen: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Wroblewski:Susan Wrobleski: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau.

Introduction: Daratumumab (DARA) is a CD38-targeting monoclonal antibody approved for the treatment of MM. The addition of DARA to standard-of-care (SOC) regimens in the phase 3 ALCYONE (D-VMP vs VMP) and MAIA (D-Rd vs Rd) studies demonstrated deep and durable responses and improved progression-free survival in transplant-ineligible NDMM patients (pts). DARA-based regimens have shown increased infection rates vs SOC in both ALCYONE (grade 3/4 infections, 22% vs 15%) and MAIA (36% vs 27%). Most common (>10 pts) grade 3/4 infection(s) was pneumonia (D-VMP/VMP; 13%/4%) in ALCYONE and were pneumonia (D-Rd/Rd; 15%/9%), influenza (3%/2%), bronchitis (3%/1%), and sepsis, urinary tract and lower respiratory tract infections (3% each) in MAIA. Most common (>10 pts) serious adverse infection(s) was pneumonia (D-VMP/VMP; 12%/3%) in ALCYONE and pneumonia (D-Rd/Rd; 14%/9%), influenza (4%/2%), bronchitis (4%/2%), and upper respiratory tract infection (3%/3%) in MAIA. Using pooled data from DARA-treated pts in ALCYONE and MAIA, we report results of an analysis to identify predictive markers of grade ≥3 or serious infections that occurred during the first 6 mo of treatment. Methods: ALCYONE pts received ≥nine 6-week cycles of VMP (V: 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; M: 9 mg/m2 orally, and P: 60 mg/m2 orally on Days 1-4 of Cycles 1-9)±DARA (16 mg/kg IV), QW during Cycle 1, Q3W Cycles 2-9, and Q4W thereafter as maintenance therapy until disease progression or unacceptable toxicity. MAIA pts received 28-day cycles of Rd (R: 25 mg PO once daily on Days 1-21; d: 40 mg PO on Days 1, 8, 15 and 22)±DARA (16 mg/kg IV) QW Cycles 1-2, Q2W Cycles 3-6, and Q4W weeks thereafter. This analysis pooled data for DARA-treated pts in ALCYONE (median follow-up, 40.1 mo) and MAIA (median follow-up, 36.4 mo). Pooled data were randomly split into training and validation data. A predictive model was developed for time to first occurrence of treatment-emergent grade ≥3 or serious infections during the first 6 mo of study treatment. To identify the set of predictors for the Cox proportional hazard multivariate model, each candidate predictor was first assessed in a univariate model. Parameters with a P value Results: In ALCYONE, a total of 706 pts were randomized (D-VMP, 350; VMP, 356); in MAIA, a total of 737 pts were randomized (D-Rd, 368; Rd, 369). A total of 710 DARA-treated pts (D-VMP, 346; D-Rd, 364) were pooled from both studies to develop the predictive model (training data, 534 pts; validation data, 176 pts). 10 significant parameters were identified from the univariate analysis (Table): age, β2-microglobulin (β2M) level, frailty status, lactic acid dehydrogenase (LDH) level, albumin level at baseline, low albumin level, high alkaline phosphatase level, and elevated baseline alanine aminotransferase (ALT), ISS stage, and cytogenetic risk. The final predictive model included age, LDH, albumin, and elevated baseline ALT levels (Table). Based on the coefficient estimate of each predictor from the final Cox model, a scoring tool was developed with the total score ranging from 0-23; (≥8, high risk; ≤7, low risk). The scoring system was applied to the training data (n = 534); 370 pts were classified at low risk and 164 pts were at high risk for infection. The infection event rate was 15.7% for low-risk pts and 29.3% for high-risk pts (HR, 2.11; 95% CI, 1.44-3.10; P = 0.0001). In the validation data (n = 176), 130 pts were classified as low-risk and 46 pts were at high risk for infection. The infection rate was 16.2% for low-risk vs 28.3% for high-risk pts (HR, 1.91; 95% CI, 0.96-3.83; P = 0.0663). Conclusion: This analysis identified predictors of grade ≥3 or serious infections during the first 6 mo of treatment in DARA-treated NDMM pts that were used to develop a risk scoring system. These data will be useful in identifying pts most at risk of infection during DARA treatment. Disclosures van de Donk: Amgen: Other: Ad Board, Research Funding; BMS: Other: Ad Board, Research Funding; Janssen: Other: Ad Board, Research Funding; Novartis: Other: Ad Board; Bayer: Other: Ad Board; Takeda: Other: Ad Board; Genentech: Other: Ad Board; Celgene: Other: Ad Board, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; 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; Sanofi: Membership on an entity's Board of Directors or advisory committees. 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. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Cavo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Celgene: 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; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria; GlaxoSmithKline: Honoraria, 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. Suzuki:Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria; Bristol-Myers Squibb, Celgene and Amgen: Research Funding. Touzeau:Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Usmani:Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Incyte: Research Funding; GSK: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Merck: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; Abbvie: Consultancy. Perrot:Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Kudva:Memorial Sloan Kettering Cancer Center: Other: non-paid consultancy; Janssen: Current Employment, Current equity holder in publicly-traded company. Van Rampelbergh:Janssen: Current Employment. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Leary:Janssen: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Qi:Janssen: Current Employment, Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company. Chari:Janssen, Celgene, Novartis, Amgen, Bristol-Myers Squibb, Karyopharm, Sanofi, Genzyme, Seattle Genetics, Oncopeptides, Millennium/Takeda, Antengene, Glaxo Smith Kline, Secura Bio: Consultancy; Janssen, Celgene, Novartis, Amgen, Pharmacyclics, Seattle Genetics, Millennium/Takeda: Research Funding.

Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10−5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.

© The Author(s)., Background: Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM). [Methods]: This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10-5 sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk. [Results]: After a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21-0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR. [Conclusion]: These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status. Trial registration: ClinicalTrials.gov, NCT02136134. Registered 12 May 2014, This CASTOR study was sponsored by Janssen Research & Development, LLC. Open access funding provided by Projekt DEAL.

Background: Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. Methods: ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. Findings: 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4–43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46–0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2–82·0) in the D-VMP group and 67·9% (62·6–72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34–0·51]; p

Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomide-refractory patients were eligible. Carfilzomib- and daratumumab-naïve patients (n = 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 initial dose, escalated to 70 mg/m2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide. The trial was registered at www.clinicaltrials.gov as #NCT01998971.

Introduction: Daratumumab (DARA) is a human IgGκ mAb targeting CD38 with both direct on-tumor and immunomodulatory mechanisms of action, and has been approved as monotherapy for RRMM and in combination with standard of care (SOC) regimens for RRMM and newly diagnosed MM (NDMM). Across three phase 3 DARA studies in RRMM and NDMM, DARA plus SOC reduced the risk of progression or death by ≥50%, enabled a doubling of CR rates, and elicited a ≥3-fold increase in MRD-negative rates. Among MRD-negative RRMM pts, pts treated with D-Rd or D-Vd rapidly achieved MRD negativity and demonstrated prolonged progression-free survival (PFS) vs MRD-positive pts (Avet-Loiseau H, et al. ASH 2016. Abstract 246). MRD assessment is being investigated as a potential surrogate for established endpoints such as overall survival (OS). When measured sequentially, sustained MRD-negativity provides an index of deep clinical responses that may provide a more robust assessment of disease control (Kumar S, et al. Lancet Oncol 2016. 17[8]:e328-e346). Here, we evaluate sustained MRD negativity with DARA plus SOC regimens and its association with PFS/OS outcomes in RRMM. Methods: Eligible pts in POLLUX and CASTOR received ≥1 prior line of therapy and were randomized (1:1) to receive SOC treatment regimens ± DARA. Pts in the POLLUX study were given lenalidomide (25 mg PO) on Days 1-21 and dexamethasone (40 mg) once per week in each 28-day cycle ± DARA (16 mg/kg IV) given weekly for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. CASTOR pts received 8 cycles (21 d/cycle) of bortezomib (1.3 mg/m2 SC) on Days 1, 4, 8, and 11 and dexamethasone (20 mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 ± DARA (16 mg/kg IV) given weekly for Cycles 1-3, Q3W for Cycles 4-8, and Q4W thereafter. MRD was assessed at the time of suspected CR and at 3 and 6 months following confirmed CR in POLLUX, and at time of suspected CR and 6 and 12 months following the first treatment dose in CASTOR. Additional MRD evaluation was required in both studies every 12 months post-CR. MRD was assessed via next generation sequencing using the clonoSEQ® assay V2.0 (Adaptive Biotechnologies, Seattle, WA). Sustained MRD negativity was defined as the maintenance of MRD negativity in the bone marrow confirmed ≥6 or ≥12 months apart and was evaluated in the intent-to-treat (ITT) population. Sustained MRD negativity was also evaluated among ≥CR pts to account for different sustained MRD negativity rates between treatment arms. Results: A total of 569 (D-Rd, n = 286; Rd, n = 283) pts in POLLUX and 498 pts (D-Vd, n = 251; Vd, n = 247) in CASTOR were randomized; median (range) number of prior lines received was 1 (1-11) and 2 (1-10), respectively. Median duration of follow up was 39.5 months in POLLUX and 31.3 months in CASTOR for this analysis. Using the ≥6-month sustained MRD cutoff, a significantly higher proportion of pts achieved sustained MRD negativity for ≥6 months when treated with D-Rd vs Rd (16% vs 0.7%; P For the ≥12-month sustained MRD cutoff, more pts achieved sustained MRD negativity when receiving D-Rd vs Rd (13% vs 0.4%; P Additional analyses, including an analysis of baseline pt characteristics for pts with sustained MRD negativity, will be presented at the meeting. Conclusions: DARA combinations with SOC regimens enable a significantly higher proportion of pts to achieve deep and durable responses of ≥CR and MRD negativity at 10-5. Importantly, the ability to reach durable MRD negativity is associated with prolonged survival, suggesting that achieving durable MRD negativity should be a treatment goal for RRMM pts. Disclosures San-Miguel: Sanofi: Honoraria; Novartis: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Casneuf:Janssen Research & Development: Employment. Iida:Chugai: Research Funding; Astellas: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; MSD: Research Funding; Gilead: Research Funding; Toyama Chemical: Research Funding; Teijin Pharma: Research Funding; Sanofi: Consultancy; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Lonial:Amgen: Research Funding. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. 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. Moreau: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; Celgene: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Plesner:Celgene: Other: Independent Response Assessment Comittee; Janssen: Consultancy. Weisel:Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, Celgene, Janssen, and Sanofi: Research Funding. Ukropec:Janssen Scientific Affairs, LLC: Employment. Okonkwo:Janssen Research & Development, LLC: Employment. Trivedi:Janssen Research & Development, LLC: Employment. Velas:Janssen Research & Development, LLC: Employment. Qin:Janssen Research & Development, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Chiu:Janssen Research & Development, LLC: Employment. Bahlis:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

Introduction: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care (SoC) regimens for multiple myeloma (MM). In randomized studies, DARA-based regimens significantly improved response rates, depth of response including minimal residual disease (MRD) negativity, and progression-free survival (PFS) in NDMM and relapsed/refractory MM pts. RVd followed by high-dose therapy (HDT), autologous stem cell transplant (ASCT), and consolidation is a SoC regimen for US pts with NDMM. This phase 2, randomized study (GRIFFIN; NCT02874742) evaluated DARA plus RVd (D-RVd) in ASCT-eligible NDMM pts. A 16-pt safety run-in showed no safety concerns. Here, we present results that adding DARA to RVd improves responses rapidly, including depth of response, which increases with longer duration of therapy. Methods: Pts were randomized 1:1 to RVd ± DARA, stratified by ISS stage and creatinine clearance. Pts received 4 induction cycles, HDT, ASCT, 2 consolidation cycles, and maintenance with R ± DARA for 24 mo. During induction and consolidation (Cycles 1-6), pts received R 25 mg PO on Days 1-14; V 1.3 mg/m2 SC on Days 1, 4, 8, and 11; and d 40 mg QW every 21 days. DARA 16 mg/kg IV was given on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of Cycles 5-6. During maintenance (Cycles 7-32), pts received R 10 mg (15 mg in Cycles 10+ if tolerated) on Days 1-21 every 28 days ± DARA 16 mg/kg IV Q8W (or Q4W per pt decision after Amendment 2). The primary endpoint was the stringent complete response (sCR) rate by the end of consolidation per IMWG computer algorithm. The study had 80% power to detect a 15% improvement with a 1-sided alpha of 0.1 (equivalent to 2-sided alpha of 0.2). MRD (10-5 per IMWG criteria) was assessed by next-generation sequencing (clonoSEQ; Adaptive Biotechnologies). Results: A total of 207 pts (D-RVd n = 104; RVd n =103) were randomized. Baseline demographics and disease characteristics were well balanced between arms. Median age was 60 yrs; 48%, 37%, and 14% of pts were ISS stage I, II, or III, respectively; 30 (15%) pts had high cytogenetic risk defined by FISH for del(17p), t(4;14), or t(14;16). The study met its primary endpoint; D-RVd improved the sCR rate by the end of consolidation (42.4% vs 32.0%; odds ratio 1.57; 95% CI, 0.87-2.82; 2-sided P = 0.1359); at the pre-set 2-sided alpha of 0.2. This improvement was observed in all pt subgroups except for the small subsets of ISS stage III or high-cytogenetic risk pts. Responses deepened over time (Figure); the sCR rate was 12% vs 7% with D-RVd vs RVd at the end of induction, increasing to 21% vs 14% after ASCT, and 50% vs 37% at the clinical cutoff (CCO; 13.5 mo median follow-up). D-RVd achieved higher overall response (99% vs 92%), ≥VGPR (91% vs 73%), and ≥CR (52% vs 42%) rates vs RVd by the end of consolidation. At the end of induction, 8/19 (42%) pts achieving ≥CR with D-RVd were MRD negative, compared to 1/13 (8%) pts achieving ≥CR with RVd. At the end of consolidation, 30/51 (59%) pts achieving ≥CR with D-RVd were MRD negative vs 10/41 (24%) pts achieving ≥CR with RVd. Due to the short median follow-up at CCO, PFS and OS were immature, with 6 PFS events in each arm. Median stem cell yield was 8.1 vs 9.4 × 106 cells/kg for D-RVd vs RVd. Median (range) time to platelet engraftment was 13 (2-31) and 12 (1-23) days for D-RVd vs RVd; median (range) time to neutrophil engraftment was 12 (3-31) and 12 (2-23) days for D-RVd vs RVd. Grade 3/4 TEAEs (≥10%) with D-RVd vs RVd included neutropenia (32% vs 15%), lymphopenia (23% vs 23%), thrombocytopenia (16% vs 8%), and leukopenia (15% vs 7%). There was no difference in the rate of grade 3/4 infections between arms. IRRs occurred in 41% of DARA-treated pts, which were primarily grade 1-2. Updated data will be presented. Conclusions: These data demonstrate that adding DARA to RVd significantly improves response rates and depth of response, including sCR and MRD negativity. As seen in other randomized studies, continued use of daratumumab improved depth of response. The overall safety profile of D-RVd is consistent with previous reports with DARA plus SoC. Likewise, similar to what was reported from CASSIOPEIA, stem cell mobilization and ASCT are feasible with D-RVd, without a significant effect on hematopoietic reconstitution. The study is ongoing, with pts continuing maintenance therapy. Disclosures Voorhees: BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GSK: Research Funding; Novartis: Consultancy; Oncopeptides: Consultancy; Takeda: Honoraria, Research Funding; TeneBio: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria. Kaufman:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Takeda: Consultancy; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; AbbVie: Consultancy; Amgen: Consultancy. Sborov:Celgene: Honoraria; Janssen: Consultancy. Reeves:Celgene: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Rodriguez:Takeda, Amgen: Consultancy, Speakers Bureau. Chari:Janssen, Celgene, Novartis Pharmaceuticals, Amgen, Bristol Myers Squibb, Pharmacyclics, Karyopharm, Sanofi, Seattle Genetics, OncoPeptides, Millenium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Silbermann:Janssen, Sanofi: Other: Consultant/Advisor. Costa:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor. Anderson:Amgen, Janssen, Takeda, Celgene: Consultancy, Speakers Bureau. Shah:Bristol-Myers Squibb: 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; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Indapta Therapeutics: Equity Ownership; University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees. Efebera:Takeda: Honoraria; Akcea: Other: Advisory board, Speakers Bureau; Janssen: Speakers Bureau. Costello:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jakubowiak:Takeda: 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; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: 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; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wildes:Carevive: Consultancy; Janssen: Research Funding. Orlowski:BioTheryX, Spectrum Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Kita Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ionis Pharmaceuticals; Legend Biotech; Molecular Partners; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shain: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; Adaptive Biotechnologies: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Cowan:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Juno: Research Funding; Sanofi: Consultancy; Cellectar: Consultancy. Murphy:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Vermeulen:Janssen R&D, LLC: Employment, Equity Ownership. de Boer:Janssen: Employment, Equity Ownership. Hoehn:Janssen: Employment, Equity Ownership. Lin:Janssen: Employment, Equity Ownership. Richardson:Karyopharm: 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; Takeda: 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; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. OffLabel Disclosure: D-RVd is being investigated in transplant-eligible NDMM

Introduction: Daratumumab (DARA), a human, IgGκ monoclonal antibody targeting CD38, is approved either as a single agent or in combination with anti-myeloma regimens for newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM). In phase 3 studies, DARA-based regimens reduced the disease progression or death risk by ≥44%, nearly doubled the rates of complete response (CR) or better, and tripled minimal residual disease (MRD)-negativity rates (10-5 sensitivity threshold) in NDMM or RRMM pts (Palumbo A, et al. N Engl J Med 2016. 375[8]:754-766; Dimopoulos MA, et al. N Engl J Med 2016. 375[14]:1319-1331; Mateos MV, et al. N Engl J Med 2018. 378[6]:518-528; Facon T, et al. N Engl J Med 2019. 380[22]2104-2015). In the phase 3 CASTOR study (median follow-up 40.0 mo), D-Vd reduced the risk of disease progression or death by 69% and induced higher rates of deeper responses vs Vd in RRMM pts. Pts who received 1 prior line (PL) of therapy achieved the greatest benefit with D-Vd. Here, we examine updated (47.0 mo median follow-up) efficacy and safety of D-Vd vs Vd in CASTOR, with a focus on pts with 1 PL of therapy. Methods: In CASTOR, pts were randomized to 8 cycles (21 d/cycle) of V (1.3 mg/m2, SC) on Days 1, 4, 8, and 11 and dexamethasone (20 mg, PO or IV) on Days 1, 2, 4, 5, 8, 9, 11, and 12 ± DARA (16 mg/kg, IV) given weekly for Cycles 1-3, Q3W for Cycles 4-8, and Q4W thereafter. Cytogenetic risk was evaluated by local fluorescence in situ hybridization or karyotyping; high risk was defined as the presence of t(4;14), t(14;16), or del17p abnormalities. Results: A total of 498 pts were randomized (D-Vd, n = 251; Vd, n = 247) and included in the intent-to-treat (ITT) population. A total of 235 pts had 1 PL of therapy (D-Vd, n = 122; Vd, n = 113). After a median follow-up of 47.0 mo, progression-free survival (PFS) was significantly prolonged with D-Vd vs Vd in the ITT population (median: 16.7 vs 7.1 mo; HR, 0.31; 95% CI, 0.25-0.39, P Among 1 PL pts, median PFS was 27.0 vs 7.9 mo (HR, 0.21; 95% CI, 0.15-0.31, P Additional data including MRD analyses will be presented. The most common (≥5%) grade 3/4 treatment-emergent adverse events (TEAEs) with D-Vd vs Vd included thrombocytopenia (46% vs 33%), anemia (16% vs 16%), neutropenia (14% vs 5%), pneumonia (10% vs 10%), lymphopenia (10% vs 3%), hypertension (7% vs 1%), and peripheral sensory neuropathy (5% vs 7%). Discontinuation rates due to TEAEs were similar for D-Vd vs Vd (10% vs 9%). The rate of invasive second primary malignancy rates were 4.9% in the D-Vd group vs 1.7% in the Vd group. Conclusions : In this updated analysis of CASTOR, D-Vd maintains significant PFS and ORR benefits in RRMM, with the greatest benefit achieved by pts who received 1 PL of therapy. The safety profile of D-Vd remains consistent with longer follow-up, with no new safety concerns reported. These data continue to suggest that administration of D-Vd to RRMM pts after first relapse may provide the greatest clinical benefit. Disclosures Weisel: Juno: Consultancy; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Honoraria. Mateos:Adaptive: Honoraria; 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; 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; EDO: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees. Hungria:BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, 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, Speakers Bureau; Abbvie: Consultancy, 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, Speakers Bureau; Takeda: 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, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Spencer:Sanofi: 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, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, 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, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Specialised Therapeutics Australia: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Estell:Janssen/ Celgene: Membership on an entity's Board of Directors or advisory committees. Barreto:Hemocentro, USP-Ribeira; Preto-SP: Employment. Corradini:Gilead: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; BMS: Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; KiowaKirin: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria. Krevvata:Janssen: Employment. Trivedi:Janssen: Employment, Equity Ownership. Qin:Janssen: Employment, Equity Ownership. Pei:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Kobos:Janssen: Employment. Qi:Janssen: Employment. Nooka:Amgen: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation.

Introduction: Daratumumab, a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, is approved in combination with standard-of-care regimens for the treatment of newly diagnosed multiple myeloma (NDMM) and RRMM. When combined with standard of care regimens across four phase 3 studies, daratumumab demonstrated ≥44% reductions in the risk of progression or death, nearly doubled complete response (CR) or better rates, and tripled minimal residual disease (MRD)-negative rates at the 10-5 sensitivity threshold in pts with RRMM or NDMM (Palumbo A, et al. N Engl J Med 2016. 375[8]:754-766; Dimopoulos MA, et al. N Engl J Med 2016. 375[14]:1319-1331; Mateos MV, et al. N Engl J Med 2018. 378[6]:518-528; Facon T, et al. N Engl J Med 2019. 380[22]2104-2015). In the phase 3 POLLUX study (median follow-up 44.3 months), D-Rd reduced the risk of disease progression or death by 56% and significantly increased the overall response rate (ORR) versus Rd alone (93% vs 76%; P 4 years of median follow-up. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to Rd (lenalidomide 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone 40 mg per week) ± daratumumab (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, then Q4W until disease progression). Cytogenetic risk was determined by local fluorescence in situ hybridization or karyotyping; pts with high cytogenetic risk had t(4;14), t(14;16), and del17p abnormalities. PFS on subsequent line of therapy (PFS2), an exploratory endpoint, was defined as time from randomization to progression after next line of subsequent therapy or death. Results: A total of 569 pts were randomized (D-Rd, n = 286; Rd, n = 283). At a median follow-up of 51.3 months, D-Rd significantly prolonged progression-free survival (PFS) versus Rd (median 45.8 vs 17.5 months; hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.35-0.54; P The median duration of treatment was 34.3 months in the D-Rd arm versus 16.0 months in the Rd arm. The most common (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs) observed with D-Rd versus Rd included neutropenia (56% vs 42%), anemia (18% vs 22%), thrombocytopenia (15% vs 16%), pneumonia (16% vs 10%), and diarrhea (10% vs 4%). Similar rates of discontinuations due to TEAEs were observed for D-Rd versus Rd (16% vs 15%). The incidence of invasive second primary malignancies was 4.9% and 5.7% for the D-Rd and Rd groups, respectively. Additional efficacy data, including minimal residual disease, and safety analyses will be presented at the meeting. Conclusion: After >4 years of median follow-up, D-Rd continues to demonstrate a significant PFS benefit and higher rates of deeper responses versus Rd alone in pts with RRMM. Although significant PFS benefit was observed with D-Rd in RRMM pts regardless of prior lines of therapy or cytogenetic risk status, the greatest benefit was observed when used in patients treated earlier with D-Rd. The significant improvement in PFS2 suggests a potential survival benefit, but OS data is still immature. No new safety concerns were identified with this additional follow-up. Disclosures Kaufman: Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Takeda: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AbbVie: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Amgen: Consultancy. Usmani:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Bahlis:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Cook:Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding. Ho:Novartis: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs. Moreau:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Krevvata:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Renaud:Janssen: Employment, Equity Ownership. Trivedi:Janssen: Employment, Equity Ownership. Kobos:Janssen: Employment. Dimopoulos:Sanofi Oncology: Research Funding.

Introduction: Patients (pts) with RRMM have a poor prognosis, with limited treatment options and poor overall survival (OS). Despite the increasing use of lenalidomide (len) in frontline treatment of multiple myeloma, len-refractory pts are often excluded from randomized studies. In the few studies including len-refractory pts, median progression-free survival (PFS) of DARA is a human IgGκ monoclonal antibody targeting CD38 approved as monotherapy in RRMM and in combination with standard-of-care regimens for newly diagnosed multiple myeloma and RRMM. K is a proteasome inhibitor approved as monotherapy and in combination with len and d for RRMM. Here, with a median follow-up of 23.7 months, we present the final analysis of the treatment arm from a phase 1b study that evaluated DARA in combination with K and d (D-Kd) in pts with RRMM, including len-refractory pts. Methods: MMY1001 (NCT01998971) is a multi-arm, phase 1b study evaluating DARA in combination with various backbone therapies. Eligible pts with RRMM in the D-Kd arm had an ECOG score of ≤2, were treated with >1 prior line of therapy, including V and an immunomodulatory drug, and were K naïve. All pts (N = 85) received 28-day cycles of D-Kd until disease progression. DARA was given weekly for Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter. 10 pts received the first DARA dose as a single infusion (16 mg/kg Cycle 1 Day 1) and 75 pts received a split first dose (8 mg/kg Cycle 1 Days 1 and 2). Pts received K weekly on Days 1, 8, and 15 of each cycle (20 mg/m2 initial dose, escalated to 70 mg/m2 thereafter), and d (40 mg) weekly. The primary endpoint was safety and tolerability. Overall response rate was a secondary endpoint, and minimal residual disease (MRD) was an exploratory endpoint. Results: Pts received a median of 2 (range, 1-4) prior lines of therapy. All pts received prior V; 81 (95%) received prior len (51 [60%] were len-refractory), and 13 (15%) received prior pom. 50 (59%) pts discontinued study treatment: 36 (42%) due to progressive disease, 6 (7%) due to patient withdrawal, 5 (6%) due to adverse event (AE), 2 (2%) due to physician decision, and 1 (1%) due to death. In the safety-analysis set (N = 85), the most common (>10%) grade 3/4 treatment-emergent AEs were thrombocytopenia (32%), lymphopenia (25%), anemia (21%), neutropenia (21%), hypertension (20%), and asthenia (15%). Serious AEs occured in 41 (48%) pts; 9%, 19%, and 14% were related to DARA, K, and d, respectively. Median left ventricular ejection fraction did not notably change over time from baseline (64% at baseline [n = 84], 62% at Cycle 6 [n = 54], 61% at Cycle 12 [n = 47], 59% at Cycle 18 [n = 22], and 63% at Cycle 24 [n = 10]). 7 (8%) pts experienced grade 3/4 cardiac AEs of interest, 2 (2%) pts each with cardiac failure and sinus tachycardia, and 1 (1%) patient each with acute pulmonary edema, left ventricular failure, atrial fibrillation, and myocardial ischemia. Infusion-related reactions occured in 6 of 10 (60%) and 31 of 75 (41%) pts receiving single- and split-first doses of DARA, respectively; the vast majority were mild (grade 1/2) and occurred during the first infusion. After a median follow-up of 23.7 (range, 0.5-34.7) months, median PFS was 25.7 months (95% confidence interval [CI], 14.8- not estimable [NE]; Figure) in all-treated and 22.3 months (95% CI, 12.0-NE) in len-refractory pts. The 24-month PFS rate was 53% in all-treated and 47% in len-refractory pts. Response and MRD-negativity rates are summarized in the Table. The median duration of response among pts that responded to treatment was 27.5 months (95% CI, 20.5-NE). A total of 32 (38%) pts received subsequent anticancer therapy, with a median time to subsequent therapy of 29.2 (95% CI, 19.5-NE) months. Median PFS on next line of therapy (PFS2) and OS were NE; the 24-month PFS2 rate was 61% (95% CI, 49-71) and the 24-month OS rate was 71% (95% CI, 60-80). The DARA pharmacokinetic profile was consistent with previous studies, and no pts were positive for anti-DARA antibodies. Conclusions: D-Kd was well tolerated, with no new safety concerns identified. Patients treated with D-Kd demonstrated deep responses and encouraging PFS outcomes, including in patients refractory to len. Disclosures Chari: Janssen, Celgene, Novartis Pharmaceuticals, Amgen, Bristol Myers Squibb, Pharmacyclics, Karyopharm, Sanofi, Seattle Genetics, OncoPeptides, Millenium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lonial:Celgene Corporation: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Martinez-Lopez:F. Hoffmann-La Roche Ltd: Honoraria; Janssen: Honoraria, Other: Advisory boards and Non-Financial Support ; Celgene: Honoraria, Other: Advisory boards and Non-Financial Support ; VIVIA Biotech: Honoraria; BMS: Honoraria, Other: Advisory boards; Incyte: Honoraria, Other: Advisory boards; Novartis: Honoraria, Other: Advisory boards; Amgen: Honoraria, Other: Non-Financial Support . Mateos:Pharmamar: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; 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: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees. Bladé:Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rodriguez Otero:Kite Pharma: Consultancy; Takeda: Consultancy; BMS: Honoraria; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria. Jakubowiak:AbbVie: Consultancy, Honoraria, 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; Juno: Consultancy, Honoraria; SkyLineDx: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; KaryoPharm Therapeutics: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Olyslager:Janssen: Employment, Equity Ownership. Wang:Janssen: Employment. Nnane:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Shreeve:Johnson & Johnson: Equity Ownership; Janssen: Employment. Qi:Janssen: Employment. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. OffLabel Disclosure: In the submitted abstract, we present data from a phase 1b clinical trial of a combination regimen that is not currently approved for the treatment of relapsed/refractory multiple myeloma. Components of the combination regimen including daratumumab and carfilzomib are, however, approved as monotherapy or in combination with standard-of-care regimens for treatment of patients with relapsed/refractory multiple myeloma.

Introduction: Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody approved as monotherapy in heavily pretreated relapsed/refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens for transplant-ineligible NDMM and RRMM. The addition of DARA to standard-of-care regimens in phase 3 studies has consistently demonstrated a near doubling of complete response (CR) rates, tripling of minimal residual disease (MRD)-negativity rates, and reduction in the risk of disease progression or death by ≥44% in patients with transplant-ineligible NDMM or RRMM. In the primary analysis of the phase 3 MAIA study (median follow-up: 28.0 months), a significant progression-free survival (PFS) benefit (median not reached [NR] vs 31.9 months; hazard ratio [HR], 0.56; P3-fold increase in MRD-negativity rates (10-5 sensitivity threshold; 24.2% vs 7.3%; P 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 36.4 months, median PFS was NR with D-Rd vs 33.8 months with Rd (HR, 0.56; 95% confidence interval [CI], 0.44-0.71; P Grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) occurring in ≥10% of patients were neutropenia (51%/35%), lymphopenia (15%/11%), pneumonia (15%/9%), anemia (14%/21%), leukopenia (11%/6%), and hypokalemia (10%/10%); grade 3/4 infection rates were 36%/27%. The most common serious TEAE was pneumonia (14%/9%). 9% of patients in the D-Rd arm and 18% of patients in the Rd arm discontinued treatment due to TEAEs. The complete updated data set will be presented at the meeting with additional efficacy endpoints, including MRD-negativity rate. Conclusion: After longer follow up, the addition of DARA to Rd continues to demonstrate a significant PFS benefit and improved rates of deeper and more durable responses vs Rd alone in patients with transplant-ineligible NDMM. The longer follow-up also demonstrated a significant improvement in PFS2 favoring D-Rd, and no new safety concerns were observed. These results continue to support the use of D-Rd in the first line of treatment for transplant-ineligible patients with NDMM. Disclosures Bahlis: Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Janssen: 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: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Plesner:Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genmab: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Quach:Sanofi: Research Funding; Karyopharm: 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; GSK: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt:ArtTempi: Honoraria; John Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Mundipharma: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Sanofi: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding. O'Dwyer:GlycoMimetics Inc: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy. Venner:Janssen: Honoraria; J&J: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Weisel:GSK: Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Celgene Corporation: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Krevvata:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Wang:Janssen: Employment. Van Rampelbergh:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Uhlar:Janssen: Employment. Kobos:Janssen: Employment. Perrot:Janssen: 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; Takeda: Honoraria; Amgen: Honoraria; Sanofi: Honoraria.

Introduction: Achievement of MRD negativity in MM is associated with prolonged progression-free survival (PFS) and is being investigated as a potential surrogate for established clinical endpoints, such as PFS and overall survival (OS). Here, we evaluated the predictive utility of MRD in patients (pts) with MM for PFS and OS using a systematic literature review (SLR) and meta-analysis, and investigated how hazard ratios (HR) for PFS and OS, stratified by MRD status, changed for various pt subgroups. Methods: A SLR was conducted to identify all studies in MM reporting survival outcomes by MRD status (through 8 June 2019). In these studies, MRD was assessed by various assays (multiparametric flow cytometry [MFC], next generation sequencing [NGS], and polymerase chain reaction [PCR]), sensitivity thresholds (10-4, 10-5, and 10-6), and disease settings (relapsed/refractory MM [RRMM], transplant-eligible [TE] and transplant-ineligible [TIE] newly diagnosed MM [NDMM]). Studies with allogeneic transplant, where MRD was measured in peripheral blood or using PET-CT, or from which PFS and OS data could not be extracted were excluded from the analysis. To obtain a pooled effect estimate of MRD status on PFS and OS HRs, a meta-analysis was performed. Subgroup analyses were performed to adjust for variables expected to impact the association of MRD and PFS/OS outcomes. Variables were selected based on available qualitative evidence from studies. Statistical analyses were performed using the 'metafor' R package for meta-analyses. Results: 143 publications met the inclusion criteria; 86 publications were included in the meta-analysis based on data availability (65 PFS and 28 OS HRs). Outcomes for PFS (N = 8590) and OS (N = 3392) were significantly improved for MRD-negative pts: PFS HR 0.35 (95% confidence interval [CI], 0.31-0.39) and OS HR 0.48 (95% CI, 0.41-0.55; P When analyzed by MRD sensitivity threshold, HRs for PFS and OS were in favor of MRD-negativity in all subgroups. Outcomes for PFS and OS improved with increasingly stringent sensitivity thresholds. HRs for PFS were 0.36 (95% CI, 0.31-0.42) at 10-4; 0.35 (95% CI, 0.30-0.41) at 10-5, and 0.26 (95% CI, 0.17-0.39) at 10-6 (all P When analyzed by disease setting, MRD negativity provided superior PFS for both TE NDMM (HR, 0.39 [95% CI, 0.32-0.46]) and TIE NDMM (HR, 0.35 [95% CI, 0.29-0.42]). Consistent with PFS, the effect of MRD-negativity on OS was less pronounced in TE NDMM (HR, 0.53 [95% CI, 0.45-0.63]) than TIE NDMM (HR, 0.40 [95% CI, 0.30-0.54]). As RRMM is an aggressive disease state, achieving MRD-negativity is important for long-term outcomes; notably, our cohort of RRRM pts had a PFS HR of 0.30 (95% CI, 0.18-0.49). Benefit for achieving MRD-negativity was confirmed for PFS in pts with high-risk cytogenetics (HR, 0.44 [95% CI, 0.35-0.57]) and standard-risk cytogenetics (HR, 0.46 [95% CI, 0.32-0.66]). A similar improvement was observed in OS for high-risk (HR, 0.66 [95% CI, 0.46-0.94]) and standard-risk cytogenetic pts (HR, 0.64 [95% CI, 0.54-0.75]). Additional analyses with survival data will be presented. Conclusions: This meta-analysis, involving a large pt cohort, confirms that MRD negativity has a positive effect on both PFS and OS in both TE and TIE NDMM. Outcomes for MRD-negative pts improve with an increase in MRD assay sensitivity. Pts with RRMM and with high cytogenetic risk also have favorable outcomes for PFS and OS with MRD negativity. Disclosures Munshi: Takeda: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Oncopep: Consultancy. Avet-Loiseau:celgene: Consultancy, Other: travel fees, lecture fees, Research Funding; takeda: Consultancy, Other: travel fees, lecture fees, Research Funding. Anderson:Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Sanofi-Aventis: Other: Advisory Board. Neri:Celgene, Janssen: Consultancy, Honoraria, Research Funding. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Dimopoulos:Sanofi Oncology: Research Funding. Kulakova:Ingress-health: Employment. Heeg:Ingress-Health: Employment. Hashim:Ingress-Health: Employment. Ukropec:Janssen: Employment, Equity Ownership. Liu:Janssen: Employment, Equity Ownership. Krevvata:Janssen: Employment. Lam:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Bahlis:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Background: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) and bortezomib and dexamethasone (Vd) for newly diagnosed MM (NDMM) and relapsed MM (RMM), respectively. CyBorD is a commonly used immunomodulatory drug-sparing regimen for MM. In the LYRA (NCT02951819) study, DARA plus CyBorD (DARA-CyBorD) demonstrated efficacy and a tolerable safety profile at the end of induction. Here, we present updated findings examining the effect of monthly DARA maintenance on the efficacy and safety of DARA-CyBorD in NDMM and RMM. Methods: LYRA is an ongoing, single-arm, open-label, phase 2 study conducted at US community oncology centers. Patients (pts) were aged ≥18 years with documented MM per IMWG criteria, an ECOG performance score (PS) of 0-2, and ≤1 prior line of therapy. Pts received 4-8 induction cycles of DARA-CyBorD (cyclophosphamide 300 mg/m2 PO on Days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 SC on Days 1, 8, and 15; and dexamethasone 40 mg PO or IV weekly [qw]) every 28 days. DARA was given at 8 mg/kg IV on Days 1 and 2 of C1, 16 mg/kg qw from C1D8 through C2, 16 mg/kg q2w for C3-6, and 16 mg/kg q4w for C7-8. After induction, eligible pts could undergo autologous stem cell transplantation (ASCT). All pts received up to 12 maintenance cycles with DARA 16 mg/kg IV q4w. Results: A total of 101 (87 NDMM, 14 RMM) pts were enrolled; 100 (86 NDMM, 14 RMM) pts received ≥1 treatment dose. Median age was 63 years; most pts were white (81%), male (64%), had ECOG PS 0-1 (94%) and had IgG (57%) MM; 36% of pts had high cytogenetic risk, defined as a del(17p), t(4:14) or t(14;16) abnormality. NDMM and RMM pts received a median of 6 and 8 cycles, respectively, of induction therapy. Thirty-nine NDMM pts and 1 RMM pt underwent ASCT. Fifty percent of pts received plerixafor; median stem cell yield for NDMM pts was 6.2 x 106 (range 2-15 x 106) CD34+ cells/kg. A total of 85 (75 NDMM, 10 RMM) pts received ≥1 dose of maintenance treatment; 63 (56 NDMM, 7 RMM) pts have received all 12 maintenance cycles. In NDMM pts, ORR was 87%, with 64% ≥VGPR and 12% ≥CR, by the end of induction. By the end of maintenance, ORR, ≥VGPR and ≥CR rates were 97%, 82% and 51% in NDMM pts who underwent ASCT and 83%, 70% and 30% in NDMM pts who did not receive ASCT. In RMM pts, ORR, ≥VGPR and ≥CR rates were 79%, 71% and 29% by the end of induction and 86%, 71% and 64% by the end of maintenance. At a median follow up of 24.8 mo in NDMM pts and 26.6 mo in RMM pts, median duration of response was not reached (NR). Median PFS (Figure) was NR in NDMM pts, regardless of transplant status, and was 21.7 mo in RMM pts; median OS was NR in NDMM pts and was 30.1 mo in RMM pts. In NDMM pts the 24-mo PFS rate was 89% in pts who underwent ASCT and 72% in pts who did not receive ASCT. The 24-mo OS rate was 90% for NDMM pts. In RMM pts, the 24-mo PFS and OS rates were 48% and 64%, respectively. All treated pts had ≥1 TEAE. Common TEAEs (≥25%) included fatigue, nausea, cough, diarrhea, upper respiratory tract infection, back pain, vomiting, insomnia, dyspnea, constipation, and headache. Grade 3/4 TEAEs were reported in 62% of pts; the most common (≥10%) was neutropenia (14%). Serious TEAEs occurred in 33% of pts; the most common (>2%) were pneumonia, atrial fibrillation and pulmonary embolism. TEAEs led to permanent treatment discontinuation in 7% of pts, with 2% related to treatment. TEAEs resulted in death in 2 pts (nephrotic syndrome, sudden death); both unrelated to treatment. Infusion reactions (IRs) occurred in 56% of pts including grades 1-2 in 52% of pts, grade 3 in 3% of pts and grade 4 in 1% of pts. Most common (>5%) IRs were chills, cough, dyspnea, nausea, pruritus, flushing and nasal congestion. Conclusion: Maintenance with DARA monotherapy for 12 mo increased the >CR rate in NDMM and RMM pts, consistent with observations in prior studies that longer DARA treatment improves depth of response. Importantly, the increase in ≥CR rate was associated with durable PFS and OS. The 24-mo PFS rates in NDMM and RMM pts compare favorably with results for DARA-VMP and DARA-Vd in NDMM and RRMM, respectively. Safety profile was consistent with previous reports of DARA, with no new safety concerns observed with longer follow-up. These data indicate that DARA-CyBorD is a safe, effective MM treatment and that DARA maintenance increases depth of response and achieves durable remissions. Disclosures Rifkin: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Faber:Cardinal Health: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Burke:Gilead: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy. Narang:Celgene: Speakers Bureau. Stevens:Astellas: Consultancy. Gunawardena:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Qi:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Lin:Janssen: Employment, Equity Ownership. Yimer:Amgen: Consultancy; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau.

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. The addition of DARA to standard-of-care regimens in phase 3 studies reduced the risk of disease progression or death by ≥44%, nearly doubled the rate of complete response or better, and induced a ≥3-fold increase in minimal residual disease (MRD)-negativity rates versus standard of care alone in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma. In the primary analysis of the phase 3 ALCYONE study (median follow-up: 16.5 months), a significant progression-free survival (PFS) benefit (median not reached vs 18.1 months; hazard ratio [HR], 0.50; P 36 months of follow-up from ALCYONE, including analysis of overall survival (OS) from a prespecified interim analysis. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age (≥65 years) or comorbidities were randomized 1:1 to receive up to nine 6-week cycles of VMP (bortezomib 1.3 mg/m2 subcutaneously on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; melphalan 9 mg/m2 orally and prednisone 60 mg/m2 orally on Days 1-4 of Cycles 1-9) with or without DARA (16 mg/kg intravenously once weekly for Cycle 1, once every 3 weeks for Cycles 2-9, and once every 4 weeks for Cycles 10+ until disease progression). The primary endpoint was PFS. Secondary endpoints included overall response rate, rate of complete response or better, rate of very good partial response or better, MRD-negativity rate (10-5 threshold), PFS on subsequent line of therapy (PFS2), OS, and safety. Results: A total of 706 patients were enrolled in this study (D-VMP: n = 350; VMP: n = 356). Patient baseline characteristics were well balanced between treatment arms. The median (range) age was 71 (40-93) years, and 29.9% of patients were ≥75 years of age. 518 (84.1%) and 98 (15.9%) of 616 patients evaluated had standard and high (del17p, t[14;16], and/or t[4;14] positive) cytogenetic risk, respectively, as assessed via local fluorescence in-situ hybridization/karyotyping. Median PFS was 36.4 months with D-VMP versus 19.3 months with VMP after a median follow-up of 40.08 months (HR, 0.42; 95% confidence interval [CI], 0.34-0.51; P Conclusions: For the first time, we demonstrate that the addition of DARA to VMP prolongs OS in patients with transplant-ineligible NDMM, with a 40% reduction in the risk of death versus VMP alone after a median follow-up of 40 months. D-VMP continued to demonstrate a significant PFS benefit, which was also maintained during the subsequent line of therapy. These findings, together with the phase 3 MAIA study (DARA plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone), continue to support the addition of DARA to frontline treatment regimens in patients with transplant-ineligible NDMM. Disclosures Mateos: Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria. Cavo:Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria; Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene: Speakers Bureau. Bladé:Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Sanofi Oncology: Research Funding. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: 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; Juno: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, 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; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Amgen: 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; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Knop:Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Lucio:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Nagy:Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cook:Celgene, Jannsen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squibb, GlycoMimetics, Seattle Genetics and Sanofi: Honoraria. Liberati:Janssen: Honoraria; Bristol & Mayer: Honoraria; Celgene: Honoraria; Servier: Honoraria, 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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Campbell:Janssen: Honoraria, Research Funding, Speakers Bureau. Garg:Novartis, Janssen: Research Funding; Janssen, Takeda, Novartis: Other: Travel expenses; Janssen: Honoraria. Krevvata:Janssen: Employment. Wang:Janssen: Employment. Kudva:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Wroblewski:Janssen: Employment, Equity Ownership. Kobos:Janssen: Employment. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.

Background: DARA, a human anti-CD38 IgGκ monoclonal antibody, is approved in many countries as monotherapy in relapsed/refractory MM (RRMM), in combination with standard-of-care (SoC) regimens in RRMM and upfront in transplant ineligible NDMM. DARA is also under investigation as part of induction, consolidation, and maintenance treatment in patients with NDMM who are transplant eligible. However, no studies have specifically compared DARA maintenance to current SoC maintenance regimens. Although deep response as measured by MRD negativity has been associated with positive long-term clinical outcomes, and previous studies have demonstrated that DARA increases MRD negativity rates when combined with SoC therapy, MRD as a primary end point has not been examined in the context of frontline DARA treatment in NDMM. The ongoing phase 3 AURIGA (MMY3021) study will evaluate whether the addition of DARA to lenalidomide maintenance therapy increases the conversion rate to MRD negativity after 1 year of maintenance treatment, compared to lenalidomide alone, in patients with NDMM who are MRD positive after ASCT. Study Design and Methods: This ongoing multicenter, open-label, randomized phase 3 study will enroll approximately 214 patients from up to 60 sites in the United States. Patients 18-79 years of age are eligible if they have NDMM, have not been previously treated with an anti-CD38 antibody, have completed 4-8 total cycles of induction therapy (and/or consolidation therapy), have undergone ASCT, have achieved a very good partial response or better by International Myeloma Working Group (IMWG) criteria after ASCT and/or consolidation therapy, are MRD-positive by next-generation flow (NGF) or next-generation sequencing (NGS), at 60-100 days post-ASCT (or ≤60 days post consolidation therapy). Patients will be stratified by cytogenetic risk status (high risk vs standard risk/unknown status) and randomized 1:1 to DARA plus lenalidomide versus lenalidomide alone. Patients in both arms will receive 10 mg lenalidomide orally continuously during each 28-day cycle. After Cycle 3, if lenalidomide is well tolerated, the dose may be increased to 15 mg at the discretion of the investigator. Patients in the DARA plus lenalidomide arm will receive DARA SC (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc.]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. Treatment will continue until disease progression, unacceptable toxicity, withdrawal, or for a maximum of 36 cycles. The primary endpoint is the MRD-negativity conversion rate (assessed at a 10-5 sensitivity threshold) at 12 months of treatment, assessed via NGS. MRD will also be assessed at 6, 18, 24, and 36 months. Importantly, use of the novel primary endpoint of MRD-negativity will allow for earlier assessment of outcomes and evaluation of deeper response than traditional endpoints such as progression-free survival (PFS) and overall survival (OS). Secondary endpoints include overall MRD-negativity rate at any time, duration of MRD negativity, rate of complete response or better (≥CR), duration of ≥CR, PFS, OS, health-related quality of life, and safety. The ClinicalTrials.gov identifier is NCT03901963. Disclosures Shah: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lutska:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Krevvata:Janssen: Employment. Kane:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Lin:Janssen: Employment, Equity Ownership. Hampras:Janssen: Employment. OffLabel Disclosure: This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.

Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed (ND) MM. CyBorD is another commonly used immunomodulatory drug-sparing regimen for MM. We evaluated the safety and efficacy of dara-CyBorD and administered the first dara infusion as a split dose over 2 days in pts with NDMM or relapsed MM (RMM) after 1 prior line of therapy. Methods: This is an ongoing, multicenter, single-arm, open-label, phase 2 study conducted at US community oncology centers in pts aged ≥18 years with documented MM per IMWG criteria; measurable disease; ECOG performance score (PS) of 0-2; and ≤1 prior line of therapy. Pts received 4-8 cycles (C) of dara-CyBorD (oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15, and 22; subcutaneous bortezomib 1.5 mg/m2 on Days 1, 8, and 15; and oral or IV dexamethasone 40 mg weekly) every 28 days. Dara was administered at 8 mg/kg IV in 500 ml on Days 1 and 2 of C1, 16 mg/kg weekly from C1D8 through C2, 16 mg/kg every 2 weeks (q2w) for C3-6, and 16 mg/kg q4w for C7-8. After induction, pts could undergo autologous stem cell transplantation (ASCT). All pts receive 12 cycles of maintenance dara 16 mg/kg IV q4w. The primary endpoint was the proportion of pts achieving very good partial response or better (VGPR+) after 4 induction cycles using a computer algorithm based upon IMWG response criteria. Results: A total of 101 (87 ND, 14 RMM) pts were enrolled; 100 (86 ND, 14 RMM) pts received at least 1 dose of study treatment. Median age was 63 years (63 ND, 68 RMM); most pts were white (81%), male (64%), had ECOG PS 0-1 (94%), and had IgG (57%) or IgA (17%) MM; 35% of pts had high-risk cytogenetics defined as del(17p), t(4:14), or t(14;16). Eighty-two ND pts completed at least 4 induction cycles, 55 at least 6 cycles, and 26 the maximum of 8 cycles; 28 ND pts underwent ASCT by the data cutoff date. After 4 induction cycles, 44% of ND pts achieved VGPR+ (5% CR) with an overall response rate (ORR) of 79%. The VGPR+ rate (57%), CR rate (14%), and ORR (71%) were similar in RMM pts. At the end of induction (median 6 cycles), the VGPR+ rate, CR rate, and ORR in ND pts were 56%, 9%, and 81%, respectively. With a median follow up of 7.9 months, median PFS and OS were not reached; the 12-month PFS and OS rates were 87% and 99%, respectively, in ND pts. All 100 evaluable pts experienced ≥1 treatment-emergent adverse event (AE). AEs with incidence ≥20% included fatigue, nausea, diarrhea, cough, insomnia, vomiting, constipation, upper respiratory tract infection, dyspnea, headache, and back pain. Grade ≥3 AEs were reported for 56% of pts; the most common (≥10%) was neutropenia. Serious AEs (SAEs) occurred in 21% of pts; the most common (≥2%) were atrial fibrillation, bacteremia, pulmonary embolism, and mental status changes. AEs led to permanent treatment discontinuation in 3% of pts. Infusion reactions (IRs) occurred in 54% of pts, including 49% at C1D1 and 4% at C1D2; 2 Grade 3 IRs (hypertension, anaphylactic reaction) occurred at C1D1; no Grade ≥4 IRs occurred. The most common (≥5%) IRs were chills, cough, dyspnea, nausea, pruritus, and flushing. Median infusion time was 4.5 hours for C1D1, 3.8 hours for C1D2, and 3.5 hours for subsequent doses. Conclusion: Dara-CyBorD was active and well tolerated in pts with ND and RMM, including pts with high-risk cytogenetics. ORR, VGPR+, and CR rates improved with cycles 5-8 of induction, indicating that longer therapy with dara results in deeper response. Preliminary PFS and OS data in ND pts in the first year are comparable to dara-VMP. The safety profile was consistent with that previously reported for dara, with no new safety signals observed. Split first daratumumab dosing was feasible, reduced Day 1 infusion time, and resulted in a similar IR rate as previously described for single-dose administration. These findings indicate that dara-CyBorD, using a split-dose first infusion, can be safely administered in the community setting and may be an effective treatment option for pts with MM. www.clinicaltrials.gov identifier: NCT02951819 Figure 1. Kaplan-Meier estimate of progression-free survival (PFS) among patients with newly diagnosed multiple myeloma. Disclosures Yimer: AstraZeneca: Speakers Bureau; Puma Biotechnology: Equity Ownership; Clovis Oncology: Equity Ownership; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Equity Ownership; Janssen: Speakers Bureau. Melear:Janssen: Speakers Bureau. Faber:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: 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. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Burke:Gilead: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Tempus Labs: Consultancy. Narang:Janssen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gunawardena:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Lutska:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Qi:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Ukropec:Janssen Scientific Affairs, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Lin:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Rifkin:Amgen: Consultancy; McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; Celgene: Consultancy; EMD Serono: Consultancy; Takeda: Consultancy; Sandoz: Consultancy.

Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved as monotherapy and in combination with Vd, Rd, and pomalidomide-d for the treatment of relapsed MM and in combination with V, melphalan, and prednisone (VMP) for treatment of ASCT-ineligible ND MM. Addition of dara to these regimens improved the depth of response including complete response (CR), stringent CR (sCR), and minimal residual disease (MRD) negativity rates. VRd followed by HDT, ASCT, and consolidation VRd has yielded high response rates in ND MM. Therefore, a safety run-in was first conducted to determine the tolerability of dara-VRd before proceeding with a larger randomized phase 2 study of dara-VRd vs. VRd in ASCT-eligible ND MM pts. Methods: This is an ongoing multicenter, randomized, open‐label, active‐controlled US study. Key eligibility criteria include: aged 18‐70 years; eligibility for HDT/ASCT; documented MM per IMWG criteria; ECOG performance score 0‐2; and no prior systemic therapy for MM. A safety run-in phase was performed in 16 pts to assess potential dose limiting toxicities (DLTs) during Cycle (C)1 of dara-VRd. Pts received 4 induction cycles of dara-VRd every 21 days followed by stem cell (SC) mobilization, HDT, ASCT; 2 consolidation cycles of dara-VRd; and maintenance therapy with dara-R for 24 months. During induction and consolidation (C1‐6), pts received R 25 mg orally on Days 1‐14; V 1.3 mg/m2 subcutaneously on Days 1, 4, 8, and 11; and d 40 mg weekly. Dara 16 mg/kg IV was given on Days 1, 8, and 15 of C1‐4 and on Day 1 of C5‐6. During maintenance (C7-32), pts received R 10 mg daily (15 mg beginning at C10 if tolerated) on Days 1‐21 every 28 days and dara 16 mg/kg IV every 56 days; this was amended to every 28 days. Maintenance R may be continued beyond C32 per local standard of care. Results: Sixteen pts were enrolled in the safety run-in, and all had completed ≥9 cycles of dara-VRd, including ≥3 cycles of maintenance, as of 18-Jul-2018. Median age was 62.5 years, and 50% were male. Four (25%) pts were ISS stage II or III; the rest were stage I. Most (63%) pts had ECOG=1. Pts have received a median of 11 (9-12) cycles, including 3-6 maintenance cycles, to date. By the end of consolidation (C6), all pts (100%) reached VGPR or better and 63% achieved CR or sCR per investigator assessments (using IMWG criteria). MRD negativity (10-5 using Clonoseq2) was seen in 8 patients. Responses continued to deepen during maintenance. All 16 pts experienced ≥1 treatment-emergent adverse event (AE), with 10 (63%) pts having ≥1 serious AE (SAE), including 3 (19%) pts with ≥1 SAE related to dara. Fourteen (88%) pts had grade 3-4 AEs, with 11 (69%) related to dara. Most commonly reported (≥10%) grade 3-4 AEs included neutropenia, pneumonia, thrombocytopenia, lymphopenia, febrile neutropenia, leukopenia, and hypophosphatemia. Twelve (75%) pts experienced infections, including pneumonia (4), E Coli bacteremia, sinusitis, and gastroenteritis (1 each). No deaths due to SAEs were reported, and no pt discontinued treatment due to an AE. Dara infusion reactions were reported in 5 (31%) pts. All 16 pts underwent successful mobilization with subsequent transplant. With a median follow-up time of 15.6 months, 15 of 16 (94%) pts remain progression free on study treatment. Conclusion: The overall safety profile of dara-VRd was consistent with those previously reported for dara and VRd, with manageable toxicity and no new safety findings with longer therapy. Dara-VRd was active with an investigator-assessed VGPR+ rate of 100% and an sCR+CR rate of 63% after consolidation therapy. MRD negativity was seen in a subset of patients, and further analysis is underway and will be presented. SC mobilization proved successful in all pts. In aggregate, these data suggest that dara-VRd may be a very effective regimen in ASCT-eligible ND MM and that dara induction does not negatively impact SC mobilization. Enrollment to the 200-pt main phase of the randomized study is now complete, and primary endpoint (sCR after consolidation) will be available next year. www.clinicaltrials.gov identifier: NCT02874742 Disclosures Voorhees: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Speakers Bureau; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Other: served on an IRC; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC. Rodriguez:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: 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. Costa:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Research Funding; Sanofi: Honoraria; BMS: Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding. Lutska:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Hoehn:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Pei:Janssen Research & Development, LLC: Employment. Ukropec:Janssen Scientific Affairs, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Lin:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Richardson:BMS: Research Funding; Karyopharm: 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; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Introduction: Daratumumab (DARA) is an anti-CD38 monoclonal antibody with on-tumor and immunomodulatory mechanisms of action which is approved as monotherapy for relapsed/refractory (RR) MM and in combination with standard of care regimens for RR and transplant-ineligible newly diagnosed MM. In clinical studies, the median duration of first intravenous (IV) infusion of DARA 16 mg/kg was 7.0 hours; subsequent infusions required approximately 3-5 hours. The feasibility of splitting the first 16 mg/kg infusion into 2 separate infusions of 8 mg/kg over approximately 4 hours each during the first 2 days of Cycle 1 was investigated through computer simulations for various recommended dosing regimens of DARA and in the multi-cohort, phase 1b MMY1001 study. Strong association has been demonstrated between DARA concentration and efficacy in RR MM (Xu XS, et al. Clin Pharmacol Ther 2017;101:721-4), highlighting the importance of attaining similar serum concentrations of DARA for the split first dose regimen compared to the corresponding approved single first dose regimen of DARA. Methods: A simulation evaluation compared PK profiles between split and single first dose DARA regimens as monotherapy and with various backbone regimens. Simulation of DARA PK following split and single first dose regimens was conducted for: DARA monotherapy, DARA + lenalidomide/dexamethasone (D-Rd), DARA + bortezomib/dexamethasone (D-Vd), DARA + pomalidomide/dexamethasone (D-Pd), DARA + bortezomib/melphalan/prednisone (D-VMP), DARA + carfilzomib/dexamethasone (D-Kd), and DARA + carfilzomib/lenalidomide/dexamethasone (D-KRd). All simulations were conducted using the RxODE package in R. Clinical PK data from 3 cohorts of the phase 1b open-label multicenter MMY1001 study were included to confirm the simulation evaluation. In 2 cohorts, 97 patients (pts) received the first 16 mg/kg DARA dose as a split dose of 8 mg/kg on Cycle 1 Day 1 (C1D1) and 8 mg/kg on C1D2: 75 pts in the D-Kd cohort and 22 pts in the D-KRd cohort. The third cohort consisted of 10 pts who received a single first dose regimen of 16 mg/kg DARA on C1D1 in the D-Kd cohort. Observed PK data are summarized by timepoint. Results: DARA concentration-time profiles for the 3 approved DARA dosing schedules (7 different treatments) were virtually identical following split and single first dose regimens (Figure). Cmax on the first day of split dosing (C1D1) was lower, however, following the second 8 mg/kg dose on C1D2, the concentration was similar compared to the single first dose regimen. Thereafter, following the second split dose of 8 mg/kg on Day 2, the difference in the simulated PK profiles became minimal (Figure). Data from the MMY1001 study confirmed that mean (SD) DARA serum concentration following the first total dose of 16 mg/kg was comparable between single first dose (C1D1: 321 [49] mg/mL) and split first dose (C1D2: 257 [69] mg/mL). At the end of weekly dosing, the mean (SD) Ctrough prior to the C3D1 dose was similar between pts who received a single first dose (517 [137] µg/mL) and those who received a split first dose (606 [237] µg/mL). Conclusions: A split or single first dose provides virtually identical PK, with the exception of the PK profile during the first day of treatment, for all approved indications and recommended dosing regimens for DARA. Therefore, it is anticipated that the efficacy and safety following the split first dose for all approved DARA regimens would be similar to that of DARA 16 mg/kg administered as a single first dose. The transient difference in concentration on C1D1 is not expected to have any impact on overall clinical outcomes. Preliminary clinical data from MMY1001 D-KRd and D-Kd cohorts have demonstrated that split first dose of DARA is safe (Jakubowiak AJ, et al. ASCO 2017. Abstract 8000; Chari A, et al. ASCO 2018. Abstract 8002). Furthermore, split first dose of DARA may provide an additional flexible option for pts as well as for infusion centers. Disclosures Xu: Janssen Research & Development, LLC: Employment. Moreau:Celgene: 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; 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Lonial:Amgen: Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Oriol:Celgene: 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; Amgen: 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. Krishnan:Takeda: Speakers Bureau; Sutro: Speakers Bureau; Onyx: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau. Bladé:Janssen: Honoraria. Luo:Janssen Research & Development, LLC: Employment. Sun:Janssen Research & Development, LLC: Employment. Zhang:Janssen Research & Development, LLC: Employment. Deraedt:Janssen Research & Development, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Ukropec:Janssen Scientific Affairs, LLC: Employment. Clemens:Janssen Research & Development, LLC: Employment.

Background: Each additional line of therapy is associated with lower rates of deeper responses, shorter durations of treatment-free intervals, and increased rates of toxicities/comorbidities in patients with multiple myeloma (MM; Yong K, et al. Br J Haematol 2016. 175[2]:252-264), all of which are factors that contribute to treatment discontinuation. In order to characterize the newly diagnosed MM (NDMM) patient population in the United States not treated with a stem-cell transplant based on the number of subsequent lines of therapy (LOT) received, we examined baseline patient characteristics and pre-existing comorbidities, frontline treatment patterns, and attrition rates for these patients according to whether subsequent LOT was received or not received. Methods: NDMM patients were identified from 3 US patient-level data sources: the Surveillance, Epidemiology, and End Results (SEER)-Medicare Linked database (from January 2007 through December 2014), the OPTUM™ Commercial Claims database (from January 2000 through March 2017), and the OPTUM™ Electronic Medical Records (EMR) database (from January 2007 through March 2016). Patients included in the assessment had 1) an index diagnosis of MM on or after 1 January 2007, 2) known gender, 3) medical prescription coverage in place at diagnosis, 4) a 1-year look-back period prior to the index diagnosis, 5) no prior malignancies in the 1-year period prior to index diagnosis, and 6) received ≥1 LOT. The analysis was limited to patients who did not receive stem cell transplantation at any time during their follow-up. Descriptive and logistic regression analyses were conducted to characterize and compare patients who received or did not receive a subsequent LOT. Results: The analysis included a total of 7,724 patients (1 LOT only: n = 3,906; 2+ LOT: n = 3,818). A summary of baseline patient characteristics and pre-existing comorbidities by LOT is summarized in Table 1. Patients who received a subsequent LOT vs those that did not were significantly younger (median age 72.0 vs 74.0 years; P The regimens used in frontline treatment included bortezomib/dexamethasone (26%), lenalidomide/dexamethasone (21%), bortezomib/lenalidomide/dexamethasone (11%), a bortezomib/alkylator ± steroid combination (6%), bortezomib monotherapy (10%), lenalidomide monotherapy (6%), thalidomide monotherapy (4%), and other (17%). The proportions of patients progressing to each subsequent line of therapy are shown in Table 2. In total, 49% of patients went on to receive a second line of therapy, and 55% of patients receiving a second line of therapy went on to receive a third line of therapy. The incidence of patients not receiving subsequent lines of therapy due to death or being lost to follow up by LOT is summarized in Table 2. Conclusions: A majority of non-transplant patients with NDMM in the study did not progress to subsequent lines of therapy, with attrition as high as 50% per line of therapy and only Disclosures Fonseca: Mayo Clinic: Employment; Amgen: Consultancy. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Mehra:Janssen Global Services, LLC: Employment. Slavcev:Janssen Global Services, LLC: Employment. Ukropec:Janssen Scientific Affairs, LLC: Employment. Lam:Janssen Global Services, LLC: Employment. Potluri:SmartAnalyst Inc.: Employment.

Introduction: The use of lenalidomide (len) in the treatment of newly diagnosed multiple myeloma (NDMM) as induction and/or maintenance therapy is increasing. The majority of patients (pts) progress and require further treatment, highlighting a need for effective regimens for these len-exposed and len-refractory RRMM pts. Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In three phase 3 studies, the addition of DARA to standard of care (SOC) regimens has doubled complete response (CR) rates, tripled minimal residual disease (MRD)-negative rates, and reduced the risk of progression or death by ≥50% vs SOC alone in RRMM and NDMM pts (Palumbo A, et al. N Engl J Med 2016. 375[8]:754-766; Dimopoulos MA, et al. N Engl J Med 2016. 375[14]:1319-1331; Mateos MV, et al. N Engl J Med 2018. 378[6]:518-528). To evaluate the efficacy of DARA plus SOC regimens in RRMM pts previously exposed or refractory to len, we evaluated data from relevant subpopulations of patients in the phase 3 CASTOR and POLLUX studies and the phase 1 MMY1001 study. Methods: CASTOR and POLLUX are both open-label, randomized, phase 3 studies of DARA plus bortezomib/dexamethasone (D-Vd) or lenalidomide/dexamethasone (D-Rd), respectively, vs SOC alone in RRMM pts with ≥1 prior line of therapy. Len-refractory pts were ineligible for POLLUX. Within MMY1001, a multi-arm phase 1b study, RRMM pts treated with DARA plus carfilzomib/dexamethasone (D-Kd) or pomalidomide/dexamethasone (D-Pd) were included in this analysis. In the phase 3 studies, progression-free survival (PFS) was assessed in the intent-to-treat (ITT) population and were compared using a stratified log-rank test. Responses were assessed in an evaluable population defined as pts with measurable disease at baseline and ≥1 post-baseline disease assessment. Minimal residual disease (MRD) was evaluated in the ITT population using clonoSEQ® V2.0 (Adaptive Biotechnologies, Seattle, WA). Results: Median (range) number of prior lines received was 2 (1-10) in CASTOR, 1 (1-11) in POLLUX, 2 (1-4) in the MMY1001 D-Kd cohort, and 4 (1-13) in the MMY1001 D-Pd cohort. A total of 493 pts (323 pts treated with DARA) received prior len across the 3 DARA studies. Among len-exposed pts in CASTOR (D-Vd, n = 89; Vd, n = 120), median PFS was 9.5 vs 6.1 months (hazard ratio [HR] 0.40; 95% confidence interval [CI], 0.28-0.58; P A total of 284 pts (203 pts treated with DARA) were len-refractory across CASTOR and MMY1001. Among 60 D-Vd and 81 Vd len-refractory pts in CASTOR, median PFS was 7.8 vs 4.9 months (HR 0.44; 95% CI, 0.28-0.68; P = 0.0002). Significantly higher response and MRD-negative rates at 10-5 were observed for D-Vd vs Vd in len-refractory pts (Table). In MMY1001, nearly all pts treated with D-Kd (n = 81/85) or D-Pd (n = 103/103) were exposed to len, and the majority of pts treated with D-Kd (n = 51/85) or D-Pd (n = 92/103) were len-refractory. Among all pts, median PFS was not reached for D-Kd after median follow-up of 12 months (12-mo PFS rate: 62%), and median PFS was 9.9 months for D-Pd after median follow-up of 28.1 months. Among the 51 len-refractory pts treated with D-Kd, median PFS was 14.1 months. In all-treated pts, ORR was 66% for D-Pd and 84% for D-Kd (79% for the len-refractory subgroup). Updated data from all 3 studies will be presented at the meeting. Conclusion: In len-exposed or -refractory patients, DARA enabled deep responses and prolonged PFS irrespective of the SOC combination partner and number of prior lines of treatment. DARA-based regimens were more effective in less heavily pretreated len-exposed or len-refractory pts, suggesting earlier use (eg, after first relapse) would provide a greater benefit. Disclosures Usmani: Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Mateos:Takeda: 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; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lentzsch:Caelum Biosciences: Consultancy, Other: Dr. Lentzsch recused herself as an investigator from the Phase 1a/b trial testing CAEL-101 in 11/2017., Patents & Royalties: Shareholder for Caelum Biosiences; BMS: Consultancy; Janssen: Consultancy; Bayer: Consultancy. Quach:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy; Sanofi Genzyme: Research Funding; Amgen: Consultancy, Research Funding. Capra:Janssen: Research Funding, Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Research Funding; Sanofi: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Sonneveld:Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Qi:Janssen Research & Development, LLC: Employment. Amin:Janssen Research & Development, LLC: Employment. Wang:Janssen Research & Development, LLC: Employment. Qin:Janssen Research & Development, LLC: Employment. Okonkwo:Janssen Research & Development, LLC: Employment. Ukropec:Janssen Scientific Affairs, LLC: Employment. Trivedi:Janssen Research & Development, LLC: Employment. Suzuki:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Ono: Consultancy, Honoraria; Sanofi Aventis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; SRL.Inc: Employment. Dimopoulos:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Cavo:GlaxoSmithKline: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nooka:Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: 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; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chari:Array Biopharma: Research Funding; The Binding Site: Consultancy; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Facon:Janssen: 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: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Background: Daratumumab (dara) is a human CD38-directed monoclonal antibody indicated for the treatment of patients (pts) with multiple myeloma (MM) who have received ≥3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMID) or who are double-refractory to a PI and an IMID. Accelerated approval was granted in the United States (US) in November 2015, based largely on the results of MMY2002, a pivotal phase 2 study in this pt population. Methods: The objectives of this multicenter, open-label early access treatment protocol (EAP) were to provide early access to dara treatment and collect safety and patient-reported outcome (PRO) data in this pt population. Eligibility criteria were similar to those of pivotal study MMY2002 and included age ≥18 years, documented MM, progression by IMWG criteria following the most recent therapy, ≥3 prior lines of therapy including a PI and an IMID or disease double-refractory to a PI and an IMID, ECOG performance status score 0-2, no known chronic obstructive pulmonary disease or persistent asthma, no ongoing MM therapy, and no prior exposure to anti-CD38 antibody therapy. Pts received dara 16 mg/kg IV weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks until disease progression, unacceptable toxicity, or 60 days after US approval. Pre- and post-infusion medications were administered as in study MMY2002. Serious adverse events (SAEs), grade 3-4 AEs, infusion related reactions (IRRs), and PRO data were collected. Results: In total, 400 pts were screened and 348 pts were enrolled and dosed at 39 US sites from July to November 2015. Median age was 65 (range 27-94) years; 72% were white, and 17% were African American. Three-fourths of pts were symptomatic with an ECOG score of 1 (58%) or 2 (16%). Pts received a median of 8 (range 1-17) doses, and median treatment exposure was 1.9 (range 0.03-6.0) months. Median durations of infusion were 7.4, 4.4, and 3.5 hours for the first, second, and all subsequent infusions, respectively. Half of pts (52%) transitioned to commercial drug after marketing authorization, whereas 37% discontinued due to progressive disease. Treatment emergent grade >3 AEs were reported in 51% of pts. The most common grade ≥3 AEs were thrombocytopenia (15%) and anemia (14%). SAEs occurred in 35% of pts, including 12% of pts with SAEs which were reported by investigators as drug-related. The most common SAEs were infections, which occurred in 11% of pts. Nine percent of pts discontinued therapy due to AEs, including 3% for drug-related AEs. Thirteen (4%) pts had an AE with a fatal outcome, including 2 (0.6%) pts with drug-related AEs (pyrexia, thrombocytopenia/ subdural hematoma). IRRs occurred in 56% of pts, including 8% with grade >3 IRRs. IRRs occurred in 56%, 2%, and 2% of first, second, and all subsequent infusions, respectively; the most common IRRs were respiratory or thoracic symptoms (cough, dyspnea, throat irritation, nasal congestion), which occurred in 31% of pts. The median change from baseline in all the domains of the EQ-5D-5L and EORTC QLQ-C30 scales after 1 and 2 cycles as well as at pts' last assessment was 0, with the exception of EQ-5D-5L VAS, which showed a median increase of 1 and 2 units after 1 and 2 cycles, respectively. Conclusions: EAP results in US pts confirmed the safety profile of dara in MM pts with >3 prior therapies including a PI and IMID or who were refractory to both PI and IMID. SAEs occurred in one-third of pts, but only 12% of pts experienced a drug-related SAE. More than half of pts experienced IRRs, which primarily occurred during the first infusion and were grade 1-2 in severity. Pts maintained their health-related quality of life during a median duration of 2 months of therapy. Disclosures Chari: Array Biopharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding. Mark:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Stockerl-Goldstein:Janssen: Speakers Bureau. Usmani:Novartis: Speakers Bureau; Pharmacyclics: Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Londhe:Janssen Scientific Affairs, LLC: Employment. Etheredge:Janssen Research & Development, LLC: Employment. Parros:Janssen Research & Development, LLC: Employment. Fleming:Janssen Global Services, LLC: Employment. Liu:Janssen Research & Development, LLC: Employment. Freeman:Janssen Scientific Affairs, LLC: Employment. Ukropec:Janssen Scientific Affairs, LLC: Employment. Lin:Janssen Scientific Affairs, LLC: Employment. Lonial:BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Onyx: Consultancy; Merck: Consultancy; Onyx: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Novartis: Consultancy.