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Although venous thromboembolism (VTE) is an important treatment and disease-related complication in myeloma, a validated risk prediction model including disease-specific variables such as cytogenetics or tumor burden is lacking. The aim of this study was to develop a new risk prediction model for VTE in the context of modern antimyeloma therapy. All consecutive patients diagnosed at the Cleveland Clinic between 2008 and 2018 and with available data on baseline candidate risk factors constituted the derivation cohort. The primary outcome was VTE (deep venous thrombosis/pulmonary embolism) within 1 year of treatment initiation. A multivariable model was used, and weights were derived from subdistribution hazard ratios to construct a risk score. The model was validated both by internal bootstrap validation and in an external validation cohort. The derivation cohort consisted of 783 patients. A 5-component risk prediction tool, named the PRISM score, was developed, including the following variables: prior VTE, prior surgery, immunomodulatory drug use, abnormal metaphase cytogenetics, and Black race. The c-statistic of the model was 0.622 (95% confidence interval [CI], 0.567-0.674). The model stratified patients into low, intermediate, and high risk, with 12-month cumulative VTE incidence of 2.7%, 10.8%, and 36.5%, respectively. Risk of VTE increased significantly with increasing score in both the derivation and the external validation data sets, with a subdistribution hazard ratio per 1-point increase of 1.28 (95% CI, 1.19-1.39; P < .001) and 1.23 (95% CI, 1.07-1.41; P = .004) respectively. Although the PRISM score can guide clinicians in identifying patients at a high risk of VTE, additional external validation is necessary for incorporation into routine clinical practice.

Background: CAEL-101 is an IgG1 monoclonal antibody intended to enable immune clearance of AL amyloid deposits. This study (NCT04304144) data allowed dose selection of CAEL-101 for the ongoing Phase 3 studies in patients with Mayo stage IIIa and IIIb AL amyloidosis cardiomyopathy newly diagnosed and treated with bortezomib, cyclophosphamide, and dexamethasone (CyBorD) alone or in combination with daratumumab. Methods: 13 patients were treated with CAEL-101 and CyBorD and an additional 5 patients were treated with CAEL-101, daratumumab, and CyBorD. Organ response data on assessable patients were evaluated per consensus criteria as per institutional standard of care. Safety, pharmacokinetic and anti-drug antibody data will be reported separately. Results: The follow up for patients receiving CAEL-101 and CyBorD is 12 to 15 months and for the CAEL-101, Daratumumab, and CyBorD is 4 to 6 months. 16 of 18 patients remain on treatment. One discontinuation was due to death from E. coli sepsis and the other due to lack of hematologic response with deterioration of heart function requiring heart transplant after only 6 doses of CAEL-101. Organ response in cardiac patients by NT pro BNP criteria occurred in 4 of 8 evaluable patients treated with CAEL-101 and CyBorD (time to organ response range 2 - 12 months) and in 2 of 3 patients treated with CAEL-101, daratumumab, and CyBorD (time to organ response range 3 - 5 months). Four patients have had repeat echocardiogram 1 year from start of CAEL-101 based therapy with interpretable global peak longitudinal strain (GLS). The GLS improved in 2 patients by -5% (-6.4% to -11.4%) and -5.1% (-12.8% to -17.9%). GLS remained stable in the other 2 patients. All 9 patients with evaluable kidney involvement by 24 hour urine protein achieved an organ response. Responses occurred in as little as 2 months in 5 patients (range 2 - 7 months). The time to organ response were similar in the daratumumab and non-daratumumab treated patients. One patient with hematologic stable disease and persistent 71% improvement in 24 hour urine protein at 10 months from start of CAEL-101 based therapy is most notable. Conclusions: CAEL-101 with anti-plasma cell therapy remains reasonably well tolerated with no unanticipated adverse effects. Organ responses, most notably renal response, have occurred early in the course of therapy and appears to be durable. Organ responses in some patients have also improved over time with some significant improvement in patient GLS evaluations by echocardiogram. These results encourage clinical trial participation in the ongoing CAEL-101 clinical trials in Mayo stage IIIa and IIIb AL amyloidosis patients. Disclosures Valent: Celgene Corporation: Speakers Bureau; Amgen: Speakers Bureau; Caelum Biosciences: Other: Clinical Trial Funding; Takeda Pharmaceuticals: Speakers Bureau. Silowsky: Caelum Biosciences: Current Employment. Kurman: Caelum Biosciences: Other: Medical Monitor. Daniel: Caelum Biosciences: Current Employment. Jobes: Caelum Biosciences: Current Employment. Harnett: Caelum Biosciences: Current Employment. Spector: Caelum Biosciences: Current Employment. Anwer: GlaxoSmithKline: Research Funding; Allogene Therapeutics: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding. Zonder: BMS: Consultancy, Research Funding; Janssen: Consultancy; Caelum Biosciences: Consultancy; Intellia: Consultancy; Regeneron: Consultancy; Amgen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy. Liedtke: Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sobolov: Caelum Biosciences: Current Employment. OffLabel Disclosure: CAEL-101 is a monoclonal antibody directed at AL amyloid deposits. The purpose is to promote immune clearance of amyloid deposits.

Introduction: Lenalidomide (LEN), a standard of care for newly diagnosed multiple myeloma, is routinely administered until disease progression. However, patients with disease that has relapsed after or become refractory to LEN have been poorly represented in recent trials investigating triplet regimens after ≤ 3 prior treatment (Tx) lines. Consequently, patients who have exhausted the benefits of LEN in early relapse are a clinically relevant population in need of proven Tx options. The trial that led to approval of pomalidomide (POM) + dexamethasone (DEX) + daratumumab (DARA) evaluated patients with heavily pretreated (median of 4 prior lines of therapy) relapsed refractory multiple myeloma (RRMM; Chari et al. Blood 2017). The phase 2 MM-014 trial (NCT01946477), which is composed of 3 cohorts, was specifically designed to investigate the outcomes of sequencing POM-based therapy immediately after first- or second-line LEN-based Tx failure in patients with RRMM. In an earlier report from cohort B of MM-014, POM + DEX + DARA demonstrated promising efficacy and safety results: the overall response rate (ORR) was 77.7%, and the 1-year progression-free survival (PFS) rate was 75.1% at a median follow-up of 17.2 months (Siegel et al. Leukemia 2020). Updated efficacy and safety results from cohort B are reported here. Methods: Patients with RRMM treated with 1-2 prior Tx lines, LEN-based Tx as their most recent regimen, and progressive disease during/after their last line of Tx received POM + DEX + DARA. POM 4 mg/day was given orally on days 1-21; DEX 40 mg/day (20 mg/day in patients aged > 75 years) was given orally on days 1, 8, 15, and 22; and DARA 16 mg/kg was given intravenously on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 for cycles 3-6, and day 1 for cycles 7+. ORR was the primary endpoint; secondary endpoints included PFS and safety. Results: In the intention-to-treat (ITT) population of 112 patients, the median age was 66.5 years, all patients had prior LEN, and 77.7% had prior bortezomib. Overall, 84 patients (75%) had LEN-refractory MM and 28 (25%) had MM that relapsed after prior LEN Tx; most patients (70 [62.5%]) received 1 vs 2 (42 [37.5%]) prior Tx lines. As of March 24, 2020, 31 patients (27.7%) were still on treatment; median follow-up was 28.4 months. The most common reasons for discontinuation in 81 patients (72.3%) were progressive disease (46 patients [56.8%]), withdrawal by patient (19 patients [23.5%]), and adverse events (AEs; 7 patients [8.6%]). The efficacy-evaluable (EE) population comprised 109 patients who received ≥ 1 dose of study Tx and had ≥ 1 post-baseline assessment and was used for supportive efficacy analyses. ORR was 77.7% (≥ very good partial response [VGPR], 52.7%) and 79.8% (≥ VGPR, 54.1%) in the ITT and EE populations, respectively. ORR was similar in patients with LEN-relapsed and LEN-refractory disease (82.1% and 76.2%, respectively). The median PFS was reached: 30.8 months in both the ITT and EE populations (Figure). Overall, 97.3% of patients had ≥ 1 grade 3/4 AE, with neutropenia (64.3%; febrile 9.8%) being the most common grade 3/4 hematologic Tx-emergent AE, followed by anemia (17.9%) and thrombocytopenia (14.3%). Grade 3/4 infections were noted in 36.6% of patients, including 16.1% with grade 3/4 pneumonia. Conclusions: POM + DEX + DARA administered in early-line Tx immediately after LEN failure continues to show a high response rate and a consistent safety profile, demonstrating the benefit of maintaining continuous immunomodulation with POM following LEN. These updated results continue to demonstrate the efficacy and safety of POM-based therapy as early as second line in patients with RRMM, even immediately after LEN failure, indicating that switching from the immunomodulatory agent class is not necessary. Furthermore, these findings support the use of POM + DEX as the foundation of novel combinations in MM. Figure 1 Disclosures Siegel: Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. Schiller:Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Deciphera: Research Funding; DeltaFly: Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; FujiFilm: Research Funding; Mateon: Research Funding; Kite Pharma: Research Funding; Karyopharm: Research Funding; Celator: Research Funding; Constellation: Research Funding; Cyclacel: Research Funding; Jazz Pharmaceuticals: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau; Astellas Pharma: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Pfizer: Current equity holder in publicly-traded company, Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Daiichi Sankyo: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida: Research Funding. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Berdeja:CRISPR Therapeutics: Consultancy, Research Funding; Cellularity: Research Funding; Celgene: Consultancy, Research Funding; Servier: Consultancy; Teva: Research Funding; Prothena: Consultancy; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Acetylon: Research Funding; Poseida: Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy; Kesios: Research Funding; Kite Pharma: Consultancy; Legend: Consultancy; Lilly: Research Funding; Novartis: Research Funding; Constellation: Research Funding. Ganguly:KITE Pharma: Speakers Bureau; Settle Genetics: Speakers Bureau; Kadmon: Other: Ad Board. Matous:Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Song:Celgene: Research Funding; Celgene, Janssen, Amgen, Takeda: Honoraria. Bar:Bristol-Myers Squibb Company: Consultancy. Anz:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Fonseca:Bristol-Myers Squibb Company: Speakers Bureau. Reece:Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Otsuka: Research Funding; Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria. Lee:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Agarwal:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria.

Background: Prevention and management of venous thromboembolic events [VTE] is an important component of supportive care in newly diagnosed multiple myeloma [MM], especially in the era of immunomodulatory drugs [IMiDs]. Recently, two validated risk assessment models [RAMs], SAVED and IMPEDE-VTE, were developed to identify patients at high risk of VTE. However, these models have following limitations: (1) Patients were not uniformly treated in the era of contemporary MM therapy (2) Disease-specific variables were not available in the databases from which these scores were derived. Our primary aim was to develop a simple predictive model for VTE in MM using patient-specific, disease-specific, and treatment-specific variables. Our secondary aim was to assess the impact of VTE on overall survival [OS]. Methods: All consecutive patients with newly diagnosed MM treated at Cleveland Clinic from 1/1/2008 to 12/31/2018 were included in our analysis. The primary objective was to identify baseline variables associated with VTE within 12 months of treatment initiation. Candidate variables included those in IMWG, SAVED, and IMPEDE-VTE models as well as additional risk-factors from literature review in MM and cancer-associated VTE. Stepwise selection with variable entry criterion of p Results: A total of 934 patients with newly diagnosed MM and available data on VTE occurrence were considered for inclusion. We excluded patients with VTE within 6 months before starting therapy [n=5] and patients on therapeutic anticoagulation or receiving >1 prophylactic regimen [n=146], resulting in a total of 783 patients for model development. The most common induction regimen was bortezomib [V]-lenalidomide [R]-dexamethasone [VRD; 41%], followed by VD [22%], RD [20%], V-cyclophosphamide-dexamethasone [VCD; 11%], and others [7%]. Median age at treatment initiation was 63 years [range, 22-91], 55% were males, and 20% were Blacks. ISS stage III disease was present in 32%, high-risk FISH in 23%, abnormal metaphase cytogenetics in 18%, and serum creatinine >2 mg/dl in 19% of patients. Notably, 76% had received a dexamethasone dose of 120-160 mg/cycle, with only 5.9% started on a higher dose [>160 mg/cycle]. The most common thromboprophylaxis agent was aspirin [60%], followed by low molecular weight heparin [LMWH; 3.8%]; 37% of patients received no thromboprophylaxis. Erythropoietin and intravenous immunoglobulin were used in 2.9% and 1.2% of patients respectively. Median time to VTE from treatment initiation was 3.2 months. Cumulative incidence of VTE at 6 and 12 months was 8.2% [95% CI, 6.6-10.1] and 11.5% [95% CI, 9.5-13.6] respectively. Factors significantly associated with development of VTE on MVA were combined to develop the PRISM score [Table 1]: Prior VTE history [HR 5.06; 8 points], Black Race [HR 1.71; 1 point], IMiD use [HR 2.17; 2 points], Surgery within 3 months [HR 3.44; 5 points], and abnormal Metaphase cytogenetics [HR 2.10; 2 points]. The theoretical score range is 0-18, with a HR of 1.28 per 1-point increase in score [c-statistic 0.62]. Internal bootstrap validation including 1,000 samples showed a c-statistic of 0.62 [IQR, 0.60-0.64]. Using three risk groups by recursive partitioning analysis, 17.8%, 74%, and 8.1% belonged to low [0], intermediate [1-6], and high-risk [>6] groups respectively. The 12-month cumulative incidence of VTE in the 3 respective groups were 2.7%, 10.8%, and 36.5% [Figure 1]. Occurrence of VTE in the first 12 months was not associated with worse OS on landmark analysis at 3, 6, 9, and 12 months. Conclusion: We have developed and internally validated a RAM for VTE in MM in the context of contemporary MM therapy including disease-specific variables. Studies of external validation and comparison with existing RAMs are warranted. The PRISM Score could be used to identify high-risk patients for thromboprophylaxis. Figure Disclosures Valent: Amgen Inc.: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau. Khouri:Sanofi Genzyme: Other: Advisory Board. Anwer:Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Khorana:Pharmacyclics: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Medscape: Honoraria; Leo Pharma: Honoraria; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Leap: Research Funding; Bayer: Honoraria; Janssen: Honoraria; Merck: Research Funding; Array: Other: Research funding (to institution); BMS: Honoraria, Research Funding.

Background: CAEL-101 is an AL amyloid fibril reactive IgG1 monoclonal antibody with potential for therapeutic immune clearance of AL amyloid deposits in AL amyloidosis (AL) patients. Phase I study of CAEL-101 did not identify any significant toxicity at doses up to 500 mg/m2 IV dosed weekly for 4 weeks as a single agent. Organ responses occurred in a majority of patients. The primary objective for this current dose escalation study (NCT04304144) is to provide a recommended phase III dose of CAEL-101 when given in combination with bortezomib, cyclophosphamide, and dexamethasone (CyBorD) for a planned randomized study in Mayo stage IIIa and IIIb AL patients. Methods: 13 AL patients (7 heart, 3 kidney, 3 both) were enrolled in a 3+3 dose escalation safety study allowing for an additional patient in each cohort if available. Five heart patients were Mayo stage IIIa with the remaining 5 Mayo stage II. Cohort 1 (n=4), 2 (n=3), and 3 (n=6) received CAEL-101 IV at 500 mg/m2, 750 mg/m2 and 1000 mg/m2 respectively over 2 hours, all weekly for 4 weeks then every other week for the remainder of the study. Premedication with diphenhydramine 25 mg po and acetaminophen 1 gram po were given 30 minutes prior to each CAEL-101 infusion. Pharmacokinetic and anti-drug antibody data will be reported separately. All patients were treated with CyBorD weekly, 3 of 5 weeks in the first cycle to align treatments with CAEL-101 and then 3 of 4 weeks for up to 6 cycles. Patients were permitted to receive up to 3 cycles of CyBorD immediately prior to enrollment. Only 3 of the 13 patients had hematologic measurable disease at enrollment. Hematologic and organ response data on assessable patients were evaluated per consensus criteria. Results: With the longest follow up of 91 days and all 13 patients receiving at least 4 doses of CAEL-101, no dose limiting toxicity has been seen with 6 patients dosed at the maximum planned 1000 mg/m2 dose. No infusion reactions occurred. Three significant adverse events occurred. One patient developed recurrent atrial fibrillation without rapid ventricular response at the 500 mg/m2 dose level not attributed to CAEL-101. Two other patients dosed at 1000 mg/m2 were hospitalized with Clostridium difficile colitis and enlarging pleural effusion not attributed to CAEL-101. Of the 3 patients with hematologic measurable disease, there have been 2 PR, and 1 that is too early to evaluate. One patient with PR had a response plateau after cycle 2 of CAEL and is the only patient off study due to need for change in anti-plasma cell therapy. Of the 7 patients currently evaluable for organ response, 2 have met organ response criteria in the 500 mg/m2 cohort (1 heart by NT pro BNP and 1 kidney by 24 hour urine protein). There is ongoing monitoring of organ responses and updated data will be presented at the meeting. Conclusions: CAEL-101 dosed at 1000 mg/m2 is the recommended phase 3 dose in combination with CyBorD for upcoming randomized, double blind, phase 3 trials. Hematologic responses do not seem to be affected by concurrent use of CAEL-101 with CyBorD. Organ responses have occurred early in the course of therapy and are expected to increase over time, particularly after completion of chemotherapy and dexamethasone. Longer follow up, the ongoing exposure to CAEL-101 after the conclusion of chemotherapy and planned phase III trials will provide more data on organ response, quality of life and survival. Disclosures Khouri: Sanofi Genzyme: Other: Advisory Board. Anwer:Astellas Pharma: Research Funding; AbbVie Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Acetylon Pharmaceuticals: Research Funding; Celgene: Research Funding; Millennium Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau. Sobolov:Caelum Biosciences: Current Employment, Current equity holder in private company. Jobes:Caelum Biosciences: Current Employment, Current equity holder in private company. Daniel:Caelum Biosciences: Current Employment, Current equity holder in private company. Spector:Caelum Biosciences: Current Employment, Current equity holder in private company. Valent:Amgen Inc.: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau. OffLabel Disclosure: CAEL-101 is a monoclonal antibody directed against amyloid fibrils not yet FDA approved.

Introduction: Daratumumab (DARA) is an anti-CD38 human monoclonal antibody FDA-approved for the treatment of multiple myeloma (MM) and has demonstrated efficacy in AL amyloidosis. Infusion-related reactions (IRRs) occur in over 50% of patients treated with DARA, most commonly with the first infusion despite premedication with corticosteroids, antipyretics, antihistamines, and post-infusion corticosteroids. If DARA is tolerated without IRRs, the infusion rate can be escalated in standardized increments to a final infusion rate administered over 90 minutes in patients with MM (Barr et al. Leukemia 2018). Rapid infusions of DARA decrease length of infusion visits, potentially improving patient satisfaction and optimizing healthcare resources. Recent studies showed that DARA is safe and highly effective in treating AL amyloidosis (Khouri et al, Br J Haematol 2018), but no information is available regarding the safety of administering rapid infusions of DARA in patients with AL amyloidosis. We hypothesized that patients with AL amyloidosis, especially those with cardiac involvement, may not tolerate a rapid administration of fluids. Thus, a DARA rapid infusion protocol for patients with AL amyloidosis was implemented at our institution in April 2018. We report findings from the protocol implementation. Methods: A retrospective observational study was conducted to review adult patients with AL amyloidosis who received rapid infusions of DARA from April 2018 to October 2018. Data collected included relevant past medical history, vitals, premedications, infusion rates, and management of IRRs. Patients were eligible for rapid DARA after tolerating two prior doses of DARA at standard infusion rates. Rapid DARA was infused at 200 mL/hr for 30 minutes, then increased to 450 mL/hr for 60 minutes. Protocol premedications included acetaminophen, diphenhydramine, famotidine, and dexamethasone. No post-infusion corticosteroids were required. The first two standard and first four rapid DARA infusions were evaluated for each patient. Results: 27 patients with AL amyloidosis were included in the study with 162 doses of rapid DARA evaluated. Baseline characteristics included age (median 72 years old), gender (55.6% male), diastolic heart failure (59.3%), combined systolic and diastolic heart failures (11.1%), chronic obstructive pulmonary disease (7.4%), asthma (7.4%), and chronic kidney disease (25.9%). 62.9% of patients had cardiac AL involvement and 51.9% had renal AL involvement. 11/27 (40.7%) patients had IRRs to the first infusion of DARA (cycle 1, day 1) requiring hypersensitivity medications. All 27 patients progressed to rapid rate DARA after both initial and subsequent rates were tolerated. 22/27 (81.5%) patients initiated the first rapid DARA with the protocol premedications. Premedication usage decreased by the fourth rapid DARA dose with only 23.1% patients receiving diphenhydramine, 57.7% receiving famotidine, and 38.5% receiving dexamethasone (Figure 1). No patients received post-infusion corticosteroids. There were no clinically significant IRRs with the DARA rapid infusion protocol across all patients, regardless of organ involvement. There were 10 cases of CTCAE grade 2-3 hypertension that did not require intervention. No hypersensitivity medications were required for any rapid DARA doses. 11/11 (100%) patients who experienced IRRs requiring hypersensitivity medications during their first or second standard DARA infusions tolerated rapid DARA administration without recurrence of IRRs. Conclusions: Rapid administration of DARA is safe and well-tolerated in patients with AL amyloidosis, regardless of organ involvement. Patients who experienced an IRR with the initial DARA dose were able to safely transition to the rapid infusion protocol without recurrence of IRRs. Furthermore, decreased premedication usage after tolerance of rapid DARA infusion did not increase IRRs, suggesting premedications can be discontinued to mitigate associated toxicities. Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau. Valent:Celgene corporation: Speakers Bureau; Amgen corporation: Speakers Bureau; Takeda pharmaceuticals: Speakers Bureau. OffLabel Disclosure: Daratumumab for the treatment of AL amyloidosis

Background: Venous thromboembolism (VTE) is a prevalent cause of morbidity in MM patients. The IMPEDE VTE score was recently proposed by Sanfilippo KM et al. in 2018 ASH annual meeting to predict VTE in MM. Herein, we report on the external validation of this score. Methods: We reviewed consecutive newly diagnosed MM patients who were treated at the Cleveland Clinic between 2010 and 2012. All treatment variables were collected as time-varying variables. Poor cytogenetic features were defined as monosomy 13 or 17, t(4;14), or t(4;16). We calculated the total IMPEDE VTE score for each patient as previously defined; immunomodulatory drug (IMiD) use (+3), BMI >25 kg/m2 (+1), pathologic pelvis/femur fracture (+2), erythropoiesis-stimulating agent use (+1), low/high dexamethasone use (+2/+4), doxorubicin use (+2), Asian race (-3), history of VTE (+3), central venous catheter use (+2), prophylactic aspirin or enoxaparin (-2), therapeutic anticoagulation (-5). Patients with IMPEDE VTE score of 6 were defined as low-, intermediate-, and high-risk groups, respectively. Cumulative incidence of symptomatic VTE after initiation of systemic treatment was calculated with death as competing risk and compared with the Gray's test. Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox analysis was used to identify independent predictors of OS. Results: We identified 210 MM patients, 102 (49%) were female, 31 (15%) were black, and median age at diagnosis was 63 years (range: 30 - 91). Fifteen (7%) patients had VTE prior to MM diagnosis and 30 (14%) patients had pathologic pelvic or femur fracture at or after MM diagnosis. Poor cytogenetic features were seen in 65 (31%) patients. ECOG performance status at diagnosis was ≥2 for 33 (16%) patients. Sixty-seven (32%), 65 (31%), and 57 (27%) patients had ISS stage I, II, and III disease, respectively. MM subtypes were IgG, IgA, and light-chain disease for 109 (52%), 46 (22%), and 52 (25%) patients, respectively. IMiDs and low-dose dexamethasone were given to 145 (69%) and 205 (98%) patients, respectively. Seventy-seven (37%) patients underwent autologous hematopoietic cell transplant. Patient and treatment characteristics were compared between patients with and without VTE after MM diagnosis in Table 1. Twenty-two (10%) patients had symptomatic VTE within 6 months after initiation of systemic treatment for MM. When IMPEDE VTE score was calculated based on the risk factors during this time period, 37 (18%), 157 (75%), and 16 (8%) patients were in low-, intermediate- and high-risk groups, respectively. Six-months cumulative incidence of VTE in low-, intermediate- and high-risk groups were 2.7% (95% CI: 0 - 7.9), 10.8% (95% CI: 6.0 - 15.7), and 25% (95% CI: 3.8 - 46.2), respectively (p=0.011) (Figure 1A). Whereas, 39 (19%) patients were diagnosed with symptomatic VTE during median follow-up of 86 months. When the highest IMPEDE VTE score for each patient was calculated based on the risk factors at any time after initiation of treatment, 16 (8%), 151 (72%), and 43 (20%) patients were in low-, intermediate-, and high-risk groups, respectively. Seven-year cumulative incidence of VTE in low-, intermediate- and high-risk groups were 9.0% (95% CI: 0 - 25.7), 16.3% (95% CI: 10.3 - 22.3), and 29.3 (95% CI: 15.2 - 43.3), respectively (p=0.014) (Figure 1B). Seven-year OS of patients with and without VTE within 6 months after initiation of treatment was 50% (95% CI: 32% - 79%) and 46% (95% CI: 39% - 55%), respectively (p=0.4). On multivariable analysis, VTE vs no VTE within 6 months after initiation of treatment did not predict OS (HR 1.10, 95% CI: 0.46 - 2.66, p=0.8), whereas each 1-year increase in age (HR 0.99, 95% CI: 0.96 - 1.02, p=0.61), each 1 increase in ECOG performance status (HR 1.77, 95% CI: 1.24 - 2.53, p=0.002) and ISS stage (HR 1.50, 95% CI: 1.06 - 1.14, p=0.024), poor vs non-poor cytogenetics features (HR 4.38, 95% CI: 2.25 - 8.57, p Conclusion: In this cohort of MM patients, we showed that IMPEDE VTE score was able to stratify patients into distinct risk groups and can be a helpful tool to provide personalized strategies for thromboprophylaxis. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Valent:Takeda pharmaceuticals: Speakers Bureau; Amgen corporation: Speakers Bureau; Celgene corporation: Speakers Bureau.

Background: Suppression of uninvolved immunoglobulins [Ig], or immunoparesis, is associated with an inferior progression-free survival [PFS] and overall survival [OS] in patients with newly diagnosed multiple myeloma [MM]. However, immunoparesis in relapsed MM can be either due to the underlying disease or prior anti-myeloma therapy or both. Data on characterization and prognostic impact of immunoparesis in relapsed MM is lacking in the era of proteasome inhibitors and immunomodulatory drugs. We hypothesized that immunoparesis in relapsed MM is a marker of high tumor burden or adverse biology and is associated with an inferior post-relapse survival. Method: We evaluated all MM patients diagnosed between 1/1/2008 and 12/31/2015 at the Cleveland Clinic and followed until 05/31/2019. Key inclusion criteria were patients experiencing first relapse requiring an additional line of therapy and available data on pre-therapy immunoglobulin levels. Both Qualitative and Quantitative immunoparesis were defined using the method described earlier [Muchtar et al. Leukemia. (2017) 31. 92-99]. Qualitative immunoparesis was categorized as No [preserved uninvolved Igs], Partial [suppression of at least one but not all uninvolved Igs], or Full [suppression of all uninvolved Igs]. For quantitative immunoparesis, the average relative difference [ARD] from the corresponding lower limit of normal was calculated. Recursive partitioning analysis was performed with a log-rank splitting method to identify an optimal ARD cut-point for OS. The primary endpoints were PFS and OS from first relapse, which were estimated using Kaplan-Meier method and groups were compared with log-rank test. Cox proportional hazards analysis was used to identify univariable and multivariable prognostic factors for PFS and OS. Results: A total of 527 patients with newly diagnosed MM were evaluated, among which, 258 [49%] experienced first relapse and formed the study cohort. The median age at first relapse was 64 years, with a median of 24.5 months from diagnosis to first relapse. Front-line therapy included bortezomib in 77% and lenalidomide in 76% of patients. A total of 217 [85%] patients relapsed on therapy, the most common being maintenance with PI or IMiD [+/- steroid]. Biochemical-only relapse happened in 56% of patients. The distribution of qualitative immunoparesis at first relapse was: No [n=24; 9%], Partial [n=76; 30%], or Full [n=158; 61%]. For quantitative immunoparesis, the median ARD was -39% [range, -92 to 241], with higher negative values indicating deeper immunoparesis. The median ARD was +67%, +15%, and -58% in No, Partial, Full immunoparesis subgroups respectively [P-50% [n=155; 60%] and ≤-50% [n=103; 40%]. Higher immunoparesis depth [ARD≤-50%] at first relapse was significantly associated with the following: abnormal karyotype at diagnosis, deeper immunoparesis at diagnosis, less than a very good partial response [VGPR] in first remission, ≤12 months from diagnosis to first relapse, high serum free light chain ratio, β-2 microglobulin, and lactate dehydrogenase at first relapse, and low hemoglobin at first relapse. Notably, relapse on therapy versus on observation was not associated with the depth of immunoparesis at first relapse. The 2-year PFS in >-50% and ≤-50% subgroup was 27% and 17% respectively [P Conclusion: Depth of immunoparesis at first relapse is an additional prognostic factor for post-relapse survival in MM in the era of novel agents and continuous therapy. The clinical implication of immunoparesis as a prognostic factor is further amplified by the widespread availability of immunoglobulin measurement. Figure 1 Disclosures Valent: Amgen corporation: Speakers Bureau; Celgene corporation: Speakers Bureau; Takeda pharmaceuticals: Speakers Bureau. Anwer:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau.

Background: Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a Phase II study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory multiple myeloma who have received a first or second line treatment of lenalidomide-based therapy. Immunomodulatory agents (IMiD® compounds) continue to be the backbone of multiple myeloma therapy especially when combined with monoclonal antibodies, more specifically pomalidomide had been shown previously to enhance T cell- and NK cell-mediated immunity. We sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. IMiD agents are the backbone of combination regimens in the treatment of patients with newly diagnosed or relapsed and/or refractory multiple myeloma. The anti-myeloma properties of these agents derive from a dual mechanism of pro-apoptotic effects on tumor cells as well as enhanced immune stimulation. An understanding of how IMiD agents interact with new monoclonal antibodies to modify patient immune profiles offers key insights into the role of such in innate and adaptive immunity in determining patient outcomes. Methods and Results: Peripheral blood samples were collected at screening, Cycle1 Days 1, 8, and 15, and Cycle 2 Days 1 and 15 to monitor pharmacodynamic changes in populations of T cells, NK cells, monocytes and MDSCs by flow cytometry. From 112 patients enrolled in Arm B, 98 patients had baseline and post-treatment specimens available for these analyses. As expected, combination treatment with POM + LoDEX + DARA led to decreased peripheral counts of CD56+CD16+ NK cells as well as CD4+CD38+ and CD8+CD38+ T cell subpopulations. Decreased counts were also noted in CD3-CD19+ B cells. In contrast, total counts of CD14+ monocytes and CD3+CD4+ or CD3+CD8+ T cells were stably maintained and pronounced increases were observed in proliferating CD4+Ki-67+ and CD8+Ki-67+ T cells. Further, when examined as a percent of total counts, increases were observed in CD14+ monocytes, CD3+CD4+ and CD3+CD8+ T-cells, with decreases in CD3-CD19+ B-cells and CD3-CD56+CD16+ NK cells. Correlation of these pharmacodynamic changes with clinical outcomes will be presented. In addition, baseline immune profiling of specific cell population subsets and associations with best overall response and progression-free survival is currently being analyzed. Conclusions: The triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed multiple myeloma patients progressed and are or refractory to lenalidomide. Immune characterization here is consistent with a model for clinical activity in which the loss of CD56+CD16+ NK cells along with a concomitant immune suppression by loss of CD38+CD4+ and CD38+CD8+ T- cells is offset by an increase in proliferating cytotoxic CD4+Ki-67+ and CD8+Ki-67+ T-cell populations. Our results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment. Pomalidomide had been shown previously to enhance T cell- and NK cell-mediated immunity; these data are consistent with a mechanism of action in which pomalidomide administration facilitates the ability to overcome immunosuppressive effects of Dara and LoDex. Potential associations of immune biomarkers with patient outcomes is ongoing and will be updated. Disclosures Pierceall: Celgene Corporation: Employment, Equity Ownership. Bahlis:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Siegel:Merck: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Berdeja:Takeda: Research Funding; Genentech: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Glenmark: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bluebird: Research Funding; Teva: Research Funding. Ganguly:Amgen: Consultancy; Daiichi Sankyo: Research Funding; Janssen: Consultancy; Seattle Genetics: Speakers Bureau. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Srinivas:VAHCSNJ: Employment. Bar:Celgene: Consultancy. Quick:CTI BioPharma: Research Funding. Fonseca:Celgene: Speakers Bureau. Reece:Janssen: 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; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Serbina:Celgene: Employment. Zafar:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership.

Background: Overall response rate and response duration in newly diagnosed multiple myeloma (ndMM) has increased in the last decade. However, majority of patients eventually progress and receive multiple lines of therapy. Progression in MM is defined by rise in monoclonal protein and/or clinical manifestations of end-organ damage. However, there is a lack of evidence on the prognostic implication of pattern of progression in the current era. We have hypothesized that patients with clinical manifestations of end-organ damage at first progression have an inferior post-progression overall survival (OS) compared to those with biochemical progression alone. Method: We evaluated all ndMM patients between 1/1/2008 and 12/31/2015 at the Cleveland Clinic. Key inclusion criterion was patients experiencing first progression requiring an additional line of therapy. Patients with primary refractory disease and those in continued 1st remission at latest follow-up were excluded. Progression was categorized into 2 groups: Biochemical Progression (BP) and Clinical Progression (CP; implying CRAB features). Patients with CP were further stratified based on the presence of extramedullary disease (EM): CP+EM and CP-EM. Progression-free survival (PFS) and OS from first progression were estimated with Kaplan-Meier curves and compared among groups with log-rank test. Cox analysis was used to identify prognostic factors for OS and PFS. Potential prognostic factors included progression pattern, age, gender, race, ISS stage at diagnosis, FISH cytogenetics at diagnosis, metaphase cytogenetics at diagnosis, time from diagnosis to first progression, best response at first remission, frontline autologous stem cell transplant (ASCT), and whether progression occurred while on therapy. Results: A total of 527 patients with ndMM were evaluated, among which, 257 experiencing 1st progression were included in our analysis. The median age at progression was 64 years. The median time from diagnosis to first progression was 23 months. An autologous stem cell transplantation (ASCT) after induction therapy in 1st remission was performed in 26% of patients. At 1st progression, BP alone was noted in 52% (n=134), CP -EM in 34% (n=87) and CP+EM in 14% (n=36) of patients. In the CP-EM group, the most common mode of progression was development of new bone lesions (76%) followed by anemia (33%), renal insufficiency (18%) and hypercalcemia (13%), with ≥1 mode in approximately one-third of patients. In the CP+EM group, the most common mode of EM progression was development of new plasmacytomas (89%), followed by emergence of circulating plasma cells (14%), with 1 patient having both. A total of 84% of patients progressed on anti-myeloma therapy, which reflects the contemporary practice of continuous therapy in MM. After first progression, 68% received proteasome inhibitors (PIs), 64% received immunomodulatory drugs (IMiDs) and 11% received monoclonal antibodies (MoAbs). Salvage ASCT in 2nd remission was performed in 12% of patients. A total of 105 patients (41%) were alive at latest follow-up, with the median follow-up of survivors being 26 months from 1st progression. Median time from diagnosis to 1st progression was shorter in the CP+EM (12 months) compared to CP-EM (25 months) and BP (24 months) groups (P Conclusion: In the era of PIs, IMiDs and MoAbs, the pattern of 1st progression in MM has a strong and independent prognostic impact on post-progression OS. Patients progressing with clinical manifestations of end-organ damage or extramedullary disease have an inferior PFS and OS compared to those progressing with biochemical criteria alone. These results should be further validated in large prospective studies with data on FISH cytogenetics at relapse. It has clinical implication at the individual level and can also inform the design of clinical trials in relapsed MM. Disclosures Majhail: Anthem, Inc.: Consultancy; Incyte: Honoraria; Atara: Honoraria.

BACKGROUND Lenalidomide (LEN) until progressive disease (PD) is an established treatment (Tx) in newly diagnosed and relapsed and/or refractory multiple myeloma (RRMM); thus, patients (pts) for whom the benefit of LEN has been exhausted are a clinically relevant population. However, LEN-refractory pts have typically been excluded from recent clinical trials investigating triplet regimens after ≤ 3 prior Tx lines. MM-014 (NCT01946477) is an ongoing phase 2 study that was designed to assess the safety and efficacy of pomalidomide (POM)-based Tx regimens in pts with RRMM and first- or second-line LEN Tx failure immediately before study entry. Earlier results from cohort A (POM + low-dose dexamethasone [LoDEX]) and cohort B (POM + LoDEX + daratumumab [DARA]) indicate that POM-based Tx is safe and effective in this setting. Here we report updated results from cohort B. METHODS Eligible pts had RRMM, had 1 or 2 prior lines of Tx, received LEN-based Tx as their most recent Tx regimen, and had PD during or after their last line of Tx. Pts received POM 4 mg/day on days 1 through 21 + LoDEX 40 mg/day (20 mg/day if aged > 75 years) on days 1, 8, 15, and 22 and DARA 16 mg/kg intravenously on DEX dosing days of cycles 1 and 2, days 1 and 15 of cycles 3 through 6, then day 1 of cycle 7 and beyond. Each Tx cycle lasted 28 days. Thromboprophylaxis was mandatory. The primary endpoint for cohort B is overall response rate (ORR) by modified International Myeloma Working Group criteria. Secondary endpoints include time to response (TTR), progression-free survival (PFS), time to progression (TTP), and safety. RESULTS The intention-to-treat (ITT) population comprised 112 pts (median follow-up, 8.2 mos); data cutoff was April 30, 2018. Median age was 66.5 years, 67.9% of pts were male, and 111 (99.1%) had ECOG PS ≤ 1. A total of 34 pts discontinued Tx: 19 due to PD, 9 due to study withdrawal, 2 due to adverse events (AEs), and 4 due to other reasons. All pts received prior LEN, and 87 (77.7%) received prior bortezomib; 84 pts (75.0%) were refractory to LEN, while 28 (25.0%) relapsed after LEN-based Tx. Median duration of the most recent prior LEN-based Tx was 23.9 mos, with 36 pts (32.1%) receiving LEN 25 mg/day during their last LEN-based Tx. ORR was 77.7%, with 33.9% of pts achieving ≥ very good partial response. Median TTR was 1.0 mo. The clinical benefit rate (≥ minimal response [MR]) was 85.7%. ORR was 80.6% in the efficacy-evaluable population (n = 108; defined as all pts who received ≥ 1 dose of study drug and had ≥ 1 post-baseline response assessment), 75.0% in LEN-refractory pts, and 76.2% in pts with 2 prior lines of Tx (n = 42). The 9-mo PFS rate was 86.3% (range, 76.5%-92.2%); median PFS was not estimable (NE; Figure). The 9-mo TTP rate was 88.1% (range, 78.3%-93.6%); median TTP was NE. The most common grade 3/4 hematologic treatment-emergent AE (TEAE) in the safety population (n = 112) was neutropenia (61.6%; Table); pneumonia was the most common grade 3/4 nonhematologic TEAE (7.1%). POM dose reductions occurred in 31 pts (27.7%); per protocol, DARA dose reductions were not allowed. POM dose interruptions due to AEs were reported in 69 pts (61.6%) and DARA dose interruptions due to AEs were reported in 82 pts (73.2%). POM and DARA dose interruptions due to neutropenia were reported in 39 (34.8%) and 42 (37.5%) pts, respectively; 25 pts (22.3%) had DARA dose interruptions due to infusion-related reactions. Median durations of POM and DARA Tx were 6.0 mos (range, 0.3-17.7 mos) and 6.6 mos (range, 0.3-18.6 mos), respectively; among those who achieved ≥ MR, pts remained on POM Tx for a median of 7.4 mos (range, 0.9-17.7 mos) and on DARA Tx for a median of 7.5 mos (range, 0.9-18.6 mos). CONCLUSIONS LEN-refractory pts with RRMM are in need of effective Tx options. MM-014 is the first prospective clinical trial to investigate a POM-based doublet or triplet regimen immediately after LEN-based Tx failure. In the context of a relatively short follow-up, the 9-mo PFS rate (86.3%) is promising. The ORR (77.7%) was higher than that previously reported with this triplet combination in heavily pre-treated pts with RRMM (≥ 2 prior lines [median, 4]; ORR, 60%), and the rate of grade 3/4 neutropenia in the present study was lower (61.6% vs 77%). These updated results from cohort B continue to demonstrate that POM + LoDEX + DARA is safe and effective following first- or second-line LEN-based Tx failure and further support earlier use of POM-based Tx in pts with RRMM Disclosures Siegel: Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Berdeja:Bluebird: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Glenmark: Research Funding; Genentech: Research Funding; Amgen: Research Funding; Teva: Research Funding; Poseida Therapeutics, Inc.: Research Funding. Ganguly:Janssen: Consultancy; Seattle Genetics: Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Bar:Celgene: Consultancy. Quick:CTI BioPharma: Research Funding. Fonseca:Celgene: Speakers Bureau. Reece:Janssen: 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; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Agarwal:Celgene Corporation: Employment, Equity Ownership. Chung:Celgene Corporation: Employment, Equity Ownership. Zafar:Celgene: Employment. Bahlis:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Introduction: Multi-organ dysfunction remains a major cause of morbidity and mortality with light chain amyloidosis (AL) especially for patients not achieving hematologic complete response. Approval of daratumumab (DARA) has revolutionized the care of multiple myeloma and its therapeutic implications have shown to be safe and highly effective in relapsed/refractory AL amyloidosis. This analysis demonstrates the activity of the combination of DARA, bortezomib, and dexamethasone in AL amyloidosis patients somewhat refractory to cyclophosphamide, bortezomib, and dexamethasone (CyBorD). Methods: Patients (pts) were identified via our IRB-approved plasma cell disorder registry. Pt selection included those who did not achieve at least a hematologic VGPR with first line treatment and who went on to receive a DARA containing second-line treatment for AL amyloidosis. Results: Since the approval of DARA for multiple myeloma, we have seen 159 pts with newly diagnosed AL amyloidosis, of which we identified 10 pts who failed to achieve a VGPR with initial treatment (CyBorD). The median age of our cohort was 67 (range, 38-75), with 80% males. At the time of diagnosis, 50% of the pts had more than one organ involvement (cardiac, renal, GI, lung, and/or bone marrow). All pts were initially treated with CyBorD with average of 4 cycles (range, 2-6), of which 60% achieved a PR and 40% had stable disease. The most common second line regimen was DARA, bortezomib, and dexamethasone (70%) followed by DARA monotherapy. The median number of cycles was 5 (range 1-9) with 50% of pts still undergoing treatment at the time of analysis. The median time to first response was 1.5 cycles (range, 1-3), with 50% achieving a PR, 30% VGPR, 10% CR and the other 10% with stable disease. The overall hematologic response rate was 90% (5 pts achieved at least a VGPR and 2 pts achieved a CR). Organ response was noted in 70% of pts by average of 2 cycles (range, 1-5). Five pts had a cardiac response by NT-proBNP criteria and 2 pts had renal response with 50% reduction in 24 hour urine protein. Toxicity included 40% of pts with a grade 2 infusion reaction with first dose DARA, grade 1-2 fatigue in 60% of pts, and there were no hospitalizations and/or deaths attributed to therapy. Notably, our institutional policy in amyloidosis pts has been to eliminate dexamethasone as a premedication after 3 DARA doses to minimize the risk of volume overload. Six out of 10 pts had dexamethasone discontinued before the end of cycle 2, and of those, half had dexamethasone stopped after the third DARA dose. One additional pt had dexamethasone stopped after the third cycle. No pts had infusion reactions after the discontinuation of dexamethasone. Of the 10 pts, only 2 pts had disease progression. Notably, 1 of the 2 patient's progressed while off therapy, but within 1 additional cycle of DARA monotherapy hematologic CR was achieved. Conclusion: Daratumumab is safe and highly effective in patients with AL amyloidosis who failed to achieve a deep hematological response with CyBorD. From our clinical experience, we have noted that DARA can induce rapid hematologic and organ responses which is critical to prevent irreversible organ damage. Monotherapy with DARA or in combination is well tolerated. Ongoing studies are investigating CyBorD with or without DARA in newly diagnosed patients. An unanswered question is whether or not CyBorD is needed at all when DARA is used in newly diagnosed patients. Exploring the molecular heterogeneity of these patients may also help identify a subset of patients that will benefit from DARA monotherapy upfront. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Background: Patients with systemic light-chain (AL) amyloidosis have a high symptom burden which can negatively impact their health-related quality of life (HRQoL). However, there is a lack of data on patient-reported outcomes (PROs) in this population in the current era of effective plasma cell directed therapies. The primary objectives of our study were to assess baseline HRQoL using FACT-G (Functional Assessment of Cancer Therapy-General) and PROMIS-GH (Patient Reported Outcomes Measurement Information System-Global Health), evaluate the degree of correlation between FACT-G and PROMIS-GH, and compare HRQoL by hematologic response to first-line therapy in systemic AL amyloidosis. Method: This was an observational study using the Cleveland Clinic Knowledge Program database, which contains HRQoL data captured at outpatient visits. FACT-G was administered every 90 days since its implementation on September 2012. PROMIS-GH was implemented in October 2015, initially administered every 30 days and subsequently every 90 days since July 2017. Results: A total of 81 patients with systemic AL amyloidosis diagnosed between September 2012 and December 2017 and ≥1 HRQoL measurement were included in our analysis. The median age at diagnosis was 64 years. Cardiac involvement at diagnosis was present in 49% of patients. The most common induction therapy was Bortezomib-Cyclophosphamide-Dexamethasone (86%). Autologous stem cell transplantation was performed in 38% of patients. Data on HRQoL at baseline (≤2 months from diagnosis) using FACT-G was available for 43 patients. The mean FACT-G total score at baseline was 74 (standard deviation [S.D.] ±15). In comparison, the mean FACT-G total score for general US population is 80.1 (±18.1) and that of US cancer patients is 79.3 (±17.0) [Normative data from Pearman et al; Cancer. 2014]. Maximal HRQoL deficit was seen in the functional well-being (FWB) domain of FACT-G, with the mean score being >0.5 S.D. below that of the general population (Table 1). Data on HRQoL at baseline using PROMIS-GH was available for 18 patients. There was a significant deficit in global physical health (GPH) compared to the general population, with a mean T-score of 37.7 (±7.8) [Mean T-score in general US population being 50±10]. The mean T-score for global mental health (GMH) was 44.4 (±6.7). A total of 72 patients had 128 outpatient visits where FACT-G and PROMIS-GH were captured concurrently (range, 1-4 visits per patient). Using Cohen's criterion, GPH domain of PROMIS-GH had a large and statistically significant correlation with FACT-G total (r=0.66), physical well being (PWB) (r=0.77) and FWB (r=0.66) scores. PROMIS GMH domain also had a strong and statistically significant correlation with FACT-G total (r=0.73), PWB (r=0.60), emotional well-being (EWB) (r=0.64) and FWB (r=0.73) scores. The scatterplots for correlation between PROMIS-GH domains and FACT-G total score is shown in Figure I. At follow-up, a total of 50 patients had data on best hematologic response and HRQoL assessment. Patients achieving a complete response (CR) to first-line therapy had a significantly superior FACT-G score at all domains compared to those with less than CR or no response. Maximal benefit in complete responders was noted in the FWB domain of FACT-G (Mean score ≥2 S.D. higher than patients with less than CR or no response; P=0.002). Conclusion: Patients with AL amyloidosis have a worse HRQoL at diagnosis compared to US cancer and general adult population. Deficit in HRQoL was most prominent in the FWB domain of FACT-G and GPH domain of PROMIS-GH. Most domains of FACT-G and PROMIS-GH had strong and significant correlation. Patients achieving a CR to first-line therapy had significantly superior HRQoL at all FACT-G domains. Clinical trials in AL amyloidosis should include patient-reported HRQoL as a key endpoint and focus on the domains of physical health and functioning to assess meaningful benefit of novel therapies. Psychometric validation of FACT-G and PROMIS-GH in AL amyloidosis would be helpful in generating robust PRO data in future studies. Disclosures Majhail: Anthem, Inc.: Consultancy; Incyte: Honoraria; Atara: Honoraria.

Introduction: There is growing interest regarding cost and affordability of cancer care, particularly in the area of pharmaco-economics. Multiple myeloma has emerged as a model for discussion given the advances in diagnosis, treatments, and subsequent improvement in patient survival. Unfortunately the cost of myeloma therapy has also increased with the advent of novel therapies. Patients are commonly treated with multi-drug combinations that are well tolerated and significantly improve symptoms and outcome, allowing them to return to pre-disease activities. Therefore it is important to consider cost and value when developing new therapeutic strategies. Approval of Daratumumab (DARA) revolutionized the care of myeloma but long infusion times are costly and cumbersome to patients. After initial infusions are administered without infusion reactions DARA is normally infused over 3.5 hours. A recent study showed that a 90-minute infusion is feasible and well-tolerated in patients who have received two prior doses of DARA at standard infusion rates (Barr H et al. Blood 2017). We sought to evaluate the cost and value benefit to patients and payers since implementing this practice change throughout our institution. Methods: We performed a retrospective chart review of patients who received standard DARA versus rapid infusion DARA between February to June 2018 at our institution. The utilization of rapid DARA infusion was implemented on April 24, 2018, so patients who received DARA prior to that date were categorized as pre-rapid DARA and those who received DARA after were considered post-rapid DARA. Pharmacy and billing data was reviewed for these patients and infusions. Results: A total of 181 patients received DARA infusions over the four month time period. 48% of patients (n=86) were treated during the standard pre-rapid DARA timeframe and 52% (n=95) were treated with rapid DARA infusions once eligible. 246 total infusions were administered at standard dosing and 305 infusions were administered as rapid infusions. An average of 2 hours infusion time was saved with each rapid DARA infusion resulting in 610 hours saved over the two months since initiating the rapid treatment protocol. Based on our financial data, we predict that will translate to approximately $7000 savings for the first 6 cycles of treatment if patients are started on rapid infusion DARA with their third treatment dose. Conclusion: There have been dramatic improvements in quality of life and survival of myeloma patients with the introduction of novel therapies. This requires clinicians to adjust their framework of care to account for cost, quality, and value as it applies to patients, providers, and payers. Our analysis shows that with two hours less infusion time both direct and indirect costs savings are achieved. This decrease in cost means less charges to the patient and payer. Therefore overall cost of DARA treatment is reduced. The savings to the patient and payer will quickly add up as patients continue on treatment until disease progression or inability to tolerate further treatment. This helps to decrease the burden of financial toxicity with prolonged treatment. It also improves opportunity cost of the patient and caregiver. With our two month data, we anticipate approximately 3500 hours of infusion time saved over twelve months. In centers with high chair utilization this can improve efficiency. Ongoing efforts should be made to provide value to patients, payers, and providers. Disclosures No relevant conflicts of interest to declare.

High dose melphalan followed by autologous stem cell transplant is the standard of care for all transplant eligible AL amyloidosis patients. Due to medical insurance approvals and pre-transplant evaluation, treatment is delayed by months. Given that there are many patients who respond quickly to bortezomib based regimens, we have adopted a bortezomib based induction regimen in an attempt to prevent early progression or death due to amyloidosis. Materials and methods: All AL amyloidosis patients treated at the Cleveland Clinic who received bortezomib 1.3 mg/m2 subcutaneous, cyclophosphamide 300mg/m2 (dose cap at 500 mg) intravenous or oral, and dexamethasone 20 mg intravenous or oral (CyBorD) on day 1,8, and15, of a 28 day cycle were included in this analysis. Patient information was obtained from an institutional review board approved database and electronic medical record review. Hematologic response was assessed every 28 days. Transplant eligible patients who achieved early complete hematologic response (CR) completed up to 6 cycles of CyBorD followed by high dose melphalan and autologous stem cell transplant (ASCT). If there was no CR at the end of 2 cycles of therapy, patients underwent high dose melphalan and ASCT. Non- transplant eligible patients completed a planned 6 cycles of CyBorD. The primary outcome of the study was to assess overall survival (OS) of all AL amyloidosis patients by Kaplan-Meier estimate. The secondary outcomes were to assess the best hematologic response1, with CyBorD plus ASCT versus CyBorD alone and evaluate if any transplant eligible patients were unable to proceed to ASCT after receiving CyBorD. Results: With a median follow up of 30 months, patients who received CyBorD plus ASCT had a 92% probability of survival. Patients who received CyBorD alone had a 47 % probability of survival. All patients who were deemed transplant eligible at diagnosis underwent high dose melphalan and ASCT. The median NT-proBNP for patients who underwent ASCT was 305 pg/ml and for patients who were transplant ineligible was 6047 pg/ml. The best hematologic response in patients who received bortezomib based induction plus transplant was CR 71%, very good partial response (VGPR) 18%, stable disease (SD) 6%, and progressive disease (PD) 6%. Patients treated with CyBorD alone had a CR 56%, VGPR 6%, SD 19%, and PD 12%. Discussion: None of the transplant eligible patients were deemed transplant ineligible after the induction therapy. The OS was excellent for patients who underwent transplant. The percentage of CR in the transplant eligible patients compared favourably to historical reports of CR with ASCT alone. Only 12 % of patients undergoing ASCT failed to achieve a VGPR compared to 37% of patients with CyBorD alone. Certainly the transplant ineligible patients had severely compromised baseline cardiac function but despite that the probability of survival at 30 months was 47%. With this data, we plan to standardize bortezomib based induction AL amyloidosis treatment with a care path for the entire Cleveland Clinic health care system. Abbreviations: NT-proBNP (amino-terminal pro-B-type natriuretic peptide). References: 1. Palladini G, Dispenzieri A, Gertz MA, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012 Dec 20;30(36):4541-9 Figure 1 Probability of survival for all AL amyloidosis patients treated with CyBorD. Figure 1. Probability of survival for all AL amyloidosis patients treated with CyBorD. Disclosures Reu: Takeda: Research Funding; Novartis: Research Funding; Signal Genetics: Consultancy; Celgene: Research Funding. Smith:Genentech: Honoraria; Abbvie: Research Funding; Spectrum: Honoraria; Celgene: Honoraria. Valent:Takeda: Speakers Bureau; Celgene: Speakers Bureau.

Background: Before SWOG S0777 (Durie BGM at al. ASH 2015, abstract #25) it was not clear whether standard upfront regimens VRd (bortezomib, lenalidomide, dexamethasone) or Rd (lenalidomide, dexamethasone) yield different survival outcomes for newly diagnosed myeloma patients (pts.) but it was known that the higher response rate of VRd comes at a higher risk for severe peripheral neuropathy. Since no test predicts who requires the more toxic regimen to avoid adverse myeloma effects we designed a carepath that tailors therapy according to early response endpoints. Methods: Newly diagnosed symptomatic MM patients (pts) with measurable disease who were not eligible for or elected against a clinical trial were advised to begin a 2-drug regimen of lenalidomide (R) and weekly dexamethasone (d) or, if cast nephropathy suspected or R copay too high, bortezomib (V) and dexamethasone (D). Depending on response assessment per IMWG 2011 criteria after each cycle, treatment intensity was to be increased with sequential addition of agents (R or V, cyclophosphamide, and then liposomal doxorubicin) when there was not at least minor response (MR) after the first, or at least partial response (PR) after the second cycle of an administered combination. Once PR was reached, pts. were evaluated for high dose melphalan (HDM) and ASCT or consolidation with their induction regimen followed in either case by lenalidomide or bortezomib maintenance. After IRB approval, pts treated on carepath were identified through our registry and electronic medical records were reviewed. Results: From Oct 2012 to Dec 2015 the carepath was used in 91 pts. Their median age at treatment start was 64 years (34-84), 40 (44%) were ≥ 65, 11 (12%) ≥ 75 years old; at least one cytogenetic risk study (MyPRS®, FISH panel, karyotype analysis) was obtained in 81 (89%) and of them 23 (28.4%) had high risk features (MyPRS® score > 45.2, del17p, 1q amp, t4;14, t;14;16 and non-hyperdiploid karyotype abnormalities), 33 (36%) had ISS stage III and 21 (23%) had serum creatinine ≥ 2mg/dL, 6 (7%) were on dialysis. At median follow up of 20.5 months (1.7-44.6), at least PR was achieved in 84 pts (92%), at least very good partial remission (VGPR) in 63 (69%), with negative immunofixation in blood and urine in 24 (26%) and complete remission (CR) documented by bone marrow exam in 6 (7%). Only one pt (1%) had progressive disease as best response, stable disease and MR were seen in 3 pts. (3%) each. Induction required 2, 3, 4 and 5 drugs in 49 (54%), 33 (36%), 8 (9%), 1 (1%) pts, respectively, and was followed by high dose melphalan and autologous stem cell transplant in 19 (21%). Sixty-three pts. (69%) remain on carepath treatment without progression, while 28 (31%) have experienced progression with skeletal events in 4 (4%) and ARF in 2 pts. (2%). Nine pts. (10%) have died, 4 while in remission of whom 3 suffered a bleed while anticoagulated for DVT or pre-existing A-fib and died 1 after transition to hospice; the remaining 5 died after progression, of infection (3), secondary plasma cell leukemia (1), or after transition to hospice (2). No patient developed shingles or second primary malignancies so far; mild peripheral neuropathy (PNP) occurred in 27 pts (30%), severe or painful PNP in 4 (4%) and 8 pts. (9%) suffered venous thromboembolism (9%) on DVT prophylaxis with aspirin. Conclusions: Carepath therapy required only two drugs during induction in over 50% of patients to achieve an overall response rate of 92% with ≥ VGPR in 69% in a real-world setting without exclusion of patients on dialysis. Reduction in costs and side effects compared to upfront use of VRd for everyone were accompanied by promising early Kaplan-Meier estimates for progression-free and overall survival (Fig. 1) supporting the carepath principle and future randomized comparison of response-adapted therapy to fixed regimens like the new SWOG S0777 defined standard triplet VRd. Disclosures Reu: Novartis: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Signal Genetics: Consultancy. Valent:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Faiman:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Takeda: Consultancy. Hamilton:Takeda: Speakers Bureau. Smith:Celgene: Honoraria; Spectrum: Honoraria; Genentech: Honoraria; Abbvie: Research Funding.