ALBERT

Description: Triplet regimens combining an immunomodulatory agent, a proteasome inhibitor (PI), and a steroid are used to treat newly diagnosed and relapsed multiple myeloma (MM). Although ixazomib (Ix), an oral PI with single agent activity, can be combined with lenalidomide (LEN), patients (pts) with relapsed/refractory (R/R) MM are often LEN-refractory. Pomalidomide (POM) has single agent activity in LEN-refractory disease, and both POM and Ix also show activity in poor cytogenetic risk pts. Methods: Primary objectives: 1) determine the maximum tolerated dose (MTD) of Ix in combination with standard dose POM and dexamethasone (DEX), and 2) evaluate the anti-tumor activity of the triplet. The treatment regimen included two dose levels (3 mg and 4 mg) of Ix on days 1, 8, 15; POM 4 mg days 1-21; and DEX 40 mg days 1, 8, 15, 22, of a 28 day cycle. Eligibility: R/R MM after 〉1 prior therapy, LEN-refractory, and ≤ grade(gr) 1 peripheral neuropathy (PN). Pts were treated until progression or unacceptable toxicity. Design: Phase I study utilizing a standard 3+3 design; dose limiting toxicities (DLTs) defined during cycle 1. Results: 32 pts treated, 31 evaluable for toxicity and response. Pts received a median 4 cycles (range 1-13); median follow-up is 5.5 months (range 1.8-21.1). Six pts treated on DL1, 25 treated on DL2, the MTD/Phase II dose (P2D). Median age: 62 years (range 38-84); median time from diagnosis: 3.7 years (range 1.0-8.9); median number prior therapies: 3 (range 1-5); prior transplant: n = 23 (74%); double (LEN/Bortezomib[BOR]) or triple (LEN/BOR/Carfilzomib[CFZ]) refractory: 19 (61%). Phase I: DL1 expanded to n=6 after 1/3 pts experienced DLT (gr3 lung infection); no further DLT seen on DL 1 or 2. Adverse events (AEs) related to POM and/or Ix: ANC decrease Gr1/2 n=11 (35%), Gr3/4 n=10 (32%), platelet decrease Gr1/2 n=9 (29%), lymphocyte decrease Gr1/2 n=8 (26%), Gr3/4 n=11 (35%), PN Gr1/2 n=9 (29%), no Gr3/4. Response: Phase I and II, n=31 pts treated. ORR: 45% (6 VGPR, 8 PR); Clinical Benefit Rate (CBR): 81% (6 VGPR, 8 PR, 3 MR, 8 SD). In the pts with high risk cytogenetics (7[23%] 1q, 3[10%] 17p, 2[6%] t(4;14)) an ORR of 58% (3 VGPR, 4 PR) was seen, and the CBR was 83%. In the double or triple refractory pts, an ORR of 26% and CBR of 79% (1 VGPR, 4 PR, 3 MR, 7 SD) were observed. Conclusions: Ix/POM/DEX is a well-tolerated oral combination therapy, and responses were seen even at DL1 and in high risk patients, including those with poor-risk cytogenetics or advanced refractory disease. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding. Lonial:Novartis: Consultancy; BMS: Consultancy; Janssen: Consultancy; Merck: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Onyx: Consultancy. Nathwani:Carevive Systems, Inc.: Research Funding. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding.

Description: Background: Maintenance therapy with lenalidomide post-autologous stem cell transplantation (ASCT) has shown to improve progression-free survival (PFS) in multiple myeloma (MM), and has largely become the standard of care. However, toxicity leads to early discontinuation in nearly one-third of patients and additional options are needed (McCarthy, et al, JCO, 2017). Ixazomib is another maintenance option that has been shown to improve PFS; however, studies comparing lenalidomide and ixazomib are lacking. In this randomized phase 2 study, we analyzed the safety and efficacy of using lenalidomide and ixazomib as part of consolidation and maintenance therapies after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, were consented prior to ASCT. Approximately 4 months following ASCT, patients received 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. Primary data on IRd consolidation were presented at ASH 2018 (Abstract 109920). One month after the last consolidation cycle, patients were randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15 of a 28-day cycle) or lenalidomide (10 mg daily months 1-3 followed by 15 mg for months 4+). The arms were stratified based on MRD-status post-consolidation. In total, 237 patients were enrolled from 10 US centers. This abstract coincides with planned interim analysis 3 which is the first comparison of ixazomib and lenalidomide maintenance. While the study was not powered to compare PFS between the two arms, the sample will provide a reasonable power to estimate non-inferiority. There is a planned stopping rule for non-inferiority set at a hazard ratio of 〉1.3 in favor of lenalidomide. Secondary end-points include MRD-negativity following 12 cycles and toxicity. Results: At time of abstract submission, 215 patients had completed IRd consolidation and 191 had begun maintenance. 90 were randomized to ixazomib and 94 to lenalidomide. 7 patients were not randomized due to toxicity during consolidation; data from these patients are not included in the analyses. The characteristics of the two arms are summarized in Table 1. Hematologic toxicity has been infrequent with ixazomib with neutropenia and thrombocytopenia occurring in 11% and 23% of patients. In comparison, neutropenia and thrombocytopenia occurred in 45% and 35% of patients on lenalidomide. The most common non-hematologic toxicities in both arms have been GI-related and infections, both expected events. 16% of patients on ixazomib have experienced Grade 3-4 non-hematologic toxicity compared to 34% on lenalidomide. No grade 3 or higher peripheral neuropathy has been reported in either arm. 11% of patients on ixazomib have discontinued due to toxicity and another 9% have required a dose reduction to 3mg. Lenalidomide toxicity has led to discontinuation in 15% of patients and another 12% were dose reduced to 5mg. Only 45% of patients receiving 4+ cycles of lenalidomide were able to titrate to the 15mg dose. After a median follow-up of 11.2 months from randomization (19.7 months post-ASCT), 30% of patients on ixazomib have discontinued treatment due to disease progression. After a median follow-up of 12.3 months from randomization (20.2 months post-ASCT), 18% patients on lenalidomide have discontinued treatment due to disease progression. Conclusion: Ixazomib and lenalidomide maintenance have been well tolerated to date. A comparison of PFS is currently being conducted as part of interim analysis 3 and final results will be presented, representing the first report directly comparing lenalidomide and ixazomib maintenance. Table 1: Disclosures Vij: Genentech: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Sanofi: Honoraria. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Fiala:Incyte: Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Kaufman:Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Janssen: Honoraria; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Takeda: Consultancy. Hofmeister:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: 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. Rosko:Vyxeos: Other: Travel support.

Description: Background: High risk AML patients (pts) have poor outcome with low complete remission (CR) rate and long term survival despite intensive chemotherapy. Tyrosine kinases play an important role in AML pathogenesis. Pre-clinical studies performed in our center (Blood. 2013 122:1900) have shown that Src family tyrosine kinases (SFK) including Lyn, Hck and Fgr are abnormally activated in AML compared to normal hematopoietic stem cell and progenitor cells. Other studies have shown that the c-Kit receptor is over-activated in a subset of AML pts and contributes to abnormal leukemia cell growth. We further show that the small molecule SFK and c-Kit inhibitor dasatinib reduces proliferation and survival of AML stem and progenitor cells. Importantly, dasatinib enhances the sensitivity of AML stem and progenitor cells to chemotherapeutic agents by inhibiting Akt signaling, increasing mdm2 phosphorylation and enhancing p53 activity in AML cells. Based on this data we conducted a phase I/II clinical study of the combination of dasatinib with conventional cytarabine-idarubicin ("7+3")-based induction chemotherapy in high-risk AML. Methods: Between September 20013 and July 2015, 18 adult AML pts were enrolled in the study. Eligibility criteria were high-risk AML, age 〉18 years, and suitability for intensive therapy. High risk AML was defined by one of the following criteria: older age (〉 60 yrs), poor-risk cytogenetic and molecular abnormalities (ELN criteria), secondary disease (AML evolving from myelodysplasia or myeloproliferative neoplasm), therapy related (t-AML), or relapsed/refractory. This Phase I study used a 3 + 3 dose escalation design for dasatinib while keeping a fixed dose of cytarabine and idarubicin (cytarabine 200 mg/m2 CIV days 1-7, idarubicin 12 mg/m2 IV days 1-3). Dasatinib was started at a dose of 70 mg (dose level 1; DL-1) days 1-7, and escalated to 100 mg orally days 1-7 (DL 1). Pts who failed to achieve CR received second re-induction with the same regimen. Pts who achieved CR received consolidation high dose cytarabine and/or allogeneic stem cell transplantation (SCT) based on donor availability. Results: Of the 18 pts enrolled on the study, 7 pts (39%) had secondary AML, 5 pts (28%) relapsed AML, 2 pts (11%) t-AML, and 4 (22%) were newly diagnosed older AML pts (one with complex karyotype, one with trisomy 8 and one cytogenetically normal with FTL3-ITD). The median age of all pts was 62 yrs (range 27-73). Of the 18 pts, 13 pts are currently evaluable for response; of which 10 (77%) achieved CR/Cri. Of the 5 non-evaluable pts, one pt withdrew from study after 2 days of therapy, one pt was taken off study after 3 days due to cytarabine neurotoxicity, one pt died of intracranial hemorrhage before the day 14 bone marrow biopsy, one pt had therapy interrupted secondary to pneumonia and sepsis, and one is still receiving therapy. None of the pts required more than one induction to achieve CR. Of the 10 pts who achieved CR/Cri, 8 patients went on to receive allogeneic SCT. As expected, the most commonly reported grade 3 and 4 adverse events (AE) were anemia 50%, thrombocytopenia 44%, neutropenia 38%, and fatigue 27%. The most common grade 1-2 AE were GI toxicities 61% and rash 33%. Correlative studies performed on blood samples obtained from pts on day 3 after initiation of treatment (n=9) demonstrated significant decrease in of SRC activity (as indicated by reduction in phospho-SRC levels on immunoblotting, 0.52±0.11 of control, p=0.01), and increased expression of p53-target genes as evaluated by Q-RT-PCT [including Puma (16.2±6.9 fold, p=0.015), P21 (4.9±1.1 fold, p=0.004), DR5 (3.4±0.9, p=0.004), Bax (3.7±0.9 fold, p=0.001) and HDM2 (2.1±0.5, p=0.02)]. Conclusion: Combination of dasatinib with conventional "7+3" induction chemotherapy is feasible in high-risk AML and leads to higher CR rate compared to historical data without increase in toxicity rate, allowing more pts to receive allogeneic transplantation. Correlative laboratory studies are consistent with pre-clinical studies suggesting that this combination is associated with significant inhibition of SRC activity and enhanced activation of p53-target genes. Disclosures Dos Santos: Amgen: Employment. Stein:Amgen: Speakers Bureau. Chen:Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; genentech: Consultancy, Speakers Bureau. Khaled:Sequenom: Research Funding.

Description: 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

Description: Abstract 3699 Background: A defining feature of HL is CD30 expression by Reed-Sternberg cells. Brentuximab vedotin, an antibody drug conjugate (ADC), selectively induces apoptotic death of CD30+ cells by binding, internalizing, and releasing monomethyl auristatin E, a microtubule agent. A pivotal phase II trial of brentuximab vedotin in heavily pretreated patients with HL demonstrated an overall objective response rate of 75% (CR, PR) and CR of 34% with manageable toxicities. This novel ADC compares favorably with historical first-line salvage regimens such as ICE and DHAP (CR 17–21%) To examine the outcomes (e.g., toxicity, response) of brentuximab vedotin when given as first-line salvage therapy for HL, we retrospectively analyzed data from a consecutive case-series of patients who received brentuximab vedotin as first -line salvage therapy at COH. Patients and Methods: Three patients received brentuximab vedotin as salvage therapy on IRB 10089 (expanded access protocol) and 8 patients received brentuximab vedotin as salvage therapy on IRB 11051 (prospective phase II trial). All patients had relapsed/refractory HL post induction therapy with ABVD, BEACOPP or a combination +/− consolidative XRT. Patients were treated with 1.8 mg/kg of brentuximab vedotin intravenously every 3 weeks as outpatients for a maximum of 4 cycles. Descriptive statistics were generated for response, toxicity, stem cell mobilization/collection and engraftment (for those patients who went on to autologous HCT). Response rate post brentuximab vedotin treatment was determined with either CT or PET at cycle 2 and CT/PET at cycle 4 as per Cheson 2007 criteria. Results: A total of 11 patients were treated at COH from 8/2011 to 7/2012 (Table 1). The median age was 34 years (22, 64); 7/11 were female. All patients received ABVD or ABVD/BEACOPP combination induction therapy. Three patients had also received consolidative radiation therapy. Six were considered primary refractory and 5 had relapsed HL. Thus far, 8 were evaluable for response and 10 were evaluable for toxicity. The overall response rate was 87.5% (7/8); CR was 50% (4/8) and PR was 37.5% (3/8); one patient achieved SD after 4 cycles. Three out of 4 patients who achieved CR did so after 2 cycles. No one developed progressive disease while on treatment. Overall the regimen is considered well tolerated. No grade 2 neuropathy was reported. The incidence of grade 1 neuropathy was 20% (2/10). There were no grade 3 or 4 adverse events or hospitalizations during brentuximab vedotin treatment. Additionally, the use of growth factors or red blood cell or platelet transfusions was not required. A total of 6/11 patients have undergone stem cell mobilization with cyclophosphamide/G-CSF priming after the 4th dose of brentuximab vedotin. The median cells dose collected was 5.87 × 10⋀6 CD34+ cells (2.78–11.13, minimum acceptable is 2 × 10⋀6 CD 34+ cells). The median time to reach the minimum collection was 1.5 days (1–5). All six patients have undergone ASCT using either BEAM or CBV for conditioning. The median time for neutrophil engraftment (ANC〉500) was 10 days (10–11) and platelet engraftment (〉20K) was 11 days (10–13). All 6/6 patients achieved CR after stem cell transplantation. The other five patients are undergoing stem cell mobilization or are have not completed brentuximab vedotin treatment. Conclusion: These data show brentuximab vedotin as first-line salvage therapy can produce an adequate ORR of 87.5% and CR of 50%. Brentuximab vedotin also has acceptable toxicity and does not adversely impact stem cell collection or post autologous HCT engraftment. Disclosures: Chen: Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel Expenses Other. Off Label Use: This clinical trial involves the use of brentuximab vedotin as first line salvage therapy in Hodgkin lymphoma, which is an off-label use. Siddiqi:Seattle Genetics, Inc.: Consultancy, Research Funding.

Description: Introduction: 18Fluoro-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and non-malignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with copper-64 via the chelator DOTA (64Cu-DOTA-Dara), led to improved sensitivity and specificity over that of FDG (Caserta et al, Blood 2018). Herein, we report the results of a Phase 1 trial (NCT#03311828) designed to 1) assess the safety and feasibility of 64Cu-DOTA-Dara PET/CT and 2) to evaluate and characterize the ability of 64Cu-DOTA-Dara to accurately detect or exclude MM lesions compared with FDG PET/CT. Methods: Patients with biopsy-proven MM and/or a plasmacytoma received an FDG PET/CT scan within 60 days of enrollment. On Day 0, patients were infused with unlabeled ("cold") Dara at one of four dose levels (0 mg, 10 mg, 45 mg, 95 mg) to optimize biodistribution of radioconjugated 64Cu-DOTA-Dara, especially in the liver and the spleen. Within 6 hours of unlabeled Dara administration, patients received 64Cu-DOTA-Dara at a dose of 13.63-16.68 mCi (~5 mg). Whole-body PET scans were obtained at 24 hours and at 48 hours (the latter scan encompassing known tumors). 64Cu-DOTA-Dara standardized uptake values (SUV) were evaluated in MM lesions and normal organs, which were then compared with values from standard FDG PET/CT. Biopsies were performed on accessible discordant lesions. Results: A total of 10 Dara-naïve patients were imaged. Patients were treated with 0 (n=3), 10 (n=3), 45 (n=3), or 95 mg (n=1) of unlabeled Dara. Four patients had newly diagnosed disease, one had biochemical relapse, one had a recurrent plasmacytoma by MRI, and four had possible recurrence by standard PET/CT. No significant adverse events were observed from either cold or 64Cu-DOTA-Dara. With the exception of the one patient with a recurrent plasmacytoma, radiolabeled antibody was eliminated from systemic circulation in subjects analyzed at the first three dose levels within 30 min post injection. In the patient with a recurrent plasmacytoma, the radiolabeled antibody was elevated in the blood for over two days. One newly diagnosed patient had extensive disease by FDG PET and had a biopsy-proven target lesion in the sternum, which had an SUVmax of 14.7 on 64Cu-DOTA-Dara PET/CT vs. 3.3 onFDG PET/CT. A second biopsy from the same patient was taken from a discordant iliac crest lesion (positive for 64Cu-DOTA-Dara but negative for FDG PET/CT) that showed 20-30% MM cell infiltration. In another patient, an iliac crest lesion was 64Cu-DOTA-Dara positive and FDG-negative; biopsy revealed 6% plasmacytosis in the bone. A third patient had an FDG PET/CT positive pleural lesion with an SUVmax of 8.98 and negative on 64Cu-DOTA-Dara (Figure 1A). The lesion did not show recurrence upon biopsy. Furthermore, 64Cu-DOTA-Dara PET/CT yielded superior imaging of bone lesions in the calvarium (Figure 1B). Escalating doses of unlabeled Dara decreased liver and spleen uptake by 64Cu-DOTA-Dara. Conclusions: In this ongoing study, 64Cu-DOTA-Dara PET/CT imaging is to date safe and provides whole body imaging of MM. Further dose escalation of cold Dara (145 mg, 195 mg) is planned to optimize background interference. This modality has the potential to improve sensitivity and specificity over FDG PET/CT scanning in early-stage MM as well as in recurrent disease. Disclosures Krishnan: Celgene, Janssen, Sanofi, BMS: Consultancy; Sutro BioPharma, zPredicta: Consultancy; Amgen, Takeda: Speakers Bureau; Celgene, Z Predicta: Other: Stock Ownership; Takeda: Research Funding. Palmer:Gilead Sciences: Consultancy. Rosenzweig:Celgene, Takeda: Speakers Bureau. Wu:ImaginAb, Inc.: Consultancy, Other: Board Member.

Description: Introduction: Despite significant progress in the treatment of multiple myeloma (MM), the disease remains incurable and typically follows a pattern of multiple responses and relapses. In the relapsed/refractory MM setting (RRMM), outcomes for patients may be particularly discouraging. New treatments that are safe and effective are therefore of urgent need for this population. Since its FDA approval in 1998 for the treatment of rheumatoid arthritis, leflunomide has been used in over 300,000 patients worldwide. Leflunomide is hepatically cleared and has a favorable toxicity profile even when given over long periods. Its primary mechanism of action is inhibition of pyrimidine synthesis by targeting dihydroorotate dehydrogenase, thus achieving anti-proliferative effects on B and T lymphocytes. The anti-neoplastic potential of this agent has been studied in a number of pre-clinical tumor models. Leflunomide's immunoregulatory action may be related to functional inhibition of CD4+ effector T cells, including Th17 cells as well as dysregulation of T regulatory cells (Tregs). We found that leflunomide-treated C57BL/KaLwRij mice engrafted with 5TGM1 cells had more robust expansion of CD8+ cytotoxic T cells and subsequent decrease of CD4+ Tregs compared to untreated mice. We have also noted that leflunomide impairs growth of MM cells at least partly through inhibition of PIM kinases and c-Myc signaling. We present here final results from a phase 1 study of leflunomide in patients with RRMM. Methods: This single center, single agent, phase 1 dose-escalation trial was designed to determine the maximum tolerated dose of leflunomide in patients with RRMM. The trial implemented a modified rolling six phase 1 dose escalation design. The primary objectives were as follows: 1) to determine the maximum tolerated dose and recommended phase 2 dose of leflunomide; 2) to assess the safety and tolerably of leflunomide at each dose level by evaluation of toxicities. Leflunomide was administered at a loading dose of 100 mg daily for the first three days, then daily in 28-day cycles. The starting dose of daily leflunomide was 20 mg daily, with dose escalation in increments of 20 mg/day, up to 60 mg/day. Dose de-escalation in decrements of 10mg/day was planned. Results: A total of 12 patients have been enrolled starting in December 2015 and treated. The median age is 68 (range 48 - 85), and the median number of prior therapies is 5 (range: 3 - 14). Nine patients had prior autologous stem cell transplant. Double refractory (lenalidomide/bortezomib) disease was noted in 9 patients. High-risk cytogenetics were observed in 5 patients including 2 patients with del17p. All 12 subjects were evaluable for toxicity. One subject was not evaluable for response because of non-compliance. Of the eleven patients evaluable for response, the median number of cycles was 3 (range 1- 15). The median follow up was 177 days (range: 42 - 602). Three patients were treated on DL 1 (20 mg) and three on DL3 (40 mg) without incidence of DLT. At DL5 (60 mg), one patient had a DLT with grade III elevation of alanine aminotransferase; an additional three patients were enrolled at this dose level without further DLTs. One out of 12 subjects remains on treatment, 8 patients were removed from study due to disease progression, two due to adverse events (bacteremia at 60 mg, possibly related to study drug and angioedema at 40 mg, not related to study drug) and one from noncompliance. The most common toxicities were hematologic. There were 4 patients with grade 1 or 2 neutropenia on the 20 and 40 mg dose levels and 1 patient with grade 4 lymphopenia on the 40 mg dose. Except for the DLT, all non-hematologic toxicities were ≤ grade 2. Response: Although not all patients were treated at the 60 mg dose, a clinical benefit rate of 90% has been seen, with 9/10 achieving stable disease (SD). The median duration of SD among 9 patients thus far is 56 days (range: 27-401). In the five evaluable patients with high risk cytogenetics, four of them achieved a clinical benefit. Two subjects had SD lasting nearly one year or longer. In this small cohort, no association between dose and benefit was observed. Conclusion: Leflunomide is a safe and well-tolerated oral option for patients with RRMM, with a clinical benefit from single agent dosing. On the basis of our preclinical work showing synergistic inhibition of MM using leflunomide, pomalidomide, and dexamethasone, we plan clinical testing of this drug combination. Disclosures Rosenzweig: Celgene: Speakers Bureau. Krishnan:Janssen: Consultancy, Speakers Bureau; Sutro: Speakers Bureau; Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Description: Background: Maintenance therapy post-autologous stem cell transplantation (ASCT) has shown to improve progression-free and overall survival in multiple myeloma (MM) and has largely become the standard of care. Consolidation therapy, a brief duration of more-intensive chemotherapy administered prior to maintenance, has been shown to further deepen responses and may improve long-term outcomes. Ixazomib, lenalidomide and dexamethasone (IRd) is an all oral regimen that has been shown to be active in newly diagnosed MM as well as relapsed disease. In this study, we are analyzing the safety and efficacy of IRd as consolidation therapy after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, are being consented prior to ASCT. Approximately 4 months following ASCT, patients receive 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. The primary end point is minimal residual disease (MRD) status. MRD is being assessed by ClonoSEQ where possible and by multi-color flow where not. Toxicity, IMWG response rate, PFS, and OS are secondary end points. One month after the last consolidation cycle, patients are randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15) or lenalidomide (15 mg daily). In total, 240 patients will be enrolled on the trial. This presentation coincides with planned interim analysis 2 which included data from the consolidation phase only. Results: As of July 2018, 172 patients with NDMM have been enrolled from 10 centers within the US. The median age was 57 (range 28-70) and 67% were male. 76% were white, 10% African-American/Black, and 13% were another race. 39% were ISS Stage I, 30% were Stage II, and 20% were Stage III. All patients received proteasome inhibitors and/or IMIDs as front-line induction and melphalan as conditioning for ASCT. IRd consolidation started at a median of 110 days post-ASCT (range 80-138). IRd has been well tolerated. Only 4% (6/154) of patients have been unable to complete the 4 cycles of consolidation to date due to toxicity. Grade 3 hematologic toxicity has been uncommon; 4% neutropenia, 3% thrombocytopenia, and 2% anemia. There has been no grade 4 hematologic toxicity. Non-hematologic grade 3-4 toxicities have included: infection (8%), nausea/vomiting/diarrhea (3%), and transaminitis (1%). No grade 3-4 peripheral neuropathy has been reported. One case of grade 5 pneumonia was reported but was not considered related to study treatment. Following ASCT, the MRD-negative rate was 26% and this improved to 37% following consolidation. In the subset of patients with Clonoseq results available, the MRD negative rate improved from 19% to 27%. Clinical response rate improved similarly; prior to consolidation the VGPR or better rate was 76% including 39% CR/sCR. Following consolidation, the VGPR or better rate was 85% including 56% CR/sCR. 137 patients went on to receive maintenance with either ixazomib (n = 71) or lenalidomide (n = 66). At time of submission, the median follow-up from start of IRd is 14 months and 28 patients have relapsed/progressed and 6 have expired. An interim analysis is planned for 2019, representing the first comparison of ixazomib and lenalidomide maintenance. Conclusion: IRd consolidation following ASCT appears to be safe and effective. The all oral regimen is convenient for patients which greatly simplifies follow-up in the peri-transplant period. Study enrollment is scheduled to complete in Q1 of 2019. Disclosures Vij: Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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, Research Funding; Amgen: 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, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees. Martin:Amgen: Research Funding; Sanofi: Research Funding; Roche: Consultancy. Deol:Kite Pharmaceuticals: Consultancy; Novartis: Consultancy. Kaufman:Janssen: Consultancy; Karyopharm: Other: data monitoring committee; BMS: Consultancy; Abbvie: Consultancy; Roche: Consultancy. Hofmeister:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Gregory:Poseida Therapeutics, Inc.: Research Funding. Berdeja:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Bluebird: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Teva: Research Funding; Sanofi: Research Funding. Chari:Pharmacyclics: Research Funding; Celgene: 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; Amgen: 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; Array Biopharma: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; The Binding Site: Consultancy.

Description: 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.

Description: 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.