ALBERT

Description: Introduction: Thrombosis is a major cause of morbidity and mortality in patients with classical myeloproliferative neoplasms (MPN), which include polycythemia vera, essential thrombocythemia and primary myelofibrosis. One third of patients with MPN suffer a thrombotic event, either arterial or venous. Despite this, there are no strong data to guide either the selection or duration of anticoagulants for MPN. Warfarin has been primarily used for long-term anticoagulation and is associated with a clear reduction in overall thrombotic events, however 20% of patients will have a recurrent thrombotic event despite ongoing warfarin anticoagulation, corresponding to a failure rate of 4-8% pt-yrs (AnnHematol 2015;94:911-918, Haematologica2008;93:372-380). The overall objective of this study was to evaluate recurrent thrombotic and major bleeding events in MPN-associated thrombosis treated with DOAC versus warfarin. Methods: The primary outcome was to compare the rate of thrombotic events in patients treated with DOAC versus warfarin for secondary thromboprophylaxis (treatment of first clot) among MPN patients. The secondary outcome compared the rate of bleeding events between the two groups. Electronic medical records for patients with a classical MPN diagnosis by PSVG criteria at the University of North Carolina Hospitals were queried to evaluate DOAC or warfarin medication orders between January 1, 2010 and May 31, 2017. Demographic laboratory data, concomitant medications, and incidence and severity of thrombotic or bleeding events were recorded for each MPN patient treated with a DOAC, warfarin, or aspirin. Descriptive statistics were used to characterize the population. Categorical variables were summarized as counts and percentages, while continuous variables were summarized as medians with first to third quartiles. The annual incidence of secondary thrombosis (ie: recurrent event) was calculated by dividing the number of events by the total number of patient-years (pt-yrs). 95% confidence intervals and comparisons were made using a Mid-P exact test. For all analyses, results were deemed significant if P

Description: Abstract 449 Background ARRY-520 is a kinesin spindle protein (KSP) inhibitor that arrests cells in mitosis and induces apoptosis due to degradation of the BCL2 family survival protein MCL-1. As previously reported, ARRY-520 has demonstrated single-agent activity in relapsed and refractory multiple myeloma (RRMM). In preclinical myeloma models, the addition of dexamethasone (Dex) increases the activity of ARRY-520, supporting clinical investigation of ARRY-520 combined with low-dose Dex (LoDex). Here, the efficacy and safety of ARRY-520 is compared in 2 Phase 2 cohorts in RRMM: as a single agent (Cohort 1) and in combination with LoDex (Cohort 2). Methods Both cohorts were designed as 2-stage single-arm Phase 2 studies. Cohort 1 evaluated the efficacy and safety of 1.5 mg/m2/d ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with prophylactic granulocyte colony-stimulating factor (G-CSF) support. Eligible patients had RRMM with 2 prior lines of therapy that included both bortezomib (BTZ) and an immunomodulatory agent (IMiD), unless refusing or ineligible for this therapy. Cohort 2 is evaluating the efficacy and safety of the same dose and schedule of ARRY-520 and G-CSF with LoDex (40 mg PO weekly). Eligible patients had RRMM with 2 prior lines of therapy, and had disease refractory to (progressed on or ≤ 60 days of treatment) their last line of therapy and that was refractory to BTZ, lenalidomide (Len) and dexamethasone. Data from Cohort 1 and the first stage of Cohort 2 are reported. Results At the time of data cutoff, a total of 32 patients were enrolled into Cohort 1 with a median age of 65 years (range 51–82) and a median of 6 prior regimens (range 2–19). All patients received prior IMiD, 90% received prior BTZ and 78% had prior autologous stem cell transplant (ASCT). The defined first stage of Cohort 2 has been enrolled with 18 evaluable patients. These patients had a median age of 67 years (range 53–78) and were more heavily pretreated, with a median of 10 prior therapies (range 5–13). Safety was similar for both cohorts. A possible trend for more infections in Cohort 2 was noted. The most commonly reported (20% of patients) treatment-related adverse events (AEs) in both cohorts included thrombocytopenia, anemia, neutropenia and fatigue. No treatment-related events of neuropathy were observed in either cohort. The most common Gr 3/4 AEs (in Cohort 1, Cohort 2) included neutropenia (38%, 33%), thrombocytopenia (44%, 44%) anemia (28%, 50%), pneumonia (3%, 17%) and fatigue (16%, 11%). Treatment discontinuations due to AEs were infrequent (9%, 11%). Of 32 patients in Cohort 1, confirmed responses (≥ Minor Response (MR)) were observed in 6 patients (19%) with 5 Partial responses (PR) (16%) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EBMT) criteria. The median treatment time was 2.1 months. In the subset of patients with disease refractory to both BTZ and Len, a 15% overall response rate (ORR ≥ MR) was observed. Among the 18 evaluable patients in Cohort 2, the ORR (≥ MR) was 28% (5/18), with 4 patients ≥ PR (22%). At the time of data cutoff, the median treatment time was 3.9 months. Summary Patients with RRMM refractory to both IMiD and proteasome inhibitor therapy have a poor prognosis with median survival of as little as 6 months1. New drugs with clinically meaningful activity in this population are needed. ARRY-520 is a novel agent with a distinct mechanism of action relative to other myeloma drugs and shows promising clinical activity both alone and combined with Dex in RRMM. Notably, in patients with triple-refractory MM, ARRY-520 + LoDex has shown a preliminary 28% ORR (≥ MR), with a manageable safety profile. These data are comparable to those reported for pomalidomide or carfilzomib in less heavily pretreated patients. Both the median time on study and ORR in Cohort 2 were greater than the activity seen for Cohort 1, despite the more advanced stage of these patients and the fact that they were heavily pretreated with Dex, suggesting that LoDex may enhance ARRY-520 activity. Based on this evidence of activity, further development of ARRY-520 + LoDex is warranted in patients who have exhausted other therapeutic options. Disclosures: Shah: Array BioPharma: 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; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: ARRY-520. Zonder:Millenium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kaufman:Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millenium: Consultancy. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walker:Array BioPharma: Employment. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Lonial:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: 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; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 2935 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent onset of apoptosis due to degradation of survival signals during mitotic arrest. While immunomodulators [IMiDs] and proteasome inhibitors have improved outcomes in MM, patients with MM that is refractory to both bortezomib (BTZ) and thalidomide (THAL) or lenalidomide (LEN) have a poor prognosis with median survival of 9 months. Since ARRY-520 is a novel agent with a unique mechanism of action (MOA) relative to current standard-of-care (SOC) agents, it might be expected to show activity in patients refractory to other drugs. Preclinically, ARRY-520 showed activity in BTZ-refractory models, suggesting prior treatments may not predict patient response to ARRY-520. Methods: This Phase 2 study was designed to evaluate the efficacy, safety and biological effects of 1.5 mg/m2/day ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both BTZ and an IMiD), unless refusing or ineligible for this therapy. Results: Thirty-two patients have been treated, with a median age of 65 years (range 51–82) and a median of 5 prior regimens (n = 31; range 2–20). Twenty-eight patients received prior BTZ, 28 patients prior LEN, 17 patients prior THAL and 25 patients had an autologous stem cell transplant. One patient has been lost to follow-up. ARRY-520 demonstrated an acceptable safety profile, confirming the safety profile observed in the Phase 1 study. The most commonly reported (≥ 10% of patients) treatment-related adverse events (AEs) included hematologic events such as anemia (11 patients [34%], 4 Grade 3/4 [12%]), neutropenia (11 patients [34%], 9 Grade 3/4 [28%]) and thrombocytopenia (20 patients [63%], 11 Grade 3/4 [34%]), as well as fatigue (4 patients [16%], 2 Grade 1/2 and 2 Grade 3) and mucositis (4 patients [13%], all Grade 1/2). No treatment-related events of alopecia or neuropathy were reported. One patient discontinued study due to a treatment-related AE of blisters. ARRY-520 has shown preliminary activity as a single agent in this heavily pretreated population. To date, of 32 evaluable patients, 3 confirmed partial responses (PR) and 2 confirmed minimal responses (MR) have been observed, per International Myeloma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 5 prior therapies (range 2–8). As observed in the Phase 1 study, the time to response with ARRY-520 was prolonged. Notably, clinical responses have been observed in this study in patients refractory to both LEN and BTZ. To date, in this ongoing study 33% (5/15) of patients with disease refractory to both LEN and BTZ achieved clinical benefit (PR + MR + SD 〉 4 months). While this trial has been fully recruited, as of July 2011, 8 patients remain on study. Conclusions: ARRY-520 is a novel agent with a differentiated MOA relative to other myeloma drugs. ARRY-520 shows promising evidence of single-agent clinical activity and an acceptable safety profile in heavily pretreated patients with MM. Notably, ARRY-520 has demonstrated activity in patients refractory to both LEN and BTZ, a population with limited treatment options. An expansion cohort is planned in order to evaluate the safety and efficacy of ARRY-520 in combination with dexamethasone in patients who are refractory to their last myeloma treatment and refractory to prior LEN, BTZ and dexamethasone. Disclosures: Lonial: Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Merck: Consultancy. Off Label Use: ARRY-520. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Benzinger:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Shah:Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, 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: Thrombosis is a major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). The mechanistic basis of thrombosis in PV/ET, however, is unknown. To better understand the pathophysiology of thrombosis in PV and ET, we first studied transcript levels of selected thrombotic, inflammatory and hypoxia- inducible factor (HIF) pathway genes in granulocytes and platelets of PV and ET patients with and without thrombosis. Genes selected for the study included: tissue factor (F3); P-selectin (SELP); serpin peptidase inhibitor clade E member 1 (SERPINE1, encoding plasminogen activator inhibitor I, PAI1); thrombospondin 1 (THBS1); interleukin 1 receptor associated kinase 1 (IRAK1); interleukin 1 receptor accessory protein (IL1RAP) and HIF-regulated genes: vascular endothelial growth factor A (VEGFA) and solute carrier family 2 (SLC2A1, encoding glucose transporter 1). We have previously reported at this meeting that PV and ET patients with a history of thrombosis had higher transcripts of F3, SERPINE1, IL1RAP, VEGFA and SLC2A1 compared to those without thrombosis. We also performed unbiased total RNA sequencing of platelets and granulocytes (Gangaraju R et al Blood, 2016;128:3143). Tissue factor (TF) is the principal initiator of coagulation in vivo. The presence of TF transcript in leukocytes and platelets may or may not reflect the translated protein level. Furthermore, TF functional activity is modulated by encryption. Therefore, we proceeded to evaluate the functional activity of microvesicle-associated TF (MVTF) in the plasma of 10 ET and 33 PV patients considered to have high thrombotic risk (Tefferi A, Barbui T Am J Hematol. 2017;92(1):94-108). TF activity was measured in MVs collected by centrifugation of patient plasma to 20,200 xg by a two-step FXa generation assay with and without an inhibitory TF antibody to determine the contribution of TF to FXa generation (Owens 3d et al. Circ Res. 2011;108(10):1284-97). We found significantly increased levels of MVTF activity in PV and ET compared to normal controls (Figure 1). However, MVTF levels in PV and ET patients with and without thrombosis were comparable (Figure 1). In the vasculature, leukocytes can synthesize TF (upon stimulation) and it has been shown that monocytes, not neutrophils, are the principal source of TF under normal conditions (Osterud B, Thromb Res. 2010;25 Suppl 1:S31-4). MPN granulocytes, in contrast to normal granulocytes, had increased levels of TF transcripts, a novel and important finding of as yet undetermined significance (Figure 2). Since TF synthesis is regulated by hypoxia-inducing factor-1 (HIF-1) (Rolfs et al. J Biol Chem. 1997;272(32):20055-62), we also examined MVTF activity in the plasma of Chuvash polycythemia (CP) patients. These patients have a germline VHLC598T mutation in the negative regulator of HIFs, the von Hippel Lindau gene (VHLC598T), and as a result they have increased levels of HIF-1, HIF-2 and transcripts of a vast array of HIF-regulated genes. CP subjects have an even higher propensity for arterial and venous thrombosis than PV. As predicted, some CP plasmas also demonstrated elevated levels of MVTF activity (Figure 1). In conclusion, hypoxia-induced increased levels of plasma MVTF activity may play a role in the increased thrombotic risk of PV and ET. TF joins TSP-1 (Sergeueva et al. Haematologica. 2017;102(5):e166-e169) and protein S (Pilly et al. Blood 2018;132(4):452-455) as a potential HIF-regulated mechanism of thrombotic risk in patients with PV/ET and CP. Granulocytes may also be a source of hypoxia-induced TF in these patients. The hypoxia-mediated upregulation of thrombotic risk is further underscored by the observation that PV patients living in moderate hypoxia at Salt Lake City have a higher risk of thrombosis than those living at sea level (Baltimore MD) in multivariate analysis (Zangari et al, Blood Coagul Fibrinolysis 2013; 24(3):311-316). The data described here may facilitate identification of novel targets and their therapies including the use of HIF-1 inhibitors such as digoxin to prevent thrombosis in these patients (Zhang et al. PNAS 2008;105(50):19579-86). Disclosures Key: UniQure BV: Research Funding.

Description: Background: Patients with multiple myeloma (MM) who have relapsed after conventional treatment have limited therapeutic options for long-term disease control. Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. In the first report of efficacy and safety for the phase 1/2 study O-12-M1 (median follow-up, 28 months), melflufen and dexamethasone demonstrated an overall response rate of 31%, a median PFS of 5.7 months, and a median OS of 20.7 months, with acceptable safety for patients with RRMM (Richardson PG, et al. Blood. 2017; Abstract 3150). Here, updated OS and PFS results from the O-12-M1 study are reported, with 18 months of additional follow-up of the patients who were still participating in long-term follow-up at the time of the final database lock in November 2017. Methods: Eligible patients had RRMM, measurable disease, and ≥2 prior lines of therapy, including bortezomib and lenalidomide. Patients must have had progressive disease (PD) on or within 60 days of completion of last therapy. Patients received melflufen 40 mg intravenously on day 1 of each 28-day cycle and oral dexamethasone 40 mg weekly for up to 8 cycles or longer at the discretion of the investigator and sponsor. Treatment continued until PD or unacceptable toxicity. Patients were followed up for 2 years after PD or start of subsequent therapy. PFS and OS were secondary end points in this study. Time to next treatment (TTNT), an exploratory end point defined as the time from start of melflufen and dexamethasone to first subsequent therapy or death, was retrospectively reviewed. Results: As of 15 May 2019, 45 patients were treated. Median age was 66 years (range, 47-78); 60% of patients had International Staging System stage II/III at study entry, and 44% had high-risk cytogenetics [del(17p), t(14;16), t(4;14), t(14;20), or gain(1q)]. The median time since initial diagnosis was 5.0 years (range, 1-21). Patients received a median of 4 prior lines of therapy (range, 2-14). All patients were exposed to IMiDs, 98% to proteasome inhibitors (PIs), 93% to alkylators (any dose of melphalan, cyclophosphamide, or bendamustine), and 80% to melphalan; 87% were refractory to last line of therapy, and 91%, 67%, and 7% were single (IMiD or PI), double (IMiD and PI), and triple (IMiD, PI, and daratumumab) refractory, respectively. After a median follow-up of 30.1 months, median PFS was 5.7 months (95% CI, 3.7-9.3; 98% events). Median OS was 20.7 months (95% CI, 13.6-not reached; 58% events; Figure). Updated PFS, OS, and TTNT data will be presented. No new adverse events (AEs) were reported. Conclusion: Melflufen and dexamethasone resulted in sustained long-term benefits (median OS, 20.7 months) and no new AEs with 1.5 years of additional follow-up of patients with late-stage, heavily pretreated RRMM who have relapsed on conventional therapy including bortezomib and lenalidomide. Further trials are ongoing to evaluate efficacy and safety of melflufen, including the phase 3 study OCEAN (OP-103; NCT03151811) of melflufen plus dexamethasone versus pomalidomide plus dexamethasone in patients with RRMM refractory to lenalidomide. Figure Disclosures Bringhen: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Voorhees:Novartis: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TeneoBio: Consultancy, Research Funding; Amgen: Research Funding; GSK: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Plesner:AbbVie: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy; Janssen: Consultancy, Research Funding. Mellqvist:Amgen, Janssen, Oncopeptides, Sanofi, Sandoz, Takeda: Honoraria. Reeves:Celgene: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria. Byrne:Oncopeptides: Consultancy; Takeda: Consultancy. Nordström:Oncopeptides: Employment, Equity Ownership. Harmenberg:Oncopeptides: Consultancy, Equity Ownership. Obermüller:Oncopeptides: Employment. Richardson:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; 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, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a Phase 1/2 investigational study of melflufen in RRMM

Description: Background ARRY-520 is a novel KSP inhibitor with encouraging activity in patients (pts) with RRMM. In preclinical models, the activity of ARRY-520 is synergistic with BTZ, providing a rationale to combine these drugs in the clinic. Methods ARRAY-520-111 is a Phase 1 study to identify the maximum tolerated dose of ARRY-520, BTZ and dex. Eligible pts have RRMM with ≥ 2 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent. ARRY-520 is administered intravenously (IV) on Days 1, 2, 15 and 16 (Schedule 1) or on Days 1 and 15 (Schedule 2); BTZ is administered IV or subcutaneously (SC) on Days 1, 8 and 15; and 40 mg oral dex, if applicable, is taken on Days 1, 8 and 15 in a 28-day cycle. Results A total of 41 pts have been treated to date at various dose levels of ARRY-520 and BTZ. Patients had a median of 5 prior regimens (range 2-10). All pts received a prior PI, 39 pts received prior BTZ, and 25 pts received at least 2 prior PI- including regimens (range 1-6). In Schedule 1, the initial dose level of ARRY-520 (1.0 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was not tolerated, with dose-limiting toxicities (DLT) in 2/3 pts (pneumonia and pseudomonal sepsis). After a protocol amendment, dose escalation resumed at reduced doses of ARRY-520 (0.5 mg/m2/day) and BTZ (1.0 mg/m2/day) without dex. The addition of prophylactic filgrastim (G-CSF) enabled escalation to full dose ARRY-520 and BTZ (1.5 and 1.3 mg/m2/day, respectively). Only 1 DLT of pneumonia was observed during the further dose escalation, at 1.0 mg/m2/day ARRY-520 and 1.0 mg/m2/day BTZ. Dex has been added to the combination at 1.25 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ and this dose level has been well tolerated. Enrollment is ongoing in the final planned dose level. In Schedule 2, the initial dose level of ARRY-520 (2.25 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was well tolerated and enrollment is ongoing at 3.0 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ + dex, the maximum planned dose of both drugs. The most commonly reported adverse events (AEs) (in ≥ 15% of pts) include anemia, diarrhea, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, neutropenia, constipation, headache, fatigue, hyperuricemia, nausea, vomiting, and dizziness. All Grade 3 – 4 non-hematologic AEs have an incidence of 〈 10%. Based on the laboratory data, Grade 4 neutropenia was observed in 15% of patients, Grade 4 thrombocytopenia was observed in 10%. Apart from the one pt described above with the DLT of pseudomonal sepsis, no other febrile neutropenic events were reported. Neuropathy (Grade 2) was observed in 1 pt. Monopolar spindles have been observed in a post-dose biopsy for a pt treated at 1.0 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, indicating that pharmacodynamic activity of ARRY-520 is maintained in the presence of full dose BTZ. Preliminary signs of efficacy have been observed in this ongoing dose-escalation study. To date, among the subset of 13 evaluable pts who received doses at ≥ 1.25 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, 4 (31%) partial responses (PR) and 1 minimal response (MR) have been observed. By contrast, in the 27 patients receiving lower doses of ARRY-520 and BTZ, only 1 MR has been reported. An additional 29 pts experienced stable disease (SD) on ARRY-520 + weekly BTZ without the use of steroids (dex), including 17 pts with disease refractory to BTZ. Conclusions ARRY-520 + BTZ with prophylactic G-CSF appears well tolerated with manageable non-hematologic AEs in this heavily pretreated pt population and has demonstrated preliminary evidence of activity, including PRs and SD in pts with disease refractory to BTZ. These data support further exploration of this novel KSP inhibitor in combination with BTZ in expansion cohorts. The authors would like to acknowledge the dedicated research staff and physicians at the participating centers of the Multiple Myeloma Research Consortium for their contribution to this study. Disclosures: Chari: Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: ARRY-520 is an investigational drug being combined with bortezomib in multiple myeloma. Zonder:Celgene Corporation: Consultancy; Onyx: Consultancy; Skyline Diagnostics: Consultancy. Jakubowiak:Millenuim: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Janssen Cilag: 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, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Kaufman:Millenium: Consultancy; Merck: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy; Janssen: Consultancy.

Description: Background The availability of multiple immunomodulators (IMiDs) and proteasome inhibitors (PIs) has resulted in improved outcomes for patients (pts) with multiple myeloma (MM). Pts refractory to these 2 classes of drugs have a poor prognosis and new drugs with novel mechanisms of action are needed. ARRY-520, a potent, selective inhibitor of the novel drug target KSP, has shown single-agent activity in MM. The acute-phase protein AAG can bind ARRY-520, reducing free drug, possibly resulting in reduced treatment effect in pts with high AAG. Methods ARRAY-520-212 is a Phase 1/2 study. The Phase 2 portion was designed to evaluate the efficacy and safety of 1.5 mg/m2/day ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with filgrastim support. 2 Cohorts have been enrolled: Cohort 1 investigated single-agent ARRY-520 in pts with relapsed or refractory MM with ≥ 2 prior lines of therapy, including both bortezomib (BTZ) and an IMiD. Cohort 2 (cohort2) investigated ARRY-520 with Low-dose dexamethasone (LoDex -40mg weekly) in pts with RRMM with ≥ 2 prior lines of therapy, refractory (progression on or within 60 days of last treatment) to last line of therapy, and refractory to BTZ, lenalidomide (Len) and dexamethasone (triple-refractory). Pts intolerant to Len or BTZ were not included in cohort2. Baseline plasma AAG levels were measured in both cohorts. Results Results are summarized in the attached table. In cohort 1, 32 pts have been treated, with a median age of 65 years and a median of 6 prior regimens. 41% of cohort 1 pts were refractory to BTZ and Len. 6/27 pts (22%) had high baseline AAG. In cohort 2, 50 pts have been treated to date, with a median age of 63 years and a median of 9 prior regimens. As described in the table, cohort 2 pts had more prior treatment regimens, were primarily triple refractory and had a short time to progression (TTP) on prior therapy. 13/44 (30%) of cohort 2 pts had high baseline AAG. ARRY-520 showed a similar safety profile in both Cohorts. The most commonly reported (≥ 10% of pts) treatment-emergent Grade 3/4 adverse events, regardless of attribution, were thrombocytopenia (44% cohort 1, 42% cohort 2), anemia (38% and 50%), neutropenia (38% and 38%), fatigue (16% and 8%), leukopenia (13 and 4%) and pneumonia (3% and 12%). The incidence of febrile neutropenia was low in both cohorts (3% and 6%). ARRY-520 has shown activity both alone and with LoDex (See table). To date, in both cohorts, pts with High AAG have had no objective responses as compared to pts with Low AAG. In the completed cohort 1, ARRY-520 showed a durable 16% overall response rate (ORR) with an 8.6 month (mo) duration of response. In pts with Low AAG a prolonged OS (median = 23 mo) was observed compared to pts with High AAG (OS = 4.5 mo). Follow-up in cohort 2 is ongoing and ARRY-520+LoDex has shown a 16% ORR to date in this very heavily pretreated population. Notably in cohort 2, 4 PR were observed in the 16 patients (25%) who were previously treated with either a novel PI (carfilzomib or MLN9708) and/or IMiD (pomalidomide). Conclusions ARRY-520 is a novel first-in class agent in MM. In this Phase 2 analysis, ARRY-520 showed a similar activity and safety profile both alone and in combination with LoDex. While transient non-cumulative neutropenia is observed, the incidence of febrile neutropenia was low. ARRY-520 showed clear activity both alone and in combination with LoDex. Activity in pts refractory to novel PI and IMiDs suggests a lack of cross-resistance with drugs with existing mechanisms of action. High levels of AAG are associated with a lack of tumor responses and shorter OS following treatment with ARRY-520, suggesting AAG may be a potential patient selection marker identifying pts unlikely to benefit from ARRY-520. Disclosures: Lonial: Millennium: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy; Celgene Corporation: Consultancy. Off Label Use: ARRY-520 (Investigational Drug). Shah:Array BioPharma: 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; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Zonder:Celgene Corporation: Consultancy; Onyx: Consultancy; Skyline Diagnostics: Consultancy. Kaufman:Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Hilder:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Walker:Array BioPharma: Employment. Orlowski:Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Resverlogix: Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity’s Board of Directors or advisory committees.

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.