Abstract: Ibrutinib (IBRU) is an oral Bruton's tyrosine kinase (BTK) inhibitor, approved by US FDA for the treatment of chronic lymphocytic leukemia (CLL/SLL) and mantle cell lymphoma (MCL) patients having received at least one prior therapy. A nonlinear mixed-effects population model was developed to describe the PK of IBRU in patients with B-Cell malignancies and to establish the effect of pathophysiological covariates on its PK behavior. The relationship between PK and BTK engagement in peripheral blood mononuclear cells (PBMC) was also explored. IBRU PK data (3477 observations in 245 patients) were available in patients with MCL, CLL/SLL and recurrent B-cell malignancies at dose levels from 1.25 to 12.5 mg/kg and at fixed doses from 420 to 840 mg once daily. An additional phase 2 study in 119 patients with MCL (772 observations) treated at 560 mg once daily was used to validate the PK model. BTK occupancy was assessed (694 observations in 127 patients) in PBMCs using a fluorescent affinity probe. Various models were tested on the data using the first-order conditional estimation method as implemented in NONMEM version 7.1. A 2-compartment linear model with sequential zero-first order absorption and first order elimination was able to accommodate available PK data, including those of the validation dataset (prediction errors & lt;15%). PK was dose- and time- independent. IBRU was rapidly absorbed, extensively distributed (volume of distribution at steady-state ~ 10,000 L) and cleared (apparent oral clearance ~1000 L/h). Relative bioavailability in the fasting state was about one third lower compared to the fed condition used in the clinical trials. No significant effect of other pathophysiological covariates on the PK was found (including sex, age or indication) except for body weight and coadministration of antacids, which had a marginal effect on the volume of distribution and duration of absorption, respectively. Analysis of PK-BTK engagement suggested that IBRU is a potent inhibitor of the BTK activity and that its interaction with BTK is rapid and durable. Citation Format: Italo Poggesi, Maria Luisa Sardu, Eleonora Marostica, Juthamas Sukbuntherng, Betty Y. Chang, Jan de Jong, Xavier Woot de Trixhe, An Vermeulen, Giuseppe De Nicolao, Susan Mary O'Brien, John C Byrd, Ranjana H Advani, Danelle Frances James, William Deraedt, Darrin Beaupre, Michael Wang. Population pharmacokinetic-pharmacodynamic (PKPD) modeling of ibrutinib in patients with B-cell malignancies. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B19.

Abstract: Introduction: Treatment of myeloma-associated anemia (both disease and treatment induced) includes erythropoiesis-stimulating agents (ESA) and/or red-blood-cell transfusions (RBCT). Limited data from patient subsets in retrospective studies have suggested that ESA may have a detrimental effect on outcomes, including reduced time-to- progression (TTP) and overall survival (OS), in patients with multiple myeloma (MM). Furthermore, ESA may increase the risk of deep-vein thrombosis (DVT) and pulmonary embolism (PE), especially in patients receiving immunomodulatory-based regimens and/or anthracyclines with glucocorticoids. Since the impact of ESA use on long-term outcomes and thromboembolic events in MM has not been extensively evaluated, we conducted a sub-analysis of the prospective multi-center, randomized, phase III VISTA trial in frontline MM (San Miguel et al. Blood 2007), to assess the potential impact of ESA use on TTP, OS and rates of DVT/PE. Methods: Patients were randomized to receive nine 6-week cycles of bortezomib (1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1–4, and days 1, 8, 22, and 29, cycles 5–9) plus melphalan (9 mg/m2) and prednisone (60 mg/m2) administered on days 1–4 of each cycle (VMP; n=340) or melphalan–prednisone (MP; n=337) alone. No protocol-specified antithrombotic prophylaxis was required. Baseline characteristics, including age, sex and disease characteristics, were similar between ESA and non-ESA groups. Results: Median Hb level at the time of ESA initiation was 9.75 g/dl in the VMP arm and 9.30 g/dl in the MP arm; consistent with current guidelines that ESA should not be initiated until Hb is & lt;10 g/dl. The incidence of treatment-emergent anemia (defined as Hb & lt; 8.0 g/dl) was lower in the VMP arm (23%) than the MP arm (33%), and fewer patients in the VMP versus MP arm were treated with ESA (30% vs 39%, respectively; erythropoietins 20% vs 24% and darbepoietin 11% vs 18%, respectively), or RBCT (26% vs 35%, respectively), potentially reflecting greater anti-myeloma activity with VMP. Median TTP was similar between patients who received ESA and those who did not in both treatment groups (Table). While one-year OS rates were similar, 2-year OS rates appeared higher for patients receiving ESA (Table). TE complications were low in both treatment arms and were not affected by ESA use (3% vs 2% for VMP, and 3% vs 1% for MP, for patients receiving or not receiving ESA, respectively). Conclusions: Our post-hoc analysis from a large, well-controlled multicenter phase III trial in frontline MM shows that ESA use did not adversely impact long-term outcomes with VMP or MP, and may be associated with a survival benefit. Furthermore, ESA use did not appear to increase the risk of TE complications with VMP or MP. These data suggest that ESA can be safely administered with VMP/MP for the treatment of anemia in frontline MM patients. Prospective, randomized studies are needed to further investigate the relationship between ESA and RBCT use, other agents and long-term outcomes in MM patients. Table. TTP and OS rates by ESA and RBCT use and per treatment VMP (n=340) MP (n=337) + ESA (n=102) − ESA (n=238) + ESA (n=131) − ESA (n=206) NE=not evaluable TTP, months (95%CI) 19.9 (18.9, NE) NE (18.3, NE) 15.0 (13.5, 21.8) 17.5 (14.7, 19.0) 1-year survival rate % (95% CI) 92.0 (86.6, 97.3) 87.8 (83.5, 92.0) 82.6 (76.0, 89.2) 81.4 (75.9, 86.9) 2-year survival rate % (95% CI) 86.7 (77.9, 95.4) 80.8 (73.1, 88.4) 77.3 (68.5, 86.1) 65.4 (55.7, 75.2) + RBCT (n=87) − RBCT (n=253) + RBCT (n=117) − RBCT (n=220) TTP, months (95%CI) NE (24.0, NE) 21.7 (18.9, NE) 14.1 (10.8, 16.6) 18.0 (15.2, 20.0) 1-year survival rate % (95% CI) 80.9 (72.4, 89.3) 91.8 (88.4, 95.3) 71.0 (62.7, 79.4) 87.7 (83.2, 92.2) 2-year survival rate % (95% CI) 67.2 (50.4, 83.9) 88.3 (83.8, 92.8) 58.3 (47.4, 69.2) 76.1 (66.9, 85.3)

Abstract: Abstract 2933 Background: MM patients have a significantly increased risk of developing certain SPMs subsequent to their initial diagnosis, including a 3.49-fold increased risk of leukemia and, specifically, an 8.32-fold increased risk of acute non-lymphocytic leukemia (but no overall increased risk of solid tumor SPMs; Surveillance, Epidemiology and End Results [SEER] data 1973–2000). The relative SPM risk increases with age and time after initial diagnosis; the risk of leukemia rises from a 1.22-fold increase within 1 year after diagnosis to 3.12-fold, 7.01-fold, and 5.45-fold increases at 1–4, 5–9, and ≥10 years, respectively. An elevated risk of SPMs may be particularly associated with the use of specific therapeutic agents, including conventional or high-dose cytotoxic chemotherapy. Here we report an analysis of data from four phase 3, randomized, controlled trials of Btz alone or in combination to determine whether Btz treatment is associated with an increased SPM risk. Methods: Data were reviewed from: 1) the APEX study of Btz versus high-dose dexamethasone (Dex), and 2) the MMY-3001 study of Btz plus pegylated liposomal doxorubicin (PLD) versus Btz in patients with relapsed or refractory MM after 1–3 prior therapies; 3) the VISTA study of Btz plus melphalan-prednisone (VMP) versus MP in previously untreated transplant-ineligible patients; and 4) the HOVON65/GMMG-HD4 study of Btz, doxorubicin, and Dex (PAD) induction plus Btz maintenance post-transplant versus vincristine, doxorubicin, and Dex (VAD) induction plus thalidomide (Thal) maintenance in previously untreated transplant-eligible patients. Planned duration of Btz therapy was 39 weeks in APEX, 24 weeks in MMY-3001, 54 weeks in VISTA, and 9 weeks induction plus 2 years of maintenance in HOVON65/GMMG-HD4. For APEX, MMY-3001, and VISTA, clinical trial databases were reviewed for events within the MedDRA system organ class of ‘neoplasms’, and new malignancies developing during or after treatment were recorded (excluding non-melanomatous skin cancers and in situ malignancies). In addition, for VISTA, data were obtained from an SPM survey after a median follow-up of 5 years. For HOVON65/GMMG-HD4, data were prospectively collected; median follow-up was 42 months. The incidence rate (IR) of SPMs was expressed as the number per 100 patient-years (pt-yrs). Results: The risk of SPMs with Btz-based therapy appeared uniformly low across all four phase 3 studies in different MM patient populations (Table). A total of 25 SPMs were seen in 1718 Btz-treated patients, including three cases of acute myeloid leukemia/myelodysplastic syndromes, one B-cell malignancy, and one case of cutaneous T-cell lymphoma (in a patient with substantial prior alkylating agent exposure for treatment of MM), plus 20 reports of solid tumors (reflecting the higher overall incidence of these tumors). The IR ranged from 0 in the single-agent Btz arm of MMY-3001 to 1.66 with VMP in VISTA, with an IR of 0.88 in APEX and 0.3 in the PAD arm of HOVON65/GMMG-HD4; median age of Btz-treated patients was highest in VISTA, at 71 years. Overall rates (%) also appeared higher in VISTA, probably due to the longer follow-up and older population, plus the potential effects of concomitant chemotherapy. In the three studies with non-Btz control arms, the IR did not appear to be increased with Btz-based therapy versus the control arm, and across all Btz-containing arms in the four studies, the IRs for hematologic malignancies and solid tumors were consistent with SEER estimates (2004–2008 data) of the overall incidence of malignancies in the US population, of 1.1, 1.9, and 2.4 per 100 pt-yrs in individuals aged 55–64, 65–74, and 75–84 years, respectively. Conclusions: Btz-based therapy for MM does not appear to be associated with an increased risk of either hematologic or solid tumor SPMs, with IRs consistent with SEER data for IRs in the overall US population. Disclosures: San Miguel: Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc: Consultancy. Richardson:Celgene: Consultancy; Janssen Research & Development: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy. Orlowski:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Onyx: Consultancy; Cephalon: Consultancy; Centocor: Consultancy; Celgene: Consultancy, Research Funding. Goldschmidt:Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Satler:Millennium Pharmaceuticals, Inc.: Employment. Esseltine:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership; Johnson & Johnson: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Ponsillo:Millennium Pharmaceuticals, Inc.: Employment. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. King:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Deraedt:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Desai:Janssen Global Services: Employment; Johnson & Johnson: Equity Ownership. Lutska:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Gifkins:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Liu:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership.

Abstract: Introduction: VMP is a standard of care regimen for transplant-ineligible NDMM outside of the United States. The VISTA trial established the dosing schedule of bortezomib (V) in VMP to be administered IV twice weekly for four 6-week cycles, and then once weekly for five 6-week cycles (San-Miguel J, et al. N Engl J Med 2008. 359:906-917). To mitigate V-associated side effects (such as peripheral neuropathy) resulting from this intensive dosing schedule, subsequent trials utilized modified dosing schedules that reduced V-associated toxicity without sacrificing efficacy. Propensity score matching (PSM), which controls for differences in baseline covariates, have previously been used to compare outcomes for patients (pts) treated with modified VMP dosing schedules in previous trials and provided evidence of benefit for a lower-intensity V regimen vs VISTA VMP (Mateos MV, et al. Ann Hematol 2016. 95[12]:2033-2041). The phase 3 ALCYONE study of D-VMP vs VMP using a modified V dosing schedule in both arms significantly improved progression-free survival (PFS; HR 0.50 [95% CI, 0.38-0.65] , P 〈 0.001) and overall response rate (ORR; P 〈 0.001) with D-VMP in transplant-ineligible pts with NDMM (Mateos MV, et al. N Engl J Med 2018. 378:518-528). To compare efficacy and safety of D-VMP in ALCYONE vs VISTA VMP, a PSM analysis was conducted with comparable follow-up (16.5 months for ALCYONE vs 16.3 months for VISTA). Methods: This PSM analysis compared the D-VMP arm of ALCYONE vs the VMP arm of VISTA. In ALCYONE, pts in the D-VMP arm received up to nine 6-week cycles of VMP (V 1.3 mg/m2 SC twice weekly [Cycle 1] and then weekly [Cycles 2-9] ; M 9 mg/m2 PO during Days 1-4 [Cycles 1-9]; P 60 mg/m2 PO during Days 1-4 [Cycles 1-9] ) and D 16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ (post VMP-treatment phase). In VISTA, pts in the VMP arm received up to nine 6-week cycles of VMP (V 1.3 mg/m2 by IV twice weekly [Cycles 1-4] and then weekly [Cycles 5-9] ; M 9 mg/m2 PO on Days 1-4 [Cycles 1-9]; and P 60 mg/m2 PO on Days 1-4 [Cycles 1-9] ). Age, gender, renal function, International Staging System (ISS), type of MM (IgG, non-IgG), and ECOG performance score (converted from Karnofsky Performance Scores in VISTA) were identified as variables for matching. Propensity scores were estimated by logistic regression, in which the treatment group was regressed on matching variables. Data from the two groups (ALCYONE D-VMP and VISTA VMP) were matched on the logit of the propensity score. A greedy algorithm was used, in which once a match was made, the match was not reconsidered. The standardized difference was determined to assess the similarity of baseline covariates between treatment groups before and after matching. Differences between groups were compared using log-rank tests for PFS and time to progression (TTP). ORR and adverse event rates were analyzed on the basis of Cochran-Mantel-Haenszel Chi-square test. As disease progression for VISTA VMP was originally based on the EBMT criteria, PFS for VISTA VMP was re-defined based on IMWG criteria to allow for comparison with D-VMP. Results: A total of 350 D-VMP pts in ALCYONE and 344 VMP pts in VISTA were randomized in their respective studies. Pts were matched (281 pairs) on renal function, ISS, type of MM, and ECOG performance scores. After matching, systematic differences between the 2 treatment groups were substantially reduced or eliminated. After matching, median PFS for D-VMP was not reached (NR) vs 20.6 months for VISTA VMP, leading to an unadjusted HR of 0.52 (95% CI, 0.38-0.71; P 〈 0.0001; Figure); the adjusted PFS HR was 0.50 (95% CI, 0.36-0.68; P 〈 0.0001). Median TTP was NR vs 21.7 months (unadjusted HR, 0.43; 95% CI, 0.30-0.63; P 〈 0.0001; adjusted HR, 0.42; 95% CI, 0.29-0.61; P 〈 0.0001). Matched ORR was 90.8% for D-VMP vs 74.5% for VISTA VMP (P 〈 0.0001). Rate of peripheral sensory neuropathy was significantly lower with D-VMP vs VISTA VMP (27.8% vs 44.5%; P 〈 0.0001), in part due to the modified V dosing schedule and use of SC vs IV V (Moreau P, et al. Lancet Oncol 2011. 12:431-440). Conclusions: This PSM analysis demonstrates that ALCYONE D-VMP significantly improves efficacy compared to VISTA VMP. As reflected in the HRs, the improvement of efficacy is similar as seen within the ALCYONE study comparing D-VMP vs VMP using a modified V dosing schedule in both arms. In addition, this analysis also shows that D-VMP is associated with a lower incidence of peripheral sensory neuropathy compared to VISTA VMP. Disclosures Cavo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria. San-Miguel:Roche: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Mateos:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Deraedt:Janssen Research & Development, LLC: Employment. Lam:Janssen Global Services, LLC: Employment. Kampfenkel:Janssen Research & Development, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. He:Janssen global services: Employment.

Abstract: Introduction: Daratumumab is a human CD38 IgGκ monoclonal antibody that demonstrated significant activity and a manageable safety profile in combination with bortezomib and dexamethasone. In a randomized phase 3 study, daratumumab in combination with bortezomib and dexamethasone (DVd) significantly prolonged progression-free survival (PFS) versus bortezomib and dexamethasone alone (Vd) in a pre-specified interim analysis of patients (pts) with relapsed or refractory multiple myeloma (RRMM; Palumbo A. N Engl J Med 2016; in press). Herein, we examine subgroups from this study to compare the efficacy of DVd vs Vd in bortezomib-naive and bortezomib-experienced pt populations. In addition, the efficacy of DVd vs Vd in pts who were refractory to lenalidomide at last prior line of therapy was also evaluated. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of Vd (bortezomib: 1.3 mg/m2 SC on Days 1, 4, 8, 11; dexamethasone: 20 mg PO on Days 1, 2, 4, 5, 8, 9, 11, 12) with or without daratumumab (16 mg/kg IV qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Pts who were refractory to bortezomib were not eligible. The primary endpoint was PFS. Bone marrow aspirate samples that had been prepared with Ficoll were evaluated for minimal residual disease (MRD) using three different thresholds (10-4, 10-5, and 10-6) based on the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA, USA). Results: Median follow-up was 7.4 months. Among bortezomib-naive pts (DVd, n=89; Vd, n=83), PFS was significantly improved with DVd vs Vd (median: not reached [NR] vs 7.5 months; HR, 0.25; 95% CI, 0.13-0.47; P & lt;0.0001); estimated 12-month PFS rates were 72% vs 28%, respectively. ORR was 88% with DVd vs 70% with Vd (P=0.0040), with ≥very good partial response (VGPR) rates of 72% vs 42% (P & lt;0.0001), and ≥complete response (CR) rates of 30% vs 20% (P=0.1199), respectively. For pts who previously received a bortezomib-containing regimen (DVd, n=162; Vd, n=164), PFS was also significantly longer with DVd vs Vd (median: 12.3 vs 6.7 months; HR, 0.46; 95% CI, 0.32-0.66; P & lt;0.0001). Estimated 12-month PFS rates were 55% vs 27%, respectively. ORR was significantly higher with DVd vs Vd (80% vs 60%; P=0.0001), along with significantly higher rates of ≥VGPR (52% vs 22%; P & lt;0.0001) and ≥CR (13% vs 3%; P=0.0019). Among pts who were refractory to lenalidomide at the last prior line of therapy (DVd, n=45; Vd, n=60), PFS was significantly longer in DVd vs Vd (median: 10.3 vs 4.4 mo; HR, 0.37; 95% CI, 0.21-0.65; P=0.0004; Figure). Within this subgroup, ORR was significantly higher for DVd vs Vd (81% vs 50%; P=0.0021), and the same trends were observed for rates of ≥VGPR (54% vs 12%; P & lt;0.0001) and ≥CR (20% vs 5%; P=0.0261). Updated efficacy and safety data, including MRD analyses across different sensitivity thresholds (10-4, 10-5, and 10-6), will be presented at the meeting. Conclusions: These analyses confirm that addition of daratumumab to Vd significantly improves outcomes for RRMM pts regardless of prior treatment with bortezomib. Importantly, this treatment benefit of DVd vs Vd was maintained in pts who were refractory to lenalidomide at the last prior line of therapy. These data lend further support to adding daratumumab to a standard-of-care regimen in RRMM. Figure Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Figure. Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Disclosures Lentzsch: BMS: Consultancy; Foundation One: Consultancy; Celgene: Consultancy, Honoraria. Quach:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Ovilla:Janssen: Consultancy. Qi:Janssen: Employment. Deraedt:Janssen: Employment, Equity Ownership. Schecter:Janssen: Employment, Equity Ownership. Amin:Janssen: Employment. Qin:Janssen: Employment. Casneuf:Johnson & Johnson: Equity Ownership; Janssen R & D, Beerse, Belgium: Employment. Chiu:Janssen: Employment. Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R & D: Employment. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

Abstract: Introduction VMP is a standard of care (SOC) for transplant ineligible NDMM. Daratumumab (D), a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumor and multifaceted immunomodulatory mechanism of action significantly improves PFS and depth of response in combination with SOC in relapsed MM. Treatment-naïve pts may benefit greatly with the addition of D to SOC regimens. Here we report the results from the ALCYONE study, where D is added to VMP in transplant ineligible NDMM. Methods Pts ≥65 years or otherwise ineligible for high-dose chemotherapy with autologous stem cell transplantation were randomized 1:1 to VMP ± D and stratified by International Staging System (ISS [I, II, III]), region (Europe vs other) and age ( & lt;75 vs ≥75 years). All pts received up to a maximum of nine 6-week cycles of VMP. V: 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, 32 (Cycle 1) and Days 1, 8, 22, and 29 (Cycles 2-9); M: 9 mg/m2 PO and P: 60 mg/m2 PO on Days 1-4 (Cycles 1-9). In the D-VMP arm, D was given at 16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ (post VMP-treatment phase) until disease progression. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, minimal residual disease (MRD)-negativity rate (10-5 threshold, Adaptive clonoSEQ® Assay), overall survival (OS), and safety. Results Of 706 pts randomized (350 D-VMP; 356 VMP), median (range) age was 71 (40-93) years; 29.9% were ≥75 years; 46.3% were male. 74.9% of pts had ECOG scores ≥1, and 19.3%, 42.4%, and 38.4% were ISS stage I, II, and III, respectively. Of 616 pts evaluable for FISH/karyotyping cytogenetic analysis, 84.1% and 15.9% were standard and high risk (positive for del17p, t[14;16], t[4;14] ), respectively. At the timepoint of the prespecified analysis after 231 PFS events on 12 June 2017, pts had received a median (range) of 12 (1-24) vs 9 (1-9) treatment cycles for D-VMP vs VMP, respectively. 80% of pts in the D-VMP arm completed 9 treatment cycles of VMP vs 62% of pts in the VMP arm. Median (range) cumulative bortezomib doses were 46.9 (1.3-55.3) mg/m2 vs 42.2 (2.6-55.0) mg/m2 for D-VMP vs VMP, respectively. At a median follow-up of 16.5 months, the hazard ratio for PFS (D-VMP vs VMP) was 0.50 (95% confidence interval, 0.38-0.65, P & lt;0.0001), representing a 50% reduction in the risk of progression or death in pts treated with D-VMP (Figure). Median PFS was not reached vs 18.1 months for D-VMP vs VMP. The PFS treatment benefit of D-VMP vs VMP was consistent across all pre-specified subgroups, including age ≥75 years, ISS stage III, and high-risk cytogenetics. ORR (90.9% vs 73.9%), ≥VGPR (71.1% vs 49.7%), ≥CR (42.6% vs 24.4%) and MRD-negativity rate (22.3% vs 6.2%) were significantly higher for D-VMP vs VMP (all P & lt; 0.0001; Table). OS data were immature after 93 deaths (45 vs 48 deaths for D-VMP vs VMP). The most common (≥20%) all-grade treatment emergent adverse events (TEAE; D-VMP/VMP) were neutropenia (49.7%/52.5%), thrombocytopenia (48.8%/53.7%), anemia (28.0%/37.6%), peripheral sensory neuropathy (28.3%/34.2%), upper respiratory tract infection (26.3%/13.8%), diarrhea (23.7%/24.6%), pyrexia (23.1%/20.9%), and nausea (20.8%/21.5%). Most common (≥10%) grade 3/4 TEAEs (D-VMP/VMP) were neutropenia (39.9%/38.7%), thrombocytopenia (34.4%/37.6%), anemia (15.9%/19.8%), and pneumonia (11.3%/4.0%). Only 1 pt in each arm discontinued treatment due to pneumonia. The rates of grade 3/4 infections were 23.1% vs 14.7% and treatment discontinuations due to infections were 0.9% vs 1.4% for D-VMP vs VMP. D-associated infusion-related reactions (27.7%) mostly were grade 1/2 (grade 3/4, 4.3%/0.6%) and most (92.7%) occurred during the first infusion. Tumor lysis syndrome occurred in & lt;1% of pts in each arm. Second primary malignancy occurred in 2.3% vs 2.5% pts in D-VMP vs VMP. Conclusion The combination of D with VMP in transplant ineligible NDMM pts doubled the PFS (HR 0.50), which was driven by more pts achieving deep responses, including significantly higher ≥CR rate and tripling of the MRD-negativity rate. No new safety signals were observed when combining D with VMP. Three phase 3 studies have now demonstrated a consistent doubling of PFS and more than threefold increase in MRD-negativity rate when combining D with SOC regimens. These results support the use of a D-based combination, D-VMP, in transplant ineligible NDMM. Disclosures Mateos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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. Dimopoulos:Novartis: Consultancy, Honoraria; Genesis Pharma: Research Funding; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology. Cavo:Celgene:: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria. Suzuki:Bristol Myers Squibb: Honoraria; Novarltis: Honoraria; Celgene: Honoraria; Ono Pharmaceuticals: Honoraria; Fujimoto: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Jakubowiak:Amgen Inc., BMS, Celgene, Janssen, Karypharm, Millennium-Takeda, Sanofi, SkylineDX: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Chicago: Employment. Knop:Bristol-Myers Squibb Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Janssen Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees. Doyen:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lucio:Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Roche: Consultancy. Cook:Amgen: Honoraria, Other: Travel support; Takeda: Honoraria; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Janssen: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding. Garg:Janssen: Other: travel support, Research Funding, Speakers Bureau; Takeda: Other: travel support; Novartis: Other: travel support, Research Funding. Chiu:Janssen: Employment. Wang:Janssen: Employment. Carson:Janssen: Employment. Crist:Janssen: Employment. Deraedt:Janssen: Employment. Nguyen:Janssen: Employment. Qi:Janssen: Employment; Johnson & Johnson, LLC: Equity Ownership. San-Miguel:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Cilag: Consultancy; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Celgene: 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.