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3110 Daratumumab (DARA) in Combination with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) in Patients with Newly Diagnosed Multiple Myeloma (MMY1001): Updated Results from an Open-Label, Phase 1b Study

Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Sunday, December 10, 2017, 6:00 PM-8:00 PM
Bldg A, Lvl 1, Hall A2 (Georgia World Congress Center)

Ajai Chari1*, Saad Z Usmani, MD2, Amrita Krishnan, MD3, Sagar Lonial, MD4, Raymond Comenzo5*, Kaida Wu6, Jianping Wang7*, Parul Doshi6*, Brendan M Weiss, MD8, Jordan Schecter7* and Andrzej J. Jakubowiak, MD9

1Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY
2Levine Cancer Institute/Carolinas HealthCare System, Charlotte, NC
3Judy and Bernard Briskin Myeloma Center, City of Hope, Duarte, CA
4Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
5Division of Hematology/Oncology, John C. Davis Myeloma and Amyloid Program, Tufts Medical Center, Boston, MA
6Janssen R&D, Spring House, PA
7Janssen Research & Development, LLC, Raritan, NJ
8Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
9Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL

Introduction: Standard of care treatments for patients (pts) with newly diagnosed multiple myeloma (NDMM) include triplet regimens containing a proteasome inhibitor (PI) or an immunomodulatory drug (IMiD), with or without autologous stem cell transplant (ASCT). Among triplets, extended treatment with KRd has emerged as a highly active combination in NDMM (Jakubowiak AJ, et al. Blood, 2012;120[9]:1801-1809). As multiple myeloma progresses, the depth and duration of clinical response is reduced with each treatment relapse, making it critical for front-line therapy to drive pts to deep and sustained clinical responses. Daratumumab (DARA) is a human IgGκ monoclonal antibody (mAb) targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action. DARA induces rapid, deep, and durable responses in combination with dexamethasone and either bortezomib or an IMiD (lenalidomide or pomalidomide) in pts with relapsed/refractory MM (RRMM; Palumbo A, et al. NEJM. 2016 375[8]:754-766; Dimopoulos MA, et al. NEJM. 2016 375[14]:1319-1331; Chari A, et al. Blood. 2017; epub, ahead of print). This open-label, multicenter, phase 1b study investigated the safety profile and efficacy of DARA in combination with KRd in NDMM.

Methods: Pts with NDMM were enrolled regardless of transplant eligibility, and had no evidence of clinically significant cardiac disease. Pts received a split first-dose of daratumumab (8 mg/kg on Days 1 and 2 of Cycle 1) and received 16 mg/kg weekly for the remainder of Cycles 1 and 2, every 2 weeks on Cycles 3-6, and every 4 weeks thereafter. Carfilzomib (K) 20 mg/m2 was administered on Cycle 1 Day 1 and escalated to 70 mg/m2 on Cycle 1 Day 8, and was administered weekly on Days 1, 8, and 15 of each cycle. Pts received lenalidomide 25 mg on Days 1-21 of each cycle and dexamethasone at a dose of 40 mg/week. Pts were treated for ≤13 treatment cycles or until elective discontinuation for ASCT. Primary endpoints included safety and tolerability; overall response rate (ORR), duration of response, time to response, infusion-related reactions (IRR), and progression-free survival (PFS) were also examined. For DARA interference on serum immunofixation (IFE), a second reflex assay using an anti-idiotype mAb was used to confirm DARA migration on the IFE.

Results: Among the 22 pts enrolled in the study, the median (range) age was 59.5 (34-74) years and 95% of pts had an ECOG score ≤1. After median (range) duration of follow-up of 13.1 (6.6-14.9) months, pts received a median (range) of 12 (1-13) treatment cycles. Treatment discontinuations were due to elective ASCT (n = 6), adverse events (AE; n = 1), and progressive disease (n = 1).

At the clinical cutoff date of June 16, 2017, the most common (>10%) grade 3/4 treatment emergent AEs (TEAEs) included lymphopenia (14 [64%]), neutropenia (4 [18%]), diarrhea (4 [18%]), and pulmonary embolism (3 [14%]). Serious TEAEs occurred in 10 (46%) pts, with pulmonary embolism being the most common (3 [14%]). A transient grade 3 cardiac failure was reported in 1 pt who resumed treatment on Cycle 2 Day 1 with a reduced K dose (56 mg/m2). IRRs (all grade 1 or 2) were reported in 27% of pts and occurred primarily during the first infusion. Median left ventricular ejection fraction did not change over time from baseline (Table).

21 response-evaluable pts achieved an ORR of 100%, including 43% stringent complete response (sCR), 14% complete response (CR), 33% very good partial response (VGPR), and 10% partial response (PR); responses deepened with treatment duration (Figure). Responses among 15 pts who did not undergo ASCT were as follows: 40% sCR, 20% CR, 27% VGPR, 13% PR. At the time of follow-up, all pts were alive and the 12-month PFS rate was 95% (95% confidence interval, 70-99). CD34+ cell collection yields were consistent with previous KRd studies (median, 10.6 x 106 cells/kg) and 15/20 eligible pts had a response of ≥VGPR prior to stem cell harvest. Among the 20 eligible pts, median (range) number of cycles received prior to stem cell harvest was 5 (4-9).

Updated safety and efficacy data will be presented.

Conclusion: DARA+KRd, with weekly K dosing, is well tolerated in pts with NDMM and demonstrates a safety profile consistent with previous reports of DARA and KRd. High response rates were observed with DARA+KRd and the depth of response improved with treatment duration. No adverse impact on stem cell collection was observed. These data support further investigation of DARA+KRd in NDMM.

Disclosures: Chari: Array BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: 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, Other: Travel, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Biotest: Other: Research funding (to AC's institution); Onyx: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Pharmacyclics: Research Funding; Bristol-Myers Squibb: Consultancy, Other: Research funding (to AC's institution); travel; Acetylon Pharmaceuticals: Other: Research funding (to AC's institution). Usmani: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Speakers Bureau; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Speakers Bureau. Krishnan: Janssen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau; Onyx: Speakers Bureau; Sutro: Consultancy. Comenzo: Janssen, Prothena, Takeda, Karyopharm: Research Funding; Janssen, Prothena: Consultancy, Research Funding. Wu: Janssen: Employment. Wang: Janssen: Employment. Doshi: Janssen: Employment. Weiss: Prothena: Honoraria; Janssen: Honoraria; Prothena: Research Funding; Alnylam: Honoraria; Janssen: Research Funding. Schecter: Janssen: Employment. Jakubowiak: University of Chicago: Employment; 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.

*signifies non-member of ASH