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691 Depth of Response to Daratumumab (DARA), Lenalidomide, Bortezomib, and Dexamethasone (RVd) Improves over Time in Patients (pts) with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Griffin Study UpdateClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Therapeutics Questions in Newly Diagnosed Myeloma
Hematology Disease Topics & Pathways:
Adult, antibodies, Biological, Diseases, multiple myeloma, Therapies, Study Population, Plasma Cell Disorders, Lymphoid Malignancies
Monday, December 9, 2019: 10:30 AM
Hall E1, Level 2 (Orange County Convention Center)

Peter M. Voorhees, MD1, Jonathan L. Kaufman, MD2, Jacob P. Laubach, MD3, Douglas W. Sborov, MD4, Brandi Reeves, MD5, Cesar Rodriguez, MD6, Ajai Chari, MD7*, Rebecca W. Silbermann, MD8, Luciano J. Costa, MD, PhD9,10, Larry D. Anderson, MD, PhD11, Nitya Nathwani, MD12, Nina D. Shah, MD13, Yvonne A. Efebera, MD, MPH14, Caitlin L. Costello, MD15, Andrzej Jakubowiak, MD, PhD16, Tanya M Wildes, MD, MSCI17, Robert Z. Orlowski, MD, PHD18*, Kenneth H. Shain, MD, PhD19, Andrew J. Cowan, MD20, Sean Murphy21*, Yana Lutska, PharmD21*, Huiling Pei, PhD22*, Jon Ukropec, PhD23, Jessica Vermeulen, MD, PhD24*, Carla de Boer24*, Daniela Hoehn, MD, PhD21, Thomas S. Lin, MD, PhD21 and Paul G. Richardson, MD3

1Levine Cancer Institute, Atrium Health, Charlotte, NC
2Winship Cancer Institute of Emory University, Atlanta, GA
3Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
4Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT
5University of North Carolina-Chapel Hill, Chapel Hill, NC
6Wake Forest University School of Medicine, Winston-Salem, NC
7Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY
8Knight Cancer Institute, Oregon Health & Science University, Portland, OR
9University of Alabama at Birmingham, Vestavia, AL
10O’ Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Vestavia, AL
11Department of Internal Medicine, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX
12Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, CA
13Department of Medicine, University of California, San Francisco, San Francisco, CA
14The Ohio State University Comprehensive Cancer Center, Columbus, OH
15Moores Cancer Center, University of California San Diego, La Jolla, CA
16University of Chicago Medical Center, Chicago, IL
17Washington University, Saint Louis, MO
18Department of Lymphoma-Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX
19Department of Malignant Hematology, Moffitt Cancer Center, Saint Petersburg, FL
20Division of Medical Oncology, University of Washington, Seattle, WA
21Janssen Scientific Affairs, LLC, Horsham, PA
22Janssen Research & Development, LLC, Titusville, NJ
23Janssen Global Medical Affairs, Horsham, PA
24Janssen Research & Development, LLC, Leiden, Netherlands

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: Takeda: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy; Novartis: Consultancy; GSK: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Adaptive Biotechnologies: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TeneBio: Honoraria, Research Funding. Kaufman: Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi/Genzyme: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tecnopharma: Consultancy, Honoraria. Sborov: Amgen: Consultancy; Janssen: Consultancy; Celgene: Honoraria. Reeves: Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Honoraria, Speakers Bureau. Rodriguez: Takeda, Amgen: Consultancy, Speakers Bureau. Chari: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: 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; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Karyopharm: Consultancy; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau. 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: Janssen: Research Funding; Carevive Systems: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. 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: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; AbbVie: Research Funding; Sanofi Genzyme: 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: Celgene: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: D-RVd is being investigated in transplant-eligible NDMM

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