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4557 Analysis of Transplant-Eligible Patients (Pts) Who Received Frontline Daratumumab (DARA)-Based Quadruplet Therapy for the Treatment of Newly Diagnosed Multiple Myeloma (NDMM) with High-Risk Cytogenetic Abnormalities (HRCA) in the Griffin and Master Studies

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Poster III
Hematology Disease Topics & Pathways:
Research, Biological therapies, Clinical Research, Diseases, Therapies, Lymphoid Malignancies, Study Population, Human
Monday, December 12, 2022, 6:00 PM-8:00 PM

Natalie Callander, MD1, Rebecca Silbermann, MD, MMS2, Jonathan L. Kaufman, MD3, Kelly N. Godby, MD4*, Jacob P Laubach, MD5*, Timothy Martin Schmidt, MD1, Douglas W Sborov6*, Eva Medvedova, MD2*, Brandi Reeves, MD7, Binod Dhakal, MBBS8, Cesar Rodriguez, MD9*, Saurabh Chhabra, MD, MS1, Ajai Chari10*, Susan Bal11*, Larry D. Anderson Jr., MD, PhD12, Bhagirathbhai Dholaria, MBBS13, Nitya Nathwani, MD14, Parameswaran Hari, MD, MRCP15, Nina Shah, MD16, Naresh Bumma, MD17, Sarah A. Holstein, MD, PhD18, Caitlin Costello, MD19, Andrzej Jakubowiak, MD, PhD20, Tanya M. Wildes, MD18*, Robert Z. Orlowski, MD, PhD21, Ken H. Shain, MD, PhD22, Andrew J. Cowan, MD23*, Huiling Pei, PhD24*, Annelore Cortoos, MD25*, Sharmila Patel, PhD25*, Thomas S. Lin, MD, PhD25, Smith Giri, MD, MHS26, Luciano J. Megala Costa, MD, PhD27, Paul G. Richardson, MD28, Saad Usmani, MD29 and Peter M. Voorhees, MD30*

1University of Wisconsin Carbone Cancer Center, Madison, WI
2Knight Cancer Institute, Oregon Health & Science University, Portland, OR
3Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
4Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham Hospital, Birmingham, AL
5Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
6University of Utah Huntsman Cancer Institute, Salt Lake City, UT
7University of North Carolina – Chapel Hill, Chapel Hill, NC
8Medical College of Wisconsin, Division of Hematology/Oncology, Department of Medicine, Milwaukee, WI
9Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
10Icahn School of Medicine at Mount Sinai, New York, NY
11University of Alabama at Birmingham Hospital, Birmingham, AL
12Myeloma, Waldenstrom’s and Amyloidosis Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX
13Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN
14Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, CA
15Medical College of Wisconsin, Milwaukee, WI
16University of California San Francisco, San Francisco, CA
17Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
18Division of Oncology & Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
19Moores Cancer Center, University of California San Diego, La Jolla, CA
20Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL
21Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX
22Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
23Division of Medical Oncology, University of Washington, Seattle, WA
24Janssen Research & Development, LLC, Titusville, NJ
25Janssen Scientific Affairs, LLC, Horsham, PA
26UAB School of Medicine Hematology & Oncology, Birmingham, AL
27University of Alabama at Birmingham Hospital, Vestavia, AL
28Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
29Memorial Sloan Kettering Cancer Center, New York, NY
30Levine Cancer Institute, Atrium Health Wake Forest Baptist, Charlotte, NC

Introduction: DARA as monotherapy and combination therapy is approved across lines of treatment for multiple myeloma. The single-arm phase 2 MASTER study (NCT03224507) evaluated DARA + carfilzomib/lenalidomide/dexamethasone (D-KRd), which demonstrated promising clinical efficacy in transplant-eligible NDMM. The primary endpoint analysis (median follow-up, 25.1 mo) showed that minimal residual disease (MRD) negativity at the 10–5 threshold was achieved by 80% of D-KRd pts (Costa, et al. JCO. 2021). The randomized phase 2 GRIFFIN study (NCT02874742) evaluated DARA + lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible NDMM; the primary endpoint analysis (median follow-up, 13.5 mo) showed that the rate of stringent complete response by the end of consolidation was significantly higher for D-RVd versus RVd (42.4% vs 32.0%; 1-sided P = 0.068, meeting the prespecified 1-sided α of 0.1) (Voorhees, et al. Blood. 2020). Here, we present an analysis of pts with HRCA, defined as having ≥1 genetic abnormality: del17p, t(4;14), t(14;16), t(14;20), and/or gain/amp1q (≥3 copies of chromosome 1q21) from MASTER (median follow-up, 31.1 mo) and GRIFFIN (median follow-up, 49.6 mo).

Methods: In MASTER, enrolled pts (no age limit with enrichment for high-risk disease) received 4 D-KRd induction cycles, autologous stem cell transplant (ASCT), and 0, 4 or 8 D-KRd consolidation cycles with treatment cessation upon achievement of 2 consecutive MRD-negative assessments, or lenalidomide (R) maintenance therapy if 2 consecutive MRD-negative assessments were not achieved. Pts received 28-day cycles of K (20/56 mg/m2 IV Days [D] 1, 8, 15), R (25 mg PO D1-21), d (40 mg PO or IV D1, 8, 15, and 22), and DARA (16 mg/kg IV: D1, 8, 15, and 22 for Cycles 1-2; D1 and 15 for Cycles 3-6; and D1 for Cycles 7+). In GRIFFIN, enrolled pts (age ≤70 years) were randomized 1:1 to receive 4 D-RVd/RVd induction cycles, ASCT, 2 D-RVd/RVd consolidation cycles, and up to 2 years of maintenance with R ± DARA. For induction/consolidation (21-day cycles), 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 PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4 and D1 of Cycles 5-6). During maintenance (28-day cycles), pts received R (10 mg PO D1-21; if tolerated, 15 mg Cycles 10+) ± DARA (16 mg/kg IV Q8W or Q4W, or 1800 mg SC Q4W per protocol amendments). Following completion of study therapy, pts could continue R maintenance per local standard of care. Before the randomized phase, a safety run-in was conducted to assess D-RVd dose-limiting toxicities.

Results: Among pts in MASTER (D-KRd, n = 123), 43% (n = 53) had standard risk (0 HRCA), 37% (n = 46) had high risk (1 HRCA), and 20% (n = 24) had ultra-high risk (≥2 HRCA) NDMM. Among 120 pts in GRIFFIN who received D-RVd (n = 104 randomized phase pts and n = 16 safety run-in pts), 56% (n = 67) had NDMM with 0 HRCA, 28% (n = 34) had 1 HRCA, 11% (n = 13) had ≥2 HRCA, and 5% (n = 6) were not evaluable. In an analysis of best response on study, rates of complete response or better (≥CR) for pts with 0, 1, and ≥2 HRCA were 91%, 89%, and 71% for D-KRd pts in MASTER, respectively, and 91%, 79%, and 62% for D-RVd pts in GRIFFIN. MRD-negativity rates at the 10–5 threshold were 80%, 86%, and 83% for D-KRd for pts with 0, 1, and ≥2 HRCA, respectively, and MRD-negativity rates at the 10–6 threshold were 68%, 80%, and 67%. For D-RVd pts, MRD-negativity rates at the 10–5 threshold were 76%, 56%, and 62% for pts with 0, 1, and ≥2 HRCA, respectively, and MRD-negativity rates at 10–6 were 45%, 26%, and 15%. MRD negativity (10‒5) with ≥CR occurred in 76%, 79%, and 67% of D-KRd pts with 0, 1, and ≥2 HRCA, respectively, and 75%, 53%, and 54% of D-RVd pts. In MASTER, 24-month progression-free survival (PFS) rates were 92%, 96%, and 66% for D-KRd pts with 0, 1, and ≥2 HRCA, respectively (Figure A). In GRIFFIN, 24-month PFS rates were 97%, 94%, and 64% for D-RVd pts with 0, 1, ≥2 HRCA, respectively, and 48-month PFS rates were 94%, 91%, and 54% (Figure B).

Conclusions: In MASTER and GRIFFIN, pts with NDMM and 0 HRCA or 1 HRCA who received DARA-based quadruplet therapy achieved high rates of ≥CR, MRD negativity, and 2-year PFS rates. These data support use of DARA-based quadruplet therapy as frontline treatment among pts with high cytogenetic risk. However, among pts with NDMM and ≥2 HRCA, results were not similar, and the subgroup was small suggesting that more research is needed for pts with the poor prognosis of ultra–high-risk disease.

Disclosures: Silbermann: Sanofi-Aventis: 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; Pfizer: Membership on an entity's Board of Directors or advisory committees. Kaufman: AbbVie, Genentech, and Bristol Myers Squibb: Consultancy; AbbVie: Other: Member of steering committee; Incyte: Other: Member of data safety monitoring committee . Laubach: Lignancies: Honoraria. Schmidt: Sanofi: Consultancy; Janssen: Consultancy. Sborov: GlaxoSmithKline, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Skyline Dx, Janssen, AbbVie, Sanofi: Consultancy; BMS: Consultancy. Reeves: Incyte, BMS, PharmaEssentia, CTI Biopharma: Honoraria; Hemostasis & Thrombosis Research Society Mentored Research Award sponsored by CSL Behring: Research Funding. Dhakal: BMS: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; Natera: Consultancy; Arcellx: Research Funding; Carsgen: Research Funding; Cartesian: Research Funding; Fate: Research Funding; Takeda: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Rodriguez: Janssen, BMS, Takeda, AbbVie, karyopharm, Artiva: Consultancy, Speakers Bureau. Chhabra: Sanofi: Research Funding; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Honoraria. Anderson: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dholaria: Vanderbilt University Medical Center: Current Employment; Gamida Cell: Consultancy; BEAM Therapeutics: Consultancy; Wugen: Research Funding; Angiocrine: Research Funding; Orca Bio: Research Funding; Arivan: Consultancy; Molecular Templates: Research Funding; MJH Biosciences: Honoraria; Janssen: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Poseida: Research Funding; Jazz Pharmaceuticals: Consultancy; BMS: Research Funding; MEI Pharma: Research Funding. Hari: Incyte: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy; AbbVie: Honoraria; GlaxoSmithKline: Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Millennium: Research Funding; Spectrum Pharmaceuticals: Research Funding; Iovance: Current Employment. Shah: GSK, Amgen, Indapta Therapeutics, Sanofi, CareDx, Kite, Karyopharm, Oncopeptides,: Consultancy; AstraZeneca: Current Employment, Current equity holder in publicly-traded company; Aztra Zeneca: Current Employment, Other: stock ownership; Celgene/BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar, Precision Biosciences: Research Funding. Bumma: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Ad Board; Sanofi, Genzyme: Other: Ad Board, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Holstein: GSK: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Secura Bio: Consultancy; Genentech: Consultancy. Costello: BMS, Takeda, Janssen, Pfizer: Consultancy, Honoraria, Research Funding. Jakubowiak: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wildes: Janssen: Consultancy; Carevive: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy. Orlowski: Abbvie, BioTheryX, Inc., Bristol-Myers Squibb, Janssen Biotech, Karyopharm Therapeutics, Inc., Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda Pharmaceutic: Honoraria, Membership on an entity's Board of Directors or advisory committees; Asylia Therapeutics, Inc.: Current equity holder in private company; CARsgen Therapeutics, Celgene/Bristol Myers Squibb, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Asylia Therapeutics, Inc., BioTheryX, Inc., Heidelberg Pharma, Inc.: Research Funding. Shain: Bristol Myers Squibb (BMS), Janssen, GlaxoSmithKline (GSK), Adaptive, Sanofi, and Takeda, and Amgen: Honoraria; GSK, Janssen and BMS: Membership on an entity's Board of Directors or advisory committees; GSK, BMS, Sanofi, Karyopharm, Takeda, Janssen, Adaptive and Amgen: Speakers Bureau; AbbVie and Karyopharm: Research Funding; Janssen and BMS: Other: PI of clinical trials. Cowan: Secura bio: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; EUSA: Consultancy; Allogene: Consultancy; AbbVie: Consultancy, Research Funding; Nektar: Research Funding; BMS: Consultancy, Research Funding; Sanofi-Aventis: Research Funding; Harpoon: Research Funding; Janssen: Consultancy, Research Funding. Pei: Janssen: Current Employment, Current equity holder in publicly-traded company. Cortoos: Janssen: Current Employment, Current equity holder in publicly-traded company. Patel: Companies of Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Lin: Janssen: Current Employment, Current holder of stock options in a privately-held company. Giri: OncLive: Honoraria; CareVive: Honoraria, Research Funding; Pack Health: Research Funding. Megala Costa: Adaptive Biotechnologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; AbbVie: Research Funding; Genentech: Research Funding. Richardson: Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; AstraZeneca: Consultancy; Protocol Intelligence: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding. Usmani: Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen Pharmaceuticals, Merck, Pharmacyclics, Sanofi, Seagen Inc., formerly Seattle Genetics, Inc., SkylineDX, Takeda: Consultancy; AbbVie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen Pharmaceuticals, Oncopeptides, Sanofi, Seagen Inc., formerly Seattle Genetics, Inc., Secura Bio, Inc., SkylineDX, Takeda, TeneoBio , Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen: Research Funding; Amgen, BMS, Janssen Pharmaceuticals, Sanofi: Speakers Bureau. Voorhees: Abbvie, Amgen, BMS, GSK, Karyopharm, Novartis, Oncopeptides, Pfizer, Sanofi, SecuraBio: Consultancy, Honoraria.

OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are

*signifies non-member of ASH