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3238 Daratumumab Plus Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) in Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): Final Analysis of Griffin Among Clinically Relevant Subgroups

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Poster II
Hematology Disease Topics & Pathways:
Research, Biological therapies, clinical trials, adult, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies, Monoclonal Antibody Therapy, Human, Study Population, Minimal Residual Disease
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Ajai Chari1*, Jonathan L. Kaufman, MD2, Jacob P Laubach, MD3*, Douglas W Sborov4*, Brandi Reeves, MD5, Cesar Rodriguez, MD6*, Rebecca Silbermann, MD, MMS7, Luciano J. Megala Costa, MD, PhD8, Larry D. Anderson Jr., MD, PhD9, Nitya Nathwani, MD10, Nina Shah, MD11, Naresh Bumma, MD12, Sarah A. Holstein, MD, PhD13, Caitlin Costello, MD14, Andrzej Jakubowiak, MD, PhD15, Tanya M. Wildes, MD13*, Robert Z. Orlowski, MD, PhD16, Kenneth H. Shain, MD, PhD17, Andrew J. Cowan, MD18*, Huiling Pei, PhD19*, Annelore Cortoos, MD20*, Sharmila Patel, PhD20*, Thomas S. Lin, MD, PhD20, Paul G. Richardson, MD21, Saad Usmani, MD22 and Peter M. Voorhees, MD23*

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

Introduction: Daratumumab (DARA) is approved across lines of therapy for multiple myeloma. In the primary analysis of the randomized phase 2 GRIFFIN trial (NCT02874742) (median follow-up, 13.5 mo), addition of DARA to RVd improved the stringent complete response (sCR) rate by end of post-autologous stem cell transplant (ASCT) consolidation (D-RVd, 42.4% vs RVd, 32.0%; odds ratio [OR], 1.57; 95% CI, 0.87-2.82; 1-sided P = 0.068, which met the pre-specified 1-sided α of 0.1) (Voorhees PM, et al. Blood. 2020). Here, we present an end-of-study post hoc analysis of clinically relevant subgroups in GRIFFIN (≥65 years; International Staging System [ISS] stage III disease; high cytogenetic risk [defined as ≥1 of the following: del17p, t(4;14), or t(14;16)]; revised high cytogenetic risk [defined as ≥1 of the following high-risk chromosomal abnormalities (HRCA): del17p, t(4;14), t(14;16), t(14;20) or gain/amp1q (≥3 copies of chromosome 1q21)]; gain/amp1q; 1 HRCA (per the revised definition); gain/amp1q plus 1 HRCA; and ≥2 HRCA). The final analysis of GRIFFIN (median follow-up, 49.6 mo) occurred after all pts completed ≥1 year of long-term follow-up after completion of study treatment, discontinued, or withdrew.

Methods: In GRIFFIN, pts with transplant-eligible NDMM were randomized 1:1 to D-RVd or RVd. All pts received 4 D-RVd/RVd induction cycles, ASCT, 2 D-RVd/RVd consolidation cycles, and maintenance with lenalidomide (R) ± DARA for 24 months. All pts received 21-day cycles of R (25 mg PO on Days [D] 1-14), bortezomib (1.3 mg/m2 SC on D1, 4, 8, 11), and dexamethasone (40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4 and D1 in Cycles 5-6). During maintenance (Cycles 7-32; 28-day cycles), pts received R (10 mg PO on Days 1-21; if tolerated, 15 mg in Cycles 10+) ± DARA (16 mg/kg IV Q8W/Q4W or 1800 mg SC Q4W per protocol amendments). The primary endpoint was the sCR rate by end of consolidation.

Results: 207 pts were randomized (D-RVd, n = 104; RVd, n = 103); each subgroup had a similar number of pts per arm: ≥65 years (n = 28; n = 28), ISS stage III disease (n = 14; n = 14), high cytogenetic risk (n = 16; n = 14), revised high cytogenetic risk (n = 42; n = 37), gain/amp1q (n = 34; n = 28), 1 HRCA (n = 32; n = 29), gain/amp1q plus 1 HRCA (n = 9; n = 6), and ≥2 HRCA (n = 10; n = 8). Outcomes for pts with baseline extramedullary plasmacytomas (D-RVd, n = 1; RVd, n = 2) were explored but not included due to small pt numbers. Among response-evaluable pts, the rate of sCR at the end of maintenance therapy was numerically higher for D-RVd versus RVd among pts with age ≥65 years (63.0% vs 40.7%; OR, 2.47; 95% CI, 0.83-7.39), high cytogenetic risk (50.0% vs 38.5%; OR, 1.60; 95% CI, 0.36-7.07), gain/amp1q plus 1 HRCA (55.6% vs 33.3%; OR, 2.50; 95% CI; 0.29-21.40), and ≥2 HRCA (50.0% vs 37.5%; OR, 1.67; 95% CI, 0.25-11.07), but similar for D-RVd and RVd pts with ISS stage III disease (64.3% vs 61.5%; OR, 1.13; 95% CI, 0.24-5.37), revised high cytogenetic risk (56.1% vs 55.6%; OR, 1.02; 95% CI, 0.42-2.52), gain/amp1q (57.6% vs 57.1%; OR, 1.02; 95% CI, 0.37-2.82), and 1 HRCA (58.1% vs 60.7%; OR, 0.90; 95% CI, 0.32-2.54). MRD-negativity (10–5) rates at the end of maintenance favored D-RVd over RVd across all subgroups (Figure A). At 49.6 months of median follow-up, PFS rates among subgroups favored D-RVd over RVd except for pts with ≥2 HRCA (Figure B).

In pts ≥65 years, grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 88.9% of D-RVd and 77.8% of RVd pts; the most common grade 3/4 TEAEs (≥20%) were neutropenia (D-RVd, 37.0%; RVd, 29.6%) and lymphopenia (25.9%; 11.1%). TEAEs led to study treatment discontinuation in 37.0% of D-RVd and 25.9% of RVd pts. In pts ≥65 years, death as outcome of a TEAE occurred in 1 D-RVd pt (pneumonia; unrelated to study treatment).

Conclusions: In this final analysis of GRIFFIN by clinically relevant subgroups, addition of DARA to RVd induction/consolidation and R maintenance, with ASCT, was associated with higher MRD-negativity (10–5) rates for all subgroups and PFS estimates favored all high-risk groups except pts with ≥2 HRCA. Among pts ≥65 years, the rates of grade 3/4 TEAEs and TEAEs leading to study treatment discontinuation were slightly higher for the D-RVd group, although only 1 pt died due to a TEAE unrelated to study treatment. Results of this subgroup analysis support the use of DARA in transplant-eligible pts with NDMM among both clinically and cytogenetic high-risk subgroups, although larger studies are needed, especially in pts with ≥2 HRCA.

Disclosures: Kaufman: AbbVie: Other: Member of steering committee; AbbVie, Genentech, and Bristol Myers Squibb: Consultancy; Incyte: Other: Member of data safety monitoring committee . Laubach: Lignancies: Honoraria. 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. Rodriguez: Janssen, BMS, Takeda, AbbVie, karyopharm, Artiva: Consultancy, Speakers Bureau. 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. Megala Costa: Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; AbbVie: Research Funding; Genentech: Research Funding. Anderson: 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; Karyopharm: 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; Pharmacyclics: 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; Sanofi: 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; AbbVie: 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. 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: Sanofi, Genzyme: Other: Ad Board, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Ad Board; Amgen: Consultancy, Speakers Bureau. Holstein: Genentech: Consultancy; Janssen: Consultancy, Research Funding; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Sanofi: 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; Sanofi: Consultancy; Seattle Genetics: Consultancy; Carevive: 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; 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; Asylia Therapeutics, Inc.: Current equity holder in private company. Shain: Janssen,BMS: Other: PI of clinical trials; AbbVie, Karyopharm: Research Funding; GSK, Janssen and BMS and speaker’s bureau for GSK, BMS, Sanofi, Karyopharm, Takeda, Janssen, Adaptive and Amgen: Other: Advisory Committee; Bristol Myers Squibb (BMS), Janssen, GlaxoSmithKline (GSK), Adaptive, Sanofi, and Takeda, and Amgen: Honoraria. 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. Richardson: Sanofi: Consultancy; Regeneron: Consultancy; AstraZeneca: Consultancy; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Abbvie: Consultancy; Secura Bio: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding. Usmani: 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, Array Biopharma, BMS, Celgene, GSK, Janssen Pharmaceuticals, Merck, Pharmacyclics, Sanofi, Seagen Inc., formerly Seattle Genetics, Inc., SkylineDX, Takeda: Consultancy; 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