Daratumumab Plus Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) in Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): A Subgroup Analysis of Griffin
Authors: Anderson Larry D. , Kaufman Jonathan L. , Laubach Jacob P. , Sborov Douglas W. , Reeves Brandi , Rodriguez Cesar , Chari Ajai , Silbermann Rebecca W. , Costa Luciano J. , Nathwani Nitya , Shah Nina , Bumma Naresh , Holstein Sarah A. , Costello Caitlin , Jakubowiak Andrzej , Wildes Tanya M. , Orlowski Robert Z. , Shain Kenneth H. , Cowan Andrew J. , Pei Huiling , Cortoos Annelore , Patel Sharmila , Bartlett J Blake , Vermeulen Jessica , Lin Thomas S. , Voorhees Peter M. , Richardson Paul G. 
Published: November 2021

Abstract
Introduction: Daratumumab (DARA) is approved across lines of therapy for multiple myeloma. In the primary analysis of the phase 2 GRIFFIN trial (NCT02874742) in pts with transplant-eligible NDMM (median follow-up, 13.5 mo), D-RVd improved the rate of stringent complete response (sCR) by the end of post-autologous stem cell transplant (ASCT) consolidation versus RVd (42.4% vs 32.0%; odds ratio [OR], 1.57; 95% CI, 0.87-2.82; 1-sided P=0.068) (Voorhees PM, et al. Blood. 2020). With longer follow-up (median, 27.4 mo) after 12 months of maintenance therapy, sCR rates deepened for D-RVd versus RVd (63.6% vs 47.4%, 2-sided P=0.0253), as did the rate of minimal residual disease (MRD; 10 -5) negativity (62.5% vs 27.2%, P&lt;0.0001) (Kaufman JL, et al. Blood. 2020). Here, we present an analysis among clinically relevant subgroups (age ≥65 years, International Staging System [ISS] stage III disease, and high cytogenetic risk [del17p, t(4;14), or t(14;16) abnormalities]) after 24 months of maintenance therapy (median follow-up, 38.6 mo).
Methods: Eligible pts with transplant-eligible NDMM were randomized 1:1 to D-RVd or RVd. Pts received 4 RVd or D-RVd induction cycles, high dose therapy, ASCT, 2 RVd or D-RVd consolidation cycles, and maintenance with lenalidomide (R) alone or with DARA (D-R) for 24 months. During induction and consolidation (21-day cycles), pts received R (25 mg PO on Days 1-14), bortezomib (1.3 mg/m 2 SC on Days 1, 4, 8, and 11), and dexamethasone (40 mg PO QW) ± DARA (16 mg/kg IV on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of 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, or Q4W per pt decision after Amendment 2) until disease progression or up to 24 months. The primary endpoint was sCR rate by the end of post-ASCT consolidation. Responses were assessed per International Myeloma Working Group criteria by a validated computer algorithm. Additional endpoints included progression-free survival (PFS) and MRD-negativity (10 -5) rate by next-generation sequencing.
Results: In total, 207 pts were randomized (D-RVd, n=104; RVd, n=103); each group had a similar number of pts with age ≥65 years (n=28; n=28), ISS stage III disease (n=14; n=14), or high cytogenetic risk (n=16; n=14). Among response-evaluable pts, the rate of sCR after 24 months of maintenance therapy was numerically higher for D-RVd versus RVd among pts ≥65 years (63.0% vs 40.7%, OR, 2.47, 95% CI, 0.83-7.39), but similar for D-RVd and RVd pts with ISS stage III disease (57.1% vs 61.5%, OR, 0.83, 95% CI, 0.18-3.88) and high cytogenetic risk (43.8% vs 38.5%, OR, 1.24, 95% CI, 0.28-5.53; Figure). MRD-negativity (10 -5) rates favored D-RVd versus RVd across all subgroups: ≥65 years (67.9% vs 17.9%), ISS stage III disease (71.4% vs 35.7%), and high cytogenetic risk (43.8% vs 28.6%; Figure). With 38.6 months median follow-up, median PFS was not reached (NR) for pts ≥65 years in either treatment group (6 pts progressed: D-RVd, n=1; RVd, n=5). Among pts with ISS stage III disease, median PFS was NR for D-RVd and 33.1 months for RVd (7 pts progressed: D-RVd, n=1; RVd, n=6). Among pts with high cytogenetic risk, median PFS was NR for D-RVd and 36.1 months for RVd (10 pts progressed: D-RVd, n=5; RVd, n=5; Figure). In pts ≥65 years, grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 88.9% of D-RVd pts and 77.8% of RVd pts; the most common (≥20%) were neutropenia (37.0%; 29.6%) and lymphopenia (25.9%; 11.1%). Serious TEAEs occurred in 55.6% and 40.7% of pts, respectively. TEAEs led to study treatment discontinuation in 33.3% of D-RVd pts and 25.9% of RVd pts. One death due to a TEAE (unrelated to study treatment) occurred in a D-RVd pt ≥65 years of age.
Conclusion: Subgroup analyses of pts in GRIFFIN show that the addition of DARA to RVd induction/consolidation and R maintenance, in conjunction with ASCT, may benefit clinically relevant subgroups. sCR rates were improved for D-RVd versus RVd in pts ≥65 years but not in pts with ISS stage III disease or high cytogenetic risk. Improved MRD-negativity rates were observed for D-RVd in all subgroups. Although immature and with limited pt numbers, PFS results also trended towards favoring D-RVd in these subgroups. Among pts ≥65 years, TEAEs and serious TEAEs were numerically higher for D-RVd. These results support the use of DARA in transplant-eligible NDMM pts among high-risk subgroups, although larger studies are needed.
Figure 1 Figure 1.

Disclosures
Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kaufman: Sutro, Takeda: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Janssen: Honoraria; Novartis: Research Funding; Heidelberg Pharma: Research Funding; Incyte, celgene: Consultancy; BMS: Consultancy, Research Funding; Amgen: Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Fortis Therapeutics: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Sborov: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; SkylineDx: Consultancy; Sanofi: Consultancy. Reeves: Pharma Essentia: Consultancy, Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Incyte Corporation: Honoraria. Rodriguez: Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Chari: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium/Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Silbermann: Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Costa: Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding. Shah: Janssen: Research Funding; Nektar: Research Funding; Kite: Consultancy; Karyopharm: Consultancy; Indapta Therapeutics: Consultancy; Bluebird Bio: Research Funding; BMS/Celgene: Research Funding; Amgen: Consultancy; CareDx: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; CSL Behring: Consultancy; GSK: Consultancy; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Teneobio: Research Funding. Bumma: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Holstein: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, GSK, Janssen, Secura Bio, Sorrento: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak: Celgene: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: 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; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Wildes: Carevive: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Shain: Sanofi Genzyme: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; Novartis Pharmaceuticals Corporation: Consultancy; GlaxoSmithLine, LLC: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Amgen Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cowan: BMS: Research Funding; Secura Bio: Consultancy; GSK: Consultancy; Harpoon: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Nektar: 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: Janssen: Current Employment. Bartlett: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Lin: Janssen: Current Employment. Voorhees: Amgen: 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; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson: AbbVie: Consultancy; Oncopeptides: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Regeneron: Consultancy; AstraZeneca: Consultancy; Secura Bio: Consultancy; Janssen: Consultancy; Protocol Intelligence: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

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