Introduction
A single ide-cel infusion showed significantly longer median progression-free survival (PFS) vs std regimens (13.3 vs 4.4 months [mo], HR 0.49, 95% CI 0.38-0.65, P < 0.001) with deep, durable responses in heavily pretreated TCE RRMM at an interim analysis (IA) of KarMMa-3 (NCT03651128); safety data were consistent with prior studies (Rodríguez-Otero et al. NEJM 2023). Ide-cel benefits were consistent across pts in high-risk subgroups and across 2-4 prior lines of therapy (Tx). Results of the preplanned final PFS analysis of KarMMa-3 with 12.3 mo additional follow-up are reported.
Methods
In the phase 3 KarMMa-3 trial, pts with RRMM who received 2-4 prior regimens, including an immunomodulatory agent, proteasome inhibitor, and daratumumab, and were refractory to last regimen were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd). In the ide-cel arm, pts could receive ≤ 1 cycle of optional bridging Tx for disease control. Pts in the std regimens arm could receive ide-cel after confirmed disease progression (PD). The primary endpoint was IRC-assessed PFS in the ITT population; final PFS was planned to be analyzed with ~289 events. Key secondary endpoints were IRC-assessed overall response rate (ORR) and overall survival (OS); other secondary endpoints included complete response rate (CRR), duration of response (DOR), minimal residual disease (MRD) status, time to next anti-myeloma Tx (TTNT; time from randomization to next anti-myeloma Tx [MTx]), event-free survival (EFS; time from randomization to first PD, next MTx or any-cause death, whichever is first), PFS2 (time from randomization to second objective PD or any-cause death, whichever is first), safety, and health-related quality of life (QOL).
Results
Of 386 randomized pts (ide-cel, n = 254; std regimens, n = 132), 225 received ide-cel and 126 received a std regimen. Baseline characteristics were generally balanced. Median follow-up from randomization to data cutoff (April 28, 2023) was 30.9 mo (range 12.7-47.8). Ide-cel significantly improved median PFS (95% CI) vs std regimens (13.8 [11.8-16.1] vs 4.4 [3.4-5.8] mo), representing a 51% reduced risk of PD or death (HR 0.49, 95% CI 0.38-0.63; Figure); 18 mo PFS rates were 41% vs 19%, respectively. Ide-cel significantly improved ORR vs std regimens (71% vs 42%) with deeper (CRR 44% vs 5%; ≥CR and MRD negative status [sensitivity level 10 -5], 22% vs 1%), more durable responses (median DOR 16.6 vs 9.7 mo; Table). PFS and ORR benefits of ide-cel vs std regimens were consistent with the IA. Interim OS will be included in the presentation. In pts who received ide-cel (n = 225) or a std regimen (n = 126), median PFS (95% CI) was 15.7 (12.5-18.9) vs 4.4 (3.4-5.8) mo, respectively. In the ITT population, median TTNT, EFS, and PFS2 were numerically longer with ide-cel vs std regimens. Median (range) TTNT was 20.9 (16.6-24.2) vs 7.0 (5.3-8.5) mo. Median (95% CI) EFS was 13.3 (11.3-15.7) vs 3.9 (3.0-5.3) mo. Median PFS2 (95% CI) was 23.5 (18.4-27.9) vs 16.7 (12.2-20.3) mo; ide-cel was next MTx in 70 (53%) pts in the std regimens arm. In the treated population, grade (gr) 3/4 infections occurred in 66/249 (27%) pts in the ide-cel arm vs 25/126 (20%) in the std regimens arm. In the ide-cel safety population, any gr cytokine release syndrome occurred in 197/225 (88%) pts, gr ≥ 3 in 11 (5%); median time to first onset was 1 d (1-14), median duration was 4 d (1-51). Any gr investigator-identified neurotoxicity occurred in 34/225 (15%) pts, gr ≥ 3 in 7 (3%); median time to onset was 3 d (range 1-317); median duration was 2.5 d (range 1-252). Ide-cel continued to demonstrate durable, clinically meaningful improvements in pt-reported outcomes, including symptoms, functioning, and QOL vs std regimens.
Conclusions
In this final PFS analysis of KarMMa-3, significantly longer PFS was maintained with ide-cel; PD or death risk reduced by 51%; responses were deeper and more durable vs std regimens. CRR with ide-cel increased since the IA, indicating a deepening response, but were unchanged with std regimens. A single ide-cel infusion vs continuous treatment with std regimens resulted in longer median TTNT and PFS2, indicating improved long-term disease control. The ide-cel safety profile was consistent with previous reports, with no parkinsonism or Guillain-Barré syndrome reported. These data continue to support use of ide-cel in pts with TCE RRMM.
Study support
2seventy bio and Celgene, a Bristol-Myers Squibb Company.
OffLabel Disclosure:
Rodríguez Otero:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Other: Honoraria for lectures; Amgen: Other: Honoraria for lectures; Roche: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures. Ailawadhi:AbbVie, Amgen, Ascentage, BMS, Cellectar, GSK, Janssen, Pharmacyclics, Sanofi: Research Funding; Beigene, BMS, Cellectar, GSK, Janssen, Pfizer, Regeneron, Sanofi, Takeda: Consultancy. Arnulf:Bristol Myers Squibb: Consultancy, Honoraria, Other: Meeting travel payments; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting travel payments; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting travel payments; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting travel payments; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting travel payments, Research Funding. Patel:Takeda: Consultancy; AbbVie; Allogene Therapeutics, Inc.; Arcellx; Bristol Myers Squibb/Celgene Corporation; Cellectis; Janssen Pharmaceuticals, Inc.; Nektar Therapeutic; Poseida Therapeutics; Precision BioSciences, Inc.; and Takeda Pharmaceuticals U.S.A., Inc.: Research Funding; AbbVie; Arcellx, AstraZeneca; Bristol Myers Squibb/Celgene Corporation; Caribou Science; Cellectis; Curio Bioscience; Genentech; Janssen Pharmaceuticals, Inc.; Karyopharm; Legend Biotech; Merck & Co., Inc.; Oncopeptides; Pfizer; Precision BioSciences: Consultancy. Cavo:Adaptive: Honoraria; Celgene/Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria; GlaxoSmithKline: Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria. 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Jagannath:Bristol Myers Squibb: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Caribou Biosciences: Consultancy; Takeda: Consultancy; Regeneron: Consultancy; DMC: Membership on an entity's Board of Directors or advisory committees; Mount Sinai Hospital: Current Employment. Raje:Immuneel: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: 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, Research Funding; Caribou Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; K36 Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. 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In the US, ide-cel is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. The current abstract presents data from the phase 3 KarMMa-3 trial of ide-cel vs standard regimens in patients with RRMM who had received two to four prior regimens and were refractory to the last regimen.
