Introduction
Patients (pts) with multiple myeloma (MM) have a higher risk of progression/death following an inadequate response to frontline ASCT (van de Velde Eur J Haematol 2017). Therapies (Tx) with novel mechanisms of action may further improve response outcomes. Ide-cel previously demonstrated frequent, deep, and durable responses in KarMMa (Munshi N Engl J Med 2021) and significantly improved median progression-free survival (PFS) and overall response rate (ORR) versus standard regimens in KarMMa-3 (Rodríguez-Otero N Engl J Med 2023) in pts with triple-class-exposed relapsed and refractory MM. KarMMa-2 (NCT03601078) is a multicohort, phase 2, multicenter trial evaluating the efficacy and safety of ide-cel in pts with MM; cohort 2c included pts with NDMM who had an inadequate response to frontline Tx with ASCT. In cohort 2c, with a median follow-up of 27.9 months, ide-cel demonstrated deep and durable responses; complete response (CR) rate was 74.2% (ORR, 87.1%), with a 24-month PFS rate of 83.1% (Dhodapkar Blood 2022). Here, we report results with an additional 11.5 months of median follow-up for updated efficacy and safety data, and health-related quality of life (HRQoL) outcomes in cohort 2c.
Methods
Eligible pts had NDMM, received ≥ 3 cycles of induction Tx (including a proteasome inhibitor, an immunomodulatory agent, and dexamethasone), had < very good partial response (VGPR) 70-110 days after ASCT (single/tandem), and had Eastern Cooperative Oncology Group performance status ≤ 1. Pts received a single infusion of ide-cel (dose range: 150-450 × 10 6 CAR+ T cells) after lymphodepletion and could receive maintenance Tx post-infusion at investigator's discretion. The primary endpoint CR rate and secondary endpoints ORR, duration of response (DOR), PFS, overall survival (OS), safety, and patient-reported outcomes on HRQoL, assessed via European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) and EORTC Quality of Life Multiple Myeloma Module 20 Questionnaire (QLQ-MY20), are reported. The exploratory endpoint of minimal residual disease (MRD) negativity (sensitivity, 10 -5) is also reported.
Results
At data cutoff (May 3, 2023), with a median follow-up of 39.4 (range, 31.6-44.7) months, all 31 pts who were infused with ide-cel were alive; 28 (90.3%) remained in follow-up, with 3 (9.7%) having discontinued due to disease progression. The ORR and CR rates were 87.1% and 77.4%, respectively ( Table); best overall response in 1 pt improved from VGPR to stringent CR. The median DOR was not reached (NR; 95% CI, NR-NR), neither was median PFS (95% CI, 38.0-NR) or median OS (95% CI, NR-NR); the 36-month event-free rates were 80.9%, 76.8%, and 100.0%, respectively. In pts who did not receive lenalidomide (LEN) maintenance, 9 (29.0%) had disease progression; of the 8 pts who received LEN maintenance post ide-cel infusion, none experienced disease progression. At 36 months, MRD negativity was confirmed in 9/14 (64.3%) evaluable pts; all 9 achieved ≥ CR.
In this extended follow-up, safety results were generally consistent with the previous data cutoff. All pts experienced ≥ 1 any-grade adverse event (AE), most commonly hematologic, including neutropenia (80.6%), anemia (38.7%), leukopenia (32.3%), and thrombocytopenia (29.0%); infection and infestation AEs occurred in 74.2% of pts. No grade 5 AEs were reported. Incidence of any-grade cytokine release syndrome (58.1%; no grade ≥ 3) was unchanged and there were no additional reports of parkinsonism since the previous report.
Overall, HRQoL improved ( Figure) and MM disease symptoms were stable over time based on the EORTC QLQ-C30 and QLQ-MY20, respectively, following ide-cel treatment; by month 3, > 75% of pts had improved or stable global health status/QoL.
Conclusions
Ide-cel continued to demonstrate deep, durable responses in pts with an inadequate response to frontline ASCT, no new safety signals were observed with extended follow-up, and no deaths were reported. No pts who received LEN maintenance post ide-cel experienced disease progression. Ide-cel treatment resulted in stable or improved HRQoL. Overall, ide-cel continued to demonstrate a favorable clinical benefit-risk profile in NDMM after ASCT.
Study support
2seventy bio and Celgene, a Bristol-Myers Squibb Company.
OffLabel Disclosure:
Dhodapkar:Sanofi: Membership on an entity's Board of Directors or advisory committees; Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Alsina:Janssen Oncology: Consultancy, Speakers Bureau; Genzyme: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Research Funding; RevHealth LLC, Red Med LLC: Honoraria. Berdeja:2seventy bio: Consultancy, Research Funding; Acetylon: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Research Funding; Poseida: Research Funding; Novartis: Research Funding; Lilly: Research Funding; Legend Biotech: Consultancy; Kite Pharma: Consultancy; Karyopharm: Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Incyte: Research Funding; Ichnos Sciences: Research Funding; GSK: Research Funding; Genentech: Research Funding; Fate Therapeutics: Research Funding; EMD Serono: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Celularity: Research Funding; Cartesian: Research Funding; CARsgen: Research Funding; C4 Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Roche: Consultancy; Teva: Research Funding. Patel: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; Takeda: Consultancy; 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. Richard:Bristol Myers Squibb: Honoraria; C4 Therapeutics: Research Funding; Heidelberg Pharma: Research Funding; Janssen: Honoraria. Vij:Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Harpoon: Honoraria; Karyopharm: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria, Research Funding; Legend: Honoraria. Leleu:Takeda: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Merck: Honoraria; AbbVie: Honoraria; Harpoon Therapeutics: Honoraria; BMS/Celgene: Honoraria. Bergsagel:CellCentric: Consultancy; Salarius: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Aptitude Health: Honoraria; Novartis: Patents & Royalties: Royalty for hCRBN mice; Mayo Clinic: Patents & Royalties: Royalty for hCRBN and Vk*MYC mice; Radmetrix: Consultancy; Omeros: Consultancy. Reshef:Gilead Sciences: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Atara Biotherapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding; Synthekine: Consultancy, Research Funding; Orca: Consultancy; MidaTech: Consultancy; Capstan: Consultancy; Jasper: Consultancy; J&J: Research Funding; Precision Biosciences: Research Funding; Bayer: Consultancy; Regeneron: Consultancy; TScan: Consultancy, Research Funding; CareDx: Research Funding; Instil Bio: Consultancy; Allogene: Consultancy; Quell Biotherapeutics: Consultancy; Sanofi: Research Funding; Immatics: Research Funding; TCR2: Research Funding. Usmani:Novartis: Membership on an entity's Board of Directors or advisory committees; EdoPharma: Membership on an entity's Board of Directors or advisory committees; K36 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; TeneoBio: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; SkylineDX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Research Funding; SecuraBio: 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; GSK: 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, Research Funding; Sanofi: 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; Moderna: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truppel-Hartmann:2seventy bio: Current Employment. Basudhar:Bristol Myers Squibb, IOCT-TRC: Current Employment. Thompson:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zheng:Bristol Myers Squibb: Current Employment; Janssen: Ended employment in the past 24 months. Eliason:GlaxoSmith-Kline: Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zhong:Bristol Myers Squibb: Current Employment. Greggio:Bristol Myers Squibb: Current Employment. Tran:Bristol Myers Squibb: Current Employment. Chaudhry:Bristol Myers Squibb: Current Employment. Carrasco-Alfonso:Bristol Myers Squibb: Current Employment; Kyverna Therapeutics: Ended employment in the past 24 months; Achilles Therapeutics: Other: Holder of stock options in a privately-held company in the past 36 months. Siegel:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celularity Scientific: Consultancy, 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, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
Ide-cel is currently approved for the treatment of patients with relapsed/refractory multiple myeloma who have received 3 or more prior treatments. Here, ide-cel efficacy and safety was explored in the newly diagnosed setting (inadequate response to frontline ASCT) in a phase 2 clinical trial.
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