KarMMa-3: A Phase 3 Study of Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy Vs Standard Regimens in Relapsed and Refractory Multiple Myeloma

BACKGROUND: Patients with relapsed and refractory multiple myeloma (RRMM) who progress on immunomodulatory agents, proteasome inhibitors (PIs), and anti-CD38 antibodies have poor outcomes, highlighting the need for novel targets for the disease. The BCMA-directed CAR T cell therapy ide-cel previously demonstrated deep, durable responses in heavily pretreated patients with RRMM (Raje N, et al. N Engl J Med. 2019;380:1726-1737; Munshi NC, et al. J Clin Oncol. 2020;38[suppl] [abstract 8503]). In the pivotal phase 2 KarMMa study, overall response rate (ORR), complete response rate, and median duration of response (DOR) were 73%, 33%, and 10.7 months, respectively, across the target dose levels of 150−450 × 106 CAR+ T cells, and 82%, 39%, and 11.3 months at the highest target dose of 450 × 106 CAR+ T cells. In order to examine the effect of ide-cel as an earlier line of treatment, the multicenter, randomized, open-label, phase 3 study, KarMMa-3, was opened to compare ide-cel vs standard regimens in patients whose disease is refractory to the last line of therapy. STUDY DESIGN: Patients with RRMM who had received 2-4 prior regimens (including ≥ 2 consecutive cycles of daratumumab [DARA], an immunomodulatory agent, and a PI [individually or in combinations]) are randomized 2:1 to receive ide-cel or one of the following standard regimens based on the patient's most recent regimen and investigator discretion: DARA + pomalidomide (POM) + dexamethasone (DEX; DPd), DARA + bortezomib + DEX (DVd), ixazomib + lenalidomide + DEX (IRd), carfilzomib + DEX (Kd), or elotuzumab + POM + DEX (EPd). Patients in the standard-regimen arm of this study are eligible to receive ide-cel after confirmed evidence of progressive disease. Randomization is stratified by age (< 65 vs ≥ 65 years), number of prior regimens (2 vs 3 or 4), and high-risk cytogenetics (t(4;14), t(14;16), or del(17p); yes vs no). Patients must be ≥ 18 years of age, have Eastern Cooperative Oncology Group performance status of 0-1, have disease that is refractory to the last treatment regimen, and have achieved minimal or better response to ≥ 1 prior regimen. Patients with nonsecretory myeloma, central nervous system involvement, prior allogeneic stem cell transplant, prior BCMA-targeted therapy, or prior gene or cellular therapy for cancer are excluded. Ide-cel is manufactured following leukapheresis and then infused (at dose levels from 150 to 450 × 106, but targeting 450 × 106, CAR+ T cells) after 2 days of rest following lymphodepletion with 3 days of fludarabine 30 mg/m2 + cyclophosphamide 300 mg/m2. Up to 1 cycle of DPd, DVd, IRd, Kd, or EPd may be given as bridging therapy while ide-cel is being manufactured. The primary endpoint is progression-free survival. The key secondary endpoints are ORR and overall survival. Other secondary endpoints include minimal residual disease, DOR, safety, pharmacokinetics, and quality of life. Immunogenicity and biomarkers are exploratory endpoints. KarMMa-3 is registered at ClinicalTrials.gov: NCT03651128. Disclosures Delforge: Amgen, Celgene, Janssen, Takeda: Honoraria. Baz:Sanofi, Karypharm, Janssen, Celgene: Other: Advisory board; Karyopharm, janssen, Bristol Myers Squibb, Celgene, Merck, Sanofi, Abbvie Inc.: Research Funding. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, 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, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Ghobadi:Atara: Consultancy; Celegene: Consultancy; EUSA: Consultancy; Wugen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau. Rodriguez-Otero:GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Kite: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Mateos:Adaptive Biotechnologies: Honoraria; GlaxoSmithKline: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; EDO Mundipharma: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria. Massaro:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Ding:Bristol-Myers Squibb Company: Current Employment. Patel:BMS: Current Employment. Pittari:Bristol-Myers Squibb Company: Current Employment. Novick:Bristol-Myers Squibb Company: Current Employment. Giralt:OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; KITE: Consultancy; MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; TAKEDA: Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Research Funding. Berdeja:Bioclinica: Consultancy; CURIS: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Constellation: Research Funding; Abbvie: Research Funding; Glenmark: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Vivolux: Research Funding; EMD Sorono: Research Funding; Kesios: Research Funding; Kite Pharma: Consultancy; Legend: Consultancy; Lilly: Research Funding; Novartis: Research Funding; Poseida: Research Funding; Prothena: Consultancy; Teva: Research Funding; Bluebird: Research Funding; BMS: Consultancy, Research Funding; Cellularity: Research Funding; Genentech, Inc.: Research Funding; Servier: Consultancy; Amgen: Consultancy, Research Funding; Acetylon: Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy.