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Moving BCMA CAR-T to the second line cut the risk of progression or death by 74% compared with standard triplets, and later improved overall survival.
CARTITUDE-4 randomised 419 patients with lenalidomide-refractory multiple myeloma after one to three prior lines to a single infusion of ciltacabtagene autoleucel (after bridging therapy) or standard of care (pomalidomide-bortezomib-dexamethasone or daratumumab-pomalidomide-dexamethasone). The primary endpoint was PFS by intention to treat. At 12 months PFS was 75.9% versus 48.6% (hazard ratio 0.26); overall response was 84.6% versus 67.3%, complete response or better 73.1% versus 21.8%, and MRD-negativity 60.6% versus 15.6%. In later follow-up overall survival was significantly better with cilta-cel (hazard ratio about 0.55). Toxicity was manageable, with lower CRS and neurotoxicity rates than in CARTITUDE-1.
CARTITUDE-4 is the first randomised trial to show that a CAR-T improves survival in myeloma, and it moved cilta-cel into second-line use (FDA approval 2024). For patients whose disease returns after first-line lenalidomide, a one-off cell therapy now competes with continuous drug combinations. Capacity, cost and the need for bridging therapy still limit who actually receives it.
KarMMa-3 was the first randomised evidence that CAR-T beats conventional drugs in myeloma and led to ide-cel's approval after two prior lines. It confirmed that earlier use of CAR-T produces deeper and longer remissions than in the end-stage setting. Because responses are shorter than with cilta-cel and OS was not improved, it also sharpened debate about which BCMA CAR-T to use and when.
CARTITUDE-1 showed that a single CAR-T infusion can put late-stage myeloma into deep, multi-year remission, leading to FDA approval of cilta-cel in 2022 for heavily pretreated disease. It set the efficacy bar for BCMA-directed therapy and motivated moving CAR-T earlier (CARTITUDE-4). Late neurological toxicity and secondary malignancies remain the safety questions.
Shares Legend Biotech, CARTITUDE-4, Ciltacabtagene autoleucel, BCMA.
Shares Legend Biotech, CARTITUDE-1: cilta-cel, a BCMA CAR-T, in heavily pretreated myeloma, Ciltacabtagene autoleucel, Relapsed or refractory multiple myeloma.
Shares Legend Biotech, Ciltacabtagene autoleucel, BCMA, Cytokine release syndrome (CRS).
Shares Ciltacabtagene autoleucel, Daratumumab, Bortezomib, Johnson & Johnson.
Shares Pomalidomide, Daratumumab, Bortezomib, Relapsed or refractory multiple myeloma.
Shares MRD negativity (myeloma, 10⁻⁵ / 10⁻⁶), Daratumumab, Bortezomib, Progression-free survival (PFS).
Shares CARTITUDE-1: cilta-cel, a BCMA CAR-T, in heavily pretreated myeloma, Ciltacabtagene autoleucel, BCMA, CAR-T cell therapy.
Shares Ciltacabtagene autoleucel, Daratumumab, Bortezomib, Johnson & Johnson.