KarMMa-3: ide-cel CAR-T versus standard regimens in triple-class-exposed relapsed myeloma
The first randomised CAR-T trial in myeloma tripled median progression-free survival (13.3 versus 4.4 months) compared with standard combinations after two to four prior lines.
KarMMa-3 randomised 386 patients with relapsed and refractory multiple myeloma after two to four prior lines, including an immunomodulatory drug, a proteasome inhibitor and daratumumab, to idecabtagene vicleucel (ide-cel) or one of five standard regimens. The primary endpoint was PFS. Median PFS was 13.3 versus 4.4 months (hazard ratio 0.49); overall response was 71% versus 42% and complete response 39% versus 5%. CRS occurred in 88% (grade 3 or higher in 5%) and neurotoxicity in 15%. Overall survival did not differ significantly, in part because more than half of standard-arm patients crossed over to ide-cel.
- 386 patients after 2-4 prior lines, triple-class exposed; ide-cel vs 5 standard regimens (2:1).
- Median PFS 13.3 vs 4.4 months; hazard ratio 0.49.
- Overall response 71% vs 42%; complete response or better 39% vs 5%.
- CRS 88% (grade 3 or higher 5%); investigator-identified neurotoxicity 15% (grade 3 or higher 3%).
- No significant OS difference after adjusting for crossover; most standard-arm patients received ide-cel at progression.
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.
- Crossover blunted the OS comparison; a survival benefit could not be shown.
- Standard-arm regimens varied and included some now regarded as suboptimal.
- Median PFS with ide-cel remains modest compared with cilta-cel in CARTITUDE-4 (indirect comparison).
- Manufacturing time and slot availability restrict real-world use.