CAR-T cell therapy in myeloma: hopes and hurdles.

Immune therapy is a new avenue in the treatment of multiple myeloma (MM). The naked anti-38 antibodies daratumumab and isatuximab are already used in frontline therapy after excellent results have been achieved in relapsed/refractory MM (RRMM).The second step was the development of immune therapies targeting B cell maturation antigen (BCMA). Genetically mod- ified autologous chimeric antigen receptor (CAR)-T cell therapy BCMA-directed were initially tested in heavily pretreated patients with RRMM exposed to the 3 main therapeutic classes, immunomodulatory drugs (iMiDs), proteasome inhibitors, and anti-CD38 antibodies (triple-class exposed). Efficacy results were unprecedented in this context and Idecabtagene vicleucel (ide-cel or Abecma) was the first BCMA-directed CAR-T cell therapy approved in MM by both Federal Drug Administration (FDA) and European Medicines Agency (EMA). This approval was based on the results of the KarMMa Phase 2 study in 128 patients with RRMM who had previously received a median number of 6 lines of therapy (LOT). 1 The response rate (RR) was 73%, including 33% of complete response (CR) or better and 26% negative min- imal residual disease (MRD). However, median progression-free survival (PFS) was only 8.8 months. The Cartitude 1 Phase1b/2 evaluated ciltacabtagene autoleucel (cilta-cel) another CAR-T cell therapy with 2 BCMA-targeting single domain antibodies in 97 heavily pretreated patients with RRMM. 2 Results were recently updated and with a median follow-up of 27.7 months, 3 the results were even more impressive with a 98% RR, including 82.5% CR or better, and 92% negative MRD in evaluable patients. The 27-month PFS was 55%. With these results, Cilta-cel (Carvykti) was