BCMA-targeting agents for refractory multiple myeloma

Anti-BCMA targeting agents are an interesting therapeutic option for refractory multiple myeloma, especially for patients exposed or refractory to proteasome inhibitors, IMiD or anti-CD38 monoclonal antibodies. Ide-cel and cilta-cel are both CAR-T cells targeting BCMA. The KarMMa and CARTITUDE trials have demonstrated efficacy of CAR-T cell therapy among heavily treated patients, including triple-refractory patients. Overall response rates (ORR) are over 70%, with a significant proportion of patients achieving negative minimal residual disease <10-5. Median progression-free survival (PFS) is significantly longer than with standard treatments. Cilta-cel yields prolonged PFS and even deeper ORR compared to ide-cel, but it is only available in a few centers. Main adverse effects associated with CAR-T cell therapy are cytokine-release syndrome (CRS), which is frequent (described in more than 80 % patients) but mostly grade 1-2, and specific neurotoxicity, seen in around 20 % patients. These results issued from clinical trials, among highly selected patients, are being confirmed by a real-life study conducted in the United States following FDA approval of ide-cel. Teclistamab and elranatamab are the only two bi-specific antibodies available off-the shelf in France. Results from the MajesTEC and MagnetisMM studies are promising, with around 60% ORR and a median PFS of a little less than a year. Most frequent adverse events are hematologic toxicity (especially neutropenia), mostly grade 3-4; and infections, described in around 60% patients. CRS are frequent, but mostly grade 1-2. There is very few specific neurotoxicity. Combinations with other drugs, and use of these agents at earlier stages of multiple myeloma management are interesting perspectives, that might change our practice in the near future. However, limited availability of CAR-T cells remains a major restrain to a wider use.