Allogeneic CAR T Cell Therapy for Multiple Myeloma: Challenges, Progress, and Future Directions

Multiple myeloma (MM) is a malignant disease characterized by the accumulation of clonal plasma cells (PCs) in the bone marrow. MM is an incurable malignancy, since often patients relapse after frontline therapy, and the mortality of patients with relapsed and/or refectory multiple myeloma (RRMM) remains high, indicating the need for new treatment approaches. Chimeric antigen receptor (CAR)-T cell therapy and T-cell engagers are among the most promising treatments for RRMM. Idedecabtagene vicleucel (ide-cel, or bb2121) and Ciltacabtagene autoleucel (cilta-cel) are two anti-BCMA CAR T products approved by the US Food and Drug Administration (FDA) in 2021 and 2022, respectively, for RRMM treatment. However, many limitations emerged from clinical trials, including adverse effects, long manufacturing time and resistance to therapy. An interesting research area is represented by allogeneic CAR T cells, which are derived by healthy donors’ T cells. This work aims to investigate the advantages and disadvantages of anti-BCMA allogenic CAR T cells in the context of multiple myeloma, with respect to current CAR T cells therapy, and evidence their potential as off-the-shelf therapies. The efficacy and safety of allogeneic in preclinical and clinical studies, and subsequent development, through the combination with γ-Secretase inhibitors, the addition of Turbodomains, or the possibility to rituximab-dependent switch-off, will be highlighted through the analysis of three papers.