Novel Approaches of Cellular Therapy in Multiple Myeloma: Focus on Chimeric Antigen Receptor T-Cells.

BACKGROUND: Recent advancements in cellular therapies, particularly chimeric antigen receptor T-cells (CAR-T) and T-cell-engaging bispecific antibodies have significantly altered the therapeutic landscape for multiple myeloma. There are two US FDA approved CAR-T products targeting BCMA available for commercial use at this time. Though these innovative therapies have demonstrated considerable efficacy in heavily pretreated multiple myeloma patients, many challenges remain, including accessibility, potential toxicities such as cytokine release syndrome and neurotoxicity and development of resistance through targeted antigen loss and T-cell exhaustion and various other mechanisms. CRISPR edited allogeneic CAR-T cells, CAR-NK cells, and structural makeover of autologous CART with safety switches are being studied to address current limitations in cellular therapy. Additionally, newer target antigens such as GPRC5D, FcRH5, armored CAR-T cells that resist immunosuppressive cytokines such as TGF-β are being investigated.

SUMMARY: This review summarizes safety and efficacy of currently available CART, discusses challenges with these therapies, and ongoing research efforts aimed at addressing resistance, mitigate treatment-related toxicities, and refining for broader applicability and prolonged efficacy.

KEY MESSAGES: CART cell therapy has shown significant benefit in treatment of multiple myeloma. Many challenges persist. Novel strategies with structural modifications are being incorporated to overcome the limitations.