Chimeric Antigen Receptor T Cell Therapy for Myeloma: Where Are We Now and What Is Needed to Move Chimeric Antigen Receptor T Cells Forward to Earlier Lines of Therapy? Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy

• Published in: Transplantation and cellular therapy Vol. 30; no. 1; pp. 17 - 37
• Main Authors: Anderson, Larry D., Dhakal, Binod, Jain, Tania, Oluwole, Olalekan O., Shah, Gunjan L., Sidana, Surbhi, Perales, Miguel-Angel, Pasquini, Marcelo C.
• Format: Journal Article Book Review
• Language: English
• Published: United States Elsevier Inc 01.01.2024
• Subjects: Antibodies, Bispecific; B cell maturation antigen; Cell- and Tissue-Based Therapy; Cellular therapy; Chimeric antigen receptor T cells; Humans; Multiple Myeloma - therapy; Neoplasm Recurrence, Local; Neoplasms, Plasma Cell; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - therapeutic use; Relapsed/refractory multiple myeloma; T cell-redirection therapy; Chimeric antigen receptor T cells; Relapsed/refractory multiple myeloma; B cell maturation antigen; T cell-redirection therapy; Cellular therapy
• ISSN: 2666-6367; 2666-6367
• DOI: 10.1016/j.jtct.2023.10.022

•BCMA-directed chimeric antigen receptor T cell (CAR-T) therapy has been highly effective in treating relapsed/refractory multiple myeloma (RRMM).•Two BCMA-directed CAR-T products have been approved by the US Food and Drug Administration, but both currently require 4 prior lines of therapy, and finding effective bridging therapy can be difficult.•BCMA-directed CAR-T therapy was superior to standard of care therapy options in 2 randomized phase 3 trials, leading to prolonged progression-free survival in second-line and third-line therapy for multiple myeloma.•We review implications for clinical practice with earlier use of BCMA-directed CAR-T therapy for treatment of multiple myeloma. Since 2021, 2 B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapies—idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel)—have been approved by the US Food and Drug Administration (FDA) for treating relapsed or refractory multiple myeloma (RRMM) after 4 or more prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. The 2 products have shown unprecedented activity in RRMM, but relapses remain common, and access to and safety of CAR-T therapy in patients with rapidly progressing advanced disease are not ideal. Sequencing CAR-T therapy with other options, including the 2 recently approved BCMA-directed T cell-engaging bispecific antibodies teclistamab and elranatamab, has become increasingly challenging owing to data showing inferior outcomes from CAR-T therapy after prior BCMA-directed therapy. This has led to the consideration of CAR-T therapy earlier in the course of disease for myeloma, when T cells are potentially healthier and the myeloma is less aggressive. To address the question of earlier use of CAR-T therapy, several trials are either ongoing or planned, and results have recently been reported for 2 randomized trials of CAR-T therapy showing improved progression-free survival compared to standard of care therapy in second-line (CARTITUDE-4) or third-line therapy (KarMMA-3). With the anticipation of the FDA possibly expanding approval of CAR-T to earlier lines of myeloma therapy, the American Society for Transplantation and Cellular Therapy convened a group of experts to provide a comprehensive review of the studies that led to the approval of CAR-T therapy in late-line therapy for myeloma, discuss the recently reported and ongoing studies designed to move CAR-T therapy to earlier lines of therapy, and share insights and considerations for sequencing therapy and optimization of patient selection for BCMA-directed therapies in current practice.