CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

Abstract

Despite recent therapeutic advances, the prognosis of multiple myeloma (MM) patients remains poor. Thus, new strategies to improve outcomes are imperative. Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape of B-cell malignancies, providing a potentially curative option for patients who are refractory to standard treatment. Long-term remissions achieved in patients with acute lymphoblastic leukemia and Non-Hodgkin Lymphoma encouraged its further development in MM. B-cell maturation antigen (BCMA)-targeted CAR T-cells have established outstanding results in heavily pre-treated patients. However, several other antigens such as SLAMF7 and CD44v6 are currently under investigation with promising results. Idecabtagene vicleucel is expected to be approved soon for clinical use. Unfortunately, relapses after CAR T-cell infusion have been reported. Hence, understanding the underlying mechanisms of resistance is essential to promote prevention strategies and to enhance CAR T-cell efficacy. In this review we provide an update of the most recent clinical and pre-clinical data and we elucidate both, the potential and the challenges of CAR T-cell therapy in the future.

Defining the cell surface proteomic landscape of multiple myeloma reveals immunotherapeutic strategies and biomarkers of drug resistance

“…1A). Notably, across these lines we detected almost all of the major immunotherapy targets in myeloma, as well as canonical flow cytometry markers for plasma cells (7,13): BCMA, CD138/SDC1, CD38, CD56, SLAMF7/CS-1, CD46, Integrin-b7 (ITGB7), CD74/HLA-DR, TACI, CD48/SLAMF2 and LY9/CD229 ( Fig. 1C; Supplementary Dataset 1).…”

“…CD38, a cell surface ectoenzyme, is well-known in myeloma as the target of the monoclonal antibodies (mAbs) daratumumab and isatuximab (32). While CD38 has been proposed as a standalone CAR-T target in myeloma, concern remains about toxicity given CD38 expression on many other hematopoietic cells and increased potency of CAR-Ts at lower antigen densities when compared to mAbs (13). CD48/SLAMF2, a CD2 ligand, has been proposed as a therapeutic target in myeloma, with prior studies confirming that >90% of myeloma primary samples tested expressed CD48 (33).…”

Recent Advances in the Treatment of Patients with Multiple Myeloma

“…There are other CAR-Ts in clinical and preclinical research targeting BCMA and many other antigens [105,106], so we may expect encouraging results in the near future, however there is still no plateau in survival in contrast to that seen with CAR-T cells treatment in other hematologic malignancies.…”

Toxicities of Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma: An Overview of Experience From Clinical Trials, Pathophysiology, and Management Strategies

“…Mechanism of action, CAR targets, preclinical and clinical data on CAR T cell therapy for MM have been extensively discussed in previous review articles (15)(16)(17), and these issues are not the main topic of our current review. Here, we will just provide a brief overview.…”