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.
Highlights
Multiple myeloma (MM), an incurable malignancy in most of the cases, is characterized by an uncontrolled proliferation of clonal plasma-cells in the bone marrow that produces aberrant quantity of monoclonal immunoglobulins (Ig) and end-organ damage
Further examples of on-target, off-tumor toxicity include carboxyanhydrase-IX-specific Chimeric antigen receptor (CAR) T-cell therapy for renal cell carcinoma that resulted in the development of cholestasis due to expression of this antigen on bile duct epithelium [203], and the infusion of HER-2/neu CAR T-cells in a patient with advanced colonic cancer that led to respiratory distress and cardiac arrest which was attributed to putative low levels of HER-2/neu expression on lung epithelial cells [204]
The treatment arsenal in MM has grown considerably during the last decade and idecabtagene vicleucel and other CAR T-cell products are on their way to approval
Summary
Multiple myeloma (MM), an incurable malignancy in most of the cases, is characterized by an uncontrolled proliferation of clonal plasma-cells in the bone marrow that produces aberrant quantity of monoclonal immunoglobulins (Ig) and end-organ damage (hypercalcemia, renal insufficiency, anemia, and/or bone lytic lesions). CAR, chimeric antigen receptor; CR, complete response; CRS, cytokine-release syndrome; CRS-RM, CRS related-mortality; Cy, cyclophosphamide; EFS, event-free survival; EGFRt, truncated epidermal growth factor receptor; FHCRC, Fred Hutchinson Cancer Research Center; FHVH33, fully human heavy-chain variable domain; Flu, fludarabine; HD, highest dose; ICANS, immune effector cell-associated neurotoxicity syndrome; m, median, mo, months; MSKCC, Memorial Sloan Kettering Cancer Center; NA, not available; NCI, National Cancer Institute; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PI3K-inh, phosphoinositide 3-kinase inhibitor; scFv, single-chain variable fragment; UPenn, University of Pennsylvania.
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