Treatment of Multiple Myeloma in Patients Refractory to Daratumumab/Anti-CD38 Monoclonal Antibodies: A Systematic Review

Background There is a lack of clear guidance on the appropriate next choice of therapy for patients with relapsed/refractory multiple myeloma who become refractory to daratumumab, an anti-CD38 antibody. This review aims to identify and compare treatments with published clinical trial evidence among patients with daratumumab-refractory multiple myeloma. Methods MEDLINE, Cochrane CENTRAL, and EMBASE databases were searched for clinical trials that evaluated treatments for patients with multiple myeloma who were refractory to daratumumab from November 2015 to October 2023. Eligible studies may have enrolled only patients who were refractory to daratumumab or reported findings on patients with daratumumab-refractory disease in subgroup analyses. Treatment outcomes of interest included response rates and survival outcomes. Screening and data extraction were done independently by two reviewers using covidence, and any discrepancy was resolved by a third reviewer. Qualitative synthesis was performed to describe and compare patient outcomes associated with different treatments. Results A total of 33 papers/published studies, representing 23 clinical trials, were eligible/included. Interventions from the eligible trials include chimeric antigen receptor (CAR)-T cell therapy, B-cell maturation antigen (BCMA)-directed antibodies, other monoclonal antibodies, cereblon E3 ligase modulators, a peptide-drug conjugate, and other targeted therapies. CAR T-cell therapy demonstrated the highest overall response rates, longer median overall, and progression-free survival in addition to significantly lower risk of death and higher odds of response compared to standard of care. Similarly, high response rates and/or long-term survival was also observed for other BCMA-directed treatments, such as elranatamab and teclistamab. Conclusion Based on the results of this systematic review, BCMA-directed therapies such as CAR-T cell therapy and bispecific antibodies demonstrate promising efficacy among patients with anti-CD38 refractory disease. However, additional evidence from randomized clinical trials is necessary to establish best practice guidelines.