The risk of second primary malignancies in patients receiving T-cell directed therapies for multiple myeloma: a systematic review

Whilst T-cell directed therapies have revolutionized the therapeutic landscape in triple-class refractory multiple myeloma, ongoing long-term safety concerns remain, including the risk of second primary malignancy (SPM) development. We systematically evaluated the incidence and distribution of SPMs in R/R MM patients post T-cell-directed therapy. MEDLINE, EMBASE, and Cochrane CENTRAL databases were searched for clinical trial and real-world studies reporting outcomes for patients infused with either chimeric antigen receptor (CAR) T-cell or bispecific antibody therapies reported until March 2025. Patient-specific characteristics and SPM outcomes were extracted from eligible studies with calculation of point estimate confidence intervals (CIs) achieved via the Clopper-Pearson Exact Method. A total of 12 studies (7 RCTs and 5 RWS) were eligible for analysis, encompassing a total of 2743 adult R/R MM patients. Eleven studies were related to CAR T-cell therapy, with only 1 study reporting on bispecific antibody therapy. The pooled SPM point estimate for CAR T-cell therapy was 6.3%, with hematological malignancies representing the most common subtype. This highlights the potential risk of SPMs in patients eligible for T-cell directed therapy. Further robust, prospective clinical trial and pharmacovigilance data will continue to inform the true level of risk in this cohort of patients.