Beyond binary: graded frailty assessment and outcomes after CAR-T cell therapy in relapsed/refractory multiple myeloma

With deep and durable responses seen in clinical trials, chimeric antigen receptor (CAR)-T cell therapy has transformed treatment outcomes for patients with relapsed/refractory multiple myeloma (RRMM) [ 1 , 2 ]. Cytokine release syndrome (CRS), immune cell effector associated neurotoxicity syndrome (ICANS), cytopenias, and infections are common but manageable toxicities of CAR-T. However, trial populations are typically younger and fitter than real-world patients, raising concern whether frailty attenuates efficacy or amplifies toxicity. Frailty, defined as a state of diminished physiologic reserve, is particularly prevalent in myeloma patients and is independently associated with inferior outcomes after intensive treatments [ 3 , 4 , 5 ]. Whether frailty, as measured by validated tools at the time of CAR-T infusion, consistently and accurately predicts efficacy or safety outcomes in RRMM remains incompletely characterized. Existing data are limited by simplified frailty assessments, with no studies directly comparing various independent frailty instruments in a uniform RRMM population. We report the first study directly comparing the Simplified Frailty Index (SFI) with an exploratory application of the Memorial Sloan Kettering Frailty Index (MSK-FI) in a cohort of patients receiving CAR-T for RRMM. The SFI is a validated, myeloma-specific frailty instrument, whereas the MSK-FI was developed and validated in a broader oncology population and has not previously been validated in multiple myeloma.