Functionally high-risk disease is associated with poor outcomes after late-line CAR T-cell therapy for multiple myeloma.

While CAR T has shown superior efficacy in earlier line of therapy [1, 2] for functionally high-risk multiple myeloma (FHRMM), outcomes with its use in later lines (3+) for FHR disease remain unknown. We describe a single-center experience of FHRMM patients (pts), defined as those with progression of disease (POD) < 24 months of frontline therapy, receiving CAR T-cell therapy. Of the 208 pts treated with CAR T, 117 (56%) had FHR disease and had received median of 5 prior lines of therapy (LOT). FHR pts had higher rates of extramedullary disease (EMD) and progression within 12 months of transplant. Median PFS were 11 and 13 months (p = 0.15), and median OS were 34 and 55 months (p = 0.025) in the FHR and non-FHR groups, respectively. On multivariable analyses, EMD and high disease burden were associated with inferior OS. FHRMM pts receiving CAR T as late LOT had inferior survival outcomes compared to those with non-FHR disease, underscoring the poor prognostic impact of POD < 24 months from frontline therapy. This association was largely driven by active EMD and high disease burden at the time of CAR T, highlighting the potential benefit of utilizing CAR T as an early LOT for FHRMM.