Early treatment failure after ciltacabtagene autoleucel in multiple myeloma with high-risk features: implications for risk-informed care

Ciltacabtagene autoleucel (cilta-cel) has demonstrated high response rates and durable progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM), although outcomes remain heterogeneous and a subset of patients experience early treatment failure. We conducted a multicenter study of RRMM patients treated with cilta-cel across 15 U.S. sites to evaluate outcomes according to high-risk (HR) features, including functional HR disease (FHR; relapse ≤18 months of first-line therapy); extramedullary disease (EMD); and a 2024 IMS-IMWG-adapted HR genomic definition (del17p; t(4;14) or t(14;16) with gain1q or del1p; or gain1q with del1p). Among 598 patients, median age was 65 years (range, 33-83) and median prior lines of therapy was 5 (range, 1-18). FHR was present in 33%, adapted IMS-IMWG HR in 42%, and EMD in 11%. With a median follow-up of 10.6 months, overall response rate and complete response rates were lower in patients with versus without HR features. Twelve-month PFS estimates were inferior across HR subgroups, including FHR (55% vs 79%), adapted IMS-IMWG HR (61% vs 80%), and EMD (59% vs 73%). In multivariable analysis, FHR, adapted IMS-IMWG HR, and EMD were independently associated with inferior PFS. Extended Cox models demonstrated that EMD, ECOG PS ≥ 2, and prior BCMA-directed therapy were associated with early treatment failure (<6 months) following cilta-cel, whereas FHR and adapted IMS-IMWG HR were associated with delayed failure (≥6 months). Elevated ferritin conferred similar risk regardless of treatment failure timing. These findings define outcomes across HR subgroups and provide a framework for risk-informed counseling and therapeutic strategies following cilta-cel in RRMM.