CAR T-CELL therapy outcomes in relapsed or refractory multiple myeloma (RRMM) varied according to high-risk disease features, with a multicentre study identifying distinct factors associated with early and delayed treatment failure following ciltacabtagene autoleucel (cilta-cel). The findings highlight the importance of risk-informed care when evaluating treatment outcomes and discussing prognosis with patients.
The study analysed 598 patients with RRMM treated with cilta-cel across 15 US centres. The median age was 65 years, and patients had received a median of five previous lines of therapy. Median follow-up was 10.6 months.
Researchers assessed three high-risk categories: functional high-risk disease, defined as relapse within 18 months of first-line therapy; extramedullary disease (EMD); and high-risk genomic features based on an adapted 2024 International Myeloma Society and International Myeloma Working Group definition.
Functional high-risk disease was present in 33% of patients, while 42% met the adapted genomic high-risk definition and 11% had EMD. Overall and complete response rates were lower among patients with high-risk features than among those without them.
Progression-free survival (PFS) at 12 months was consistently lower across the high-risk subgroups. Estimates were 55% versus 79% for patients with and without functional high-risk disease, respectively. For patients with and without adapted genomic high-risk features, the corresponding estimates were 61% and 80%. Patients with EMD had an estimated 12-month PFS of 59%, compared with 73% among those without EMD.
Multivariable analysis identified functional high-risk disease, adapted genomic high-risk features and EMD as independent factors associated with inferior PFS. These findings indicate that high-risk characteristics may provide clinically relevant information when assessing the likelihood of sustained disease control following cilta-cel.
Extended Cox models distinguished factors associated with treatment failure before six months from those associated with failure at six months or later. EMD, an Eastern Cooperative Oncology Group performance status of at least 2, and previous B-cell maturation antigen (BCMA) directed therapy were associated with early treatment failure. In contrast, functional high-risk disease and adapted genomic high-risk features were associated with delayed failure. Elevated ferritin was associated with risk irrespective of when treatment failure occurred.
Together, these findings provide a framework for risk-informed counselling and therapeutic planning after cilta-cel. Identifying patients with features associated with early treatment failure may help clinicians consider individual risk profiles when discussing expected outcomes and subsequent treatment strategies. The results also support distinguishing between early and delayed failure when evaluating outcomes in patients with RRMM receiving this therapy.
Hansen DK et al. Early treatment failure after ciltacabtagene autoleucel in multiple myeloma with high-risk features: implications for risk-informed care. Blood Cancer J. 2026;DOI:10.1038/s41408-026-01649-x.
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