FORTRESS-CART: Focused Observation and Risk Testing for Robust Evaluation of Safety in Chimeric Antigen Receptor T-Cell Therapy (CAR-T): Real-World Predictors of Second Primary Malignancies (SPMs) Among Patients Treated With CAR-T

BACKGROUND: Chimeric antigen receptor-T (CAR-T) cell therapies are highly effective in treating hematologic malignancies. Cases of second primary malignancies (SPMs) have been reported post-treatment, although risk factors remain unclear. This real-world study evaluated predictors of SPMs among patients treated with CAR-T. METHODS: Patients with multiple myeloma (MM) or lymphoma/leukemia treated with CAR-T were identified from the Komodo Research Database (January 1, 2016-June 30, 2024). Incidences of SPMs and hematologic SPMs were evaluated following CAR-T infusion (index date) and predictors were evaluated 12 months pre-index. LASSO regression was used to identify predictors of SPMs and hematologic SPMs, separately. Multivariate Cox regression was used to assess the magnitude and direction of each predictor. RESULTS: Among 2,609 patients receiving CAR-T (MM: 683, lymphoma/leukemia: 1,926) and over a median follow-up of 14.5 months, the incidences of SPMs and hematologic SPMs were 11.8% and 5.0%, respectively (0.3% for peripheral T-cell lymphoma). Median time-to-event was approximately 8 months for SPMs and hematologic SPMs. Adjusting for other predictors in the models, there was no association between CAR-T indicated for MM versus lymphoma/leukemia and the risk of SPMs (hazard ratio: 0.85, P = .32). Relative to lymphoma/leukemia, MM was associated with a significantly lower risk of hematologic SPMs (hazard ratio: 0.24, P < .05). CONCLUSIONS: This study found no association between CAR-Ts used in MM versus lymphoma/leukemia and the risk of subsequent SPMs, while a lower risk of hematologic SPMs was observed in patients with MM. T-cell malignancies were infrequent. Ongoing research into potential risk factors of SPMs following CAR-T could help inform individualized management strategies.