Impact of Disease Biology and Bridging Strategy on Outcomes After CAR-T Cell Therapy in Relapsed/Refractory Multiple...

Bridging therapy is commonly administered prior to B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR)-T cell therapy in relapsed/refractory multiple myeloma (RRMM) to maintain disease control during the manufacturing period. However, the optimal choice and intensity of bridging therapy remain unclear, and it is debated whether outcomes are primarily influenced by bridging strategy or underlying disease biology. We aimed to evaluate the impact of different bridging strategies on outcomes after BCMA-directed CAR-T cell therapy in RRMM, while accounting for disease biology, response prior to infusion, and baseline hematopoietic reserve. This retrospective multicenter real-world study included 90 consecutive patients with RRMM treated with BCMA-directed CAR-T cells (idecabtagene vicleucel or ciltacabtagene autoleucel) in Austria between January 2024 and July 2025. Bridging approaches were categorized as polychemotherapy (PCHT), talquetamab-based regimens (Tal), or other strategies. Survival outcomes were estimated using the Kaplan-Meier method, and factors associated with progression-free survival (PFS) were analyzed using univariable and multivariable Cox proportional hazards models. Logistic regression models were applied to assess associations with early toxicity. After a median follow-up of 9.9 months, estimated median PFS was 17.1 months. In unadjusted analyses, PCHT was associated with inferior PFS compared with other bridging approaches. However, this association was not retained after adjustment for extramedullary disease/plasma cell leukemia (EMD/PCL) and International Myeloma Working Group high-risk status. CAR-T product type and number of prior lines of therapy showed no effect on PFS. EMD/PCL emerged as the strongest independent predictor of inferior PFS in multivariable analysis (adjusted hazard ratio 4.85), whereas International Myeloma Working Group high-risk status was not independently prognostic. In a secondary model, achieving at least a very good partial response prior to CAR-T infusion was associated with a trend toward improved PFS but did not reach statistical significance. Talquetamab-based bridging was associated with numerically favorable PFS without increased toxicity. The CAR-HEMATOTOX score independently predicted inferior PFS. Importantly, PCHT was not associated with higher CAR-HEMATOTOX scores, prolonged cytopenia, increased infectious complications, or lower ALC levels as a surrogate for CAR-T expansion. In this nationwide real-world analysis, disease biology-particularly the presence of EMD/PCL-was the dominant determinant of outcome after CAR-T cell therapy, outweighing the impact of bridging strategy. These findings suggest that inferior outcomes observed after intensive bridging are largely driven by adverse baseline disease characteristics rather than treatment-related effects, supporting a biology-adapted approach to bridging and emphasizing the importance of achieving optimal disease control prior to CAR-T infusion.