Early Treatment Failure in Patients With Relapsed/Refractory Multiple Myeloma Receiving Bispecific T-Cell Engagers: Development and Validation of the CHARGE Prognostic Index

Purpose Outcomes with bispecific T-cell engagers (TCEs) in relapsed/refractory multiple myeloma (RRMM) are heterogeneous. A practical tool to guide prognosis is needed. We developed a model integrating clinical, biological, and treatment-related variables to predict progression-free survival (PFS) in patients receiving B-cell maturation antigen (BCMA)- or G-protein–coupled receptor class 5 member D-directed TCEs. Methods We evaluated outcomes of 577 BCMA-directed and 366 talquetamab treatments across 15 US Multiple Myeloma Immunotherapy Consortium centers. Variables significantly associated with inferior PFS in a multivariate Cox model were incorporated into a prognostic score and validated in an independent multicenter International Myeloma Foundation cohort. Results With a median follow-up of 8.4 months, the median PFS was 6.4 months (7.0 months for BCMA TCE; 6.1 months for talquetamab); 92% of patients were triple-class-refractory. Six variables significantly associated with inferior PFS—high-risk cytogenetic abnormalities (HRCAs) [del(17p) or ≥2 HRCAs], hyperferritinemia (≥600 ng/mL), anemia (hemoglobin <9 g/dL), early relapse (<18 months from frontline therapy), general performance status (Eastern Cooperative Oncology Group Performance Status ≥2), and exposure to prior BCMA-directed therapy—were combined to form the CHARGE index, stratifying patients into three risk groups. The median PFS was 21.8 months (95% CI, 11.7 to not reached), 7.1 months (95% CI, 6.1 to 10.1), and 1.6 months (95% CI, 1.2 to 2.5) in the low-, intermediate-, and high-risk groups, respectively; hazard ratios (HRs) were 2.0 (95% CI, 1.5 to 2.7) and 4.8 (95% CI, 3.5 to 6.7) for intermediate- and high-risk versus low-risk groups. External validation (n = 173) showed that the median PFS was not reached, 7.0 months, and 3.0 months, with corresponding HRs of 2.9 (95% CI, 1.7 to 4.9) and 4.8 (95% CI, 2.6 to 8.7). Conclusion The CHARGE index provides a simplified and externally validated framework for predicting treatment outcomes in patients with RRMM receiving TCEs.