Development and Validation of a Prediction Model of Outcome After B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Multiple Myeloma

Abstract

Purpose: Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T.

Patients and methods: This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti-B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups.

Results: The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression (P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups.

Conclusion: Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.

FIG 1.

Flow diagram of cohort selection. CAR-T, chimeric antigen receptor T-cell therapy.

FIG 2.

Response rates after CAR-T (A) in the total cohort of 269 patients and (B) according to region. CR, complete remission; MRD, measurable residual disease; ORR, overall response rate; PR, partial remission; VGPR, very good partial remission.

FIG 3.

(A) Relapse, (B) PFS, and (C) overall survival of the European versus US cohort. PFS of patients with relapse within 5 months from CAR-T-cell infusion in the (D) European and (E) US cohorts. CAR-T, chimeric antigen receptor T-cell therapy; PFS, progression-free survival.

FIG 4.

(A and B) Relapse/progression, (C and D) progression-free survival, and (E and F) overall survival according to MyCARe risk groups in the European and US cohorts, respectively. CAR-T, chimeric antigen receptor T-cell therapy; MyCARe, Myeloma CAR-T Relapse.