Early Free Light‐Chain Suppression as a Prognostic Marker in Relapsed and Refractory Myeloma Patients Treated With BCMA‐Directed CAR‐T Cells

Abstract

BACKGROUND Relapsed/refractory multiple myeloma (RRMM) remains difficult to treat despite advances in therapy. B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapies, such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), have improved outcomes, yet many patients relapse within a year. Current International Myeloma Working Group (IMWG) criteria for deep response require prolonged observation. Early, practical biomarkers could enable timelier risk stratification and intervention. OBJECTIVE To evaluate whether serum free light-chain (FLC) suppression at Day +28 after BCMA-directed CAR-T infusion predicts progression-free survival (PFS) and overall survival (OS) in RRMM. METHODS We conducted a retrospective multicenter analysis of 80 consecutive RRMM patients treated with in-label ide-cel or cilta-cel between January 2022 and July 2024 at four tertiary centers. Patients with oligo-/non-secretory myeloma were excluded. FLC suppression-defined as undetectable κ or λ light chains using the Freelite assay-was assessed at Day +28 (window: Days 27-31) and at 3 months post-infusion. Survival analyses used a landmark approach from Day +28. Multivariate Cox regression adjusted for prior BCMA/T-cell-directed therapy, high-risk cytogenetics (HRC), extramedullary disease (EMD), and pre-CAR-T response status. RESULTS At Day +28, 51 patients (63.8%) achieved FLC suppression. Median follow-up was 11.8 months. FLC suppression correlated with markedly longer median PFS (23.4 vs. 4.1 months, p < 0.001) and improved OS (12-month OS: 88.0% vs. 18.1%, p = 0.013). Benefits were observed across CAR-T products, but suppression rates were higher with cilta-cel (81.6%) than ide-cel (45.2%). HRC remained an adverse factor even in suppressed patients, while EMD showed a less consistent effect. In multivariate analysis, absence of FLC suppression independently predicted inferior PFS. CONCLUSIONS FLC suppression at Day +28 post-CAR-T is an early, inexpensive biomarker associated with superior PFS and OS in RRMM. It often precedes IMWG-defined complete response and could support risk-adapted post-CAR-T management. Prospective validation is warranted to integrate FLC suppression into early response assessment strategies. TRIAL REGISTRATION The authors have confirmed clinical trial registration is not needed for this submission.