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

Tim Richardson; Hishan Tharmaseelan; Guido Kobbe; Ben-Niklas Baermann; Tobias A W Holderried; Friederike Schmitz; Martina Crysandt; Philipp Gödel; Nathan Wolfensberger; Daniel Schütte; Michael Hallek; Christof Scheid; Udo Holtick

doi:10.1002/jha2.70139

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

EJHaem. 2025 Aug 30;6(5):e70139. doi: 10.1002/jha2.70139. eCollection 2025 Oct.

Authors

Tim Richardson^{1

2}, Hishan Tharmaseelan^{1

2}, Guido Kobbe^{2

3}, Ben-Niklas Baermann^{2

3}, Tobias A W Holderried^{2

4}, Friederike Schmitz^{2

4}, Martina Crysandt^{2

5}, Philipp Gödel^{1

2}, Nathan Wolfensberger^{1

2}, Daniel Schütte^{1

2}, Michael Hallek^{1

2}, Christof Scheid^{1

2}, Udo Holtick^{1

2}

Affiliations

¹ Department I of Internal Medicine, Medical Faculty and University Hospital of Cologne University of Cologne Cologne Germany.
² Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD) Aachen Germany.
³ Department of Hematology, Oncology, and Clinical Immunology Heinrich Heine University Düsseldorf Düsseldorf Germany.
⁴ Department of Hematology, Oncology, Stem Cell Transplantation, Immune and Cell Therapy, Clinical Immunology and Rheumatology University Hospital Bonn Bonn Germany.
⁵ Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital Aachen Aachen Germany.

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.

Keywords: CAR‐T cells; biomarker; multiple myeloma; response assessment.