Richardson Tim, Tharmaseelan Hishan, Kobbe Guido, Baermann Ben-Niklas, Holderried Tobias A W, Schmitz Friederike, Crysandt Martina, Gödel Philipp, Wolfensberger Nathan, Schütte Daniel, Hallek Michael, Scheid Christof, Holtick Udo
Department I of Internal Medicine, Medical Faculty and University Hospital of Cologne University of Cologne Cologne Germany.
Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD) Aachen Germany.
EJHaem. 2025 Aug 30;6(5):e70139. doi: 10.1002/jha2.70139. eCollection 2025 Oct.
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.
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.
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 or 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.
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, < 0.001) and improved OS (12-month OS: 88.0% vs. 18.1%, = 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.
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.
The authors have confirmed clinical trial registration is not needed for this submission.
尽管治疗取得了进展，但复发/难治性多发性骨髓瘤（RRMM）的治疗仍然困难。靶向B细胞成熟抗原（BCMA）的嵌合抗原受体T细胞（CAR-T）疗法，如idecabtagene vicleucel（ide-cel）和ciltacabtagene autoleucel（cilta-cel），改善了治疗结果，但许多患者在一年内复发。当前国际骨髓瘤工作组（IMWG）关于深度缓解的标准需要长时间观察。早期实用的生物标志物可以实现更及时的风险分层和干预。
评估在接受靶向BCMA的CAR-T输注后第28天血清游离轻链（FLC）抑制是否能预测RRMM患者的无进展生存期（PFS）和总生存期（OS）。
我们对2022年1月至2024年7月期间在四个三级中心接受标准剂量ide-cel或cilta-cel治疗的80例连续RRMM患者进行了回顾性多中心分析。排除寡分泌/无分泌型骨髓瘤患者。使用Freelite检测法将FLC抑制定义为检测不到κ或λ轻链，在输注后第28天（窗口期：第27 - 31天）和输注后3个月进行评估。生存分析采用从第28天开始的标志性方法。多变量Cox回归模型校正了既往BCMA/T细胞靶向治疗、高危细胞遗传学（HRC）、髓外疾病（EMD）和CAR-T治疗前反应状态。
在第28天，51例患者（63.8%）实现了FLC抑制。中位随访时间为11.8个月。FLC抑制与显著更长的中位PFS（23.4个月对4.1个月，P < 0.001）和改善的OS（12个月OS：88.0%对18.1%，P = 0.013）相关。在所有CAR-T产品中均观察到了益处，但cilta-cel的抑制率（81.6%）高于ide-cel（45.2%）。即使在实现抑制的患者中，HRC仍然是一个不利因素，而EMD的影响不太一致。在多变量分析中，未实现FLC抑制独立预测较差的PFS。
CAR-T治疗后第28天的FLC抑制是一种早期、低成本的生物标志物，与RRMM患者更好的PFS和OS相关。它通常先于IMWG定义的完全缓解出现，并可支持CAR-T治疗后的风险适应性管理。需要进行前瞻性验证，以将FLC抑制纳入早期反应评估策略。
作者已确认本研究无需进行临床试验注册。
