CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
低频 PPM1D 基因突变对多发性骨髓瘤 BCMA 靶向 CAR-T 细胞治疗反应的影响
英文原题：Low-Frequency PPM1D Gene Mutations Affect Treatment Response to BCMA-Targeted CAR T-Cell Therapy in Multiple Myeloma.
查看英文原题
Low-Frequency PPM1D Gene Mutations Affect Treatment Response to BCMA-Targeted CAR T-Cell Therapy in Multiple Myeloma.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
中文摘要
靶向BCMA的嵌合抗原受体（CAR）T细胞疗法已彻底改变了复发/难治性多发性骨髓瘤（RRMM）的治疗。然而，该疾病仍无法治愈，CAR-T 细胞治疗后的疾病进展仍是一项挑战。克隆性造血，特别是DNA损伤应答基因PPM1D的突变，已被发现与接受细胞治疗的淋巴瘤患者的治疗耐药和较差生存相关。PPM1D突变对MM患者接受CAR-T 细胞治疗后结局的影响尚不明确。
我们开展了一项回顾性单中心研究，纳入2022年至2025年间接受idecabtagene vicleucel或ciltacabtagene autoleucel治疗的83例RRMM患者。对CAR-T 细胞输注前采集的外周血单个核细胞进行下一代测序，以鉴定PPM1D第6外显子突变（变异等位基因频率> 0.01）。我们分析了突变状态、临床特征、毒性和生存之间的关联。
14.5%（12/83）的患者检测到PPM1D突变。与野生型患者相比，PPM1D突变患者既往接受自体干细胞移植的比例更低（50% vs. 82%，p = 0.02），并表现出更晚期的疾病负荷和不良预后特征（R-ISS III期 58% vs. 20%，p = 0.05）。值得注意的是，PPM1D状态并未影响初始疗效；两组之间的完全缓解率相当（67% vs. 69%）。然而，PPM1D突变与较差的无进展生存期（PFS）显著相关（中位PFS：6个月 vs. 16个月，p = 0.04）。在毒性方面，突变亚组的2级细胞因子释放综合征发生率显著更高，并呈现神经毒性增加的趋势（25% vs. 7%）。
PPM1D克隆性造血在RRMM中常见，尽管初始缓解深度较深，但携带PPM1D突变的患者面临显著更高的早期复发风险。PPM1D突变可作为缓解持久性差的生物标志物，并应在更大规模的前瞻性试验中进一步评估。
展开英文摘要原文
Background : BCMA-targeted Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of Relapsed/Refractory Multiple Myeloma (RRMM).
However, the disease is not curable and progression after CAR T-cell treatment remains a challenge. Clonal hematopoiesis, specifically mutations in the DNA damage response gene PPM1D , has been linked to therapy resistance and inferior survival in lymphoma patients undergoing cellular therapy. The impact of PPM1D mutations on MM patient outcome after CAR T-cell therapy remains undefined.
Methods : We conducted a retrospective single-center study of 83 patients with RRMM patients treated with idecabtagene vicleucel or ciltacabtagene autoleucel between 2022 and 2025. Next-generation sequencing was performed on peripheral blood mononuclear cells collected prior to CAR T-cell infusion to identify PPM1D exon 6 mutations (variant allele frequency > 0. 01).
We analyzed associations between mutational status, clinical characteristics, toxicity, and survival. Results : PPM1D mutations were detected in 14. 5% (12/83) of patients. PPM1D -mutated patients had fewer prior autologous stem cell transplantation compared to wild-type patients (50% vs. 82%, p = 0. 02) and presented more advanced disease burden and adverse prognostic features (R-ISS stage III 58% vs. 20%, p = 0. 05).
Notably, PPM1D status did not impact initial efficacy; complete remission rates were comparable between groups (67% vs. 69%).
However, PPM1D mutations were significantly associated with inferior progression-free survival (PFS) (median PFS: 6 months vs. 16 months, p = 0. 04). Regarding toxicity, the mutated subgroup exhibited significantly higher rates of grade 2 cytokine release syndrome and a trend toward increased neurotoxicity (25% vs. 7%).
Conclusions : PPM1D clonal hematopoiesis is frequent in RRMM and despite deep initial responses, patients harboring PPM1D mutations face a significantly higher risk of early relapse. PPM1D mutations may serve as a biomarker for poor durability of response and should be further evaluated in larger, prospective trials.
论文信息
- 作者
- van der Weg K、Bertschinger M、Bacher U、Hoffmann M、Nilius H、Seipel K、Pabst T
- 单位
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.Switzerland
- 期刊
- Cancers2026 Jun 23
- 原文标识
- PubMed 42449578 · DOI 10.3390/cancers18132032