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Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China.
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou, China.
Lancet Haematol. 2025 May;12(5):e365-e375. doi: 10.1016/S2352-3026(25)00048-1. Epub 2025 Apr 12.
For patients with multiple myeloma progression after anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, the optimal salvage treatment strategies remain unclear. GPRC5D-directed CAR T cell might be a potential option. The aim of this trial was to investigate the activity and safety of anti-GPRC5D CAR T cells in patients with progressive multiple myeloma after anti-BCMA CAR T-cell therapy.
In this phase 2, open-label, single-arm, phase 2 trial, at the Affiliated Hospital of Xuzhou Medical University in China, we enrolled patients (aged 18-70 years old) with relapsed or refractory multiple myeloma who had progressed disease after anti-BCMA CAR T-cell therapy and a life expectancy of more than 12 weeks without active infections, serious liver, heart, or other diseases. Patients were assigned to receive a single dose of intravenous anti-GPRC5D CAR T cell at 2 × 10 cells per kg. The primary endpoint was the overall response rate, including stringent complete response, complete response, very good partial response, and partial response, according to the standard International Myeloma Working Group response assessment criteria. Activity and safety analyses were done in the patients who received a dose of anti-GPRC5D CAR T cell as defined in the protocol. This trial is registered with the Chinese Clinical Trial Registration Center, ChiCTR2100048888, and is ongoing.
Between Dec 1, 2021, and May 1, 2024, 42 patients were screened, 37 were enrolled and received anti-GPRC5D CAR T-cell therapy. Median age was 59 years (IQR 51-65), 17 (46%) of 37 patients were male and 20 (54%) female. All patients were Asian. At a median follow-up of 12·6 months (IQR 8·2-20·8), the overall response rate was 84% (95% CI 68-94, 31 of 37 patients), including 13 (35%) complete responses or better. The most common grade 3-4 adverse events were haematological toxicities, including leukopenia (34 [92%] of 37 patients), lymphopenia (36 [97%]), neutropenia (29 [78%]), anaemia (23 [62%]), and thrombocytopenia (23 [62%]). 26 (70%) of 37 patients had cytokine release syndrome, which was of grade 3 in two (5%) patients. One case of grade 1 immune effector cell-associated neurotoxicity syndrome was observed. There were no treatment-related deaths in the trial.
Anti-GPRC5D CAR T-cell salvage therapy induced a high response rate, and could be a potential treatment option in relapsed or refractory multiple myeloma patients who have progressed after anti-BCMA CAR T-cell treatment. Further investigations are warranted to establish the long-term efficacy and safety of this therapeutic approach.
National Natural Science Foundation of China and the General Project of Jiangsu Commission of Health.
对于接受抗BCMA嵌合抗原受体（CAR）T细胞治疗后病情进展的多发性骨髓瘤患者，最佳挽救治疗策略仍不明确。靶向GPRC5D的CAR T细胞可能是一种潜在选择。本试验旨在研究抗GPRC5D CAR T细胞在抗BCMA CAR T细胞治疗后病情进展的多发性骨髓瘤患者中的活性和安全性。
在这项中国徐州医科大学附属医院开展的2期开放标签单臂试验中，我们纳入了年龄在18至70岁之间、抗BCMA CAR T细胞治疗后病情进展的复发或难治性多发性骨髓瘤患者，预期寿命超过12周且无活动性感染、严重肝脏、心脏或其他疾病。患者接受每千克体重2×10⁸细胞的单剂量静脉注射抗GPRC5D CAR T细胞。主要终点是根据国际骨髓瘤工作组标准反应评估标准的总缓解率，包括严格完全缓解、完全缓解、非常好的部分缓解和部分缓解。对按照方案接受一剂抗GPRC5D CAR T细胞的患者进行活性和安全性分析。本试验已在中国临床试验注册中心注册，注册号为ChiCTR2100048888，试验正在进行中。
2021年12月1日至2024年5月1日期间，42例患者接受筛查，37例入组并接受抗GPRC5D CAR T细胞治疗。中位年龄为59岁（四分位间距51 - 65岁），37例患者中17例（46%）为男性，20例（54%）为女性。所有患者均为亚洲人。中位随访12.6个月（四分位间距8.2 - 20.8个月）时，总缓解率为84%（95%置信区间68 - 94，37例患者中31例），包括13例（35%）完全缓解或更好的缓解。最常见的3 - 4级不良事件是血液学毒性，包括白细胞减少（37例患者中的34例[92%]）、淋巴细胞减少（36例[97%]）、中性粒细胞减少（29例[78%]）、贫血（23例[62%]）和血小板减少（23例[62%]）。37例患者中有26例（70%）发生细胞因子释放综合征，其中2例（5%）为3级。观察到1例1级免疫效应细胞相关神经毒性综合征。试验中无治疗相关死亡。
抗GPRC5D CAR T细胞挽救治疗诱导了较高的缓解率，可能是抗BCMA CAR T细胞治疗后病情进展的复发或难治性多发性骨髓瘤患者的一种潜在治疗选择。有必要进一步研究以确定这种治疗方法的长期疗效和安全性。
国家自然科学基金和江苏省卫生健康委面上项目。
