含塞利尼索方案治疗复发难治多发性骨髓瘤的疗效与安全性分析:一项中国多中心真实世界研究

Effectiveness and safety of selinexor-based regimens in the treatment of relapsed and refractory multiple myeloma:a multicenter real-world study from China

目的:评价真实世界中含塞利尼索方案治疗复发难治多发性骨髓瘤(RRMM)患者的疗效及安全性。方法:回顾性分析2020年7月—2021年12月就诊于中国11个中心应用含塞利尼索方案治疗的53例RRMM患者的临床资料,评估疗效、生存及不良反应。结果:53例RRMM患者接受以塞利尼索为基础的联合方案治疗的中位年龄为60(范围41~79)岁。患者应用塞利尼索的时间距离初次诊断的中位时间为30(范围1~156)个月,中位既往治疗线数为4(范围1~11),既往行自体造血干细胞移植者22例(41.5%,22/53),既往行CAR-T细胞治疗者8例(15.1%,8/15),蛋白酶体抑制剂、免疫调节剂双重耐药者34例(64.2%,34/53),蛋白酶体抑制剂、免疫调节剂、达雷妥尤单抗三重耐药者20例(37.7%,20/53)。起病时伴有高危细胞遗传学[17p-/t(14;16)/t(4;14)/1q21]者24例(66.7%,24/36),应用塞利尼索时伴有高危细胞遗传学异常者20例(55.6%,20/36)。47例患者可评估疗效,总有效率为44.7%(21/47),其中完全缓解3例(6.4%),非常好的部分缓解4例(8.5%),部分缓解14例(29.8%)。应用塞利尼索前合并高危细胞遗传学异常患者的总有效率与不伴有高危细胞遗传学异常的患者相比有降低的趋势(33.3%vs 66.7%,P=0.056)。中位起效时间为1.1(范围0.7~2.7)个月,中位缓解持续时间(疗效≥部分缓解的患者)为7.8(95%CI 5.3~10.2)个月,中位无进展生存期为5.4(95%CI 2.6~8.2)个月,中位总生存期未达到。亚组分析结果显示,伴有髓外浸润、既往治疗线数≥8线的患者倾向于更短的无进展生存期;SPd方案与非SPd方案相比,无进展生存期有延长的趋势。应用塞利尼索时伴有髓外浸润、既往治疗线数≥8线是影响总生存期的不良预后因素(P<0.05)。主要不良反应为血液学毒性,3~4级中性粒细胞降低、淋巴细胞减低、血小板降低发生率分别为39.6%、20.7%、49.0%。因骨髓抑制导致塞利尼索药物减低剂量的发生率为7.7%。非血液学不良反应中,最常见的3~4级不良反应为感染(18.9%)、乏力(16.3%)、恶心呕吐(11.3%)。结论:真实世界中含塞利尼索方案治疗RRMM具有较好的疗效,安全性可控。

Objective: To evaluate the effectiveness and safety of selinexor-based regimens in the treatment of patients with relapsed and refractory multiple myeloma(RRMM) in real world settings. Methods: The clinical data of 53 patients with RRMM who were treated with selinexor-based regimens in 11 centers in China from July 2020 to December 2021 were retrospectively analyzed, and the response, survival and adverse events were evaluated. Results: The median age of the 53 patients with RRMM at the time of treatment with the selinexor-based regimens was 60 years old(range: 41-79). The median time since initial diagnosis was 30 months(range: 1-156). The median number of prior lines of therapy was 4(range: 1-11), including 22 cases(41.5%, 22/53) who had received autologous hematopoietic stem cell transplantation, 8 cases(15.1%, 8/53) who had received CAR-T cell therapy, 34 cases(64.2%, 34/53) who were double-class refractory(proteasome inhibitors and immunomodulators), and 20 cases(37.7%, 20/53) who were triple-class refractory(proteasome inhibitors, immunomodulators and daratumumab). Twenty-four cases(66.7%, 24/36) had high-risk cytogenetics[17 p-/t(14;16)/t(4;14)/1 q21]at onset of the disease, and 20 cases(55.6%, 20/36) had high-risk cytogenetic abnormalities when using selinexor. The responses were evaluable in 47 patients, and the overall response rate was 44.7%(21/47), including 3 cases(6.4%) with complete remission, 4 cases(8.5%) with very good partial remission, and 14 cases(29.8%) with partial remission. Univariate analysis showed that the overall response rate of patients with high-risk cytogenetic abnormality tended to be lower than that of patients without high-risk cytogenetic abnormality(33.3% vs 66.7%, P=0.056). In the responders, the median time to the first response was 1.1 months(range: 0.7-2.7), and the median duration of response was 7.8 months(95%CI 5.3-10.2). The median progression-free survival was 5.4 months(95%CI 2.6-8.2), and the median overall survival had not been reached. Subgroup analysis showed that patients with concomitant extramedullary disease when selinexor was used and a previous treatment line ≥ 8 lines tended to have shorter progression-free survival;compared with the non-SPd regimen, the SPd regimen showed a tendency to prolong the progression-free survival. The extramedullary disease and the number of previous treatment ≥ 8 lines were poor prognostic factors for overall survival(P<0.05). The major grade 3-4 adverse events were hematological toxicity, and the incidences of grade 3-4 neutropenia, lymphopenia, and thrombocytopenia were 39.6%, 20.7% and 49.0%, respectively. The incidence of dose reductions of selinexor due to myelosuppression was 7.7%. Among the non-hematological adverse events, the most common grade 3-4 adverse events were infection(18.9%), fatigue(16.3%), and nausea/vomiting(11.3%). Conclusion: In the real world, the selinesor-based regimens have good effectiveness and safety profile in the treatment of RRMM.