Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy.
Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy.
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DOI：
10.1038/s41408-023-00802-0
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发表时间：
2023-02-27
影响因子：
12.8
通讯作者：
Bianchi G
中科院分区：
文献类型：
--
作者：
Moscvin M;Liacos CI;Chen T;Theodorakakou F;Fotiou D;Hossain S;Rowell S;Leblebjian H;Regan E;Czarnecki P;Bagnoli F;Bolli N;Richardson P;Rennke HG;Dimopoulos MA;Kastritis E;Bianchi G
血栓性微血管病(TMA)被报道发生在多发性骨髓瘤(MM)患者与卡菲佐米治疗相关，卡菲佐米是一种不可逆转的蛋白酶体抑制剂(PI)。TMA的特点是血管内皮损伤导致微血管病理性溶血性贫血、血小板消耗、纤维蛋白沉积和小血管血栓形成并导致组织缺血。卡菲佐米相关TMA的分子机制尚不清楚。补体替代途径中的种系突变最近被证明预示着儿童患者在异基因干细胞移植中发生非典型溶血性尿毒症综合征(AHUS)和TMA的风险增加。我们假设补体替代途径中的胚系突变可能类似地使多发性骨髓瘤患者易患卡菲佐米相关的TMA。我们确定了10名临床诊断为TMA的多发性骨髓瘤患者，在卡菲佐米治疗的背景下，并评估了补体替代途径中种系突变的存在。10例接受卡非佐米治疗但临床未发现TMA的MM患者作为阴性对照。我们发现在多发性骨髓瘤患者中，补体因子H基因3和1(delCFHR3-CFHR1)以及基因1和4(delCFHR1-CFHR4)的缺失频率高于普通人群和匹配对照组。我们的数据提示补体替代途径失调可能增加多发性骨髓瘤患者血管内皮损伤的易感性，并易于发生卡菲佐米相关的TMA。需要进行更大规模的回顾性研究，以评估是否有必要进行补体突变筛查，以适当地向患者提供有关使用卡菲佐米的TMA风险的建议。
Thrombotic microangiopathy (TMA) has been reported to occur in multiple myeloma (MM) patients in association with treatment with carfilzomib, an irreversible proteasome inhibitor (PI). The hallmark of TMA is vascular endothelial damage leading to microangiopathic hemolytic anemia, platelet consumption, fibrin deposition and small-vessel thrombosis with resultant tissue ischemia. The molecular mechanisms underlying carfilzomib-associated TMA are not known. Germline mutations in the complement alternative pathway have been recently shown to portend increased risk for the development of atypical hemolytic uremic syndrome (aHUS) and TMA in the setting of allogeneic stem cell transplant in pediatric patients. We hypothesized that germline mutations in the complement alternative pathway may similarly predispose MM patients to carfilzomib-associated TMA. We identified 10 MM patients with a clinical diagnosis of TMA in the context of carfilzomib treatment and assessed for the presence of germline mutations in the complement alternative pathway. Ten, matched MM patients exposed to carfilzomib but without clinical TMA were used as negative controls. We identified a frequency of deletions in the complement Factor H genes 3 and 1 (delCFHR3-CFHR1) and genes 1 and 4 (delCFHR1-CFHR4) in MM patients with carfilzomib-associated TMA that was higher as compared to the general population and matched controls. Our data suggest that complement alternative pathway dysregulation may confer susceptibility to vascular endothelial injury in MM patients and predispose to development of carfilzomib-associated TMA. Larger, retrospective studies are needed to evaluate whether screening for complement mutations may be indicated to properly counsel patients about TMA risk with carfilzomib use.
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