Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Clinica São Germano, São Paulo, Brazil.
Br J Haematol. 2022 Jul;198(2):244-256. doi: 10.1111/bjh.18185. Epub 2022 Apr 3.
Immunomodulatory imide drugs (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (MoAbs) are the pillars of modern multiple myeloma (MM) therapy. The prognosis of patients with MM that became refractory to these three classes (triple-class refractory [TCR]) is historically poor. Observational studies indicate an overall response rate of ~30% and overall survival inferior to 1 year with existing therapies. While no randomised trial has been completed in this setting, several agents exploring new mechanisms of action showed activity in TCR MM in single-arm trials, including anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cells, anti-BCMA antibody-drug conjugates and exportin 1 (XPO1) inhibitors. Among agents in development, anti-BCMA bispecific T-cell engagers (TCE), and non-BCMA TCEs demonstrated activity in most patients. Additionally, specific agents may exhibit unique activity in biologically defined patient subsets, as exemplified by venetoclax in t(11;14) MM. The main open questions in TCR MM are preferred sequence of existing therapies, the utility of sequential use of agents with similar mechanism of action, but different immunotherapy target and the relative efficacy of the different anti-BCMA platforms. Here, we summarise the existing literature and provide general guidance on selecting therapy for this challenging and heterogenous group of patients.
免疫调节亚胺类药物（IMiDs）、蛋白酶体抑制剂（PIs）和抗 CD38 单克隆抗体（MoAbs）是现代多发性骨髓瘤（MM）治疗的三大支柱。既往对于对这三类药物（三重难治性 [TCR]）耐药的 MM 患者，预后较差。观察性研究表明，现有治疗方法的总体缓解率约为 30%，总生存期不到 1 年。虽然在此背景下尚未完成随机试验，但在 TCR MM 的单臂试验中，一些探索新作用机制的药物显示出活性，包括抗 B 细胞成熟抗原（BCMA）嵌合抗原受体 T 细胞、抗 BCMA 抗体药物偶联物和 exportin 1（XPO1）抑制剂。在开发中的药物中，抗 BCMA 双特异性 T 细胞衔接器（TCE）和非 BCMA TCE 在大多数患者中均表现出活性。此外，特定的药物可能在生物学定义的患者亚群中表现出独特的活性，如 t（11；14）MM 中的 venetoclax。在 TCR MM 中，主要的开放性问题是现有治疗方案的首选顺序、具有相似作用机制的药物序贯使用的效用、不同免疫治疗靶点的相对疗效以及不同的抗 BCMA 平台的相对疗效。在这里，我们总结了现有文献，并为这组具有挑战性和异质性的患者选择治疗方法提供了一般指导。
