肿瘤细胞治疗研究
英文原题：Understanding and addressing resistance to IMiDs immunomodulatory compounds in multiple myeloma.
免疫调节药物（IMiDs），包括来那度胺和泊马度胺联合蛋白酶体抑制剂、地塞米松和抗CD38单克隆抗体，在新诊断和复发阶段的多发性骨髓瘤（MM）治疗中发挥着核心作用。
免疫调节药物（IMiD），包括来那度胺和泊马度胺，与蛋白酶体抑制剂、地塞米松及抗 CD38 单克隆抗体联用，在新诊断和复发阶段的多发性骨髓瘤（MM）治疗中均发挥核心作用。这些方案显著改善了全球患者结局，使 IMiD 成为 MM 治疗的骨干药物之一。当前正在开发一类更强效的新一代化合物——脑磷脂 E3 连接酶调节剂（CELMoD），有望取代传统 IMiD。此外，以嵌合抗原受体（CAR）T、T 细胞衔接剂和抗体药物偶联物为代表的新型免疫治疗，也越来越多用于复发和难治性骨髓瘤。然而，尽管治疗不断进步，IMiD 方案耐药仍不可避免，是重要临床挑战。了解 IMiD 治疗耐药的生物学基础，对于患者在含 IMiD 方案治疗期间复发时规划并最大化治疗选择至关重要。新兴证据强调，遗传和表观遗传改变、下游信号变化以及骨髓免疫微环境失调均可驱动治疗耐药。本综述探讨耐药发生相关的分子和免疫机制，并提出克服耐药的方法及未来选择，重点关注 IMiD 或 CELMoD 与免疫治疗联用，以及新型药物。
Immunomodulatory drugs (IMiDs), including lenalidomide and pomalidomide in combination with proteasome inhibitors, dexamethasone and anti-CD38 monoclonal antibodies, play a central role in the treatment of multiple myeloma (MM) across newly diagnosed and relapsed stages. These treatment regimens have significantly improved patient outcomes worldwide, establishing IMiDs as one of the backbones of MM therapy. A new generation of more potent compounds called cereblon E3 ligase modulators (CELMoDs) is now being developed to potentially replace the older IMiDs. In addition, novel immunotherapeutic approaches led by chimeric antigen receptor (CAR T), T-cell engagers and antibody-drug conjugates are also increasingly used in relapsed and refractory myeloma patient care. However, despite these advances, resistance to IMiD-based therapies inevitably develops and represents a major clinical challenge. Understanding the biological basis of resistance to IMiD-based therapy is crucial to plan and maximise treatment options for patients when they relapse on IMiD containing regimens. Emerging evidence underscores the role of genetic and epigenetic alterations, changes in downstream signalling, and dysregulation of the bone marrow immune microenvironment in driving therapeutic resistance. In this review, we explore current literature on the molecular and immune mechanisms related to the onset of therapeutic resistance. We then suggest ways to overcome resistance and exemplify options for the future, focusing on immunotherapy combinations with IMiDs or CELMoDs and novel agents.
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