■多发性骨髓瘤(MM)的治疗正在迅速发展。我们已经看到四联疗法结合了蛋白酶体抑制剂,免疫调节药物(IMiDs),CD38单克隆抗体成为新诊断MM的标准治疗选择,以及批准用于复发/难治性MM的许多新疗法。然而,在多种治疗环境中仍然需要新的治疗选择,包括对一线护理标准的抗拒。
■靶向降解淋巴转录因子IKZF1和IKZF3-Ikaros和Aiolos-通过调节小脑,E3连接酶底物招募者/受体,是IMiDs和称为CELMoD试剂的较新的一类化合物的关键作用机制。两名CELMoD特工,伊伯多胺和美齐多胺,已在MM中表现出实质性的临床前和临床活性,并已进入3期研究。使用文献检索方法,包括检索PubMed(无限时间范围)和国际血液学/肿瘤学会议摘要(2019-2023),包括IKZF1,IKZF3,Ikaros,Aiolos,CELMoD,IMiD,伊伯多米,甲草胺,MM,本文回顾了Ikaros和Aiolos在MM中的重要性,IMiDs和CELMoD试剂的作用机制及其靶向Ikaros和Aiolos的相对效力,和临床前和临床数据的伊伯多胺和美齐多胺。
■新数据表明,伊伯多胺和美齐多胺具有良好的活性,包括在抗IMiD设置中,and,等待第三阶段的调查结果,可以为MM患者提供额外的治疗选择。
UNASSIGNED: The treatment of multiple myeloma (MM) is evolving rapidly. Quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies have emerged as standard-of-care options for newly diagnosed MM, and numerous novel therapies have been approved for relapsed/refractory MM. However, there remains a need for novel options in multiple settings, including refractoriness to frontline standards of care.
UNASSIGNED: Targeting degradation of IKZF1 and IKZF3 - Ikaros and Aiolos - through modulation of cereblon, an E3 ligase substrate recruiter/receptor, is a key mechanism of action of the IMiDs and the CELMoD agents. Two CELMoD agents, iberdomide and mezigdomide, have demonstrated substantial preclinical and clinical activity in MM and have entered phase 3 investigation. Using a literature search methodology comprising searches of PubMed (unlimited time-frame) and international hematology/oncology conference abstracts (2019-2023), this paper reviews the importance of Ikaros and Aiolos in MM, the mechanism of action of the IMiDs and CELMoD agents and their relative potency for targeting Ikaros and Aiolos, and preclinical and clinical data on iberdomide and mezigdomide.
UNASSIGNED: Emerging data suggest that iberdomide and mezigdomide have promising activity, including in IMiD-resistant settings and, pending phase 3 findings, may provide additional treatment options for patients with MM.