Targeting ikaros and Aiolos: reviewing novel protein degraders for the treatment of multiple myeloma, with a focus on iberdomide and mezigdomide.

The treatment of multiple myeloma (MM) is evolving rapidly. We have seen quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies emerge as standard-of-care options for newly diagnosed MM, and numerous novel therapies approved for relapsed/refractory MM. However, there remains an ongoing need for novel treatment options in multiple treatment settings, including refractoriness to frontline standards of care. Targeting degradation of the lymphoid transcription factors 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 more recent class of compounds known as 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) for terms including IKZF1, IKZF3, Ikaros, Aiolos, CELMoD, IMiD, iberdomide, mezigdomide, and MM, 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. Emerging data suggest 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.