mezigdomide + tazemetostat + dexamethasone

**mezigdomide + tazemetostat + dexamethasone** is an investigational all-oral combination therapy for relapsed/refractory multiple myeloma. The regimen combines: - **Mezigdomide**, a next-generation Cereblon E3 ligase modulator (CELMoD), which induces degradation of specific transcription factors (Ikaros and Aiolos) in myeloma cells, leading to immune system activation and direct tumor cell killing. - **Tazemetostat**, an oral inhibitor of Enhancer of Zeste Homolog 2 (EZH2), a methyltransferase in the PRC2 complex that is frequently dysregulated in myeloma, resulting in epigenetic silencing of tumor suppressor genes. - **Dexamethasone**, a synthetic glucocorticoid steroid that is broadly immunosuppressive and cytotoxic to myeloma cells, also used to synergize and reduce inflammation. Clinical trials (CA057-003, NCT05372354) show the combination has a promising response rate (about 60%), including in heavily pre-treated, triple-class refractory multiple myeloma, with a manageable safety profile, and no new safety signals beyond single-agent mezigdomide. Mezigdomide-based combinations activate key T-cell subsets, enhancing immune function in patients who failed prior immunotherapies. The regimen is notable for using entirely oral agents and is being investigated in phase 1/2 settings for refractory disease[1][2][3][5][6].