Mezigdomide as a single agent increased preclinical activity in rearranged (KMT2A-r) and nucleophosmin-mutant (NPM1c) acute myeloid leukemia (AML) cell lines, including those resistant to lenalidomide and iberdomide, according to a recent study.
Meanwhile, combining mezigdomide with the menin inhibitor VTP-50469 improved patient survival and prevented or overcame MEN1 mutations that mediate resistance in patients treated with menin inhibitor monotherapy. In fact, mezigdomide had the greatest capacity to synergize with menin inhibitors and MEN1 mutant models.
Wallace Bourgeois, MD, and colleagues discovered that mezigdomide was efficacious in five patient-derived xenograft models of KMT2A-r and one of NPM1c AML. This efficacy is attributed to the increased depth, rate, and duration of IKAROS protein degradation of mezigdomide.
“These results support prioritization of mezigdomide for early-phase clinical trials in KMT2A-r and NPM1c AML, either as a single agent or in combination with menin inhibitors,” the researchers concluded.
Reference
Bourgeois W, Cutler JA, Aubrey BJ, et al. Mezigdomide is effective alone and in combination with menin inhibition in pre-clinical models of KMT2A-r and NPM1c AML. Blood. 2023. doi.org/10.1182/blood.2023021105