Menin Inhibitors: A New Era of Targeted Therapies in Acute Myeloid Leukemia.

opinion statementMenin is involved in protein-protein interactions that are critical in the leukemogenesis of AML, particularly in patients with KMT2A rearrangements (KMT2Ar) and mutations in NPM1 (NPM1m). Revumenib is a first-in-class menin inhibitor approved by the U.S. Food and Drug Administration (FDA) in November 2024 for relapsed/refractory (R/R) acute leukemia with KMT2Ar. Revumenib was subsequently FDA-approved in October 2025 for R/R NPM1m AML, followed by approval of another oral menin inhibitor, ziftomenib, for R/R NPM1m AML in November 2025. These agents, along with other investigational menin inhibitors including bleximenib and enzomenib are being investigated in ongoing clinical trials as both single-agents and in combination with other chemotherapy agents in AML. Menin inhibitors have demonstrated clinical activity as single agents in KMT2Ar and NPM1m AML. However, the pharmacokinetics, safety profile, and selective activity varies among the available and investigational menin inhibitors. Despite these encouraging results, resistance mechanisms have been identified via mutations of the MEN1 gene and structural mutations in the menin binding pocket. As current and future clinical trials are completed, menin inhibitors are likely to play a large role in frontline and R/R treatment in KMT2Ar and NPM1m AML with likely expansion into populations of other genetic abnormalities.