Presentation on Menin Inhibitors Strives to Stay Ahead of the Progress

Eunice Wang, MD, chief of the leukemia service at Roswell Park Comprehensive Cancer Center, was candid about the tall order she faced delivering an overview of menin inhibitors near the end of the 67th American Society of Hematology Annual Meeting & Exhibition. She joked that hers was “the 234th session on menin inhibitors during this ASH meeting,” and that “the major challenge in giving this talk was to continually update my slides for the latest presentation here during this meeting.”

Humor aside, Wang delivered on a major task before a packed session: menin inhibitors already have offered a breakthrough in targeted therapy for acute leukemias that harbor KMT2A rearrangements or NPM1 mutations. And there’s more to come.

Eunice Wang, MD | Image: Roswell Park CCC

Wang explained that while the menin gene was "initially identified as a germline mutation in patients with multiple endocrine neoplasm type 1 syndrome," researchers discovered it plays a crucial role in leukemia genesis.

She reviewed the menin protein’s function as a nuclear scaffold protein that interacts with the KMT2A transcriptional complex. Rather than targeting this complex directly, which she noted had been attempted “for years with no success,” menin inhibitors block the protein-protein interaction between menin and the KMT2A complex.

In doing so, Wang explained, “We can inhibit the activation and function of the KMT2A complex, removing it from the DNA and leading to downstream biological processes, including cell death as well as myeloid blast differentiation.”

Her presentation and an accompanying paper,1 coauthored with Rahul Thakur, MD, reviewed clinical data from multiple menin inhibitors now in development. Two agents—revumenib (Revuforj; Syndax) and ziftomenib (Komzifti; Kura Oncology)—have received FDA approval.2,3 Across all inhibitors, which include investigational agents bleximenib (Johnson & Johnson) and enzomenib (Sumitomo), monotherapy achieves composite complete remission rates of approximately 20% to 30% in relapsed/refractory disease, with overall response rates reaching 40% to 60%.1

However, Wang noted a critical limitation. “The median duration of response in the relapse refractory population is about 4 to 6, maybe 7 or 8 months,” she said. “So, we are not getting a year or more survival with monotherapy with these agents, and therefore we need to move beyond them.”

Managing Toxicities

Wang spent time explaining differentiation syndrome, a “dose-limiting toxicity” of early studies. This adverse event (AE) typically occurs in cycle 1 with a median presentation somewhere between 14 to 15 to 16 days, she said. Patients present with increased white blood cell counts, she said, and “almost like an HLH-like clinical syndrome,” or hemophagocytic lymphohistiocytosis, due to cytokine release. Management strategies include prophylactic steroids for high-risk patients, hydroxyurea to reduce white blood cell counts before treatment initiation, and close monitoring.

Wang doesn’t take chances. “For some patients that live at a distance, I have them admitted for the first 3 to 5 days of initiating a menin inhibitor,” she said.

QTC prolongation emerged as another significant concern, particularly with revumenib, affecting “up to 20% or more patients developing grade 3 or more treatment-related” AEs. Other agents demonstrated lower rates of this complication.

Triplet Therapy Offers a Path Forward

Investigators now seek more durable responses by combining menin inhibitors with standard chemotherapy backbones, and Wang presented data showing dramatic improvements with triplet regimens. In relapsed/refractory settings, combinations with venetoclax (Venclexta; AbbVie) and azacitidine (Onureg; Bristol Myers Squibb) achieved “overall response rates now about 80%,” and the complete response (CR) rates have climbed as well. “Instead of being 23%, [they] are now doubled with the addition of the other 2 agents,” she said.

In newly diagnosed patients, results were even more impressive. Multiple trials demonstrated response rates of 90% to 100%; Wang noted that in the Beat AML trial, there were “no patients with refractory disease after 1-2 cycles.”4,5 Importantly, differentiation syndrome rates decreased with combination therapy due to “the cytotoxic features and the cytoreduction that you're getting with the combination regimens.”

Resistance and Future Directions

Wang acknowledged that rapid development of resistance mutations remains a challenge, with mutations emerging “within a matter of months.” In their paper, Thakur and Wang note the possibility of the development of somatic mutations that could create cross-resistance to other menin inhibitors, driving the need for next-generation therapies and more combination approaches.1

“We are all eagerly awaiting phase 3 randomized trial data,” she said, which will determine whether menin inhibitors combined with intensive or nonintensive chemotherapy should become standard of care.

She’s optimistic. “These response rates suggest that they may at some point overtake what we consider a standard of care in the current era."

References

1. Thakur RK, Wang ES. The promise of menin inhibitors: from approval to triplet regimens. Hematology Am Soc Hematol Educ Program. 2025;2025(1):599-606. doi:10.1182/hematology.2025000755
2. Joszt L. Revumenib granted FDA approval for R/R NPM1-mutated AML. AJMC. October 24, 2025. Accessed December 14, 2025. https://www.ajmc.com/view/revumenib-granted-fda-approval-for-r-r-npm1-mutated-aml
3. Joszt L. FDA approves ziftomenib for R/R NPM1-mutated AML. AJMC. November 13, 2025. Accessed December 14, 2025. https://www.ajmc.com/view/fda-approves-ziftomenib-for-r-r-npm1-mutated-aml
4. Beat AML is transforming treatment for people with acute myeloid leukemia. Blood Cancer United. Accessed December 14, 2025. https://bloodcancerunited.org/research/beat-aml-bringing-precision-medicine-patients-clinical-trial
5. Zeidner JF, Lin TL, Welkie RL, et al. Azacitidine, venetoclax and revumenib for newly diagnosed NPM1-mutated or KMT2A-rearranged AML. J Clin Oncol. 2025;43(23):2606-2615. doi:10.1200/JCO-25-00914.