Posted on January 30, 2026 by OncologyTube TeamThis article discusses the latest developments in menin inhibitors for AML as of 2026.
In this exclusive interview from the MOASC Hematology Spotlight 2026, Dr. Kiran Naqvi, MD, MPH, Associate Clinical Professor of Hematology-Oncology at UCI Health, shares groundbreaking insights into AML advances. Drawing from the latest ASH 2025 data, she discusses the PARADIGM study’s impact on treatment paradigms, the rapidly evolving landscape of menin inhibitors like enzomenib, revumenib, and ziftomenib, and the promise of triplet therapies such as ziftomenib with azacitidine and venetoclax. Whether you’re a hematologist, oncologist, or patient advocate, this deep dive into AML treatment innovations is essential reading.
Kiran Naqvi, MD | UCI Health | Orange County, CA
Dr. Kiran Naqvi, MD, MPH – Expert in AML and Hematology-Oncology at UCI Health
What Is Acute Myeloid Leukemia (AML) and Why Are These Advances Crucial?
Acute myeloid leukemia (AML) is a fast-progressing blood cancer that affects the bone marrow and blood cells. In 2026, AML remains a challenging disease, with relapsed/refractory cases posing significant hurdles. Recent AML advances, including targeted therapies like menin inhibitors, are shifting the treatment landscape from intensive chemotherapy to more tolerable, precision-based options. Dr. Naqvi highlights how these developments, informed by ASH 2025 plenary sessions, could improve survival rates, quality of life, and reduce financial burdens for patients.
Acute myeloid leukemia (AML) morphology: What to know
AML cells under a microscope, illustrating the aggressive nature of this leukemia.
Key AML subtypes discussed include those with KMT2A rearrangements (KMT2Ar) and NPM1 mutations (NPM1m), which account for about 35-40% of cases. These genetic alterations drive leukemogenesis, making them prime targets for menin inhibitors.
PARADIGM Study: A Game-Changer for Fit Patients with Newly Diagnosed AML
The PARADIGM study, presented at ASH 2025’s plenary session, is a phase 2 randomized trial comparing azacitidine plus venetoclax (Aza-Ven) to conventional intensive chemotherapy (IC) in newly diagnosed fit adults with AML. As Dr. Naqvi explains, “The study indicated superior overall response rates and high composite CR rates compared to chemotherapy, though CR rates were similar.”
Key Findings from PARADIGM:
- Patient Population: 172 patients randomized 1:1 to Aza-Ven or IC (7+3 or CPX-351). Median follow-up: 22 months.
- Primary Endpoint Met: Event-free survival (EFS) was superior with Aza-Ven (14.6 months) vs IC (6 months), HR 0.57.
- Response Rates: Overall response rate (ORR) 96% vs 84%; composite complete remission (CRc) 93% vs 72%; CR/CRh 83% vs 70%.
- Safety Advantages: 0% 30/60-day mortality with Aza-Ven vs 5% with IC; fewer infections and bleeding events.
- Quality of Life and Economics: Better QOL, reduced hospitalizations/ICU stays, and lower financial burden with Aza-Ven.
- Transplant Outcomes: Higher transplant rates (36% vs 24%) with Aza-Ven, maintaining EFS benefit post-adjustment.
Dr. Naqvi notes, “For patients with adverse features who are eligible for intensive chemo, PARADIGM supports Aza-Ven as a valid option.” This could mark a paradigm shift away from traditional IC, especially for adverse-risk AML.
For more on AML induction therapies, check our guide to azacitidine and venetoclax in AML.
The Evolving Landscape of Menin Inhibitors in AML
Menin inhibitors target the menin-KMT2A interaction, reversing oncogenesis in NPM1m and KMT2Ar AML. As Dr. Naqvi states, “The landscape of menin inhibitors is growing rapidly.” Two are FDA-approved: revumenib (October 2025 for NPM1m and KMT2Ar) and ziftomenib (November 2025 for NPM1m).
Approved Menin Inhibitors:
- Revumenib: Approved for relapsed/refractory (R/R) KMT2Ar and NPM1m AML. ORR ~63% in KMT2Ar, ~47% in NPM1m; CR/CRh ~23%. Boxed warnings for differentiation syndrome (DS) and QTc prolongation.
- Ziftomenib: Approved for R/R NPM1m AML. ORR ~33%; CR/CRh ~22%. Lower DS (~25%) and QTc (~12%) rates; boxed warning for DS.
Emerging: Enzomenib (DSP-5336)
From the phase 1/2 trial (ASH 2025 abstract 763), enzomenib shows promise in R/R AML:
- Safety: Favorable profile; DS ~13% (Grade ≥3: 7.8%); QTc prolongation ~9.5% (Grade ≥3: 2.6%). No DLTs, treatment-related deaths, or permanent discontinuations due to DS/QTc.
- Efficacy in KMT2Ar: At RP2D (300 mg BID), ORR 73%, CRc 60%, CR/CRh 40%; median DoR 12.5 months; median OS 11.8 months.
- Efficacy in NPM1m: Dose optimization ongoing; CR/CRh 44% at ≥200 mg BID; median DoR 5.7 months; median OS 8.5 months.
- Advantages: Wide therapeutic index, minimal accumulation, no major azole interactions—ideal for patients at risk of drug interactions.
Dr. Naqvi emphasizes, “Enzomenib has a very wide therapeutic index… safety profile is really good in terms of differentiation and QTc prolongation, a little bit better than other menin inhibitors.”
Comparison of Menin Inhibitors (Monotherapy Data):
| Feature | Revumenib | Ziftomenib | Enzomenib | Bleximenib |
|---|---|---|---|---|
| ORR | ~63% (KMT2Ar), ~47% (NPM1m) | ~33% | ~73% (KMT2Ar), ~59% (NPM1m) | ~48-50% |
| CR/CRh | ~23% | ~22% | ~40-47% | ~33% |
| DS (Any/Grade ≥3) | ~28%/16% | ~25%/15% | ~13%/8% | ~13%/7% |
| QTc (Any/Grade ≥3) | ~25%/14% | ~12%/8% | ~9.5%/2.6% | ~1%/1% |
Data sourced from ASH 2025 and recent publications. For full comparisons, see ASH abstracts on menin inhibitors.
Dr. Naqvi likens selection to CML TKIs: “We try to see what comorbidities the patient may have… For heart rhythm issues, revumenib may be more concerning due to QTc; ziftomenib is once-daily for better compliance.”
Triplet Therapies: Adding Menin Inhibitors to Aza-Ven
Triplet regimens are revolutionizing frontline and R/R AML. Dr. Naqvi highlights the KOMET-007 trial (ASH 2025 abstract 766) for ziftomenib + Aza-Ven in newly diagnosed NPM1m AML:
- Study Design: Phase 1b; 40 patients; ziftomenib 600 mg QD + standard Aza-Ven.
- Safety: Comparable to Aza-Ven alone; Grade ≥3 TEAEs 85%; low DS (2.5%, Grade 2) and QTc (2.5%).
- Efficacy: CR 73%, CRc 86%, ORR 89%. In co-mutated subgroups: FLT3 (CR/CRh 77%), IDH (89%).
- MRD Negativity: 68% by central NGS (sensitivity 0.005%); increased with cycles.
- Outcomes: Median DoR/OS not reached after 26.1 weeks follow-up.
As Dr. Naqvi says, “Adding on the ziftomenib, the responses are even more robust… This is definitely a game changer, and in particular, the MRD negativity rate is significantly better with the triple combo.”
In R/R settings (KOMET-007 abstract 764), ziftomenib + Aza-Ven showed ORR 65% (NPM1m) and 41% (KMT2Ar), with CRc 48% and 28%.
These results support ongoing phase 3 trials like KOMET-017.
Clinical trial response rates chart for AML treatments, highlighting menin inhibitor efficacy.
Future Directions and Unmet Needs in AML Treatment
Dr. Naqvi envisions personalization: “It’s going to be very much like CML… choose based on comorbidities, compliance, and side effects.” Challenges include resistance, monitoring for DS/QTc, and optimizing doses. Emerging combinations with intensive chemo or FLT3 inhibitors (e.g., enzomenib + gilteritinib) show promise.
