Early data from the phase 1 trial (NCT05651932) of the MMSET/NSD2 inhibitor gintemetostat (KTX-1001) revealed that the agent was tolerable and produced encouraging antitumor activity in a heavily pretreated population of patients with relapsed or refractory multiple myeloma, including those with triple-class–refractory disease and high-risk features such as t(4;14). These results were presented at the
Among 40 patients treated with gintemetostat, 1 patient had a very good partial response, 1 patient had a partial response, 2 patients had a minimal response, and 12 patients had stable disease.
“Single-agent activity was demonstrated in heavily pretreated R/R multiple myeloma including t(4;14) positive patients across different dose-escalation cohorts,” said lead author Saad Usmani, MD, MBA, chief of Myeloma Service at Memorial Sloan Kettering Cancer Center.
Safety and Tolerability
The safety profile from the phase 1 study showed that 75% of patients experienced treatment-emergent adverse events (TEAEs) potentially related to gintemetostat and 45% experienced grade 3 or higher potentially gintemetostat-related TEAEs. Three patients had TEAEs that required a dose reduction.
Twelve patients remained on treatment at the data cutoff date of June 13, 2025. Of the 28 patients who discontinued treatment, progressive disease was the cause for 82%, physician decision for 7.1%, consent withdrawal for 7.1%, and TEAE for 3.6% (1 patient).
The most common grade 3/4hematologic TEAEs were thrombocytopenia (grade 3, 10%; grade 4, 20%), anemia (25%; 0%), neutropenia (25%; 5%), and febrile neutropenia (5%; 0%). The most common grade 3 nonhematologic TEAEs were infections (12.5%) and fatigue (10%).
There were 2 patient deaths, both of which were not related to gintemetostat treatment. One patient death was due to respiratory failure and the other was due to pleural effusion.
Study Background, Design, and Patient Characteristics
Regarding the rationale for the study, Usmani explained, “Overexpression of MMSET—also known as NSD2—often results from t(4;14) and is associated with poor clinical outcomes in patients with multiple myeloma.”
Accordingly, Usmani et al sought to explore the safety and efficacy of gintemetostat, an oral, first-in-class, potent and selective inhibitor of MMSET4 in patients with R/R multiple myeloma.
The ongoing, open-label, multicenter phase 1 dose escalation/expansion study of gintemetostat has accrued 40 patients with R/R multiple myeloma. The study is enrolling patients aged ≥18 years with R/R multiple myeloma who have received at least 3 prior therapies, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody.
The median age of the 40 patients in the dose-escalation phase was 69 years (range, 50–83) and 52.5% of patients were female. The ECOG performance status was 0 (22.5%) and 1 (77.5%). The median time since initial diagnosis was 8 years (range, 2–20). About one-third (32.5%) of patients had extramedullary disease and 30% had high-risk multiple myeloma per IMWG criteria.
Regarding cytogenetic abnormalities, 47.5% of patients had t(4;14), comprising 20% with t(4;14) with 1q+ or del(1p32), and 27.5% with t(4;14) alone. Further, 1 patient had t(14;20), 5 had 1q21 amplification, and 4 had del(17p).
The median number of prior lines of therapy was 6.5 (range, 3–25), with 77.5% of patients having received at least 5 lines of therapy. Seventy percent of patients had prior stem cell transplant.
Prior drug classes of therapy received included IMiD/PI (100%), anti-CD38 (98%), BCMA CAR-T (42.5%), BCMA-targeted bispecific antibodies (BsAb) and antibody-drug conjugates (57.5%), GPRC5D-targeted BsAb (32.5%), and FcRH5-targeted BsAb (7.5%). All patients except 1 were triple-drug exposed and 80% were penta-drug exposed.
Overall, 9 dose levels have been assessed using a 3+3 dose-escalation design. Gintemetostat is being administered orally in a 28-day cycle. Usmani did not provide the specific details of the what the different dose levels were.
Regarding pharmacokinetics, Usmani said, “Gintemetostat plasma concentrations increased with dose across all 9 dose levels tested, and at steady-state, moderate variability in exposure of gintemetostat was observed.”
Summary and Next Steps
In a news release accompanying the presentation at the ASH meeting, a statement from Usmani summarized the findings and next steps with gintemetostat.
“In the dose-escalation phase, gintemetostat monotherapy showed a favorable safety and tolerability profile and demonstrated disease control and efficacy. Pharmacodynamic data confirm target engagement, and we look forward to advancing into the dose-expansion phase to evaluate combinations with proteasome inhibitors, IMiDs, and next-generation CELMoDs such as mezigdomide,” stated Usmani.2
References
1. Usmani S, Bories P, Gasparetto C, et al. Phase 1 study of ktx-1001, a first-in-class oral MMSET/NSD2 inhibitor, demonstrates clinical activity in relapsed/refractory multiple myeloma. Blood. 2025;146(suppl 1): 250. doi:10.1182/blood-2025-250
2. K36 Therapeutics announces presentation of First-in-Human Clinical Data for Gintemetostat (KTX-1001) Demonstrating Target Engagement and Clinical Activity in Multiple Myeloma at ASH 2025 and the Appointment of Dr. Shinta Cheng, M.D., Ph.D., as Chief Medical Officer. Published online December 5, 2025. Accessed December 7, 2025.