First-in-Class MMSET Inhibitor Gintemetostat Shows Clinical Activity in Heavily Pretreated Multiple Myeloma
核心洞察
Gintemetostat (搜索) (KTX-1001), a first-in-class oral MMSET (搜索)/NSD2 (搜索) inhibitor, demonstrated encouraging antitumor activity and manageable safety in 40 heavily pretreated patients with relapsed/refractory multiple myeloma.
Among treated patients, 1 achieved very good partial response, 1 had partial response, 2 had minimal response, and 12 had stable disease, with particularly promising results in t(4;14)-positive patients.
The therapy showed a favorable safety profile with 75% experiencing treatment-related adverse events, while 12 patients remained on treatment at data cutoff.
K36 Therapeutics (搜索) presented promising first-in-human clinical data for gintemetostat (搜索) (KTX-1001), a novel oral MMSET (搜索)/NSD2 (搜索) inhibitor, at the 67th American Society of Hematology Annual Meeting. The Phase 1 dose escalation study demonstrated encouraging antitumor activity and manageable safety in heavily pretreated patients with relapsed or refractory multiple myeloma.
Clinical Efficacy Results
Among 40 patients treated with gintemetostat (搜索) monotherapy, the agent produced measurable clinical responses across different dose levels. One patient achieved a very good partial response, one patient had a partial response, two patients experienced minimal response, and 12 patients achieved stable disease. The activity was particularly notable in patients with t(4;14) translocation, a high-risk genetic abnormality associated with poor prognosis.
"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.
Patient Population and Treatment History
The study enrolled a heavily pretreated population with a median age of 69 years (range 50-83), where 52.5% were female. Patients had received a median of 6.5 prior lines of therapy (range 3-25), with 77.5% having received at least 5 lines of treatment. The median time since initial diagnosis was 8 years (range 2-20).
Notably, 47.5% of patients harbored the t(4;14) translocation, comprising 20% with t(4;14) plus 1q+ or del(1p32), and 27.5% with t(4;14) alone. About one-third (32.5%) had extramedullary disease and 30% had high-risk multiple myeloma per International Myeloma Working Group criteria.
All patients except one were triple-drug exposed, and 80% were penta-drug exposed. Prior therapies included immunomodulatory drugs and proteasome inhibitors (100%), anti-CD38 (搜索) antibodies (98%), BCMA (搜索) CAR-T therapy (42.5%), BCMA-targeted bispecific antibodies and antibody-drug conjugates (57.5%), and GPRC5D (搜索)-targeted bispecific antibodies (32.5%).
Safety and Tolerability Profile
The safety analysis revealed that 75% of patients experienced treatment-emergent adverse events potentially related to gintemetostat (搜索), with 45% experiencing grade 3 or higher potentially treatment-related events. Only three patients required dose reductions due to adverse events.
The most common grade 3/4 hematologic adverse events included thrombocytopenia (grade 3: 10%; grade 4: 20%), anemia (25%; 0%), neutropenia (25%; 5%), and febrile neutropenia (5%; 0%). Among nonhematologic events, grade 3 infections (12.5%) and fatigue (10%) were most frequent.
Twelve patients remained on treatment at the data cutoff date of June 13, 2025. Of the 28 patients who discontinued, progressive disease accounted for 82% of discontinuations, while only one patient (3.6%) discontinued due to treatment-related adverse events. Two patient deaths occurred, both unrelated to gintemetostat (搜索) treatment.
Mechanism and Target Engagement
Gintemetostat (搜索) represents a first-in-class approach targeting MMSET (搜索)/NSD2 (搜索), a methyltransferase whose overexpression often results from t(4;14) translocation and is associated with poor clinical outcomes in multiple myeloma. The oral small molecule demonstrated target engagement through pharmacodynamic data, with plasma concentrations increasing proportionally across all nine dose levels tested.
"We are highly encouraged by the durable disease control achieved with oral, single-agent gintemetostat (搜索), and by the strength of our emerging clinical data, including patients who continue to experience long-standing benefit while remaining on monotherapy," said Dr. Shinta Cheng, newly appointed Chief Medical Officer of K36 Therapeutics (搜索).
Clinical Development Strategy
The ongoing Phase 1 study follows a 3+3 dose-escalation design with gintemetostat (搜索) administered orally in 28-day cycles. The company plans to advance into dose-expansion phases evaluating combinations with established therapies including proteasome inhibitors, immunomodulatory drugs, and next-generation CELMoDs such as mezigdomide.
"Gintemetostat (搜索) is a first-in-class MMSET (搜索) inhibitor with a novel mechanism of action and is being evaluated in combination with both standard and next-generation therapies. Its favorable safety and tolerability profile further support its potential as a foundational therapy for patients with t(4;14) multiple myeloma," Dr. Cheng noted.
Addressing Unmet Medical Need
Multiple myeloma represents the second most common hematologic malignancy, with approximately 36,000 new cases diagnosed annually according to the American Cancer Society. While recent therapeutic advances have extended survival, the disease remains incurable with most patients eventually experiencing relapse.
High-risk multiple myeloma, characterized by genetic abnormalities such as t(4;14), is associated with aggressive disease biology, shorter survival, and limited benefit from standard-of-care regimens. This population represents one of the greatest unmet needs in myeloma research and treatment, making gintemetostat (搜索)'s targeted approach particularly significant for addressing this challenging patient subset.