Q&A: First-in-Class NSD2 Inhibitor KTX-1001 Shows Promise in High-Risk Multiple Myeloma

In an interview with Pharmacy Times, Saad Usmani, MD, MBA, FACP, FASCO, myeloma specialist and cellular therapist at Memorial Sloan Kettering Cancer Center, discusses KTX-1001 (Gintamatostat; K36 Therapeutics), a first-in-class oral NSD2 inhibitor designed to target a high-risk subtype of multiple myeloma associated with translocation 4;14. Phase 1 results demonstrated early clinical activity, including stable disease, minimal responses, and durable responses lasting up to a year in heavily pretreated patients. The safety profile was largely manageable, with thrombocytopenia as the primary dose-limiting toxicity and limited high-grade non-hematologic adverse events. Usmani emphasized the unmet need in relapsed or refractory myeloma and outlined future plans to combine KTX-1001 with other therapies to improve outcomes across diverse patient populations.

Pharmacy Times: What do the updated Phase 1 results of KTX-1001 tell us about its potential, particularly the 40% disease control rate and durability of response?

Saad Usmani, MD, MBA, FACP, FASCO: We conducted a Phase 1 dose-escalation and dose-expansion study in relapsed or refractory multiple myeloma patients who had received three or more prior lines of treatment with proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. The drug is dosed twice a day, and we started with a very low dose to assess safety and tolerability. In the roughly 40 patients treated so far, the more common adverse events were hematologic, particularly thrombocytopenia, with very few grade 3 or higher issues. Grade 3 or higher infection was observed in 12.5% of patients, and fatigue occurred in about 10%.

We began to see early clinical activity even at lower doses in both translocation 4;14 patients and non–translocation 4;14 patients, including stable disease and minimal response. We also observed a very good partial response, with patients continuing on therapy for 10 to 12 months and beyond. Even in the early cohorts, this demonstrated clinical activity in a difficult-to-treat patient population.

Pharmacy Times: How does KTX-1001’s molecular mechanism differ from existing myeloma therapies, and why does that matter clinically?

Usmani: This compound is a novel agent that selectively inhibits MMSET, or NSD2, making it a targeted therapy. This differs from other myeloma treatments, such as monoclonal antibodies, bispecifics, or CAR T-cell therapies, which are more disease-subtype agnostic. KTX-1001 is a more directed treatment for a specific subtype of myeloma, and that is what makes it different from other available therapies.

Pharmacy Times: In heavily pretreated, relapsed or refractory patients, what is the significance of seeing responses last up to a year?

Usmani: We do not have many options for patients once they become triple-class exposed or refractory, or refractory to newer treatments such as bispecific antibodies and CAR T-cell therapies. In this study, more than half of the patient population was BCMA-exposed and refractory, which is important to highlight. Seeing these types of disease responses tells us there is meaningful activity. The next step would be to combine this treatment with other therapies to see if we can achieve better outcomes, as this remains an area of unmet need.

Pharmacy Times: How would you describe the safety and tolerability profile of KTX-1001 based on the Phase 1 data?

Usmani: I alluded to the safety profile earlier, particularly regarding hematologic adverse events such as thrombocytopenia. Thrombocytopenia was the dose-limiting toxicity at dose level eight at grade 4, and patients at dose level nine also experienced thrombocytopenia. This has been a consistent observation. Aside from that, non-hematologic treatment-emergent adverse events were mostly grade 1 or 2, with very few grade 3 events. Grade 3 infection occurred in 12.5% of patients, and grade 3 fatigue occurred in 10%.

Pharmacy Times: Multiple myeloma disproportionately affects Black patients. How could a targeted therapy like KTX-1001 help address unmet needs in this population?

Usmani: This is a very important question. Over the past five to six years, the field has worked hard to be more inclusive in clinical trial enrollment. To my knowledge, there is no disproportionate prevalence of translocation 4;14 in the Black population. However, this treatment would benefit eligible patients equally. The next steps involve combining KTX-1001 with proteasome inhibitors, immunomodulatory drugs, and potentially other immune therapies to improve outcomes for this subset of myeloma patients, regardless of racial or ethnic background.