Saad Z. Usmani, MD, MBA, FACP, FASCO, spoke with CancerNetwork^® about the findings and potential clinical implications of a phase 1 trial (NCT05651932) evaluating gintemetostat (KTX-1001) as a treatment for patients with relapsed/refractory multiple myeloma, including those whose disease harbor t(4;14). According to findings presented at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition, single-agent gintemetostat demonstrated clinical activity in a heavily pretreated population of patients across different dose-escalation cohorts.

Among 40 evaluable patients, the novel MMSET/NSD2 inhibitor produced 1 very good partial response, 1 partial response, 2 minimal responses, and 12 instances of stable disease. Data also showed a favorable safety and tolerability profile.

Usmani detailed the rationale for investigating gintemetostat based on its unique mechanism of action and ability to target t(4;14) in select patients with multiple myeloma. Additionally, he described how future research initiatives may prioritize combining the agent with other standards of care.

“While we’re all excited about immune therapies, there are patients with high-risk features, including t(4;14), who will have a disease relapse despite those treatments and will need [other] treatment options,” Usmani said. “Developing small molecules that target [this] particular abnormality are going to be important.”

Usmani is a multiple myeloma specialist, cellular therapist, and chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center. He is also a member of the International Myeloma Foundation’s Scientific Advisory Board.

CancerNetwork: What was the background for assessing KTX-1001 among patients with relapsed/refractory multiple myeloma?

Usmani: Multiple myeloma is the second most common blood cancer that occurs in the US. It’s not one disease; there are many different subsets. Among the various biologic subsets, there are [patients with multiple] myeloma who have t(4;14) within the cancer cells. That accounts for about 10% to 15% of all newly diagnosed cases. It’s a unique biologic subtype with clinical characteristics and a different disease course. Historically, these patients would have relapses early. When multiple myeloma cells have t(4;14), that results in an overexpression of this gene called MMSET. It’s also known as NSD2. KTX-1001, is an oral drug that is a potent and selective inhibitor of that gene and leads to epigenetic reprogramming of the multiple myeloma cells and can down regulate the oncogenic signals in those cells.

Mechanistically, what advantages might this novel MMSET/NSD2 inhibitor offer compared with other drug classes in multiple myeloma?

For [patients with] t(4;14) multiple myeloma, we don’t have any therapies available that are specifically targeting that particular pathway. KTX-1001, or gintemetostat, is the first-in-class therapy of this sort that’s being evaluated in this patient population. [It has a] very different mechanism of action and approach compared with other treatments that have been tried for this population in the past.

What were the key efficacy findings to emerge from this study?

This clinical trial was a dose-escalation phase 1 study. Whenever we have a new drug, we must figure out the right dosing to make sure it’s safe for patients. During that process, we also look at efficacy.

Roughly 40 patients were treated on the various cohorts. Almost half of the patients had t(4;14), the rest of the patients had other high-risk karyotypic abnormalities. This was a very heavily pretreated patient population. Most patients had more than 6 prior lines of treatment. They had seen a BCMA CAR T-cell therapy, bispecific [antibody], and a BCMA antibody drug conjugate [ADC]; almost 40% of the patients had received other non-BCMA bispecifics targeting GPRC5D or FcRH5. These patients did not have many options before they went on the study. What we observed both in t(4;14) and some non-t(4;14) [diseases] was durable control of disease, stable disease, minimal responses, and even 1 very good partial response in a [patient without] t(4;14).

What did safety data reveal about KTX-1001 in this population?

The hematologic AEs were significant for thrombocytopenia, and about 30% of the patients had grade 3 or 4 [events]. The rates of neutropenia of grade 3 or higher were lower compared with what we would have expected for this patient population, roughly around 30%, but very well expected for what we would see here in the non-hematologic AEs. Interestingly, infection was not as common. Grade 3 infections were seen in about 12.5% of the patients, along with fatigue in about 10% of the patients as grade 3. No other grade 3 or 4 events were observed as part of this study.

As an oral drug, this bodes well in general for the safety profile that we saw with the hematologic AEs. We’ll have to see as we combine this with other treatments how that signal emerges, but it appears to be consistent for what we would expect for this patient population.

What are the next steps for further researching KTX-1001 in relapsed/refractory multiple myeloma or other populations?

The signal, for [patients with] t(4;14) where we are seeing activity in a heavily pretreated population, appears to be a good signal. Now, the idea is [if] can we combine it with other treatments such as proteasome inhibitors or novel cellular [therapies]. That’s the next step for this t(4;14) patient population. What we know about multiple myeloma is that you have to utilize multiple mechanisms of actions to control the disease, so that is essentially the next step. How do we incorporate this treatment, evaluate it with existing mechanisms of actions, and hope to improve outcomes for these patients over a long duration?

Reference

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