Preliminary Gintemetostat Outcomes Draw Attention to t(4;14) in R/R MM

Translocation 4;14 (t[4;14]) is a high-risk cytogenetic feature that represents a difficult-to-treat subset of relapsed/refractory multiple myeloma (R/R MM). Because it is driven by overexpression of the histone methyltransferase MMSET, inhibition of MMSET/NSD2 is being investigated as a way to treat the t(4;14) subtype more effectively, as patients with this subtype may continue to have disease progression even after receiving the most effective novel therapies.

Results of a phase 1 dose escalation study (NCT05651932) of gintemetostat (KTX-1001), which showed demonstrated favorable efficacy and tolerability, were presented at the 2025 American Society of Hematology Annual Meeting and Exposition.¹ The agent showed activity in 40 patients with or without t(4;14). The patients had a median of 6.5 prior lines of therapy, including B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy and other therapies aimed at treating patients with relapsed/refractory disease.

In an interview with Targeted Oncology, Saad Z. Usmani, MD, MBA, FACP, FASCO, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, New York, and member of the International Myeloma Foundation’s Scientific Advisory Board, discussed the implications of the dose-escalation part of the trial and what role he thinks this agent could play in addressing the unmet need in the t(4;14) population.

Targeted Oncology: What is the background for using gintemetostat in multiple myeloma?

Saad Z. Usmani, MD, MBA, FACP, FASCO: Multiple myeloma is not 1 disease. We have 7 or 8 different biologic subtypes, depending on how you look at it, but 1 common translocation that occurs in the myeloma cells is t(4;14), and it’s present in about 10% to 15% of newly diagnosed patients. It’s a distinct biologic entity, and [patients with this translocation] historically have been known to be at high risk of early relapse or even dying from the disease. This particular kind of myeloma overexpresses the MMSET gene, also called NSD2, and gintemetostat is an oral, first-in-class selective inhibitor of MMSET/NSD2. It binds to and inhibits the catalytic set domain of MMSET, and that reprograms the myeloma cells and decreases the oncogenic signaling.

What is the patient population of this study?

In this clinical trial, we have treated about 40 patients so far in the different cohorts. The majority of these patients, about half of them, had t(4;14); the rest had deletion 17p, 1q amplification, or t(14;20). The median [number of] treatment cycles was more than 6 lines, and all patients were [immunomodulatory drug]– and proteosome inhibitor-refractory. Almost everyone had received an anti-CD38 monoclonal antibody. [Approximately] 40% of the patients had BCMA CAR T in the past, [and] 55% to 57% of the patients had received a BCMA-directed bispecific or antibody-drug conjugate. We also had patients who had had GPRC5D- and FcRH5-targeted bispecific antibodies. Almost 40% of the patients had even the non-BCMA bispecific, so [these are] very late-line patients.

What were the most important findings reported so far from this trial?

What we observed in this heavily pretreated patient population is that, from a safety standpoint, there weren’t many grade 3 or higher [adverse events] when it came to nonhematologic…issues. We did see grade 3 or 4 thrombocytopenia and some neutropenia in patients.

But for the most part, this oral therapy was fairly safe to give, and even with this lower dose going to a higher dose in different cohorts, we started to see clinical activity. Patients who had seen everything remained in stable disease or minimal response. Even patients who did not have t(4;14) did have sustainable responses; in particular, 1 patient had a very good partial response for more than 10 months.

How are the outcomes so far in those with t(4;14) vs other patients?

We were expecting to see clinical responses in the dose escalation, but until you get to a certain dose, which we call the recommended phase 2 dose, we typically treat a lot more patients on that dose, and that’s what we’re doing right now. But we saw clinical activity with both t(4;14) and some non-t(4;14) patients, and we’re trying to understand how that happens, but I suspect it’s likely due to epigenetic downregulation of oncogenic pathways that might be relevant in the non-t(4;14) as well as the t(4;14) patients. But given the clinical activity and what we’re seeing from a safety profile perspective, gintemetostat is now being combined with carfilzomib [Kyprolis] as well as the investigational CELMoD [cereblon E3 ligase modulatory drug] mezigdomide in separate cohorts to see its activity and tolerability.²

What are your plans for the dose-expansion phase and beyond?

The focus now would be again to figure out the right recipe or the dosing of these drugs together, and then look at the clinical activity. We know from many years of developing therapies in myeloma and knowing about its disease biology being heterogeneous [that] you need combination therapies to actually improve outcomes for patients, and that would be the line of investigation here.

What is the role you see this agent playing in multiple myeloma in the future?

I think this is a targeted therapy for translocation for t(4;14) patients. [Although] we’re seeing excellent outcomes in late-relapse patients with T-cell–redirecting therapies, for certain subsets of [patients with myeloma who] have biomarkers that are targetable, we will likely be developing treatments in combination with immunotherapies and other mechanisms of action. That would be the next line of investigation. But first, we have to start with the initial combinations and see what that signal looks like before we move forward, so stay tuned.

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. A study of an MMSET inhibitor in patients with relapsed and refractory multiple myeloma. ClinicalTrials.gov. Updated January 9, 2026. Accessed February 9, 2026. https://clinicaltrials.gov/study/NCT05651932