How Can a Novel Small Molecule Manage a Unique Multiple Myeloma Subtype?

Although there is much excitement surrounding novel immunotherapies in the multiple myeloma landscape, it is critical to provide options to patients with unique subsets of disease and abnormalities such as t(4;14), according to Saad Z. Usmani, MD, MBA, FACP, FASCO.

In a conversation with CancerNetwork^®, Usmani discussed the aim of a phase 1 trial (NCT05651932) assessing gintemetostat (KTX-1001) monotherapy among patients with triple-class refractory multiple myeloma. Usmani noted that t(4;14) expression can be observed in approximately 10% to 15% of newly diagnosed multiple myeloma cases, which may correlate with overexpression of MMSET or NSD2 and early relapses. Gintemetostat, an investigational small molecule inhibitor of NSD2, may serve as a therapeutic strategy in this subpopulation of patients.

Data shared at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition showed that among 40 evaluable patients, gintemetostat produced a very good partial response (PR) in 1 patient, a PR in 1, minimal responses in 2, and stable disease in 12.

Usmani is a 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.

Transcript:

Multiple myeloma is the second most common blood cancer that occurs in the US. But 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 kind of a disease course. Historically, these patients would have relapses early. When 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 particular gene and leads to epigenetic reprogramming of the myeloma cells and can down regulate the oncogenic signals in those cells.

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. Developing small molecules that target [this] particular abnormality are going to be important.

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