Multiple myeloma (MM) is a malignancy of plasma cells marked by high epigenetic plasticity, enabling cancer cells to survive, evolve, and acquire resistance to therapy without altering their underlying DNA sequence. One key epigenetic driver of this plasticity is H3K36me2 which is catalyzed by NSD2.
NSD2 is frequently overexpressed in MM, particularly in patients harboring the t(4;14) chromosomal translocation, a high-risk cytogenetic subtype associated with poor prognosis. Elevated NSD2 activity leads to global increases in H3K36me2, altering chromatin structure and activating transcriptional programs that drive tumor growth, immune evasion, and resistance to proteasome inhibitors and other standard therapies.

At K36, we are developing KTX-1001, a potent and selective NSD2 inhibitor designed to reduce H3K36me2 levels and reverse oncogenic transcriptional programs in NSD2-dysregulated myeloma. By restoring epigenetic balance, KTX-1001 represents a novel approach to re-sensitize tumors to treatment and disrupt key survival pathways.

In preclinical studies, KTX-1001 has demonstrated:

•    Robust reduction in H3K36me2 in t(4;14)+ MM models
•    Suppression of proliferation and induction of apoptosis in NSD2-high MM cell lines
•    Synergistic activity when combined with proteasome inhibitors, IMiDs, and CELMoDs

These findings support a strategy of epigenetic priming, where NSD2 inhibition enhances the effectiveness of existing therapies and overcomes adaptive resistance mechanisms.

KTX-1001 is currently in clinical development for patients with relapsed/refractory MM, including those with high-risk cytogenetics. Early clinical data demonstrate:

•    Target engagement, as measured by H3K36me2 suppression in patient samples
•    Emerging signals of clinical activity in heavily pretreated patients
•    A manageable safety profile consistent with a first-in-class epigenetic therapy

By targeting a core epigenetic driver of disease progression, KTX-1001 offers a new therapeutic avenue for patients with advanced MM. Our goal is to establish NSD2 inhibition as a foundational strategy in the treatment of epigenetically dysregulated, therapy-resistant MM.