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Armin Sobh, PhD, discusses the therapeutic potential of selectively targeting NSD2 in the treatment of multiple myeloma.
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“[These findings] point to potential therapeutic strategies that can be used, which involve combining immunotherapies with NSD2 inhibition to get a better response in patients with t(4;14) myeloma."
Armin Sobh, PhD, discussed the therapeutic potential of selectively targeting NSD2 in the treatment of multiple myeloma, particularly in the context of t(4;14)–associated disease. NSD2 is a histone methyltransferase that has been implicated in the pathogenesis of t(4;14) myeloma, where its overexpression contributes to aberrant chromatin remodeling and oncogenic signaling.
According to Sobh, the development of a potent and selective NSD2 inhibitor—currently under clinical investigation—represents a promising strategy to disrupt the epigenetic mechanisms sustaining malignant plasma cell survival. In preclinical models, NSD2 inhibition has demonstrated the capacity to impair myeloma cell viability and enhance immunogenicity, thereby promoting antitumor immune responses. These findings suggest that NSD2 may act as a dual therapeutic target by modulating both intrinsic tumor biology and the extrinsic tumor immune microenvironment.
Sobh emphasized the relevance of this approach in t(4;14) multiple myeloma, a molecular subtype associated with high-risk features and suboptimal outcomes with conventional therapies. NSD2 inhibition in this context may sensitize myeloma cells to immunotherapeutic agents, offering a rationale for combination strategies that pair NSD2 inhibitors with immune-based therapies, such as checkpoint blockade, CAR T-cell therapy, or bispecific antibodies.
Future research is aiming to establish a murine model of NSD2 overexpression to further explore its immunomodulatory effects in vivo, and although achieving stable overexpression of NSD2 in murine cells has been technically challenging, model optimization is ongoing, Sobh said. Once validated, the mouse model will be used to examine NSD2-driven changes in myeloma cells to determine whether pharmacologic targeting of NSD2 can restore immune function and enhance antitumor responses. These investigations will also assess the downstream effects on immune cell activation and cytokine production.
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