Amin Sobh, PhD, is a research assistant professor in the Division of Hematology/Oncology at the University of Florida College of Medicine

Amin Sobh, MD

“[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.

Videos

Armin Sobh, PhD, discusses the therapeutic potential of selectively targeting NSD2 in the treatment of multiple myeloma.

Dr Sobh on the Therapeutic Potential of Selectively Targeting NSD2 in Multiple Myeloma

Dr Sobh on Ongoing Investigations of NSD2 in Modulating Immune Surveillance in Myeloma

"We have done a lot of the in vitro components, but the next step would be working in a mouse model. We're trying to optimize the conditions. We had some challenges overexpressing NSD in mouse cells, but we're heading toward success with this model."

Amin Sobh, PhD, a research assistant professor in the Division of Hematology/Oncology at the University of Florida College of Medicine, discussed ongoing efforts to investigate the role of NSD2 expression in modulating immune surveillance in multiple myeloma, with a focus on the development of in vivo models to validate prior in vitro findings.

NSD2 is a histone methyltransferase that is frequently overexpressed in patients with multiple myeloma harboring the t(4;14) translocation. In addition to its role in driving oncogenic transcriptional programs, NSD2 has emerged as a potential contributor to immune evasion in the tumor microenvironment. Prior work has demonstrated that NSD2 overexpression could alter immune signaling and reduce tumor immunogenicity, highlighting it as a candidate therapeutic target.

Following completion of in vitro studies, such as the one presented by Sobh and colleagues at the 2025 AACR Annual Meeting, future research is aiming to establish a murine model of NSD2 overexpression to further explore its immunomodulatory effects in vivo. 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 how NSD2-driven changes in myeloma cells affect immune recognition and clearance, he added.

In addition to characterizing the impact of NSD2 overexpression on immune surveillance, Sobh and colleagues plan to evaluate the efficacy of NSD2 inhibition in vivo. A selective NSD2 inhibitor currently in clinical development will be tested in these models 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.

Amin Sobh, PhD, discusses ongoing efforts to investigate the role of NSD2 expression in modulating immune surveillance in multiple myeloma.

Dr Sobh on the Effects of NSD2 Overexpression in Multiple Myeloma

“Our major finding so far is that we noticed that NSD2 over-expressing cells result in cell secreting something that can express MHC class II molecules on immune cells, and we believe that this will have immunosuppressive effects in an in vivo environment.”

Amin Sobh, PhD, a research assistant professor in the Division of Hematology/Oncology at the University of Florida College of Medicine, discussed findings from a study investigating the role that NSD2 plays in modulating immune surveillance in multiple myeloma.

NSD2 is a histone methyltransferase gene that is overexpressed in approximately 15% of patients with multiple myeloma harboring 4;14 translocations (t(4;14)), and overexpression of this gene may lead to immune evasion in tumors. Therefore, NSD2-mediated immune suppression may have therapeutic benefits in certain subsets of patients with this malignancy.

Based on this knowledge, Sobh and colleagues performed a multiomics analysis to investigate the role of NSD2 on immune surveillance in isogenic t(4;14) multiple myeloma cell lines with various NSD2 expression levels.

Preliminary findings from this study presented at the 

 showed that NSD2 overexpression affects cell metabolism and metabolite secretion, Sobh said. Overexpression of NSD2 leads to both secretion of metabolites that can inhibit the immune system and inhibition of metabolites that can stimulate the immune system, he explained. NSD2 overexpression also leads to cell secretion of soluble factors that suppress MHC class II molecules on immune cells, which may have immunosuppressive effects in vivo and contribute to the aggressiveness of this disease subset, he reported. 

Furthermore, flow cytometry demonstrated that genetic or pharmacological NSD2 disruption increased MHC-II expression levels. Additionally, cytokine profiling of human and murine myeloma cell lines showed that NSD2 inhibition suppressed production of interleukin-10, which is a known suppressor of MHC-II expression. Ongoing research in MOPC315.BM multiple myeloma mouse models may further demonstrate the effects of NSD2 on immune response. 

Amin Sobh, PhD, discusses findings from a study investigating the immune surveillance–modulating capabilities of NSD2 overexpression in multiple myeloma.

Amin Sobh, PhD

Articles

Dr Sobh on the Therapeutic Potential of Selectively Targeting NSD2 in Multiple Myeloma

Dr Sobh on Ongoing Investigations of NSD2 in Modulating Immune Surveillance in Myeloma

Dr Sobh on the Effects of NSD2 Overexpression in Multiple Myeloma