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    Myeloma Novel Drug Targets and agents

    (OA-40) A Novel Dual Proteasome and HDAC6 Inhibitor I3MV-8b Potentiates Anti-CD38 Monoclonal Antibody Efficacy in Multiple Myeloma

    Saturday, September 20, 2025
    11:10 - 11:20 East Coast USA Time
    Location: Room 718

      Abstract Presenter(s)

    • Lanting Liu, MD

      technician
      State Key Laboratory of Experimental Hematology; National Clinical Research Center for Blood Diseases;Haihe Laboratory of Cell Ecosystem; Institute of Hematology & Blood Diseases Hospital; Chinese Academy of Medical Sciences & Peking Union Medical College
      tianjin, Tianjin, China (People's Republic)

    Introduction: Anti-CD38 mAbs are key in multiple myeloma (MM) treatment, with D-VRD as frontline standard. But over 20% of patients develop resistance. Our prior research found I3MV-8b, a new dual proteasome/HDAC6 inhibitor with anti-MM effects. This study showed 8b boosts CD38 on MM cells, restores NK cell cytotoxicity, and enhances anti-CD38 mAb efficacy in MM treatment.

    Methods:

    The study used C57BL/KaLwRij and NK-humanized NSG mouse models to evaluate 8b's immunomodulatory effects and Dara-mediated ADCC efficacy in vivo. Mouse bone marrow immune profiling was done by multicolor spectral flow cytometry. An in vitro human NK-MM co-culture system used luciferase assays to assess antibody-dependent cytotoxicity. RNA-seq, ATAC-seq, and ChIP-seq were used to study epigenetic mechanisms.

    Results:

    Compound 8b demonstrated potent immunomodulatory effects in vivo. It expanded the populations of natural killer (NK) cells, CD8⁺T cells, dendritic cells, and γδT cells, and simultaneously enhanced the production of interferon-γ (IFN-γ) within the tumor immunosuppressive microenvironment. Concurrently, 8b attenuated the infiltration of myeloid-derived suppressor cells (MDSCs) and downregulated the TIGIT exhaustion markers on NK and CD8⁺T cells. Furthermore, 8b significantly enhanced the efficacy of anti-CD38 antibodies (Dara) in both NK-humanized NSG mouse models and human NK-MM co-culture systems. Considering the crucial role of CD38 antigen expression in therapy and the biological characteristics of 8b, a dual inhibitor of proteasome and histone deacetylase 6 (HDAC6), we evaluated the impact of 8b on CD38 expression in MM cells and explored the underlying mechanisms. Transcriptomic and flow cytometry analyses revealed that 8b induced CD38 upregulation in MM cell lines and primary cells. Mechanistically, Western blot analysis showed that 8b significantly increased CD38 levels by enhancing histone H3 lysine 27 acetylation (H3K27ac). Co-immunoprecipitation (Co-IP) data indicated that 8b disrupted the binding between H3K27ac and HDAC6. Chromatin immunoprecipitation sequencing (ChIP-seq) confirmed the enrichment of the CD38 enhancer, and integrated assay for transposase-accessible chromatin using sequencing (ATAC-seq) and ChIP-quantitative polymerase chain reaction (ChIP-qPCR) validated the epigenetically-driven transcriptional activation of CD38 in MM cells. Simultaneously, proteasome modulation counteracted PSMB4-driven CD38 degradation in patients resistant to the D-VRD regimen. Treatment with 8b significantly suppressed CD38 degradation.

    Conclusions: Our findings show I3MV-8b is a new therapeutic strategy. It overcomes MM resistance through dual epigenetic/proteasomal regulation. It activates CD38 transcriptionally via chromatin remodeling, stabilizes its protein expression, restores NK cytotoxicity synergistically (enhancing IFN-γ/suppressing TIGIT), and potentiates anti-CD38 antibody efficacy.