Synergistic targeting of the ARID2-MYC axis by pomalidomide and panobinostat overcomes intrinsic IMiD resistance in multiple myeloma.

Multiple myeloma remains a therapeutic challenge despite recent advances with proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies. Among new approaches, the combination of IMiDs and histone deacetylase inhibitors has shown promise in relapsed or refractory multiple myeloma. Here, we elucidate the molecular basis of their synergy and its role in overcoming drug resistance in myeloma cells. We demonstrate that these agents converge to downregulate the master oncogene MYC, resulting in synergistic cytotoxicity. Importantly, this effect persists even in models intrinsically resistant to IMiDs, where the canonical IKZF1/3-IRF4/MYC axis is functionally uncoupled. In this context, the combination engages an alternative ARID2-MYC axis, mediated by the synergistic downregulation of the IMiD neosubstrate ARID2. This finding highlights the functional relevance of IMiD's inherent polypharmacology in circumventing primary resistance mechanisms at the cellular level. Together, our results identify the ARID2-containing PBAF complex as a critical vulnerability in resistant myeloma cells and provide a mechanistic rationale for designing combination strategies that co-target this complex, with the potential to enhance therapeutic efficacy by overcoming drug resistance.