EZH2-dependent STAT3 stabilization drives pomalidomide resistance and is targetable by EZH2 inhibition in multiple myeloma.

Relapsed/refractory multiple myeloma (RRMM) is characterized by high mortality rates and limited survival, with real-world studies reporting substantial mortality and median survival of only a few years after relapse. Immunomodulatory drugs (IMiDs) are a cornerstone of first-line multiple myeloma (MM) therapy, yet resistance remains a major clinical challenge. Resistance to pomalidomide has been attributed to multiple mechanisms, including CRBN downregulation and activation of pro-survival signaling pathways such as NF-κB; however, the contribution of epigenetic regulators, particularly the STAT3EZH-STAT3 axis, remains insufficiently explored. In this study, our analysis of public datasets identifies significant upregulation of enhancer of zeste homolog 2 (EZH2) in RRMM patients together with an association between EZH2 expression and poor prognosis. Using two established pomalidomide-resistant MM models, we confirm elevated EZH2 expression in pomalidomide-resistant MM cell lines, and demonstrate targeting EZH2 via small interfering RNA or the selective inhibitor GSK343 elicits potent anti-myeloma effects in pomalidomide-resistant MM models. Notably, EZH2 knockdown increases the sensitivity of RRMM cells to pomalidomide, providing a rationale for combining EZH2 inhibition with pomalidomide therapy. Consistent with this observation, GSK343 synergizes with pomalidomide to suppress MM progression both in vitro and in vivo. To better understand the mechanisms involved, we conduct RNA sequencing and investigate potential mediators of EZH2. We find that EZH2 contributes to pomalidomide resistance through stabilizing STAT3 protein, thereby supporting myeloma cell survival under therapeutic stress. In conclusion, EZH2 inhibition can enhance the therapeutic efficacy of pomalidomide against RRMM, indicating that EZH2 offers a promising target for overcoming drug resistance in MM.