Proinflammatory Macrophages Promote Multiple Myeloma Resistance to Bortezomib Therapy

Multiple myeloma (MM) is a plasma cell neoplasia commonly treated with proteasome inhibitors such as bortezomib. While bortezomib has demonstrated enhanced survival benefit, some patients relapse and subsequently develop resistance to such therapy. Here, we investigate the mechanisms underlying relapse and refractory MM following bortezomib treatment. We show that bortezomib-exposed pro-inflammatory macrophages promote an enrichment of MM-tumor initiating cells (MM-TICs) both in-vitro and in-vivo. These effects are regulated in part by IL-1β, as blocking the IL-1β axis by a pharmacological or genetic approach abolishes bortezomib-induced MM-TIC enrichment. In MM patients treated with bortezomib, high pro-inflammatory macrophages in the bone marrow negatively correlates with survival rates [(HR-1.722 (95%CI:1.138,2.608)]. Furthermore, a positive correlation between pro-inflammatory macrophages and TICs in the bone marrow was also found. Overall, our results uncover a pro-tumorigenic cross-talk involving pro-inflammatory macrophages and MM cells in response to bortezomib therapy, a process that enriches the MM-TIC population. Implications: Our findings suggest that pro-inflammatory macrophages in bone marrow biopsies represent a potential prognostic biomarker for acquired MM resistance to bortezomib therapy.