Multiple Myeloma Cell-Derived Secretome Modulates Bone Marrow Mesenchymal Stromal Cell Migration In Vitro.

Multiple myeloma (MM) depends on a permissive bone marrow microenvironment that supports malignant plasma cell survival and disease progression. Bone marrow mesenchymal stromal cells (BM-MSCs) are key components of this niche, but the mechanisms by which they are recruited by MM cells remain unclear. Here, we show that the MM-derived secretome (MM-Sec) promotes BM-MSC wound closure and transwell migration-associated responses in vitro. A small extracellular vesicle (sEV)-enriched pellet was isolated from MM.1S-Sec by differential ultracentrifugation and characterized, and the relative contributions of the sEV-enriched fraction and sEV-depleted secretome (post-100,000× g) to BM-MSC migration were assessed. The results show that the sEV-depleted secretome is more effective than the sEV-enriched fraction in promoting BM-MSC recruitment. Chemokine profiling of MM.1S-Sec identified CCL3 (MIP-1α) and CCL5 (RANTES) as abundant secreted factors and exploratory candidate contributors. Recombinant CCL3 and CCL5 increased the BM-MSC transwell migration response at high concentrations. Priming with MM.1S-Sec was associated with increased transwell migration-associated responses in the presence of CCL3 and CCL5. Together, these exploratory findings suggest that both vesicle-associated and soluble non-vesicular components may contribute to BM-MSC migration, while CCL3 and CCL5 may participate as candidate contributors within a broader network of soluble mediators. These findings identify secretome-mediated modulation of stromal migration as a relevant component of MM-microenvironment crosstalk that warrants further mechanistic investigation.