Multiple myeloma (MM) remains incurable due to the development of drug resistance. We previously showed that communication between bone marrow stromal cells (BMSCs) and MM cells supports MM growth and triggers therapy resistance. This communication occurs through a plethora of mechanisms, including the release of cytokines and small extracellular vesicles (sEVs). The PDZ protein syntenin is a master regulator of intercellular communication, in particular via sEVs. In this study, we aimed to explore whether targeting syntenin, by genetic alteration or pharmacological inhibition, can disrupt BMSC-MM crosstalk, thereby rendering the MM cells more sensitive to therapy. We found that syntenin (SDCBP) is highly expressed in inflammatory BMSC of MM patients and that its expression in BM aspirates correlates with poor patient survival. Using in vitro models, we established that knockout of syntenin in BMSC alters their secretome and abolishes BMSC-induced bortezomib resistance of MM cells via regulation of STAT3, MAPK, and AKT-mTOR pathways. Pharmacological inhibition of syntenin decreases syntenin and IL-6 sorting into BMSC sEVs and enhances bortezomib-induced MM cell death. Finally, we validated the therapeutic added value of syntenin inhibition in combination with bortezomib in vivo, using the 5TGM1 MM mouse model. In conclusion, our findings show that syntenin supports the secretion of pro-tumoral factors by BMSCs and qualifies as a possible novel therapeutic target in MM.