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Background Renal impairment (RI) caused by deposition of Multiple myeloma (MM) derived free light chains (FLC), is associated with worse MM patient outcomes. Reciprocally, early reduction of serum-FLC improves survival. Proteasome inhibitors (PIs), which target immunoglobulin production in MM, have improved MM survival times but PI-resistance is a major problem. Therefore, novel treatments that target MM cell survival and block FLC secretion are urgently required. Methods MM cell lines and primary cells were treated with VaN with and without PIs and responses assessed using cell viability, annexin V and caspase flow cytometry assays. Autophagy induction was assessed using LC3 westerns. Drug effects on FLC expression was measured using intracellular flow cytometry, qRT-PCR and immunofluorescence. Secretion of FLC in vitro, and in an NSG mouse JJN3-xenograft model was assessed by ELISA. VaN-induced mitochondrial stress was measured using fluorescence probes for mitochondrial membrane potential and reactive oxygen species (ROS). Total RNA sequencing identified modulation of the unfolded protein response by VaN which was validated by western blotting, immunoprecipitations, and immunofluorescence. Results VaN had potent, selective and multifactorial anti-MM activity, including targeting MM cell mitochondrial function and induction of oxidative stress. Importantly, VaN treatment resulted in a rapid and sustained inhibition of FLC secretion in MM cell lines, primary MM samples and in an NSG- xenograft model. VaN induced endoplasmic reticulum stress and activation of the terminal unfolded protein response (UPR) mediated through IRE1α/XBP1 and phosphorylation of PERK. Combining VaN with low doses of the PIs bortezomib (BTZ) or carfilzomib (CFZ) significantly enhanced induction of the UPR, producing higher levels of the terminal UPR protein CHOP and greater MM cell killing. Furthermore, VaN was able to successfully restore induction of CHOP protein expression, terminal UPR and cell killing in BTZ- and CFZ resistant AMO1 MM cells. Conclusion Our findings demonstrate potent anti-MM activity against both PI-sensitive and PI-resistant MM cells. Of particular clinical importance was the ability of VaN to also rapidly and sustainably inhibit FLC secretion. Given the good safety profiles of each drug, we propose VaN as a novel anti-MM therapy with potential in PI-refractory disease and for frailer MM patients.