Aberrant lipid metabolism is now recognized as a key feature of cancer cells. Our initial research on mass spectrometry-based analysis of lipids in a multiple myeloma (MM) cell line showed a significant accumulation of lipids in MM cells after proteasome inhibition. This finding prompted us to hypothesize that MM cell survival depends on the maximal utilization of abnormally accumulated lipids. Therefore, we explored whether lipid metabolism-modulating agents would synergize with proteasome inhibitors (PIs).The abnormal massive lipid accumulation in MM cells was detected using mass spectrometry. Cell viability and cell apoptosis were detected to assess the synergistic effect of lipid regulators and PIs. Otherwise, a novel stable derivative (FCE) of fenofibrate (FEN) was synthesized and used to treat MM cells in vitro and in vivo along with ixazomib. ChIP-seq, western blotting and RT-qPCR were performed to explore the potential mechanism underlying the increase in lipid levels in MM cells after proteasome inhibition.The accumulation of lipids in MM cells was induced by proteasome inhibition. Lipid-lowering drugs and MG-132 exerted a synergistic effect to kill MM cells. FCE showed significant synergistic activity in vitro and in vivo with ixazomib. The abnormal lipid accumulation in MM cells that was enhanced by proteasome inhibitors might be due to the elevated SREBP1/2 expression induced by ATF4.In summary, the results provide a proof of principle and rationale for the further clinical evaluation of the combination of lipid-modulating drugs with proteasome inhibitors.This article is protected by copyright. All rights reserved.