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Phospholipase D1 (PLD1) is an enzyme of the phospholipase D (PLD) superfamily. It is involved in the occurrence of various tumors. However, its role in multiple myeloma (MM) remained undefined. This study aimed to investigate the mechanism of PLD1 in the therapy of myeloma disease. Cell lines U266 and H929 were treated with PLD1 specific inhibitor VU0359595 combined bortezomib, a proteasome inhibitor. Their effects on MM cell proliferation, apoptosis, and relevant signal pathways of apoptosis were determined by cell counting kit-8 (CCK-8), real-time polymerase reaction chain (RT–PCR), ATP assay, and western blot. PLD1 was highly expressed in U266 and H929 cells. VU0359595 didn't affect the proliferation and apoptosis of MM cells. However, VU0359595 could enhance growth inhibition, decreasing mitochondrial membrane potentials (MMPs) and ATP levels of bortezomib treated MM cells. VU0359595 also strengthened bortezomib-induced apoptosis via activating caspase-8, caspase-9, caspase-3; and down-regulating the expressions of anti-apoptosis proteins BCL-2. In addition, the bortezomib-induced cytotoxicity on MM cells was significantly augmented by VU0359595 through efficient suppression of the mTOR/NF-κB signal pathway. PLD1 inhibition can remarkably exert antitumor effects with bortezomib on MM, which is a novel potentially targeting therapeutic agent, especially for drug-resistant MM patients. [ABSTRACT FROM AUTHOR]