Interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes the proliferation, survival and chemoresistance of MM. The mTOR pathway plays a key role in these undesirable BM microenvironment-mediated events. We synthesized a novel alkaloid compound, DCZ0358, that effectively inhibits mTOR signaling via dual mTORC1/2 inhibition and exhibits potent anti-MM activity in cultured and primary MM cells, as well as a MM xenograft model but has little effect on normal cells. Importantly, we show that this compound can block the BM stromal cell-mediated activation of mTOR/Akt signaling and antagonizes the protective effect of the BM microenvironment. Moreover, DCZ0358 abrogates the bortezomib-triggered activation of Akt, leading to the synergism of DCZ0358 and bortezomib in MM cells. Taken together, our results provide the proof-of-concept for clinical evaluation of DCZ0358, alone or in combination, as an anti-MM agent in MM therapy. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved.