Multiple myeloma (MM) and Primary effusion lymphoma (PEL) are two aggressive hematologic cancers against which Bortezomib and JQ-1, proteasome and BET inhibitors respectively, have been shown to have a certain success. However, the combination of both seems to be more promising than the single treatments against several cancers, including MM. In the latter indeed, proteasome inhibition upregulated NRF1, and such pro-survival effect was counteracted by BET inhibitors. In the present study, we found that JQ-1/Bortezomib induced a strong cytotoxic effect against PEL and discovered new insights into the cytotoxic mechanisms induced by such drug combination in PEL and MM cells. In particular, a stronger c-Myc downregulation, leading to an increased DNA damage, was observed in these cells following treatment by JQ-1/Bortezomib compared to the single drugs. To such effect contributed the mTOR-p-4EBP1 axis inhibition, also occurring through c-Myc downregulation. However, besides the pro-death effects, JQ-1/Bortezomib activated UPR and autophagy as pro-survival mechanisms. In conclusion this study demonstrates that JQ-1/Bortezomib combination could be a promising treatment for MM and PEL, unveiling new molecular mechanisms underlying its cytotoxic effect and suggests that UPR and autophagy inhibition could be exploited to further potentiate the cytotoxicity of JQ-1/Bortezomib.