Proteasome inhibitors (PIs) are effective in the treatment of multiple myeloma (MM), which is a plasma cell malignancy. Different options for treating MM are a subject of research. Targeting toll-like receptors (TLRs) have been identified as a drug sensitization strategy in MM therapy. Combining anti-apoptotic protein inhibitors with PIs was effective in a broader range of patients. The aim of this study was to investigate the synergistic effects of the TLR1/2 ligand, anti-apoptotic protein inhibitor, and PIs. We activated TLR1/2 with Pam3CSK4 in U266 and NCI-H929 cell lines and investigated the cytotoxic effects of carfilzomib (CFZ), ixazomib (IXS), and venetoclax (VNT) using the WST-1 assay; BCL2, BCLXL, IRAK4, and TRAF6 expression using quantitative PCR; and BH3-interacting domain death agonist (Bid) expression using western blotting. IC₅₀ values were lowest in both cell lines following treatment with CFZ + vNt and IXS + VNT in the presence of ligand. At the transcriptional level, BCL2, IRAK4, and TRAF6 expression was up- or down-regulated depending on the combination. By contrast, BCLXL expression was downregulated with all combinations. At the translational level, enhanced protein expression of tBid was detected when the cells were treated with IXS + VNT in the presence of ligand compared with other combinations. IXS appeared to synergize the truncation of Bid, which crosslinks the extrinsic and intrinsic apoptotic pathways, in the presence of ligand and VNT. Our results provide a preclinical framework for evaluating the effects of PIs in combination with other agents to develop a new therapeutic strategy for MM.