Proposed model of high-risk multiple myeloma development in reference to 1q21/PSMD4 copy number. (A) At time of first presentation, low-risk multiple myeloma has cells with variable 1q21/PSMD4 copy number (2, 3, or 4), whereby higher copy numbers are associated with Bz resistance. (B) A major mechanism of Bz's action could be to upset the protein load to protein capacity (PL:PC) balance in the myeloma cells. This imbalance leads to unfolded protein response (UPR)–induced apoptosis. The 4-copy 1q21/PSMD4 myeloma cells have an expanded proteasome and global increase in miRNAs, which causes increased protein capacity and decreased protein production. At relapse, the 4-copy myeloma cells are able to evade the UPR.