Abstract: Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) are currently used for the treatment of multiple myeloma (MM); however, CD38 monoclonal antibody (anti-CD38 monoclonal antibody, anti-CD38), CAR-T cell (chimeric antigen receptor T-cell) therapy, and other new drugs have substantially improved the therapeutic efficacy and survival rate of patients with MM in recent years. Among them, PIs are still the basic drugs for MM treatment. Due to its unique therapeutic mechanisms, carfilzomib (CFZ), a new-generation PI, is extensively used in relapsed or refractory MM (RRMM) and drug-resistant MM than bortezomib (BTZ) and ixazomib (IXZ), and its efficacy has been confirmed by a large number of data. Nevertheless, some patients developed resistance to carfilzomib. Based on the recent studies on carfilzomib resistance, this study aims to analyze the resistance mechanism of carfilzomib from five aspects: autophagy level, drug metabolism, proteasome structure and quantity, gene modification, and cell metabolism, and thereby provide potential therapeutic options. These novel therapeutic options are expected to enhance the efficacy of carfilzomib, reduce the emergence of drug resistance, and prolong the overall survivalrate.