Proteasome inhibitor analogs (PIs) have significantly improved the degree of remission and survival rate of patients with multiple myeloma. However, serious adverse events (AEs) have hindered their clinical application. This study analyzed the AEs reported in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database to determine the safety profile and differences for the PI drugs bortezomib, carfilzomib, and ixazomib. The reporting odds ratio (ROR) was used to detect safety signals. Significant safety signals were detected based on system-organ classification (SOC). For bortezomib, the most significant SOC signal was "blood and lymphatic system disorders" (ROR = 3.47, 95% CI 3.37-3.57), while the most significant PT signal was "enteric neuropathy" (ROR = 134.96, 95% CI 45.67-398.79). For carfilzomib, the most significant SOC signal being "blood and lymphatic system disorders" (ROR = 4.34, 95% CI 4.17-4.53), while the most significant PT signal was "light chain analysis increased" (ROR = 76.65, 95% CI 57.07-102.96). For ixazomib, the most significant SOC signal was "gastrointestinal disorders" (ROR = 2.04, 95% CI 1.96-2.12), while the most significant PT signal was "light chain analysis increased" (ROR = 67.15, 95% CI 45.36-99.42). For bortezomib and carfilzomib, the top 20 reported PTs were consistent with AEs listed in the drug information. For ixazomib, six unexpected AEs were observed: asthenia, malaise, pyrexia, decreased appetite, dehydration, and falls. The PIs were consistent with the early failure model based on time-series analysis of the occurrence of adverse reactions to the drug. The data mined from FAERS generates new AE signals, and further clinical studies are needed to validate these findings.