<p>The current study aimed to compare the real-world safety profiles of first-line multiple myeloma regimens—lenalidomide plus dexamethasone (Rd), bortezomib plus lenalidomide and dexamethasone (VRd), and daratumumab plus lenalidomide and dexamethasone (DRd)—using the FDA Adverse Event Reporting System (FAERS) database. A large-scale retrospective analysis was conducted on 54,243 cases from the FAERS database (2004–2025). Analytical methods included trend analysis, disproportionality analysis (using Bayesian Information Component and Reporting Odds Ratio), co-medication assessment for drug-drug interactions, and time-to-onset analysis with Weibull modeling. Trend analysis reveals a steady increase in DRd adoption since its introduction in 2016, contrasting with a decline in Rd reports after 2021 and a modest decrease in VRd cases after 2020, potentially reflecting the emergence of new therapeutic alternatives and growing safety concerns. Disproportionality analyses confirm significantly elevated signals for infections associated with DRd and neurological disorders linked to VRd across multiple subgroup analyses. Co-medication assessments suggested potential drug-drug interaction signals associated with increased reporting frequencies of these adverse events. Time-to-onset analysis indicates an earlier manifestation of infectious complications with DRd. The findings support the potential value of regimen-specific safety monitoring: proactive infection prophylaxis for DRd recipients and subcutaneous bortezomib with neurological surveillance for VRd patients. This real-world evidence complements clinical trials and guides personalized treatment strategies to optimize the risk–benefit balance in multiple myeloma management.</p> Graphical Abstract <p></p> <p><b>Graphical Abstract Description</b> This graphical abstract summarizes a retrospective FAERS database analysis comparing the safety profiles of frontline multiple myeloma regimens: Rd (Lenalidomide + Dexamethasone), VRd (Bortezomib + Lenalidomide + Dexamethasone), and DRd (Daratumumab + Lenalidomide + Dexamethasone). Based on 54,243 cases (2004-2025), the study identifies distinct adverse event patterns: DRd demonstrates significantly higher reporting frequency of infections and infestations, while VRd is associated with increased nervous system disorders. Co-medication analysis revealed that drug-drug interactions can significantly exacerbate these specific adverse reaction risks. These findings underscore the necessity for regimen-specific monitoring and cautious concomitant medication use to optimize the risk-benefit balance in myeloma treatment.</p>