Triple-M Overlap Syndrome Associated with Immune Checkpoint Inhibitors: A FAERS Pharmacovigilance Analysis

Background/Objectives: Immune checkpoint inhibitors (ICIs) improve cancer outcomes but may induce immune-related adverse events. Myasthenia gravis (MG), myositis, and myocarditis may co-occur as an overlap syndrome ("Triple-M"), but population-level data remain limited. This study aimed to characterize the pharmacovigilance profile, overlap patterns, and reported fatality of Triple-M associated with ICIs. Methods: A FAERS pharmacovigilance analysis was conducted using OpenVigil FDA and the openFDA API. Disproportionality metrics (ROR, PRR, χ²) were used to evaluate signals for MG, myositis, and myocarditis across nine ICIs. Triple-M was defined as the co-reporting of all three events and was evaluated over the study period from August 2016 to September 2025. Results: Among 272,753 ICI reports, 1395 (0.51%) MG, 3173 (1.16%) myocarditis, and 2018 (0.74%) myositis cases were identified; all nine ICIs met signal-detection criteria for all three toxicities (χ² > 4). Pembrolizumab and nivolumab accounted for the highest absolute report counts, whereas nivolumab-relatlimab demonstrated the strongest disproportionality (ROR = 109.5 for MG, 106.4 for myocarditis, and 29.0 for myositis). Triple-M occurred in 114 unique reports (0.04% of all ICI-related adverse events), representing 8.2% of MG, 5.6% of myositis, and 3.6% of myocarditis cases. Co-reporting was common: among 5308 unique reports involving these toxicities, 1164 reports (21.9%) included at least two components of the triad. Triple-M cases were more common in men (56%), with a median age of 74 years (IQR 68-79), a median time-to-onset of 21 days (IQR 18-28), and 50% mortality among cases with available outcomes. Conclusions: Triple-M appears to be a severe overlap phenotype reported in association with immune checkpoint inhibitors, characterized by early onset, frequent co-reporting, and substantial reported fatality. Early recognition and coordinated multidisciplinary assessment may warrant further clinical evaluation and investigation of this overlap phenotype.