What does this research mean for the field?

The 'Triple-M' overlap syndrome (concurrent myasthenia gravis, myositis, and myocarditis) is a severe, early-onset adverse event associated with immune checkpoint inhibitors, characterized by high disproportionality, frequent co-reporting, and a 50% mortality rate. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This study aimed to characterize the pharmacovigilance profile and patterns of Triple-M overlap syndrome associated with immune checkpoint inhibitors.

May 28, 2026Open Access

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

Key Points

This study aimed to characterize the pharmacovigilance profile and patterns of Triple-M overlap syndrome associated with immune checkpoint inhibitors.
FAERS pharmacovigilance analysis using OpenVigil FDA and openFDA API.
Signals for myasthenia gravis, myositis, and myocarditis were evaluated across nine immune checkpoint inhibitors using disproportionality metrics.
Triple-M was defined as co-reporting of all three events and evaluated from August 2016 to September 2025.
Among 272,753 ICI reports, 0.51% were myasthenia gravis cases, 1.16% myocarditis, and 0.74% myositis.
Triple-M cases were identified in 114 unique reports, accounting for 8.2% of MG, 5.6% of myositis, and 3.6% of myocarditis.
50% mortality was observed among cases with available outcomes.

Abstract

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.

Read Full Paperexternally

Mark Helpful

Bookmark

Relay

View Full Paper