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Triple-M Overlap Syndrome Associated with Immune Checkpoint Inhibitors: A FAERS Pharmacovigilance Analysis
Bader Alshamsan1, Terry L Ng2,3,4
1Department of Medicine, College of Medicine, Qassim University, Buraydah 52571, Saudi Arabia.
Healthcare (Basel, Switzerland)
|June 12, 2026
Summary
Immune checkpoint inhibitors (ICIs) can cause a severe "Triple-M" overlap syndrome (myasthenia gravis, myositis, myocarditis) with early onset and high fatality. Early recognition of this ICI-related adverse event is crucial.
Area of Science:
- Immunology
- Oncology
- Pharmacovigilance
Background:
- Immune checkpoint inhibitors (ICIs) are vital cancer therapies but can trigger immune-related adverse events.
- Myasthenia gravis (MG), myositis, and myocarditis can co-occur as a severe overlap syndrome, termed "Triple-M."
- Population-level data on the Triple-M syndrome associated with ICIs are limited.
Purpose of the Study:
- To characterize the pharmacovigilance profile of the Triple-M syndrome.
- To investigate overlap patterns and reported fatality of Triple-M associated with ICIs.
- To evaluate signal detection for MG, myositis, and myocarditis across nine ICIs.
Main Methods:
- A pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) was performed.
- Disproportionality metrics (ROR, PRR, χ²) were used to identify safety signals for MG, myositis, and myocarditis.
- Triple-M was defined as the co-reporting of all three conditions in ICI-associated adverse event reports.
Main Results:
- All nine evaluated ICIs showed significant safety signals for MG, myositis, and myocarditis.
- Nivolumab-relatlimab exhibited the strongest disproportionality for all three toxicities.
- Triple-M occurred in 0.04% of ICI reports, with 50% mortality in cases with available outcomes, and early median onset of 21 days.
Conclusions:
- The Triple-M syndrome is a severe, early-onset overlap phenotype associated with ICIs.
- Frequent co-reporting of these conditions and substantial fatality underscore the severity.
- Early recognition and multidisciplinary assessment are warranted for this ICI-related adverse event.
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