Background: Immune checkpoint inhibitors (ICIs) have improved outcomes in various malignancies but can lead to potentially fatal neurological and cardiovascular immune-related adverse events (irAEs). Myocarditis, myositis and myasthenia gravis may co-occur as an overlapping "triple M" syndrome. Management is challenging because conventional investigations can be nonspecific and prompt intervention before confirmatory testing is required for better patient outcomes.
Case summary: A 68-year-old man with metastatic thymic/non-small cell lung cancer received carboplatin, paclitaxel and pembrolizumab. Four days after cycle 2 of pembrolizumab monotherapy, he presented with progressive fatigue, dyspnoea and neck pain, and transient pleuritic chest pain. Investigations demonstrated elevated troponin-T (2579 ng/L), creatine kinase (2551 U/L) and BNP (1424 ng/L), with normal inflammatory markers and an unremarkable transthoracic echocardiogram. Electrocardiogram was non-diagnostic for acute coronary syndrome. CT pulmonary angiography was incomplete but did not show significant pulmonary emboli. The patient deteriorated with type 2 respiratory failure and junctional arrhythmia, requiring intubation and inotropic support. Subsequent Coronary angiography and ventriculogram were unremarkable. He later developed progressive proximal weakness, fatigability, and diplopia. Neurology assessment favoured an ICI related myasthenic syndrome, with elevated Acetylcholine receptor antibody titers at 12.31. Together with features of myocarditis and myositis, a diagnosis of triple M syndrome was made. He was treated empirically with high-dose intravenous corticosteroids, intravenous immunoglobulin, pyridostigmine and mycophenolate mofetil, with gradual clinical and biochemical improvement.
Conclusion: This case highlights the diagnostic challenges inherent to ICI-mediated triple M syndrome. The combination of recent ICI therapy, concurrent elevated cardiac biomarkers despite unremarkable cardiac investigations, alongside evolving neuromuscular compromise with respiratory failure strongly supported a diagnosis of triple M syndrome necessitating empiric treatment prior to more confirmatory testing. There is an urgent need for validated diagnostic criteria, risk stratification, and surveillance strategies to facilitate early recognition and treatment of these syndromes.