Immune Checkpoint Inhibitor Overlap Syndrome: Myocarditis, Myositis, and Myasthenia Gravis in a Patient With Metastatic Melanoma

Immune checkpoint inhibitors can produce severe immune-mediated toxicity involving multiple organ systems. A rare manifestation is the myocarditis, myositis, and myasthenia gravis (MMM) overlap syndrome, also referred to as triple M syndrome or immune-related MMM overlap syndrome, characterized by concurrent myocarditis, myositis, and myasthenia gravis and capable of rapid progression to life-threatening cardiac and neuromuscular complications. A 78-year-old man with metastatic melanoma developed palpitations, profound fatigue, proximal muscle weakness, diplopia, and ptosis two weeks after initiation of nivolumab and ipilimumab. Initial evaluation revealed marked elevations in high-sensitivity troponin (11,399 ng/L), creatine kinase (6,046 U/L), and transaminases, with sinus tachycardia on electrocardiography and preserved systolic function on echocardiography. Intravenous methylprednisolone was started, and immunotherapy was discontinued; however, his biomarkers continued to rise, and his condition rapidly deteriorated after transferring to a tertiary cardiac intensive care unit. He developed a complete heart block requiring transvenous pacing and subsequently demonstrated severe biventricular systolic dysfunction on cardiac imaging. Coronary angiography showed no obstructive disease. Despite escalation to pulse-dose steroids, his neuromuscular weakness worsened, and he progressed to respiratory failure requiring mechanical ventilation, followed by malignant ventricular arrhythmias and hemodynamic collapse before additional therapies, including plasmapheresis, could be initiated. Care was transitioned to comfort measures, and death occurred shortly thereafter. Endomyocardial biopsy confirmed lymphocytic myocarditis with myocyte necrosis. This case highlights that early neuromuscular symptoms accompanied by marked troponin and creatine kinase elevation may represent the first manifestations of MMM overlap syndrome and can precede rapid progression to life-threatening cardiac and respiratory complications.