The Triple-M Syndrome is a rare and severe immune-mediated adverse event associated with Immune Checkpoint Inhibitors, characterized by the concomitant occurrence of myocarditis, myositis, and myasthenia gravis. To date, approximately 50 cases have been reported, mainly following pembrolizumab or nivolumab administration in patients with melanoma, lung, or renal cancer, with an estimated mortality of 38%. Clinical management is challenging and not standardized. High-dose corticosteroids are considered first-line therapy, while intravenous immunoglobulins, plasma exchange, pyridostigmine, and other immunosuppressive agents have been used in steroid-refractory cases. We report a rare case of Triple-M Syndrome following a single dose of pembrolizumab. A 69-year-old hypertensive male with no previous cardiovascular history was diagnosed with stage IIB superficial spreading melanoma (Clark level IV). Fifteen days after the first administration of pembrolizumab (200 mg), he developed rapidly progressive dyspnea, myalgias, neck pain, palpitations, and oppressive chest pain, associated with mild hypoxemia (SpO₂ 91% on room air). Laboratory tests showed AST/ALT 121/342 U/L, LDH 830 U/L, CPK 1230 U/L, potassium 5.5 mmol/L, NT-proBNP 7664 ng/L, and hs-cTnT 1147 ng/L. Arterial blood gas revealed respiratory alkalosis with mild hypoxemia. Suspecting ICI-related cardiotoxicity, the patient was admitted to the Cardiac Intensive Care Unit. Transthoracic echocardiography showed a left ventricular ejection fraction of 40% with septal and infero-basal hypokinesia, without pericardial effusion. During hospitalization, left eyelid ptosis and dysphagia developed. ECG showed sinus tachycardia, right bundle branch block, diffuse repolarization abnormalities, ventricular bigeminy, and intermittent alternation with left bundle branch block. Coronary angiography excluded obstructive coronary artery disease. A diagnosis of Triple-M Syndrome was established, and high-dose intravenous methylprednisolone (1 g/day) was initiated. On day two, rapid neurological deterioration occurred with bilateral ptosis, dysphonia, hypoventilation, and hypercapnic respiratory failure requiring intubation. Intravenous immunoglobulins and plasma exchange were added, but the patient died approximately 65 hours after admission. ICI-related Triple-M Syndrome remains a rare, fulminant, and often fatal condition. Early recognition and prompt multidisciplinary management are crucial, yet prognosis remains poor.
Associazione Nazionale Medici Cardiologi Ospedalieri
