Rajesh, S.T.

Abstract Immune checkpoint inhibitor (ICI) therapy has significantly advanced cancer treatment, particularly for metastatic melanoma, but it is associated with severe, life-threatening adverse effects. A rare but critical complication is the overlap syndrome of Myositis, Myocarditis, and Myasthenia Gravis (MMM), affecting approximately 0.21% of ICI-treated solid tumor patients with an in-hospital mortality rate of up to 60%. Early recognition and management are crucial for improving outcomes. Case Presentation: A 76-year-old male with metastatic melanoma, coronary artery disease, ischemic cardiomyopathy (EF 35%), chronic kidney disease, diabetes, and chronic respiratory failure (baseline oxygen requirement of 2L) presented two weeks after starting Nivolumab and Relatlimab. He developed worsening exertional dyspnea, orthopnea, diplopia, dysarthria, and progressive proximal muscle weakness. On presentation, he was hemodynamically stable, with elevated troponin T (1241 ng/L) and NT-proBNP (2698 pg/mL). Initial investigations, including EKG and chest X-ray, were unremarkable with no thymoma. Left heart catheterization revealed severe multivessel coronary artery disease but no treatable lesions. He was noted to have fatigable ptosis and he subsequently developed bulbar symptoms, including hypophonia and dysphagia. A diagnosis of Myasthenia Gravis was suspected. Further evaluation showed respiratory muscle weakness (NIF -12 cm H2O, vital capacity 2L, mild hypercarbia on ABG) and progressive weakness, leading to intubation. Elevated creatine kinase (1527 U/L), persistent troponin elevation, and global hypokinesis on repeat echocardiography pointed to a likely diagnosis of myocarditis/myositis. Electromyography revealed neuropathy without acute findings, and serological testing for acetylcholine receptor antibodies, HMG-CoA reductase antibodies, and myositis was negative. ICI-induced MMM was diagnosed, and the patient was treated with methylprednisolone, IVIG, pyridostigmine, and ICI discontinuation. Despite plasmapheresis, his condition deteriorated. He developed septic shock from multiple infections (E-Coli bacteremia, Stenotrophomonas pneumonia) and progressed to cardiogenic shock, requiring vasopressors. Subsequent imaging revealed pneumoperitoneum concerning bowel perforation, but further diagnostic workup was declined by the family. Comfort care was initiated, and the patient passed away. Discussion: ICI use has grown rapidly, with agents like Nivolumab expanding treatment options for metastatic melanoma. However, MMM, a rare but severe complication, demands prompt recognition. Presentation often occurs within 21 days of ICI initiation, and patients may display elevated CPK and stable or rising troponin levels. Myasthenia gravis within MMM can cause rapid respiratory failure, with significant morbidity. Management includes corticosteroids, IVIG and immediate ICI discontinuation. Treatment should begin without waiting for confirmatory tests, given the syndrome's high mortality. Early, multidisciplinary intervention is essential in managing this fatal condition effectively.