Confirmed Myocarditis-Myositis Overlap Without Myasthenia Gravis: Evaluating for Triple M Syndrome Following Combined Enfortumab Vedotin and Pembrolizumab Therapy

A 64-year-old male with Stage III urothelial carcinoma of the right ureter presented to the emergency department 3 weeks after a single cycle of combined enfortumab vedotin and pembrolizumab with chest tightness, neck weakness, drop head, and myalgias.Laboratory findings included markedly elevated highsensitivity troponin I, creatine phosphokinase, lactate dehydrogenase, and transaminases.Electrocardiography showed anterolateral ST depression and left anterior fascicular block, which was new as compared to a prior tracing.He was managed in the cardiovascular intensive care unit.Cardiac catheterization revealed concurrent 90% mid-left anterior descending artery stenosis, treated with drugeluting stent placement.Endomyocardial biopsy confirmed focal moderate lymphocytic myocarditis.Cardiac MRI demonstrated mildly reduced biventricular function and a non-ischemic pattern of late gadolinium enhancement consistent with myocarditis sequelae.Given the overlapping multisystem presentation, a multidisciplinary team (cardiology, neurology, and oncology) elected to treat with high-dose methylprednisolone (1 g QOD x 5 days), the guideline-recommended first-line therapy for ICI-associated myocarditis, and intravenous immunoglobulin (400 mg/kg QOD x 5 days), with biochemical improvement.IVIG was added given clinical concern for possible neuromuscular junction involvement in the setting of concurrent myositis and possible overlap syndrome, reflecting a precautionary approach to a potentially rapidly progressive presentation.Myasthenia gravis was considered but not confirmed: repeated neurological examinations demonstrated no fatigable weakness, and serology was negative for acetylcholine receptor binding and muscle-specific kinase antibodies.Both implicated agents were permanently discontinued.This case illustrates the spectrum and severity of multisystem immune-related toxicity from combined antibody-drug conjugate and immune checkpoint inhibitor therapy.