Refractory Pembrolizumab-Induced Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome With Concurrent Hepatitis...

Immune checkpoint inhibitors (ICIs) have transformed oncologic care but can trigger a spectrum of immune-related adverse events. The triad of myocarditis, myositis, and myasthenia gravis, termed MMM overlap syndrome, is a rare but life-threatening complication. Reports have predominantly involved melanoma and lung cancer; cases of endometrial carcinoma have rarely been described. A 77-year-old woman with stage IV serous endometrial carcinoma presented 24 days after a single dose of carboplatin, paclitaxel, and pembrolizumab, with progressive weakness, ptosis, diplopia, and respiratory compromise. Initial evaluation revealed creatine kinase (CK) of 13,000 IU/L, peak high-sensitivity troponin I of 15,000 ng/L, a new right bundle branch block (RBBB) with intermittent high-degree atrioventricular (AV) block, transaminitis, and thyrotoxicosis, indicating concurrent four-organ toxicity. Acetylcholine receptor (AChR), MuSK, and LRP4 antibodies were all negative, consistent with seronegative ICI-induced myasthenia gravis. She was treated with pulse corticosteroids and plasma exchange (PLEX), with rituximab added after the second session for an inadequate response. Persistent myocarditis with sustained troponin elevation prompted further escalation to abatacept and ruxolitinib. Symptoms and serum biomarkers subsequently improved, and she was discharged on continued corticosteroids and ruxolitinib with a planned graded taper. To our knowledge, this is the second reported case of MMM overlap syndrome in endometrial carcinoma and the first implicating pembrolizumab in this malignancy. The case is distinguished by refractory disease requiring four sequential lines of immunosuppression, concurrent immune-mediated hepatitis and thyroiditis, and a seronegative myasthenia gravis profile, consistent with the more heterogeneous, non-antibody-mediated mechanisms increasingly recognized in ICI-induced disease. It informs treatment escalation in refractory cases and underscores three principles essential to managing this high-mortality syndrome: early recognition, systematic screening for all syndromic components once any one is identified, and timely escalation through multiple lines of immunosuppression when disease proves refractory.