Immune Checkpoint Inhibitor-Associated Myocarditis With Myasthenia Gravis And Myositis: A Fatal Case Of Triple “M” Syndrome

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Author Block: Nabel Rajab Basha¹, Imran Aziz², Cory Benjamin³, Omar Abdelkader⁴, Gregg Lanier². ¹Department of Internal Medicine, Westchester Medical Center, Valhalla, NY; ²Division of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY; ³Department of Hematology and Oncology, Westchester Medical Center, Valhalla, NY; ⁴Department of Neurology, Westchester Medical Center and New York Medical College, Valhalla, NY
Disclosure Block: N. Rajab Basha: None.

Introduction: Immune checkpoint inhibitors (ICI) have improved outcomes in multiple malignancies but can cause severe immune-related adverse events (irAEs). Although rare, ICI-associated myocarditis carries high mortality and may occur with myositis and myasthenia gravis (MG), termed “Triple-M overlap syndrome” which has a reported inpatient mortality of 40%. Prompt recognition and initiation of steroids is of utmost importance.
Case Discussion: A 70-year-old woman with metastatic endometrial cancer on ICI therapy (last dose 6 weeks prior) presented with acute diplopia. Neuroimaging was negative for stroke or intracranial pathology; however, cardiac biomarkers were elevated, prompting cardiology consultation. On admission, hs-troponin I was 513 ng/L, CK 2,964 U/L, and BNP 85 pg/mL. ECG showed sinus tachycardia without ischemic changes, and TTE demonstrated preserved EF (70%) without wall motion abnormality. She was initially treated for possible ACS with antiplatelet therapy, statin, and anticoagulation. Shortly after admission, she developed new-onset AF with RVR and new conduction abnormalities (RBBB, LAFB), with troponin rising to 4,023 ng/L. On the same day, she developed symptomatic bradycardia progressing to complete heart block requiring emergent transvenous pacemaker (TVP) placement. Cardiac catheterization showed non-obstructive CAD, elevated filling pressures and reduced cardiac index (Fick CI 1.5 L/min/m²). Endomyocardial biopsy was obtained and empiric IV methylprednisolone 1g daily was initiated for suspected ICI myocarditis. Given concomitant ptosis, generalized weakness, rising CK, and biopsy findings of lymphocytic myocarditis (figure), Triple-M overlap syndrome was suspected. Treatment was escalated to IVIG followed by abatacept. Despite immunosuppressive therapy, she remained pacer-dependent and developed myasthenic crisis requiring mechanical ventilation. Her course was complicated by acute renal failure requiring CRRT and refractory septic shock with multiorgan failure. Following goals of care discussion, comfort-focused measures were initiated and she passed away.
Take-Home Message: ICI-associated myocarditis may initially present with incidental troponin elevation and rapidly progress to fulminant myocarditis with cardiogenic shock and conduction abnormalities. Early recognition and prompt aggressive immunosuppression (steroids, IVIG, and rescue agents such as abatacept) are critical but may not prevent rapid multiorgan failure and death.