Smoldering Myocarditis Unmasked by Pembrolizumab-Induced Myositis: Delayed-Onset Double M Syndrome

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but can trigger immune-related adverse events, including rare, variable double M syndromes combining myocarditis and myositis.

A 67-year-old woman with stage IIb triple-negative breast cancer treated per KEYNOTE-522 protocol presented 4 months after ICI use with worsening myalgias, weakness, low-grade fever, and transaminitis. Laboratory results showed creatine kinase 7,760 U/L, aspartate aminotransferase 369 U/L, alanine transaminase 626 U/L, high-sensitivity cardiac troponin I >15,000 ng/L, and creatine kinase-MB 185 ng/mL. Electrocardiogram revealed sinus tachycardia with diffuse ST-segment depressions. Transthoracic echocardiography showed preserved left ventricular ejection fraction. Coronary angiography ruled out obstructive disease. Endomyocardial biopsy confirmed ICI-associated myocarditis with CD8+ T-cell infiltrates and PD-L1 overexpression. She was treated with pulse-dose steroids and a prednisone taper with multidisciplinary follow-up. Advanced imaging 2 months later showed complete resolution.

ICI-related double M syndromes are rare, high-risk, and typically present acutely. This delayed, smoldering case highlights the need for recognizing subacute presentations.

Timely recognition and use of multimodal imaging in ICI-related double M syndromes, even in delayed or asymptomatic cases, are essential for improving outcomes.