Case Presentation: 84-year-old male with a history of metastatic castration-resistant prostate cancer (mCRPC) and metastatic squamous carcinoma of the left lung presented with progressive fatigue, exertional dyspnea, chest discomfort, and diplopia following his 2nd cycle of atezolizumab infusion. After his mCRPC diagnosis in April 2021, he progressed through multiple treatments, including androgen deprivation therapy, darolutamide, enzalutamide, and abiraterone. In October 2023, squamous lung carcinoma was diagnosed during staging scans for his prostate cancer, which was treated with radiation. By July 2024, liver metastases prompted the initiation of atezolizumab.On examination, vital signs were normal, but noted to have diplopia on upward gaze, mild ptosis, mild dysarthria, and proximal muscle weakness involving all extremities. Labs showed elevated troponin (1,000 ng/L, trending to 621 ng/L), creatine kinase (2,824 U/L), and liver enzymes (AST 264 U/L, ALT 195 /L). EKG revealed no ischemic changes, ruling out acute coronary syndrome. CT angiogram ruled out pulmonary embolism.CT head was negative. Based on the findings, immune checkpoint inhibitor (ICI)-induced myocarditis, myositis, and myasthenia gravis (MMM overlap syndrome) was strongly suspected. He was promptly started on intravenous methylprednisolone (2 mg/kg/day), along with intravenous immunoglobulins (IVIG). Cardiac MRI confirmed the diagnosis of myocarditis. Testing for myositis-specific antibodies, acetylcholine receptor antibodies, and MUSK antibodies returned negative.The patient underwent a 5-day course of IVIG and high-dose IV methylprednisolone with multidisciplinary support to address the risks of MMM overlap syndrome. Following the stabilization of his symptoms, including improvement in biomarkers and the absence of arrhythmias or respiratory compromise, he was transitioned to oral prednisone at 1 mg/kg daily. He was subsequently discharged in stable condition on oral prednisone and a comprehensive outpatient follow-up plan was in place. Atezolizumab was permanently discontinued.
Discussion: ICI-induced MMM overlap syndrome is a rare but life-threatening immune-related adverse event (irAE) with an in-hospital mortality rate of 38%. Early recognition and treatment are crucial. Presenting symptoms frequently include ptosis (58%), dyspnea (48%), diplopia (42%), and myalgia (36%). Myocarditis affects 1% of ICI-treated patients, with 25% of these cases also involving myositis and 11% concurrent myasthenia gravis. The combination of all three conditions is exceedingly rare, with limited documentation in the literature. Diagnosis relies on clinical presentation and biomarkers. Cardiac magnetic resonance imaging is the preferred modality for myocarditis, with endomyocardial biopsy as the gold standard. Myositis lacks formal diagnostic criteria but is assessed using creatine kinase, aldolase, inflammatory markers, and, when available, imaging or muscle biopsy.
Conclusions: Corticosteroids are the cornerstone of treatment and should be initiated promptly, even before confirmatory tests, as early intervention reduces morbidity and mortality. Severe cases may require adjunctive therapies such as IVIG, plasma exchange, or pyridostigmine. Multidisciplinary collaboration is critical to optimize irAE management while balancing the efficacy of cancer treatment. Understanding the varied presentations of MMM overlap syndrome is essential for timely and effective care.