Triple-M syndrome after immune checkpoint inhibitors: a systematic review of cases-early recognition is critical to survival.

Immune checkpoint inhibitors have markedly improved outcomes in advanced malignancies by enhancing antitumor immunity, but they may also disrupt immune tolerance and induce immune-related adverse events involving multiple organs; among these, the overlap of myositis, myocarditis, and Myasthenia Gravis (triple-M syndrome) represents a rare but potentially fatal condition with limited evidence guiding its management. We performed a systematic review of case reports and case series published until July 2025 to describe the clinical characteristics, diagnostic findings, treatments, and outcomes of patients developing triple-M syndrome after immune checkpoint inhibitor therapy. The syndrome typically occurred early after treatment initiation and presented with rapidly progressive and heterogeneous features, including ocular and bulbar symptoms, muscle involvement, and cardiac manifestations; diagnosis was often challenging due to low sensitivity of routine tests, variable antibody positivity, and limited feasibility of advanced investigations, making clinical suspicion crucial. High-dose corticosteroids were the most frequently used first-line treatment, often combined with intravenous immunoglobulins or plasma exchange, although steroid monotherapy was associated with clinical worsening in some cases; emerging therapies, including targeted monoclonal antibodies and next-generation immunomodulatory agents, have the potential to provide more rapid and effective disease control. Overall prognosis remains poor, with high rates of respiratory failure, severe complications, and oncologic progression following treatment discontinuation. Triple-M syndrome is a severe and under-recognized complication requiring early diagnosis and prompt multidisciplinary management, and further studies are needed to improve diagnostic strategies and optimize treatment while preserving oncologic benefit.