Rapidly Progressive Triple M Overlap Syndrome After Immune Checkpoint Inhibitor Therapy

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment, but can cause immune-related adverse events affecting multiple organ systems. Triple M overlap syndrome (TMOS) is a rare and often fatal complication, consisting of the triad of ICI-mediated myositis, myocarditis, and myasthenia gravis. An 85-year-old man with metastatic renal cell carcinoma was initiated on combination ICI-based therapy with pembrolizumab and lenvatinib. Approximately four weeks after initiation of immunotherapy, he presented to the emergency department following a two-week history of progressive neck extensor weakness, downward gaze, worsening proximal upper and lower extremity weakness, recurrent falls, dysphagia, and dysphonia. On evaluation, myositis, myocarditis, and clinical evidence of a myasthenia gravis-like syndrome were noted, and TMOS was diagnosed. Initial treatment with high-dose intravenous corticosteroids and intravenous immunoglobulin was started, yet the patient's condition deteriorated. Despite aggressive treatment, due to hemodynamic instability and liver injury, he could not be started on plasmapheresis or second-line immunosuppression. With progressive multiorgan failure, the patient's management was shifted to comfort-based measures. Although an increasing number of immunosuppressive agents have shown efficacy in TMOS management, this case illustrates how the multiorgan injury inherent to TMOS can itself create contraindications to the very therapies required for definitive treatment. This self-reinforcing cycle of therapeutic limitation highlights the importance of early recognition and aggressive management of TMOS prior to end-organ damage, narrowing the treatment window.