Triple M syndrome following immune checkpoint inhibitors: Clinical features and mortality drivers of a severe irAE.

Abstract

e23431 Background: Triple M overlap syndrome (TMOS) is a rare but lethal immune related adverse event (irAE) characterized by the concurrent development of myositis, myasthenia gravis, and myocarditis, with reported mortality rates up to 60%. Despite the severity, data on the incidence, treatment and outcomes remain quite limited. This study evaluates a single center cohort enriched for a Hispanic population to identify major clinical risk factors associated with TMOS. Methods: We conducted retrospective analysis of patients diagnosed with TMOS following ICI therapy between January 2022 and December 2025 at University of Miami. Cases were identified through multidisciplinary clinical services and confirmed by electronic health record review. TMOS was defined as the concurrent presence of myocarditis, myositis, and myasthenic features temporally associated with ICI exposure. Demographic and clinical data were abstracted and summarized descriptively. Logistic regression analyses were performed to evaluate clinical variables associated with mortality. Analyses were conducted using R version 4.5.2. Results: Out of 12 patients with TMOS, 83% were male, and 50% were Hispanic White with mean age 71 years. Most patients had good baseline performance status (ECOG 0-1). TMOS occurred early after ICI exposure (median 1 prior dose), 67.% patients had received nivolumab (single agent, 33%) or with ipilimumab combination (33%). All patients received high-dose corticosteroids, with concurrent use of IVIG (67%) and plasmapheresis (58%). New cardiac arrhythmias (3 complete heart block, 1 ventricular tachycardia) occurred in 50% of patients and all TMOS-related deaths. All fatal cases had preserved LV function on echocardiography. Median time from symptom onset to treatment initiation was 10 days. ICU admission was required in 58% of cases with TMOS related mortality rate of 33%. Multivariate logistic regression analysis showed new-onset arrhythmia was associated with increased odds of death (p = 0.016). Conclusions: In our study, TMOS was early-onset, highly lethal, with a strong male predominance. Nivolumab exposure and new-onset cardiac arrhythmias were strongly associated with mortality, suggesting a cardiac-driven phenotype. Delays in pre-hospital recognition persisted despite rapid and aggressive inpatient treatment. Earlier recognition, optimized treatment, and biomarker identification are needed to improve outcomes. Clinical characteristics of TMOS cases. Variable ICU Admission (n = 7, 58%) Mortality (n = 4, 33.3%) Age, mean ± SD (years) 69.0 ± 9.3 71.0 ± 9.9 Male sex, n (%) 7 (100%) 4 (100%) Non-Hispanic White ethnicity, n (%) 4 (57.1%) 3 (75.0%) ECOG performance status, median (IQR) 0 (0-1) 0 (0-1) Acute-onset cardiac arrhythmia, n (%) 6 (85.7%) 4 (100%) Time to treatment initiation, median (IQR), days 8 (3-12) 8 (2-21) ICI doses prior to TMOS onset, median (IQR) 1 (1-1) 1 (1-5)