Case Presentation: A 70-year-old man with a history of stage III melanoma, previously treated with surgical resection and pembrolizumab, presented with diplopia and ptosis. Laboratory results showed significantly elevated high-sensitivity troponins and creatine kinase-MB. Initial electrocardiogram revealed complete atrioventricular block without ST-segment changes, necessitating the placement of a transvenous pacemaker. Echocardiogram showed an ejection fraction of 50%. Given his recent exposure to pembrolizumab, ICI-induced myocarditis was suspected. Muscle enzymes, including creatine kinase and aldolase, were also elevated, suggesting myositis. Testing for acetylcholine receptor-binding antibodies was 0.65 nmol/L (negative < 0.30 nmol/L), while acetylcholine receptor-blocking antibodies and antinuclear antibodies were negative.Methylprednisolone pulse therapy was initiated for suspected ICI-induced myocarditis, leading to some improvement in his weakness, though muscle enzyme levels remained elevated. Abatacept was also administered but did not result in significant improvement. Due to worsening clinical status, the patient was transferred to another facility, where he received intravenous immunoglobulin (IVIG) and ruxolitinib. However, he subsequently experienced cardiac arrest and passed away.
Discussion: Myocarditis, myositis, and MG are recognized complications of pembrolizumab therapy, typically presenting independently, though their precise incidence remains unclear. Some systematic reviews report low incidence rates, with 0.94% for ICI-related MG and myocarditis ranging from 0.04% to 1.14% [2, 3]. Despite the low incidence, myocarditis carries a mortality rate of 39.7% to 50% and a median onset time of 30 days after therapy initiation [4, 5]. In contrast, reports on IM3OS are limited when compared to isolated case studies with mixed outcomes [6].Given the rarity of IM3OS, treatment strategies are still evolving. A case series indicated that early treatment with corticosteroids and IVIG improved outcomes in IM3OS patients [1]. Similarly, a meta-analysis suggested that early administration of IVIG and plasmapheresis may reduce mortality in cases of ICI-induced myocarditis [4]. In this case, although corticosteroids were administered promptly, a delay in IVIG initiation may have impacted the clinical outcome.
Conclusions: This case highlights the importance of vigilant monitoring and early detection of these potentially fatal complications. While documentation on immune-related adverse events (IRAEs) is extensive, description of the triple M overlap syndrome remains limited, emphasizing the need for further research.