Case Presentation: A 76-year-old female with a history of hypertension, BMI 48 kg/m2, hypothyroidism, and metastatic melanoma presented with a 2-week history of progressive myalgia, weakness, and dyspnea 3 weeks after the first infusion of nivolumab and relatlimab.In July 2019, she was diagnosed with stage IIB (cT4a, cN0, cM0) melanoma of the left leg (4.2 mm) that was resected. In September 2022, tumor recurrence was noted with metastases to the sternum and lumbar spine. A week after the first infusion of nivolumab and relatlimab, she developed myalgias, weakness, dyspnea with minimal exertion, and diplopia. A physical exam revealed bilateral ptosis and lateral gaze palsy. Labs showed elevated creatine kinase (CK) at 8,494 U/L (normal range [NR] < 201 U/L), cardiac troponin (T-hs Gen5) at 1,136 ng/L (NR < 9 ng/L), lactate dehydrogenase at 1,174 U/L (NR < 192 U/L). Alanine aminotransferase level was elevated at 774 U/L (NR < 35 U/L), aspartate aminotransferase at 423 U/L (NR < 41 U/L). Immunological testing was negative for rheumatoid factor, antibodies to anti-citrullinated peptide, acetylcholine receptor, and anti-muscle specific kinase. The echocardiogram showed a left ventricular ejection fraction of 65%. Patient was suspected to have severe ICI-related toxicity and was transferred to a tertiary center for further studies and management.Electromyography showed no confirmatory evidence for a neuromuscular transmission disorder. There were electrical findings in selected muscles consistent with myopathy. No muscle biopsy was performed. Cardiac MRI was postponed due to the severity of the patient’s condition.She was treated with high-dose IV steroids (methylprednisolone 1 g/day for 5 days, then 1.5 mg/kg/day, and switched to prednisone taper), and IVIG for 5 days. On day 5 of admission, the patient developed worsening respiratory failure requiring intubation and later underwent a tracheostomy. The patient currently remains hospitalized. Notably, she developed anxiety/panic attacks prompting more rapid steroid tapering. CK and LFTs normalized, unlike cardiac troponin which trended down initially and then had risen again. Given rising troponin, the patient was started on mycophenolate. She was also enrolled in a clinical trial of abatacept receiving either standard of care (SoC) + placebo or SoC + abatacept.

Discussion: An ICI-induced myopathy is a heterogenous syndrome involving the neuromuscular system. ICI-induced myocarditis is associated with up to 50% mortality rate1. Although most cases of ICI‐related myocarditis occur in isolation, simultaneous development of myositis and/or myasthenia gravis has been reported in up to 40% of cases2. The reported case highlights the challenges in diagnosis such as confusing clinical presentation, nonspecific symptoms as well as the importance of early diagnosis and prompt treatment. In this case, the diagnosis was made in the emergency department with the early involvement of a multidisciplinary team and prompt steroid initiation. It is also important to monitor the progression and assess the need for adjunctive immunosuppressive therapies in patients without improvement on steroids. It is also vital to closely monitor for respiratory failure.

Conclusions: ICI-related overlapping neuromuscular toxicities including myocarditis, myositis, and MG are complex syndromes with high morbidity and mortality rates. This highlights the need to recognize multiple concurrent immune-related adverse events early and employ a multidisciplinary approach.