What are the treatment adjustments and monitoring strategies for a patient on Keytruda (pembrolizumab) who develops myositis?

Management of Pembrolizumab-Induced Myositis

For patients on Keytruda (pembrolizumab) who develop myositis, immediately hold the drug, assess for life-threatening cardiac involvement with troponin and ECG, and initiate high-dose corticosteroids (prednisone 1 mg/kg/day or methylprednisolone 1-2 mg/kg IV) while urgently referring to rheumatology and/or neurology. 1

Critical Initial Assessment

The first priority is distinguishing true myositis from simple myalgia, as this determines treatment intensity:

• Assess for muscle weakness, not just pain - True myositis presents with proximal muscle weakness (difficulty standing from a chair, lifting arms overhead, walking) rather than pain-limited movement 1
• Check creatine kinase (CK) immediately - Elevated CK ≥3× upper limit of normal indicates inflammatory myositis requiring aggressive treatment 1
• Obtain troponin and ECG emergently - Myocardial involvement is life-threatening with high mortality and requires permanent discontinuation of pembrolizumab plus aggressive immunosuppression 1
• Perform urinalysis for myoglobinuria - Screen for rhabdomyolysis, which can cause acute kidney injury 1

Additional laboratory workup includes aldolase, AST, ALT, LDH, ESR, and CRP to assess inflammation severity 1

Severity-Based Treatment Algorithm

Grade 1 (Mild weakness with or without pain):

• Continue pembrolizumab cautiously if CK is normal and weakness is minimal 1
• Initiate acetaminophen or NSAIDs for symptom control 1
• However, if CK is elevated with any muscle weakness, escalate to Grade 2 management 1

Grade 2 (Moderate weakness limiting instrumental activities of daily living):

• Hold pembrolizumab temporarily 1
• Initiate prednisone 0.5-1 mg/kg/day if CK is elevated ≥3× upper limit of normal 1
• Refer urgently to rheumatology or neurology 1
• Consider permanent discontinuation in most patients with Grade 2 symptoms plus objective findings (elevated enzymes, abnormal EMG, abnormal muscle MRI, or positive biopsy) 1
• May resume pembrolizumab only if symptoms resolve to Grade 1 or less, CK normalizes, and prednisone dose is <10 mg/day 1

Grade 3-4 (Severe weakness limiting self-care or life-threatening):

• Hold pembrolizumab and strongly consider permanent discontinuation 1
• Hospitalize immediately for severe weakness, respiratory compromise, dysphagia, or rhabdomyolysis 1
• Initiate high-dose corticosteroids: prednisone 1 mg/kg/day orally OR methylprednisolone 1-2 mg/kg IV for severe compromise 1
• Permanently discontinue pembrolizumab if any myocardial involvement 1
• Urgent rheumatology and neurology consultation 1

Advanced Immunosuppression for Refractory Cases

If symptoms worsen or fail to improve after 2 weeks of high-dose corticosteroids:

• Consider plasmapheresis - Faster onset than IVIG, particularly for acute or severe disease 1, 2, 3
• Consider IVIG therapy - Effective but slower onset; note that plasmapheresis immediately after IVIG will remove immunoglobulin 1, 2, 3
• Add biologic agents such as rituximab, TNF-α antagonists, or IL-6 antagonists for severe refractory disease 1

For maintenance therapy if symptoms and CK levels do not resolve after 4 weeks:

• Steroid-sparing agents: methotrexate, azathioprine, or mycophenolate mofetil 1
• Rituximab is used in primary myositis but exercise caution given its long biologic duration 1

Monitoring Strategy

• Serial CK, ESR, and CRP every 4-6 weeks after treatment initiation 1
• Repeat troponin and cardiac monitoring if any cardiac symptoms develop 1
• Monitor serum creatinine twice daily if rhabdomyolysis is suspected, with goal urine output >0.5 mL/kg/hour 4

Critical Pitfalls to Avoid

Do not assume pembrolizumab-induced myositis is benign - This is a rare but potentially fatal complication, more common with anti-PD-1/PD-L1 agents than anti-CTLA-4 agents 1, 5, 6

Always evaluate for cardiac involvement - Concomitant myocarditis dramatically worsens prognosis with high mortality rates 1, 3

Screen for myasthenia gravis overlap - Patients with concomitant myasthenia gravis have ominous prognosis; check for anti-acetylcholine receptor and anti-striated muscle antibodies 1, 2, 7

Distinguish from polymyalgia-like syndrome - This presents with pain but not true weakness, has normal CK levels, and requires different management (lower-dose corticosteroids starting at 20-40 mg/day prednisone) 1

Exercise extreme caution with rechallenge - Pembrolizumab should generally not be restarted after Grade 2 or higher myositis, especially if objective findings were present 1

Patients with thymic neoplasms may be particularly susceptible to fulminant forms of immune-related myositis due to abnormal thymic physiology 3