What medications are contraindicated with lenalidomide in patients with multiple myeloma or other hematologic malignancies?

Absolute Contraindications to Lenalidomide

There are no absolute drug contraindications to lenalidomide based on drug-drug interactions; however, anticoagulation is mandatory—not contraindicated—when lenalidomide is combined with high-dose dexamethasone or multiagent chemotherapy due to severe thrombotic risk. 1

Key Clinical Context: Thromboprophylaxis is Required, Not Contraindicated

The critical issue with lenalidomide is not what drugs are contraindicated, but rather what drugs are required to prevent life-threatening venous thromboembolism (VTE):

High-Risk Scenarios Requiring Therapeutic Anticoagulation

Patients receiving lenalidomide with high-dose dexamethasone (≥480 mg per month), doxorubicin, or multiagent chemotherapy must receive either LMWH (enoxaparin 40 mg daily) or warfarin (INR 2-3)—this is not optional. 1

• The incidence of DVT reaches 26% with lenalidomide plus high-dose dexamethasone without prophylaxis, compared to 12% with low-dose dexamethasone 1
• VTE rates with lenalidomide/high-dose dexamethasone were 11-19% in case-control studies without routine thromboprophylaxis 1

Lower-Risk Scenarios Where Aspirin Suffices

For patients with ≤1 VTE risk factor receiving lenalidomide with low-dose dexamethasone, melphalan, or as monotherapy, aspirin 81-325 mg daily is adequate prophylaxis. 1

• Single-agent lenalidomide does not constitute high VTE risk and prophylaxis may not be required 1
• Aspirin prophylaxis reduced VTE incidence to <10% in patients receiving lenalidomide with low-dose dexamethasone 1

Relative Contraindications to Anticoagulation (Not to Lenalidomide Itself)

When anticoagulation is contraindicated, lenalidomide use becomes problematic in high-risk regimens. Avoid lenalidomide in high-risk combinations if the patient has: 1

• Active uncontrollable bleeding
• Active cerebrovascular hemorrhage
• Severe thrombocytopenia (platelet count <50,000/μL) 1
• Recent neurosurgery or intracranial bleeding 1
• Dissecting or cerebral aneurysm 1

Renal Dosing Adjustments (Not Contraindications)

Lenalidomide requires dose reduction in renal impairment but is not contraindicated: 1

• LMWH should be used with caution and may require anti-Xa monitoring in renal dysfunction 1
• Fondaparinux is contraindicated with creatinine clearance <30 mL/min 1

Critical Pitfall to Avoid

Do not confuse lenalidomide with thalidomide—thalidomide causes significant peripheral neuropathy while lenalidomide rarely does, making duloxetine or other neuropathic pain medications generally unnecessary with lenalidomide. 2 The primary toxicity of lenalidomide is myelosuppression (neutropenia, thrombocytopenia, anemia), not neurotoxicity. 2, 3, 4