Revlimid - Drug Monograph

Introduction

Revlimid (lenalidomide) is an oral immunomodulatory agent derived from thalidomide, developed by Celgene Corporation (now Bristol Myers Squibb). It represents a significant advancement in the treatment of various hematologic malignancies, particularly multiple myeloma and myelodysplastic syndromes. Unlike its predecessor thalidomide, Revlimid demonstrates enhanced efficacy with a different adverse effect profile while maintaining potent immunomodulatory properties.

Mechanism of Action

Lenalidomide possesses multiple mechanisms of action that contribute to its therapeutic effects:

1. Immunomodulation: Enhances T-cell and natural killer (NK) cell activation and proliferation 2. Anti-angiogenic effects: Inhibits basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) 3. Direct antitumor activity: Induces G1 cell cycle arrest and apoptosis in malignant cells 4. Cytokine modulation: Alters production of various cytokines including TNF-α, IL-6, and IL-10 5. Bone marrow microenvironment modification: Disrupts stromal support for malignant cells

The drug binds to cereblon, a component of the E3 ubiquitin ligase complex, leading to degradation of specific transcription factors (Ikaros family zinc finger proteins 1 and 3) that are essential for multiple myeloma cell survival.

Indications

FDA-approved indications include:

1. Multiple myeloma: - In combination with dexamethasone for newly diagnosed patients - Maintenance therapy following autologous hematopoietic stem cell transplantation - In combination with dexamethasone for patients who have received at least one prior therapy

2. Myelodysplastic syndromes (MDS): For transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality

3. Mantle cell lymphoma: For relapsed or refractory disease after two prior therapies, one of which included bortezomib

4. Follicular lymphoma: In combination with rituximab for previously treated disease

5. Marginal zone lymphoma: In combination with rituximab for previously treated disease

Dosage and Administration

• Combination therapy: 25 mg orally once daily on days 1-21 of repeated 28-day cycles
• Maintenance therapy: 10 mg orally once daily on days 1-28 of repeated 28-day cycles

• 10 mg orally once daily

• 25 mg orally once daily on days 1-21 of repeated 28-day cycles

• Renal impairment: Dose adjustments required based on creatinine clearance
• Hepatic impairment: No specific recommendations (use with caution)
• Elderly patients: Consider starting at lower end of dosing range

• Take with water at approximately the same time each day
• May be taken with or without food
• Do not break, chew, or open capsules

Pharmacokinetics

Contraindications

1. Pregnancy (Category X) - absolute contraindication 2. Hypersensitivity to lenalidomide or any component of the formulation 3. Patients who have not complied with the Revlimid REMS program requirements

Warnings and Precautions

1. Embryo-fetal toxicity: May cause birth defects or embryo-fetal death. Females of reproductive potential must use two forms of contraception 2. Hematologic toxicity: Neutropenia and thrombocytopenia requiring dose adjustments 3. Venous thromboembolism: Increased risk of DVT and PE, requiring thromboprophylaxis

• Second primary malignancies: Increased risk of acute myeloid leukemia and B-cell malignancies
• Hepatotoxicity: Liver failure including fatal cases reported
• Severe skin reactions: Including Stevens-Johnson syndrome and toxic epidermal necrolysis
• Tumor lysis syndrome
• Impaired stem cell mobilization

Drug Interactions

1. Erythropoietin-stimulating agents: May increase risk of thrombosis 2. Digoxin: Lenalidomide may increase digoxin concentrations (P-glycoprotein inhibition) 3. CYP substrates: Lenalidomide is not a significant inhibitor or inducer of CYP enzymes 4. Other myelosuppressive agents: Additive hematologic toxicity 5. Live vaccines: Avoid concurrent administration

Adverse Effects

• Neutropenia (42-80%)
• Thrombocytopenia (20-54%)
• Anemia (10-24%)
• Fatigue (31-43%)
• Diarrhea (20-39%)
• Constipation (20-30%)
• Nausea (20-28%)
• Rash (20-26%)
• Pyrexia (19-26%)

• Venous thromboembolism (3-12%)
• Severe neutropenia (5-15%)
• Severe thrombocytopenia (5-12%)
• Second primary malignancies (3-7%)
• Hepatotoxicity (1-3%)
• Severe skin reactions (<1%)

Monitoring Parameters

• Complete blood count with differential
• Renal function (creatinine clearance)
• Liver function tests
• Pregnancy test (for females of reproductive potential)
• Thrombosis risk assessment

• Weekly CBC for first 8 weeks, then monthly
• Liver function tests monthly for first 3 months, then periodically
• Signs/symptoms of thrombosis
• Skin examinations
• Pregnancy testing monthly for females of reproductive potential

• Secondary malignancy screening
• Renal function periodically
• Thyroid function (if symptoms develop)

Patient Education

1. Pregnancy prevention: Use two reliable forms of contraception simultaneously. Participate in Revlimid REMS program 2. Dosing: Take exactly as prescribed at same time each day 3. Missed dose: Take as soon as remembered unless接近 next dose 4. Side effects: Report immediately: - Fever, chills, sore throat (neutropenia) - Unusual bleeding/bruising (thrombocytopenia) - Shortness of breath, chest pain (thrombosis) - Yellow skin/eyes, dark urine (hepatotoxicity) - Severe skin rash

5. Storage: Keep at room temperature in original packaging 6. Handling: Do not break or crush capsules. If powder contacts skin, wash thoroughly 7. Follow-up: Keep all scheduled appointments for monitoring

• Avoid pregnancy for at least 4 weeks after discontinuation
• Males must use condoms during treatment and for 4 weeks after discontinuation
• Do not donate blood or sperm during treatment

References

1. Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2023. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 3.2023. 3. Dimopoulos MA, et al. Lenalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123-2132. 4. List A, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352(6):549-557. 5. Weber DM, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133-2142. 6. FDA Revlimid REMS Program. Accessed October 2023. 7. Rajkumar SV. Multiple myeloma: 2022 update on diagnosis, risk-stratification, and management. Am J Hematol. 2022;97(8):1086-1107. 8. Zhu YX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118(18):4771-4779.