What is lenalidomide?

Lenalidomide: An Immunomodulatory Agent for Multiple Hematologic Malignancies

Lenalidomide is a thalidomide analogue immunomodulatory drug with antiangiogenic and antineoplastic properties that is FDA-approved for treating multiple myeloma, myelodysplastic syndromes with del(5q), mantle cell lymphoma, and certain types of lymphoma. 1

Mechanism of Action

Lenalidomide works through multiple mechanisms:

• Immunomodulation through activation of immune cells
• Inhibition of angiogenesis
• Modulation of cytokine production
• Anti-proliferative effects on cancer cells
• Effects on the tumor microenvironment 2

FDA-Approved Indications

Lenalidomide is approved for:

1. Multiple Myeloma (MM):

   • In combination with dexamethasone for previously treated MM
   • As maintenance therapy after autologous stem cell transplantation

2. Myelodysplastic Syndromes (MDS):

   • Specifically for deletion 5q MDS (where part of chromosome 5 is missing)
   • Particularly effective for transfusion-dependent anemia in these patients 2

3. Mantle Cell Lymphoma (MCL):

   • For relapsed/refractory disease after two prior therapies (including bortezomib)

4. Follicular Lymphoma (FL) and Marginal Zone Lymphoma (MZL):

   • In combination with rituximab for previously treated disease 1

Clinical Efficacy

In Multiple Myeloma

• Superior to dexamethasone alone in relapsed/refractory MM
• Improves time to progression, response rates, and overall survival 3

In Myelodysplastic Syndromes

• In del(5q) MDS: 66% of patients achieve red blood cell transfusion independence
• 76% achieve cytogenetic responses (55% complete cytogenetic responses)
• In non-del(5q) MDS: 26% achieve transfusion independence with a median hemoglobin rise of 3.2 g/dL 2

In Chronic Lymphocytic Leukemia (CLL)

• Single-agent lenalidomide shows overall response rates of 32-47% in relapsed/refractory CLL
• In combination with rituximab, response rates are higher (77-94% depending on age) 2

Dosing and Administration

• Oral administration, typically 25 mg daily for 21 days of a 28-day cycle for MM
• For CLL, lower starting doses (2.5-5 mg) are recommended due to risk of tumor flare and tumor lysis syndrome
• Dose adjustments required for renal impairment as lenalidomide is renally excreted 1, 2
• Dose modifications often needed for cytopenias

Important Safety Considerations

Pregnancy Risk

• SEVERE TERATOGENIC EFFECTS: Absolutely contraindicated in pregnancy
• Requires participation in REMS program
• Both male and female patients must follow strict contraceptive measures 1

Hematologic Toxicity

• Neutropenia (70% grade 3-4 in some studies)
• Thrombocytopenia (45% grade 3-4)
• Anemia (18% grade 3-4)
• Regular blood count monitoring required 2, 4

Thromboembolism Risk

• Increased risk of venous thromboembolism, particularly when combined with dexamethasone
• Prophylactic anticoagulation often recommended in MM but not routinely in CLL 2

Tumor Flare Reaction

• Common in CLL (30-90% of patients)
• Presents as painful lymph node enlargement, spleen enlargement, fever, rash
• More common with larger baseline lymph nodes
• Usually managed with steroids and antihistamines 2

Tumor Lysis Syndrome

• Risk in CLL patients with high lymphocyte counts
• Prophylaxis with allopurinol recommended during initial cycles 2

Practical Management Tips

1. Start at appropriate dose based on indication and patient factors:

   • Lower starting doses (2.5-5 mg) for CLL with gradual escalation
   • Dose adjustment for renal impairment

2. Monitor for and manage adverse events:

   • Weekly blood counts initially, then monthly
   • For tumor flare: steroids for lymph node inflammation, antihistamines for rash
   • Consider tumor flare prophylaxis with steroids for patients with bulky disease

3. Avoid common pitfalls:

   • Never use standard MM dosing (25 mg) as initial dose in CLL due to excessive toxicity
   • Always adjust dose for renal impairment
   • Never use in pregnant patients or those who may become pregnant

Lenalidomide represents an important therapeutic option across multiple hematologic malignancies with manageable toxicity when appropriate monitoring and dose adjustments are implemented.