Multiple Myeloma: Lenalidomide is used in combination with Dexamethasone for the treatment of adult patients with multiple myeloma. It is also used as maintenance therapy in adult patients after autologous hematopoietic stem cell transplantation (auto-HSCT).

Myelodysplastic Syndromes (MDS): Lenalidomide is indicated for adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q abnormality, with or without other cytogenetic abnormalities.

Mantle Cell Lymphoma (MCL): Lenalidomide is used in adult patients with mantle cell lymphoma whose disease has relapsed or progressed after at least two prior therapies, including one containing Bortezomib.

Follicular Lymphoma (FL): Lenalidomide in combination with a Rituximab product is used for the treatment of adult patients with previously treated follicular lymphoma.

Marginal Zone Lymphoma (MZL): Lenalidomide in combination with a Rituximab product is also indicated for adult patients with previously treated marginal zone lymphoma.

Limitation of Use: Lenalidomide is not recommended for the treatment of chronic lymphocytic leukemia (CLL) outside controlled clinical trials.

Lenalidomide is a derivative of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Its cellular actions are mediated through binding to cereblon, a component of the cullin RING E3 ubiquitin ligase complex. In vitro, in the presence of drug substrate proteins (including Aiolos, Ikaros, and CK1α), these proteins undergo ubiquitination and degradation, resulting in direct cytotoxic and immunomodulatory effects. Lenalidomide inhibits proliferation and promotes apoptosis of certain hematopoietic tumor cells (including multiple myeloma, mantle cell lymphoma, and del(5q) myelodysplastic syndromes) in vitro. It can delay tumor growth in some in vivo nonclinical hematopoietic tumor models. Its immunomodulatory activity includes enhanced T-cell and natural killer (NK) cell activation, leading to increased antibody-dependent cellular cytotoxicity (ADCC), along with increased secretion of interleukin-2 and interferon-gamma, increased NKT cells, and suppression of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In multiple myeloma, the combination of lenalidomide with dexamethasone shows synergistic inhibition of cell proliferation and induction of apoptosis.

Absorption: Lenalidomide is rapidly absorbed after oral administration. In patients with multiple myeloma or myelodysplastic syndromes, peak plasma concentrations are reached between 0.5 to 6 hours after single or multiple doses. Pharmacokinetics is linear, with AUC and Cmax increasing proportionally with dose. Multiple dosing at recommended levels does not lead to drug accumulation. Administration of a single 25 mg dose with a high-fat meal reduces the rate and extent of absorption (approximately 20% decrease in AUC and 50% decrease in Cmax). In clinical studies, lenalidomide was administered regardless of food intake. The absorption profile in mantle cell lymphoma patients is similar to that observed in multiple myeloma or MDS patients.

Distribution: In vitro studies using radiolabeled Lenalidomide ([14C]) show approximately 30% plasma protein binding. The drug is detectable in semen at 2 hours (1379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after a 25 mg dose.

Elimination: The average elimination half-life is about 3 hours in healthy individuals and ranges from 3 to 5 hours in patients with multiple myeloma, MDS, or mantle cell lymphoma.

Metabolism: Lenalidomide undergoes minimal metabolism. The parent drug remains the predominant circulating component. Two identified metabolites—5-hydroxy-lenalidomide and N-acetyl-lenalidomide—each account for less than 5% of circulating levels.

Excretion: Lenalidomide is primarily eliminated via the kidneys. Following a single oral dose of radiolabeled 25 mg, approximately 90% of radioactivity is recovered within 10 days (about 4% in feces and 90% in urine). Around 82% of the administered dose is excreted unchanged in urine within 24 hours. The metabolites 5-hydroxy-lenalidomide and N-acetyl-lenalidomide account for about 4.6% and 1.8% of the excreted dose, respectively. Renal clearance exceeds the glomerular filtration rate.

Lenalidomide Combination Therapy: The recommended starting dose of Lenalidomide is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with Dexamethasone. For patients greater than 75 years old, the starting dose of Dexamethasone may be reduced. Treatment should be continued until disease progression or unacceptable toxicity. In patients who are not eligible for auto-HSCT, treatment should continue until disease progression or unacceptable toxicity. For patients who are auto-HSCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a Lenalidomide-containing therapy.

Lenalidomide Maintenance Therapy Following Auto-HSCT: Following auto-HSCT, initiate Lenalidomide maintenance therapy after adequate hematologic recovery (ANC at least 1000/mcL and/or platelet counts at least 75,000/mcL). The recommended starting dose of Lenalidomide is 10 mg once daily continuously (Days 1-28 of repeated 28-day cycles) until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, the dose can be increased to 15 mg once daily if tolerated.

Recommended Dosage for Myelodysplastic Syndromes: The recommended starting dose of Lenalidomide is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings. Continue treatment until disease progression or unacceptable toxicity.

Recommended Dosage for Mantle Cell Lymphoma: The recommended starting dose of Lenalidomide is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity. Treatment is continued, modified or discontinued based upon clinical and laboratory findings.

Recommended Dosage for Follicular Lymphoma or Marginal Zone Lymphoma: The recommended starting dose of Lenalidomide is 20 mg orally once daily on Days 1-21 of repeated 28-day cycles for up to 12 cycles of treatment in combination with a Rituximab product.

Administration: Patients should be advised to take Lenalidomide orally at about the same time each day, either with or without food. Patients should be advised to swallow Lenalidomide capsules whole with water and not to open, break, or chew them.

Patients should be advised to take Lenalidomide orally at approximately the same time each day, with or without food. Capsules should be swallowed whole with water and must not be opened, broken, or chewed.

Digoxin: When Digoxin was co-administered with multiple doses of Lenalidomide (10 mg/day), Digoxin Cmax and AUCinf increased by about 14%. Regular monitoring of Digoxin plasma levels is recommended based on clinical judgment and standard practice during Lenalidomide therapy.

Concomitant Therapies That May Increase the Risk of Thrombosis: Erythropoietic agents or other drugs that may increase thrombosis risk (e.g., estrogen-containing therapies) should be used cautiously after assessing the benefit-risk balance in patients receiving Lenalidomide.

Warfarin: Co-administration of Lenalidomide (10 mg/day) with a single dose of Warfarin (25 mg) showed no effect on the pharmacokinetics of Lenalidomide or R- and S-Warfarin. However, interaction with dexamethasone cannot be ruled out. Close monitoring of PT and INR is recommended in patients with MM receiving Warfarin.

Pregnancy: Lenalidomide may cause fetal harm when administered during pregnancy. Limb abnormalities were observed in animal studies (monkeys) during organogenesis at all tested doses. Due to these findings and its similarity to thalidomide (a known teratogen), Lenalidomide is contraindicated in pregnant women. If pregnancy occurs during treatment, the patient should be informed of the potential risk to the fetus.

Severe Hypersensitivity Reactions: Lenalidomide is contraindicated in patients with a history of severe hypersensitivity reactions.

Embryo-fetal toxicity, hematologic toxicity, venous and arterial thromboembolism, increased mortality in patients with CLL, secondary primary malignancies, hepatotoxicity, severe cutaneous reactions, tumor lysis syndrome, tumor flare reactions, impaired stem cell mobilization, thyroid disorders, early mortality in patients with MCL, and hypersensitivity reactions have been reported. Severe hypersensitivity reactions such as angioedema, Stevens-Johnson syndrome, and toxic epidermal necrolysis may occur; therefore, Lenalidomide is contraindicated in patients with known hypersensitivity.

Based on its mechanism of action, Lenalidomide can cause embryo-fetal harm and is contraindicated during pregnancy. There is no available information on its presence in human milk, its effects on the breastfed infant, or on milk production. Because many drugs are excreted in human milk and due to the potential for adverse effects in breastfed infants, women should be advised not to breastfeed during treatment with Lenalidomide.

Lenalidomide REMS Program: Because of the risk of embryo-fetal toxicity, Lenalidomide is available only through a restricted program called the Lenalidomide REMS (Risk Evaluation and Mitigation Strategy). Requirements include:

• Prescribers must be certified and comply with REMS requirements.
• Patients must be enrolled and meet all conditions of the REMS program.
• Female patients of reproductive potential must comply with pregnancy testing and contraception requirements.
• Pharmacies must be certified and dispense only to authorized patients.

Hematologic Toxicity: Lenalidomide may cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection, and thrombocytopenia for bleeding. Dose interruption and/or reduction may be required.

Venous and Arterial Thromboembolism: Increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke has been reported. Thromboprophylaxis is recommended based on individual risk assessment.

Increased Mortality in Patients with CLL: Lenalidomide is not recommended for use in patients with chronic lymphocytic leukemia (CLL) outside controlled clinical trials.

Second Primary Malignancies: Monitor patients for the development of secondary malignancies. Consider the benefit-risk profile before treatment.

Increased Mortality with Pembrolizumab Combination: Increased mortality has been observed when Lenalidomide is used with pembrolizumab; such combinations are not recommended outside clinical trials.

Hepatotoxicity: Liver injury has been reported, including fatal cases. Monitor liver function regularly and discontinue if severe abnormalities occur.

Severe Cutaneous Reactions: Serious skin reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS may occur. Discontinue permanently if these reactions develop.

Tumor Lysis Syndrome: Monitor patients at risk and take appropriate preventive measures.

Tumor Flare Reaction: Symptoms may include lymph node swelling, fever, rash, and bone pain. Manage appropriately and consider temporary interruption if severe.

Impaired Stem Cell Mobilization: Lenalidomide may reduce the ability to collect stem cells. Consider early stem cell collection in eligible patients.

Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Monitor thyroid function before and during treatment.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

There is no specific experience in the management of Lenalidomide overdose in patients with MM, MDS, or MCL.

Cytotoxic Chemotherapy

Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.