Lenalidomide is a structural analog of thalidomide that has immunomodulatory, antiangiogenic, and antineoplastic properties. It is indicated for the treatment of adult patients with myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma. Use of lenalidomide for the treatment of chronic lymphocytic leukemia is not recommended outside a clinical trial. Lenalidomide is contraindicated in pregnancy due to a risk for birth defects or embryo-fetal death. Routine pregnancy testing is required. All prescribers, pharmacists, and patients must be registered in the Lenalidomide REMS program to prescribe, dispense, or receive lenalidomide. Information about the drug and the program can be found at www.lenalidomideREMS.com or by calling 1-888-423-5436.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
-Wash the exposed area immediately and thoroughly with soap and water if powder from lenalidomide capsules come into contact with skin; flush thoroughly with water if lenalidomide come into contact with mucous membranes.
Emetic Risk
-Minimal/Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take lenalidomide with or without food at approximately the same time each day.
-Swallow capsules whole; do not crush, break, or chew.
-If a dose is missed, take within 12 hours of missing the dose. If more than 12 hours have passed, skip the dose of the day and take the dose the next day at the scheduled time.
-No more than a 28-day supply should be dispensed at one time.
Deterioration of general physical health occurred in 2% of patients with relapsed or refractory mantle cell lymphoma who received lenalidomide in a single-arm trial (n = 134); grade 3 or 4 deterioration of general physical health was reported in 1% of these patients.
Grade 3 or 4 multiorgan failure was reported in 1% of patients with myelodysplastic syndrome who received lenalidomide in a single-arm study (n = 148).
Hematologic toxicity including anemia (9% to 44%; grade 3 or higher, 4% to 18%), neutropenia (35% to 79%; grade 3 or higher, 28% to 59%), thrombocytopenia (15% to 72%; grade 3 or higher, 2.3% to 50%), febrile neutropenia (grade 3 or higher, 1% to 17%), pancytopenia (grade 3 or higher, 4% or less), leukopenia (8% to 32%; grade 3 or higher, 4% to 24%), and lymphopenia (4% to 18%; grade 3 or higher, 2.8% to 17%) has been reported with lenalidomide therapy in clinical trials. Monitor complete blood counts (CBC) in patients receiving lenalidomide therapy as follows: for myelodysplastic syndrome, obtain a CBC weekly for 8 weeks and then monthly thereafter; for multiple myeloma, obtain a CBC weekly for the first 2 cycles, on days 1 and 15 of cycle 3, and then every 4 weeks thereafter; for mantle cell lymphoma, obtain a CBC weekly for the first 4 weeks (cycle 1), every 2 weeks during cycles 2 to 4, and then monthly thereafter; and for follicular or marginal zone lymphoma, obtain a CBC weekly for the first 3 weeks (cycle 1), every 2 weeks during cycles 2 to 4, and then monthly thereafter. Grade 3 or 4 granulocytopenia was reported in patients with myelodysplastic syndrome (MDS) who received lenalidomide in a single-arm study (n = 148); hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, and refractory anemia were reported in patients with MDS in other studies. In pooled results from 2 studies, pancytopenia and hemolytic anemia occurred in 1% or more of relapsed or refractory multiple myeloma patients who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353).
Bleeding has been reported with lenalidomide therapy in clinical trials. Monitor patients for bleeding or bruising. GI bleeding, rectal bleeding, intracranial bleeding/subarachnoid hemorrhage, and post-procedural bleeding were reported in patients with myelodysplastic syndrome who received lenalidomide in a single-arm study (n = 148). In pooled results from 2 studies, GI bleeding occurred in 1% or more of relapsed or refractory multiple myeloma patients who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353).
Gastrointestinal (GI) toxicity including abdominal pain (10% to 20%; grade 3 or 4, 4% or less), upper abdominal pain (8% or less; grade 3 or 4, less than 1%), anorexia (23% or less; grade 3 or 4, 3% or less), constipation (5% to 41%; grade 3 or 4, 2% or less), diarrhea (31% to 54%; grade 3 or 4, 2% to 10%), dysgeusia (15% or less; grade 3 or 4, less than 1%), dyspepsia (11% or less; grade 3 or 4, less than 1%), nausea (11% to 30%; grade 3 or 4, 7% or less), vomiting (5% to 12%; grade 3 or 4, 4% or less), and xerostomia (7% or less) has been reported with lenalidomide therapy in clinical trials. Loose stools occurred in 6% of patients with myelodysplastic syndrome (MDS) who received lenalidomide in a single-arm study (n = 148); ischemic colitis, GI perforation, GI obstruction, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, and perirectal abscess were reported in patients with MDS in other studies. In pooled results from 2 studies, glossodynia occurred in 1% or more of relapsed or refractory multiple myeloma patients who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353). Stomatitis occurred in 5% of patients with previously untreated follicular lymphoma or marginal zone lymphoma who received lenalidomide plus rituximab (n = 176) in a randomized trial.
Venous thromboembolism (VTE) and arterial thromboembolism (ATE) including deep vein thrombosis (DVT) (2% to 10%), pulmonary embolism (PE) (4% or less), myocardial infarction (MI) (2.4% or less), and stroke/cerebrovascular accident (CVA) (2.3% or less) have been reported with lenalidomide therapy in clinical trials. Thromboprophylaxis is recommended in patients with multiple myeloma who receive lenalidomide and dexamethasone; the agent used for prophylaxis may be chosen based on an assessment of the patient's underlying risks. Monitor for signs of thromboembolism and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling. In pooled results from 2 studies, thrombotic events were reported in 21.5% of patients relapsed or refractory multiple myeloma patients who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353) and no thromboprophylaxis; cerebral ischemia occurred in 1% or more of patients in this analysis. Thrombotic events occurred in 17.4% of patients with newly diagnosed multiple myeloma patients who received thromboprophylaxis with lenalidomide and dexamethasone therapy until disease progression (n = 532) in a randomized trial. DVT, ischemia, superficial thrombo-phlebitis, thrombosis, MI or myocardial ischemia, CVA, and transient ischemic attack were reported in patients with myelodysplastic syndrome who received lenalidomide in a single-arm study (n = 148). VTE (3.4%) and ATE (0.6%) occurred in patients with previously untreated follicular lymphoma or marginal zone lymphoma who received lenalidomide plus rituximab (n = 176) in a randomized trial.
New primary malignancy including hematologic (e.g., acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS)) and solid tumor malignancy such as skin cancer (e.g., squamous cell carcinoma and basal cell carcinoma (BCC)) has been reported in 0.4% to 14.9% of patients who received lenalidomide. Perform a benefit/risk assessment prior to starting lenalidomide therapy. Monitor patients for the development of new primary malignancies. Acute leukemia, AML, bronchoalveolar carcinoma, metastatic lung cancer, lymphoma, and metastatic prostate cancer were reported in patients with MDS who received lenalidomide in a single-arm study (n = 148). BCC was reported in patients with relapsed or refractory mantle cell lymphoma who received lenalidomide in a single-arm trial (n = 134).
Nervous system adverse events including headache (1% to 20%; grade 3 or 4, 2% or less), dizziness (23% or less; grade 3 or 4, 3% or less), peripheral neuropathy (15% or less; grade 3 or 4, 4% or less), paresthesias (13% or less; grade 3 or 4, less than 1%), hypoesthesia (7% or less), and grade 3 or 4 syncope (3% or less) were reported with lenalidomide therapy in clinical trials. Falls occurred in 8% of newly diagnosed multiple myeloma patients who received lenalidomide and dexamethasone therapy until disease progression (n = 532) in a randomized trial. In pooled results from 2 studies, tremor (21%) and neuropathy (7%) occurred in patients with relapsed or refractory multiple myeloma who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353). Aphasia, depressed level of consciousness, falls, abnormal gait, dysarthria, migraine, and spinal cord compression occurred in patients with myelodysplastic syndrome who received lenalidomide in clinical studies.
Cardiovascular adverse events including hypotension (10% or less; grade 3 or 4, 3% or less), hypertension (8% or less), atrial fibrillation (7% or less; grade 3 or 4, 4% or less), chest pain (unspecified) (8% or less; grade 3 or 4, 2% or less), and congestive heart failure (CHF) (10% or less; grade 3 or 4, 1% or less) were reported with lenalidomide therapy in clinical trials. In pooled results from 2 studies, grade 3 or 4 sinus tachycardia (2%), bradycardia (1% or more), and angina pectoris (1% or more) occurred in patients with relapsed or refractory multiple myeloma who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353). Palpitations occurred in 5% of patients with myelodysplastic syndrome (MDS) who received lenalidomide in a single-arm study (n = 148); increased troponin I level, angina pectoris, aortic disorder, cardiac arrest, cardio-respiratory arrest, cardiomyopathy, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia, and ventricular dysfunction were reported in patients with MDS in other studies. Supraventricular tachycardia (SVT) was reported in 1.1% of patients with previously untreated follicular lymphoma or marginal zone lymphoma who received lenalidomide plus rituximab (n = 176) in a randomized trial. SVT was also reported in patients with relapsed or refractory mantle cell lymphoma who received lenalidomide in a single-arm trial (n = 134).
Musculoskeletal adverse events including back pain (32% or less; grade 3 or 4, 7% or less), muscle cramps/spasms (33% or less; grade 3 or 4, 2% or less), arthralgia (22% or less; grade 3 or 4, 2% or less), bone pain (16% or less; grade 3 or 4, 3% or less), extremity pain (15% or less; grade 3 or 4, 2% or less), musculoskeletal pain (13% or less; grade 3 or 4, less than 1%), muscular weakness (8% or less; grade 3 or 4, 6% or less), and myalgia (9% or less; grade 3 or 4, 1% or less) were reported with lenalidomide therapy in clinical trials. Musculoskeletal chest pain (11%; grade 3 or 4, 1%), neck pain (8%; grade 3 or 4, less than 1%), and noncardiac chest pain (5%; grade 3 or 4, less than 1%) occurred in newly diagnosed multiple myeloma patients who received lenalidomide and dexamethasone therapy until disease progression (n = 532) in a randomized trial. Pain occurred in 7% of patients with myelodysplastic syndrome (MDS) who received lenalidomide in a single-arm study (n = 148); arthritis, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate deposits, and bone fractures were reported in patients with MDS in other studies.
Endocrine disorders have been reported with lenalidomide therapy in clinical trials. Obtain baseline thyroid function tests and monitor thyroid function during lenalidomide therapy. Hirsutism occurred in 1% or greater of patients with previously treated multiple myeloma who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353) in pooled results from 2 multinational, double-blind, placebo-controlled studies. Acquired hypothyroidism was reported in 7% of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) who received lenalidomide in a multicenter, single-arm study (n = 148). Basedow's disease occurred in MDS patients who received lenalidomide in other clinical studies. Hypothyroidism and hyperthyroidism have been reported in postmarketing surveillance of lenalidomide.
Hepatotoxicity with hepatocellular, cholestatic, and mixed characteristics was reported in 15% of patients who received lenalidomide in clinical trials; serious hepatotoxicity occurred in 2% of patients with multiple myeloma and 1% of patients with myelodysplastic syndromes (MDS). Monitor liver function tests periodically during treatment. Therapy interruption and a dose reduction may be necessary in patients who develop elevated hepatic enzymes during treatment. Elevated hepatic enzymes including increased ALT (10% or less; grade 3 or 4, 4% or less) and AST (6% or less; grade 3 or 4, 3% or less) levels and hyperbilirubinemia (15% or less; grade 3 or 4, 2% or less) were reported with lenalidomide therapy in clinical trials. Abnormal liver function tests occurred in 1% or more of patients with previously treated multiple myeloma who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353) in pooled results from 2 studies. Hyperbilirubinemia, cholecystitis, and hepatic failure occurred in MDS patients who received lenalidomide in clinical studies. Hepatic failure (some cases fatal), toxic hepatitis (toxic, cytolytic, cholestatic, and mixed cytolytic/cholestatic), and transient elevated hepatic enzymes have been reported in postmarketing surveillance of lenalidomide.
Hyperhidrosis (10% or less; grade 3 or 4, 1% or less), night sweats (10% or less), pruritus (4% to 42%; grade 3 or 4, 2.8% or less), xerosis (14% or less), and contusion (8% or less; grade 3 or 4, less than 1%) were reported with lenalidomide therapy in clinical trials. Ecchymosis and erythema each occurred in 5% of patients with myelodysplastic syndrome (MDS) who received lenalidomide in a single-arm study (n = 148); acute febrile neutrophilic dermatosis occurred in MDS patients who received lenalidomide in other clinical studies. Exanthem and skin hyperpigmentation each were reported in 1% or more of patients with relapsed or refractory multiple myeloma who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353).
Renal failure (unspecified) occurred in 9% or less (grade 3 or 4, 5% or less) of patients who received lenalidomide in clinical trials; renal failure resulting in death has been reported. Dysuria occurred in 7% of patients with myelodysplastic syndrome (MDS) who received lenalidomide in a single-arm study (n = 148); hematuria, azotemia, ureteric calculus, renal mass, and increased creatinine level were reported in patients with MDS in other studies. Additionally, acute kidney injury/nephrotoxicity occurred in 1.7% of patients with previously untreated follicular lymphoma or marginal zone lymphoma who received lenalidomide plus rituximab (n = 176) in a randomized trial; grade 3 or 4 acute kidney injury was reported in 1.1% of these patients.
Metabolic adverse events and electrolyte disturbances including hypokalemia (4% to 17%; grade 3 or 4, 7% or less), hypocalcemia (11% or less; grade 3 or 4, 4% or less), hypomagnesemia (7% or less), hyponatremia (less than 5%; grade 3 or 4, 2% or less), hypophosphatemia (7% or less; grade 3 or 4, 6% or less), dehydration (7% or less; grade 3 or 4, 3% or less), gout (less than 5%; grade 3 or 4, 2% or less), and weight loss (20% or less; grade 3 or 4, 2% or less) were reported with lenalidomide therapy in clinical trials. Hypoglycemia and hypernatremia occurred in patients with myelodysplastic syndromes who received lenalidomide in clinical studies.
Pulmonary adverse events including cough (10% to 28%; grade 3 or 4, 1.1% or less), dyspnea (24% or less; grade 3 or 4, 6% or less), epistaxis (15% or less; grade 3 or 4, 1% or less), rhinitis (15% or less; grade 3 or 4, less than 1%), rhinorrhea (5% or less), hypoxia (2% or less; grade 3 or 4, 1% or less), pleural effusion (7% or less; grade 3 or 4, 1% or less), oropharyngeal pain (10% or less), respiratory distress (grade 3 or 4, 2% or less), respiratory failure (grade 3 or 4, 1.1% or less), and chronic obstructive airways disease (COPD) (1.7% or less; grade 3 or 4, 1.1% or less) were reported with lenalidomide therapy in clinical trials. Hoarseness occurred in patients with relapsed or refractory multiple myeloma who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353). Grade 3 or 4 pneumonitis and pulmonary hypertension were each reported in 1% of patients with myelodysplastic syndrome (MDS) who received lenalidomide in a single-arm study (n = 148); exacerbated COPD, respiratory failure, interstitial lung disease, lung infiltration, and wheezing occurred in patients with MDS who received lenalidomide in other clinical studies. Pneumonitis has been reported in postmarketing surveillance of lenalidomide.
Edema (10% or less) and peripheral edema (26% or less) have been reported with lenalidomide therapy in clinical trials.
Libido decrease and impotence (erectile dysfunction) each occurred in 1% or greater of patients with previously treated multiple myeloma who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353) in pooled results from 2 multinational, double-blind, placebo-controlled studies. Pelvic pain was reported in patients with myelodysplastic syndromes in clinical trials.
Visual impairment has been reported with lenalidomide therapy. In pooled results from 2 multinational, double-blind studies, blindness (1% or greater), blurred vision (17%), cataracts (grade 3 or 4, 2%), ocular hypertension (1% or greater), and unilateral cataracts (grade 3 or 4, 1%) occurred in relapsed or refractory multiple myeloma patients who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353). Cataracts (14%; grade 3 or 4, 6%) and subcapsular cataracts (less than 5%; grade 3 or 4, 1%) were reported in newly diagnosed multiple myeloma patients who received lenalidomide and dexamethasone therapy until disease progression (n = 532) in a randomized trial.
Infection has been reported in 5% to 47% of patients who received lenalidomide therapy; death due to sepsis and/or pneumonia has occurred. Monitor neutropenic patients for signs of infection. Infectious adverse events including influenza/influenza-like illness (10% or less; grade 3 or 4, 1% or less), pharyngitis (16% or less), naso-pharyngitis (35% or less; grade 3 or 4, less than 1%), sinusitis (14% or less), pneumonia (7% to 17%; grade 3 or 4, 3.4% to 11%), bronchitis (47% or less; grade 3 or 4, 2% or less), respiratory tract infection (10% or less; grade 3 or 4, 1% or less), upper respiratory tract infection (11% to 27%; grade 3 or 4, 3% or less), lower respiratory tract infection (6% or less; grade 3 or 4, 3% or less), urinary tract infection (4% to 14%; grade 3 or 4, 2% or less), cellulitis (5% or less; grade 3 or 4, 2% or less), sepsis (6% or less), neutropenic infection (18% or less; grade 3 or 4, 12% or less), lung infection (9% or less; grade 3 or 4, 8% or less), bacteremia (2% or less; grade 3 or 4, 2% or less), herpes zoster infection (10% or less; grade 3 or 4, 2% or less), gastroenteritis (23% or less; grade 3 or 4, 2% or less), and oral herpes (10% or less) were reported with lenalidomide therapy in clinical trials. Central line infection, ear infection/otitis, fungal infection, kidney infection, septic shock, and urosepsis occurred in patients with myelodysplastic syndrome who received lenalidomide in clinical studies. Clostridium difficile colitis developed in 2 or more mantle cell lymphoma patients who received single-agent lenalidomide treatment. Viral reactivation (such as hepatitis B virus and herpes zoster) and progressive multifocal leukoencephalopathy were reported in postmarketing surveillance of lenalidomide.
Psychiatric adverse events including depression (11% or less; grade 3 or 4, 2% or less) and insomnia (28% or less; grade 3 or 4, less than 1%) have been reported with lenalidomide therapy in clinical trials. In pooled results from 2 studies, hallucinations and mood swings occurred in 1% or more of relapsed or refractory multiple myeloma patients who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353). Confusion was reported in patients with myelodysplastic syndromes who received lenalidomide in clinical studies.
Vertigo was reported in patients with myelodysplastic syndromes who received lenalidomide in clinical trials. Additionally, vertigo occurred in 1% to 10% of patients with mantle cell lymphoma who received single-agent lenalidomide.
Fever (8% to 27%; grade 3 or 4, 3% or less) and chills/rigors (10% or less) have been reported with lenalidomide therapy in clinical trials.
Asthenia (30% or less; grade 3 or 4, 8% or less) and fatigue (11% to 44%; grade 3 or 4, 1% to 9%) have been reported with lenalidomide therapy in clinical trials. Lethargy was reported in 1% to 10% of patients with relapsed or refractory mantle cell lymphoma who received lenalidomide in a single-arm trial (n = 134). In pooled results from 2 studies, lethargy (7%) and malaise (1% or more) occurred in patients with relapsed or refractory multiple myeloma who received lenalidomide plus oral pulse high-dose dexamethasone (n = 353). Malaise was reported in 7% of patients with previously untreated FL or MZL who received lenalidomide plus rituximab (n = 176) in a randomized trial.
Tumor flare reaction (TFR) has been reported in patients who received lenalidomide therapy, including fatalities. Monitor patients with mantle cell lymphoma (MCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) for symptoms of TFR during therapy (e.g., lymph node swelling, low-grade fever, pain, and rash). Interruption of therapy and a dosage reduction may be necessary in patients who develop severe TFR. Symptomatic treatment with corticosteroids, non-steroidal anti-inflammatory drugs (NSAID), and/or narcotic analgesics may be beneficial. Grade 1 or 2 TFR was reported in 10% of patients with relapsed or refractory MCL who received lenalidomide in a multicenter, single-arm trial (n = 134). All cases occurred in cycle 1 and 1 patient experienced recurrent TFR in cycle 11. TFR occurred in 11% of patients with previously untreated FL or MZL who received lenalidomide plus rituximab (n = 176) in a randomized trial; grade 3 or 4 TFR was reported in less than 1% of these patients. Grade 1 or 2 TFR was also reported in 4.1% of patients with FL or MZL (n = 222) in another trial. Additionally, TFR has been reported in postmarketing surveillance of lenalidomide.
Angioedema, anaphylaxis/anaphylactoid reactions, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in postmarketing surveillance of lenalidomide; some cases were fatal. Symptoms of DRESS include rash or exfoliative dermatitis, eosinophilia, fever, or lymphadenopathy; systemic complications such as hepatitis, interstitial nephritis, pneumonitis, myocarditis, or pericarditis may also occur. Rash has been reported in 8% to 36% (grade 3 or 4, 1% to 7%) of patients who received lenalidomide in clinical trials. Therapy interruption or discontinuation should be considered in patients who develop a grade 2 or 3 skin rash. Permanently discontinue lenalidomide if a patient develops angioedema, anaphylactoid reactions, grade 4 rash, exfoliative or bullous rash, or SJS, TEN, or DRESS. The term rash includes maculopapular rash, erythematous rash, exfoliative rash, follicular rash, DRESS, erythema multiforme. Hypersensitivity and transfusion reactions were reported in patients with myelodysplastic syndrome in clinical studies. Dermatitis acneiform occurred in 4.5% of patients with previously untreated follicular lymphoma or marginal zone lymphoma who received lenalidomide plus rituximab (n = 176) in a randomized trial; grade 3 or 4 dermatitis acneiform was reported in 1.1% of these patients.
Diabetes mellitus (less than 5%; grade 3 or 4, 2%) and hyperglycemia (12%; grade 3 or 4, 5%) occurred in newly diagnosed multiple myeloma patients who received lenalidomide and dexamethasone therapy until disease progression (n = 532) in a randomized trial.
Impaired stem cell mobilization has been reported following more than 4 cycles of lenalidomide therapy in patients who are eligible for an autologous stem-cell transplant. A prompt referral to a transplant center is appropriate for transplant eligible patients. Use of a granulocyte colony-stimulating factor (G-CSF) with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered in patients who received more than 4 cycles of a lenalidomide-containing treatment or who had an inadequate numbers of CD34+ cells collected in 4 cycles of lenalidomide.
Acute graft-versus-host disease (GVHD) following allogeneic hematopoietic transplant and solid organ transplant rejection have been reported in postmarketing surveillance of lenalidomide.
Lenalidomide is structurally similar to thalidomide, which causes teratogenesis. Lenalidomide produced limb malformations in the offspring of pregnant female monkeys. It may cause birth defects or intrauterine fetal death if administered during pregnancy. In order to prevent fetal exposure, lenalidomide is only approved for marketing through a special restricted distribution program called the Lenalidomide REMS program, which is approved by the US Food and Drug Administration. If a patient becomes pregnant while taking lenalidomide, apprise the patient of the potential hazard to the fetus. Also, report any suspected fetal exposure to lenalidomide to the FDA by calling 1-800-332-1088 and to Celgene by calling 1-888-423-5436.
Tumor lysis syndrome (TLS) occurred in 2 patients (1.1%) with previously untreated follicular lymphoma (FL) and marginal zone lymphoma (MZL) who received lenalidomide plus rituximab (n = 176) in a randomized trial; hyperuricemia (6%; grade 3 or 4, less than 1%) was also reported in this trial. Grade 3 TLS occurred in 1 patient (0.5%) with FL or MZL (n = 222) in another trial. Additionally, TLS has been reported in postmarketing surveillance of lenalidomide. Monitor patients at risk for TLS (e.g., high tumor burden prior to treatment) and take precautionary measures (e.g., hydration, uric acid-lowering therapy).
Severe hypersensitivity reactions including serious rash (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with lenalidomide therapy; some cases were fatal. Use is contraindicated in patients who have experienced an allergic reaction (e.g., angioedema, SJS, TEN) to lenalidomide. Do not administer lenalidomide in patients with a history of grade 4 rash with thalidomide therapy (thalidomide hypersensitivity). Therapy interruption or discontinuation should be considered in lenalidomide-treated patients who develop a grade 2 or 3 skin rash. Permanently discontinue lenalidomide if a patient develops angioedema, anaphylaxis, grade 4 rash, exfoliative or bullous rash, or SJS, TEN, or DRESS.
Venous (e.g., deep vein thrombosis, pulmonary embolism) and arterial (e.g., myocardial infarction, stroke) thromboembolism has been reported with lenalidomide use. There was an increased incidence of venous and arterial thrombotic events in patients with multiple myeloma who received lenalidomide in combination with dexamethasone compared with dexamethasone alone in clinical trials. Patients with hyperlipidemia, hypertension, tobacco smoking, or a history of thrombosis may be at greater risk; minimize modifiable risk factors when possible. In clinical trials that did not use thromboprophylaxis, the overall rate of thrombotic events was higher in patients with refractory or relapsed multiple myeloma who received lenalidomide plus dexamethasone compared with dexamethasone alone; the median time to first thrombotic event was 2.8 months. Thromboprophylaxis is recommended in patients with multiple myeloma who receive lenalidomide and dexamethasone; the agent used for prophylaxis may be chosen based on an assessment of the patient's underlying risks. Monitor for signs of thromboembolism and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Hematologic toxicity, including severe thrombocytopenia and neutropenia, has been reported with lenalidomide therapy. Monitor complete blood counts (CBC) in patients receiving lenalidomide therapy as follows: for myelodysplastic syndrome, obtain a CBC weekly for 8 weeks and then monthly thereafter; for multiple myeloma, obtain a CBC weekly for the first 2 cycles, on days 1 and 15 of cycle 3, and then every 4 weeks thereafter; for mantle cell lymphoma, obtain a CBC weekly for the first 4 weeks (cycle 1), every 2 weeks during cycles 2 to 4, and then monthly thereafter; and for follicular or marginal zone lymphoma, obtain a CBC weekly for the first 3 weeks (cycle 1), every 2 weeks during cycles 2 to 4, and then monthly thereafter. Monitor neutropenic patients for signs of infection. Advise patients to report unusual bleeding or bruising, especially if they are also receiving other agents that increase the risk of bleeding. Therapy interruption and dose adjustments are necessary in patients who develop significant hematologic toxicity.
Renal failure has been reported with lenalidomide therapy. Use lenalidomide with caution in patients with pre-existing renal disease. An initial dose reduction is necessary in patients with moderate (creatinine clearance (CrCl) of 30 to 60 mL/min) and severe (CrCl less than 30 mL/min) renal impairment including patients on dialysis; base subsequent lenalidomide dosage adjustments on individual patient tolerance.
Hepatotoxicity has been reported with lenalidomide use, including hepatic failure resulting in death. Use caution in patients with moderate or severe hepatic disease/impairment; lenalidomide has not been evaluated in these patients. Monitor liver function tests periodically during treatment. Therapy interruption and a dose reduction may be necessary in patients who develop elevated hepatic enzymes during treatment. Patients with viral hepatitis, elevated hepatic enzymes at baseline, or who are receiving concomitant medications may have an increased risk for developing hepatotoxicity.
Avoid blood donation during lenalidomide therapy, during dosage interruptions, and for 4 weeks after the last lenalidomide dose due to the risk of blood being given to a pregnant female patient.
Tumor lysis syndrome (TLS) has been reported with lenalidomide therapy; some cases resulted in death. Monitor patients at risk for TLS (e.g., high tumor burden prior to treatment) and take precautionary measures (e.g., hydration, uric acid lowering therapy). Tumor flare reaction (TFR), including fatal cases, has been reported in lenalidomide-treated patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (unapproved use), and follicular and marginal zone lymphoma; TFR may mimic progressive disease. In a clinical trial in patients with MCL, most cases of TFR occurred in the first cycle. Monitor MCL and lymphoma patients for TFR symptoms during lenalidomide therapy (e.g., lymph node swelling, low-grade fever, pain, and rash). Hold therapy in patients who develop grade 3 or 4 TFR. Administer symptomatic treatment with corticosteroids, non-steroidal anti-inflammatory drugs (NSAID), and/or narcotic analgesics in patients who develop TFR.
New primary malignancy (e.g., acute myelogenous leukemia, myelodysplastic syndrome, lymphomas, squamous cell and basal cell carcinoma of the skin, lung cancer, and prostate cancer) has been reported with lenalidomide therapy. Initiate lenalidomide after performing a benefit/risk assessment. Monitor patients for the development of new primary malignancies.
Hypothyroidism and hyperthyroidism have been reported with lenalidomide use. Obtain baseline thyroid function tests and monitor thyroid function during lenalidomide therapy.
Lenalidomide capsules contain lactose. Use lenalidomide with caution in patients with lactose intolerance or lactase deficiency.
Reduced CD34+ cell collection has been reported in patients who received more than 4 cycles of lenalidomide therapy. Peripheral blood stem cell (PBSC) mobilization should occur within four 28-day treatment cycles in patients who are eligible for an autologous stem-cell transplant. Refer eligible patients to a transplant center. If inadequate CD 34+ cells are collected in patients who have received more than 4 cycles of lenalidomide, consider using granulocyte colony-stimulating factor (G-CSF) plus cyclophosphamide or G-CSF plus a CXCR4 inhibitor (e.g., plerixafor) for PBSC mobilization.
Use lenalidomide with caution in geriatric patients; serious adverse events have been reported more frequently in elderly patients compared with younger patients who received lenalidomide. Additionally, closely monitor renal function in these patients.
The use of a PD-1 or PDL1 blocking antibody with a thalidomide analogue plus dexamethasone is not recommended for multiple myeloma treatment outside of a clinical trial. Two clinical trials were halted due to an increased risk of death in patients who received pembrolizumab and dexamethasone in combination with an immunomodulatory agent (lenalidomide or pomalidomide) for the treatment of multiple myeloma.
Lenalidomide is contraindicated for use during pregnancy. Lenalidomide is structurally similar to thalidomide, which is a known teratogen that causes severe, life-threatening human birth defects. Lenalidomide produced limb malformations in the offspring of pregnant female monkeys. It may cause birth defects or intrauterine fetal death if administered during pregnancy. In order to prevent fetal exposure, it is only available through a restricted distribution program, the Lenalidomide REMS program. This program requires prescribers, pharmacists, and patients to comply with certain conditions prior to prescribing, dispensing, or receiving lenalidomide. It can be prescribed only by licensed prescribers who are registered in the Lenalidomide REMS program and understand the potential risk of teratogenicity if used during pregnancy. If pregnancy does occur during treatment, immediately discontinue lenalidomide. Prescribers are encouraged to report all cases of pregnancy to the REMS Call Center at 1-888-423-5436 or to the FDA MedWatch program at 1-800-332-1088. Refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Counsel patients about the reproductive risk and contraception requirements during lenalidomide treatment. Do not initiate therapy in females of reproductive potential (e.g., sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months) until pregnancy testing is performed twice with confirmed negative results. Administer the first test within 10 to 14 days and the second test 24 hours prior to prescribing lenalidomide. Once treatment is started, continue pregnancy testing weekly during the first 4 weeks of treatment, then every 4 weeks in females with regular menstrual cycles and every 2 weeks in females with irregular menstrual cycles. Effective contraception must be used by all females of reproductive potential for at least 4 weeks before beginning treatment, during therapy and dosage interruptions, and for 4 weeks following discontinuation of therapy. Women must commit to abstain from heterosexual intercourse or to use 2 methods of reliable birth control, including at least 1 highly effective method (e.g., intrauterine device (IUD), hormonal contraception, tubal ligation, or partner's vasectomy) and 1 additional effective method (e.g., latex condom, diaphragm, or cervical cap). Follow these contraceptive requirements even in patients with a history of infertility, unless a hysterectomy has been performed. Discontinue treatment, test for pregnancy, and counsel any woman of reproductive potential who experiences menstrual irregularity (e.g., dysfunctional uterine bleeding) or misses her period. Advise patients that if her doctor is not available, she can call 1-888-423-5436 for information on emergency contraception. Lenalidomide passes into semen and there is potential for male-mediated teratogenicity. Male patients must use barrier contraception (latex condom) during sexual intercourse with a woman of reproductive potential while on therapy, during interruptions, and for 4 weeks after discontinuing therapy, even if he has undergone successful vasectomy. Male patients should be warned against sperm donation during lenalidomide therapy and for up to 4 weeks after stopping it.
It is not known if lenalidomide is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during lenalidomide therapy.
Treatment with lenalidomide was associated with a 92% increased risk of death (hazard ratio = 1.92; 95% CI, 1.08 to 3.41) and a higher incidence of serious cardiovascular adverse reactions (e.g., atrial fibrillation, myocardial infarction, heart failure) compared with chlorambucil in a randomized clinical trial in patients with chronic lymphocytic leukemia (CLL); therefore, use of lenalidomide for the treatment of CLL is not recommended outside of a clinical trial.
For the treatment of myelodysplastic syndrome (MDS):
NOTE: Lenalidomide has been designated as an orphan drug for the treatment of myelodysplastic syndromes.
-for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities:
Oral dosage:
Adults: 10 mg orally daily; adjust the dose based on clinical toxicity and laboratory findings. Transfusion independence was reported in 67% of patients with red blood cell transfusion-dependent anemia in low- or intermediate-1-risk myelodysplastic syndromes with a deletion 5q cytogenetic abnormality who received lenalidomide in a clinical study (n = 148). Transfusion independence was defined as the absence of a red blood cell transfusion during any consecutive 56 days during the treatment period. The median transfusion-free period in responding patients was 44 weeks; 90% of responding patients achieved a transfusion benefit within 3 months of starting lenalidomide treatment.
-for the treatment of patients with transfusion-dependent anemia due to lower-risk MDS without a deletion 5q cytogenetic abnormality who are ineligible for or refractory to erythropoiesis-stimulating agents*:
Oral dosage:
Adults: 10 mg orally daily for 24 weeks was evaluated in a randomized double-blind, placebo-controlled, phase 3 trial (the MDS-005 trial; n = 239). Patients who achieved transfusion independence for 8 weeks or longer or who had an erythroid response could continue to receive lenalidomide beyond 24 weeks until unacceptable toxicity or disease progression. Treatment cycles were 28 days in length. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.
For the treatment of multiple myeloma:
NOTE: The FDA has designated lenalidomide as an orphan drug for the treatment of multiple myeloma.
-for the treatment of newly diagnosed multiple myeloma, in combination with dexamethasone:
Oral dosage:
Adults and Geriatric patients 75 years or younger: 25 mg orally once daily for 21 days in combination with dexamethasone 40 mg orally on days 1, 8, 15, and 22. In patients who are ineligible for autologous stem-cell transplantation, repeat treatment cycles every 28 days until disease progression. In patients who are eligible for autologous stem-cell transplantation, hematopoietic stem-cell mobilization should occur within four 28-day treatment cycles. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.
Geriatric patients older than 75 years: 25 mg orally once daily for 21 days in combination with dexamethasone 20 mg orally on days 1, 8, 15, and 22. Repeat treatment cycles every 28 days until disease progression. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.
-for the treatment of multiple myeloma following at least 1 prior therapy, in combination with dexamethasone:
Oral dosage:
Adults: 25 mg orally once daily for 21 days; repeat treatment cycles every 28 days until disease progression. For the first 4 cycles, administer lenalidomide in combination with dexamethasone 40 mg orally on days 1, 2, 3, and 4; days 9, 10, 11, and 12; and days 17, 18, 19, and 20; thereafter, give lenalidomide in combination with dexamethasone 40 mg orally on days 1, 2, 3, and 4 of each 28-day cycle. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. Treatment with lenalidomide plus dexamethasone led to significantly improved median time to disease progression (TTP) and overall survival (OS) time compared with dexamethasone alone in patients with relapsed or refractory multiple myeloma in 2 multinational, placebo-controlled, phase 2 trials (MM-009 and MM-010 trials); both trials were stopped early based on favorable efficacy results demonstrated in the lenalidomide arm at an interim analysis. In a pooled analysis of these trials, the median age was 63 years (range, 33 to 86 years), about 20% of patients had received 1 prior therapy, about 80% had received 2 or more prior therapies, and approximately 58% had previously received a stem-cell transplantation. At a median follow-up time of 17.6 months, treatment with lenalidomide and dexamethasone resulted in a significantly longer median TTP (primary endpoint) compared with placebo plus dexamethasone (11.1 months vs. 4.7 months; hazard ratio [HR] = 0.35; 95% CI, 0.27 to 0.37; p less than 0.001) in patients with relapsed or refractory multiple myeloma in a multicenter, randomized, double-blind, phase III trial (n = 353; the MM-009 trial). At a median follow-up time of 26.2 months in the lenalidomide/dexamethasone arm and 12.9 months in the placebo/dexamethasone arm, the median OS time was significantly improved with lenalidomide/dexamethasone treatment (29.6 months vs. 20.2 months; HR = 0.44; 95% CI, 0.3 to 0.65; p less than 0.001); 58% of patients from the placebo/dexamethasone arm crossed over to receive treatment with lenalidomide/dexamethasone. At a median follow-up time of 16.4 months, treatment with lenalidomide and dexamethasone resulted in a significantly longer median TTP (primary endpoint) compared with placebo plus dexamethasone (11.3 months vs. 4.7 months; p less than 0.001) in patients with relapsed or refractory multiple myeloma in a multicenter, randomized, phase 3 trial (n = 351; the MM-010 trial). The median OS time was significantly improved in the lenalidomide/dexamethasone arm (median time not reached vs. 20.6 months; HR = 0.66; 95% CI, 0.45 to 0.96; p = 0.03). In a pooled analysis of the MM-009 and MM-010 trials (n = 703), the median OS time continued to be significantly improved in patients who received lenalidomide plus dexamethasone (38 months) compared with patients who received placebo plus dexamethasone (31.6 months; p = 0.045) at a median follow-up time of 48 months; 47.6% of patients from the placebo/dexamethasone arm crossed over to receive treatment with lenalidomide/dexamethasone.
-as maintenance therapy following autologous hematopoietic stem-cell transplantation (HSCT) in patients with multiple myeloma:
Oral dosage:
Adults and Geriatric patients 70 years and younger: 10 mg orally once daily as continuous therapy until disease progression. Begin therapy following adequate hematologic recovery (defined as an absolute neutrophil count of 1,000 cells/mcL or more and/or platelet count of 75,000 cells/mcL or more) after an autologous hematopoietic stem cell transplantation (HSCT). After three 28-day treatment cycles, the dose can be increased to lenalidomide 15 mg once daily, if tolerated. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. The progression-free survival (PFS) time was significantly improved in patients who had nonprogressive disease after first line autologous HSCT and who received maintenance therapy with lenalidomide compared with placebo (41 months vs. 23 months; hazard ratio [HR] = 0.5; p < 0.001) in a multinational, randomized, double-blind, placebo-controlled, phase 3 trial (n = 614; median age, 55 years; range, 22 to 67 years). At a median follow-up time of 45 months, the estimated 4-year PFS rates were 43% and 22% (HR = 0.5; p less than 0.001), and the estimated 4-year overall survival (OS) rates were 73% and 75% in the lenalidomide and placebo arms, respectively. At a planned interim analysis (median follow-up of 18 months), the time to disease progression (TTP) was significantly improved in patients who had stable disease or better at 100 days after an autologous HSCT and received maintenance therapy with lenalidomide compared with placebo (39 months vs. 21 months; p less than 0.001) in a randomized, double-blind, placebo-controlled, phase 3 trial (n = 460; median age, 59 years; range, 29 to 71 years). Based on these results, the trial was stopped and cross-over from placebo to the lenalidomide arm was permitted. At a median follow-up of 34 months, the median TTP were 46 months and 27 months (p less than 0.001), the 3-year PFS rates were 66% and 39% (HR = 0.5; p less than 0.001), and the 3-year OS rates were 88% and 80% (HR = 0.62; 95% CI, 0.4 to 0.95) in the lenalidomide and placebo arms, respectively.
-for the treatment of relapsed multiple myeloma in patients who have received 1 to 3 prior lines of therapy, in combination with carfilzomib and dexamethasone*:
NOTE: Carfilzomib is FDA approved in combination with lenalidomide and dexamethasone for the treatment of relapsed multiple myeloma in patients who have received 1 to 3 prior lines of therapy.
Oral dosage:
Adults: 25 mg orally once daily for 21 days in combination with dexamethasone (40 mg orally or intravenously on days 1, 8, 15, and 22) and carfilzomib. Treatment cycles are repeated every 28 days until disease progression or unacceptable toxicity; maximum of 18 cycles for carfilzomib only. Cycle 1: carfilzomib 20 mg/m2 intravenous over 10 minutes on days 1 and 2; if tolerated, increase to a target dose of 27 mg/m2 intravenous over 10 minutes on days 8, 9, 15, and 16. Cycles 2 to 12: carfilzomib 27 mg/m2 intravenous over 10 minutes on days 1, 2, 8, 9, 15, and 16. Cycles 13 to 18: carfilzomib 27 mg/m2 intravenous over 10 minutes on days 1, 2, 15, and 16. Dose carfilzomib at a maximum body surface area of 2.2 m2; dose adjustment is not necessary for patients with a weight change of 20% or less. Premedication: Give dexamethasone 30 minutes to 4 hours before carfilzomib (on carfilzomib dosing days only). Supportive care: Prehydrate with both oral and intravenous fluids before each carfilzomib dose in cycle 1. Additional intravenous hydration may be given after the carfilzomib infusion in cycle 1. Oral and/or intravenous hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. Thromboprophylaxis is recommended. Consider giving an antiviral agent and an antacid medication. In a prespecified interim analysis of a multinational, randomized, open-label, phase 3 trial (n = 792; the ASPIRE trial), the median progression-free survival time (primary endpoint) was significantly increased with carfilzomib plus lenalidomide/dexamethasone (26.3 months) compared with lenalidomide/dexamethasone alone (17.6 months; hazard ratio (HR) = 0.69; 95% CI, 0.57 to 0.83; p = 0.0001) in patients with relapsed multiple myeloma who had received 1 to 3 prior therapies (age range, 31 to 91 years; median of 2 prior therapies). In this study, some patients had previously received bortezomib (65.8%) and/or lenalidomide (19.8%). The median overall survival (OS) time had not been reached in either study arm at the time of the interim analysis (median follow-up: carfilzomib arm, 32.3 months; lenalidomide/dexamethasone alone, 31.5 months). The estimated 24-month OS rates were 73.3% and 65% in the carfilzomib/lenalidomide/dexamethasone and lenalidomide/dexamethasone arms, respectively (HR = 0.79; 95% CI, 0.63 to 0.99; p = 0.04); prespecified criteria for stopping the study due to OS benefit was not met and this study is ongoing.
-for the treatment multiple myeloma in patients who have received at least 1 prior therapy, in combination with daratumumab and dexamethasone*:
NOTE: Daratumumab is FDA approved in combination with lenalidomide and dexamethasone for this indication.
Oral dosage:
Adults: 25 mg orally daily for 21 days in patients with creatinine clearance (CrCl) greater than 60 mL/min (or 10 mg orally daily for 21 days in patients with a CrCl of 30 to 60 mL/min) in combination with daratumumab and dexamethasone repeated every 28 days until disease progression or unacceptable toxicity was evaluated in a multinational, randomized, open-label, phase 3 trial (n = 569; POLLUX trial). The daratumumab dosage is 16 mg/kg (actual body weight) intravenous weekly on weeks 1 to 8 (8 doses), 16 mg/kg intravenous every other week on weeks 9 to 24 (8 doses), and then 16 mg/kg intravenous every 4 weeks starting on week 25 until disease progression. Administer standard pre- and post-infusion medications with daratumumab infusions. The dexamethasone dosage is 40 mg orally once weekly (or 20 mg orally once weekly for patients older than 75 years or with a BMI lower than 18.5).
-for the treatment of relapsed or refractory multiple myeloma in patients who have received at least 1 prior therapy, in combination with daratumumab/hyaluronidase and dexamethasone*:
NOTE: Daratumumab; hyaluronidase is FDA approved in combination with lenalidomide and dexamethasone for this indication.
Oral dosage:
Adults: 25 mg orally once daily on days 1 to 21 repeated every 28 days plus dexamethasone 40 mg PO/IV once weekly in combination with 1,800 mg daratumumab and 30,000 units hyaluronidase subcutaneously weekly on weeks 1 to 8 (8 doses), 1,800 mg daratumumab and 30,000 units hyaluronidase every other week on weeks 9 to 24 (8 doses), and then 1,800 mg daratumumab and 30,000 units hyaluronidase every 4 weeks starting on week 25 until disease progression was evaluated in a single-arm cohort (n = 65) of a multicohort, open-label trial (the PLEIADES trial). The overall response rate was 91% in patients with relapsed or refractory multiple myeloma who received daratumumab/hyaluronidase, lenalidomide, and dexamethasone. Dexamethasone was given at a reduced dose of 20 mg PO/IV once weekly in patients older than 75 years or who had a body-mass index less than 18.5. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.
-for the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant, in combination with daratumumab and dexamethasone*:
NOTE: Daratumumab is FDA approved in combination with lenalidomide and dexamethasone for this indication.
Oral dosage:
Adults: 25 mg orally daily for 21 days in patients with creatinine clearance (CrCl) greater than 50 mL/min (or 10 mg orally daily for 21 days in patients with a CrCl of 30 to 50 mL/min) in combination with daratumumab and dexamethasone repeated every 28 days until disease progression or unacceptable toxicity was evaluated in a multinational, randomized, open-label, phase 3 trial (n = 737; MAIA trial). The daratumumab dosage is 16 mg/kg (actual body weight) intravenous weekly on weeks 1 to 8 (8 doses), 16 mg/kg intravenous every 2 weeks on weeks 9 to 24 (8 doses), and then 16 mg/kg intravenous every 4 weeks starting on week 25 until disease progression. Administer standard pre- and post-infusion medications with daratumumab infusions. The dexamethasone dosage is 40 mg orally once weekly (or 20 mg orally once weekly for patients older than 75 years or with a BMI lower than 18.5). In the MAIA trial (median follow-up, 56.2 months), the median progression-free survival (time not reached vs. 34.4 months; hazard ratio (HR) = 0.53; 95% CI, 0.43 to 0.66, p less than 0.0001) and overall survival (time not reached in either arm; HR = 0.68; 95% CI, 0.53 to 0.86) times were significantly improved in the daratumumab plus lenalidomide and dexamethasone arm compared with the lenalidomide and dexamethasone arm in patients (median age, 73 years; range, 45 to 90 years) with newly diagnosed multiple myeloma who were ineligible for a stem-cell transplant.
-for the treatment of newly diagnosed multiple myeloma, in combination with bortezomib and dexamethasone*:
Oral dosage:
Adults: 25 mg orally daily on days 1 to 14 repeated every 21 days for 8 cycles (SWOG S0777 trial); 25 mg orally daily on days 1 to 14 repeated every 21 days for 3 cycles prior to stem-cell transplantation (SCT) followed by 2 cycles after SCT (IFM 2009 trial); and 25 mg orally daily on days 1 to 14 repeated every 21 days for 12 cycles (ENDURANCE trial) in combination with bortezomib and dexamethasone (VRd regimen) have been evaluated in 3 randomized, phase 3 trials. Maintenance therapy consisted of lenalidomide and dexamethasone or lenalidomide only. In one study, the lenalidomide dose was reduced to 20 mg in patients with a creatinine clearance (CrCl) of 30 to 59 mL/min; the dose could be increased if the CrCl increased to at least 60 mL/min. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.
-for the treatment of multiple myeloma in patients who have received 1 to 3 prior therapies, in combination with elotuzumab and dexamethasone*:
NOTE: Elotuzumab is FDA approved in combination with lenalidomide and dexamethasone for this indication.
Oral dosage:
Adults: 25 mg orally daily on days 1 through 21 in combination with elotuzumab 10 mg/kg IV once weekly on cycles 1 and 2 (on days 1, 8, 15, and 22), then 10 mg/kg IV every 2 weeks (on days 1 and 15) thereafter and dexamethasone 28 mg orally (taken 3 to 24 hours prior to elotuzumab) on days 1, 8, 15, and 22 on cycles 1 and 2 and on days 1 and 15 of subsequent cycles. Give dexamethasone 40 mg orally on days 8 and 22 of cycles 3 and beyond. Repeat treatment cycles every 28 days until disease progression. Administer the following premedications 45 to 90 minutes prior to each elotuzumab infusion: acetaminophen 650 to 1,000 mg orally, diphenhydramine 25 to 50 mg orally or IV (or equivalent), an IV or oral H2-blocker, and dexamethasone 8 mg IV. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. At a median follow-up time of 24.5 months, the median progression-free survival time was significantly improved with elotuzumab plus lenalidomide and dexamethasone (median duration of therapy, 17 months) compared with lenalidomide and dexamethasone alone (19.4 months vs. 14.9 months; hazard ratio (HR) = 0.7; 95% CI, 0.57 to 0.85; p less than 0.001) in patients with relapsed and/or refractory multiple myeloma in a planned interim analysis of a multicenter, randomized, open-label, phase 3 trial (n = 646; the ELOQUENT-2 trial). In this study, patients had received a median of 2 prior therapies (range, 1 to 4 therapies); 35% of patients had refractory disease to the last therapy and 54% of patients had previously received an autologous stem cell transplantation. The overall survival time was improved in the elotuzumab-containing arm (48.3 months vs. 39.6 months; HR = 0.82; 95% CI, 0.68 to 1) at the final analysis (minimum follow-up time of 70.6 months). In subgroup analyses, the median OS times were significantly improved in elotuzumab-treated patients who had received 2 or 3 prior therapies (51 months vs. 33.6 months; HR = 0.71; 95% CI, 0.54 to 0.92), were refractory to their most recent therapy (40.4 months vs. 25.9 months; HR = 0.67; 95% CI, 0.49 to 0.91), or were less than 65 years of age (63.5 months vs. 47.7 months; HR = 0.7; 95% CI, 0.52 to 0.96).
-for the treatment of newly diagnosed multiple myeloma in patients who are eligible for autologous stem-cell transplant, in combination with daratumumab, bortezomib, and dexamethasone*:
Oral dosage:
Adults 70 years and younger: 25 mg orally daily on days 1 to 14 repeated every 21 days on cycles 1, 2, 3, and 4 followed by high-dose chemotherapy and an autologous stem-cell transplant and then 2 additional cycles of lenalidomide 25 mg PO daily on days 1 to 14 repeated every 21 days (cycles 5 and 6) plus bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11 and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16 repeated every 21 days for 6 cycles (VRd regimen) with daratumumab was evaluated in a randomized, phase 2 trial (the GRIFFIN trial; n = 207). Daratumumab treatment consisted of 16 mg/kg IV on days 1, 8, and 15 repeated every 21 days on cycles 1, 2, 3, and 4 and 16 mg/kg IV day 1 repeated every 21 days on cycles 5 and 6. Maintenance therapy was given for up to 2 years and consisted of daratumumab 16 mg/kg IV on day 1 repeated every 4 or 8 weeks and lenalidomide 10 mg orally daily on days 1 to 21 (increased to 15 mg after 3 cycles if tolerated) repeated every 28 days. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.
-for the treatment of multiple myeloma in patients who have received at least 1 prior therapy, in combination with ixazomib and dexamethasone*:
NOTE: Ixazomib is FDA approved in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received at least 1 prior therapy.
Oral dosage:
Adults: 25 mg orally daily on days 1 through 21 in combination with ixazomib 4 mg orally on days 1, 8, and 15 and dexamethasone 40 mg orally on days 1, 8, 15, and 22. Repeat treatment cycles every 28 days until disease progression. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. The median progression-free survival time was significantly improved with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone (20.6 months vs. 14.7 months; hazard ratio (HR) = 0.74; 95% CI, 0.59 to 0.94; p = 0.01) in patients with relapsed and/or refractory multiple myeloma who had received 1 to 3 prior therapies in a multinational, randomized, double-blind, phase 3 trial (n = 722; TOURMALINE-MM1 trial). At a median follow-up time of 85 months, the median overall survival time was not significantly improved in the ixazomib-containing arm (53.6 months vs. 51.6 months; HR = 0.939; 95%CI, 0.784 to 1.125). In this trial, subsequent lines of therapy were given in 71.7% and 69.9% of patients who received ixazomib plus lenalidomide and dexamethasone (median, 2 subsequent therapies; range, 1 to 9) and lenalidomide and dexamethasone (median, 3 subsequent therapies; range, 1 to 12), respectively. The median age of patients in this study was 66 years (range, 30 to 91 years); prior therapy included a stem-cell transplant in 57% of patients, proteasome inhibitor therapy in 70% of patients, and immunomodulatory drug therapy in 55% of patients. Thromboprophylaxis was recommended for all patients.
For the treatment of mantle cell lymphoma (MCL):
NOTE: There was an increased risk of early death in the lenalidomide arm compared with the control arm (12.9% vs. 7.1%) in a clinical trial in patients with MCL. Risk factors for early death included a high tumor burden, a high MCL International Prognostic Index (MIPI) score at diagnosis, and a high white blood cell count (greater than 10 X 109 cells/L) at baseline.
-for the treatment of relapsed or progressive MCL following 2 prior therapies, including bortezomib:
Oral dosage:
Adults: 25 mg orally once daily for 21 days repeated every 28 days; continue therapy until disease progression. Therapy interruption, dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. In patients with relapsed or refractory mantle-cell lymphoma (MCL), treatment with lenalidomide has resulted in overall response rates (ORR) of 28% to 53% in phase 2 trials. At a median follow-up of 13.2 months, treatment with lenalidomide led to a median progression-free survival (PFS) time of 4 months and a median overall survival (OS) time of 20.9 months in patients with relapsed or refractory MCL who had received prior treatment including bortezomib in a multinational, open-label, phase 2 trial (n = 134; MCL-001 [EMERGE] trial). Patients (median age, 67 years; range, 43 to 83 years) in this study had previously received a median of 4 therapies (range, 2 to 10 therapies). At a median follow-up of 15.9 months, the median PFS time was significantly improved with lenalidomide compared with investigator's choice therapy (8.7 months vs. 5.2 months; hazard ratio [HR] = 0.61; 95% CI, 0.44 to 0.84; p = 0.004) in patients with relapsed or refractory MCL who were ineligible for intensive chemotherapy or stem-cell transplantation in a multinational, randomized (2:1), open-label, phase 2 trial (n = 254; MCL-002 [SPRINT] trial). The median OS times were not significantly different between the lenalidomide and investigator's choice arms (27.9 months vs. 21.2 months; HR = 0.89; 95% CI, 0.62 to 1.28); however, 46% of patients in the investigator's choice arm crossed over to the lenalidomide arm upon disease progression. Investigator's choice chemotherapy consisted of monotherapy with rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Patients (median age, 68.5 years; range, 44 to 88 years) who received lenalidomide in this study had previously received a median of 2 regimens (range, 1 to 3 regimens); 12% of patients had received prior treatment with bortezomib.
-for the treatment of MCL, in combination with rituximab*:
Oral dosage:
Adults: 20 mg orally once daily on days 1 to 21 repeated every 28 days in combination rituximab was evaluated in phase II trials. In patients with relapsed or refractory mantle-cell lymphoma (MCL), lenalidomide was continued until disease progression (median of 2 cycles; range, 1 to 26 cycles) and rituximab 375 mg/m2 intravenous was administered weekly starting on day 1 for a total of 4 doses on cycle 1 only. In patients with newly diagnosed MCL, induction therapy (weeks 1 to 48) consisted of 12 cycles of lenalidomide; rituximab 375 mg/m2 IV was given once on weeks 1, 2, 3, 4, 13, 21, 29, 37, and 45 for a total of 9 doses. The lenalidomide dose could be escalated to 25 mg after the first cycle if no dose-limiting adverse events occurred. Maintenance therapy consisted of lenalidomide 15 mg PO daily on days 1 to 21 repeated every 28 days (starting week 49) plus rituximab 375 mg/m2 intravenous once every 8 weeks (starting week 52); treatment was continued for up to 36 cycles or until disease progression.
For the treatment of amyloidosis*:
-for the treatment of systemic amyloid light-chain amyloidosis, in combination with cyclophosphamide and dexamethasone*:
Oral dosage:
Adults: 15 mg orally daily on days 1 to 21 in combination with cyclophosphamide and dexamethasone repeated every 28 days has been evaluated in nonrandomized, phase II studies. Treatment duration, drug dosages of cyclophosphamide and dexamethasone, and thromboprophylaxis agents/recommendations varied in these studies. In one study, 12 cycles of lenalidomide, cyclophosphamide (300 mg/m2 IV on days 1 and 8 for 6 cycles; then 300 mg/m2 IV on day 1 for an additional 6 cycles), and dexamethasone (20 mg PO on days 1, 2, 3, 4, 9, 10, 11, and 12 for 6 cycles; then 20 mg PO on days 1, 2, 3, and 4 for an additional 6 cycles) were given and then maintenance therapy with lenalidomide and dexamethasone was administered for 3 additional years or until disease progression. Patients with a glomerular filtration rate (GFR) less than 50 mL/min received a reduced lenalidomide dose of 10 mg and patients with a GFR less than 30 mL/min received a reduced lenalidomide dose of 5 mg. Patients with cardiac stage III had an upfront dose modification of dexamethasone. In another study, lenalidomide, cyclophosphamide (500 mg PO on days 1, 8, and 15), and dexamethasone (40 mg PO on days 1, 8, 15, and 22) therapy was given for a maximum of 9 cycles; treatment was discontinued after cycle 6 if a complete response or partial response/very good partial response plus organ response was obtained. In this study, patients with fluid retention over 3% of body weight despite optimal diuretic use received a lower dose of dexamethasone (20 mg once weekly). In a third study, cycles of lenalidomide, cyclophosphamide (300 mg/m2 PO on days 1, 8, and 15), and dexamethasone (40 mg PO on days 1, 8, 15, and 22) were continued until disease progression, unacceptable toxicity, or up to 2 years; however, cyclophosphamide was given for up to a maximum of 12 cycles only.
-for the treatment of systemic amyloid light-chain amyloidosis, in combination with melphalan and dexamethasone*:
Oral dosage:
Adults: 10 mg orally daily on days 1 to 21 in combination with melphalan and dexamethasone repeated every 28 days has been evaluated in nonrandomized studies. Treatment duration, the melphalan dosage, and thromboprophylaxis agents/recommendations varied in these studies. In 1 study, lenalidomide plus melphalan (0.18 mg/kg PO daily on days 1, 2, 3, and 4) and dexamethasone (40 mg PO on days 1, 8, 15, and 22) therapy was given for a maximum of 9 cycles; single-agent lenalidomide was continued in responding patients. In another study, lenalidomide, melphalan (5 mg/m2 PO daily on days 1, 2, 3, and 4), and dexamethasone (40 mg PO on days 1, 8, 15, and 22) were continued until disease progression, unacceptable toxicity, or up to 12 cycles.
For the treatment of non-Hodgkin's lymphoma (NHL):
NOTE: The FDA has designated lenalidomide as an orphan drug for the treatment of follicular lymphoma and marginal zone lymphoma.
-for the treatment of previously treated marginal zone lymphoma, in combination with rituximab:
Oral dosage:
Adults: 20 mg orally once daily for 21 days repeated every 28 days for a maximum of 12 cycles; give in combination with rituximab as follows: 375 mg/m2 IV weekly in cycle 1 (on days 1, 8, 15, and 22) and then 375 mg/m2 IV on day 1 of every 28-day cycle on cycles 2, 3, 4 and 5. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. At a median follow-up of 28.3 months, the median progression-free survival (PFS) time was significantly improved in patients (median age, 63; range, 26 to 88 years) with relapsed or refractory grades 1 to 3a follicular lymphoma (n = 295) or marginal zone lymphoma (n = 63) who received lenalidomide plus rituximab compared with placebo plus rituximab (39.4 months vs. 14.1 months; hazard ratio (HR) = 0.46; 95% CI, 0.34 to 0.62) in a multinational, randomized, phase 3 trial (the AUGMENT trial). Patients had received a median of 1 prior regimen (range, 1 to 12 regimens) in this trial. Overall survival (OS) was not significantly different between treatment arms (HR = 0.61; 95% CI, 0.33 to 1.13); however, OS data was not mature at the time of analysis. PFS was not significantly improved with lenalidomide plus rituximab (HR = 1; 95% CI, 0.47 to 2.13) in the subgroup of patients with marginal zone lymphoma.
-for the treatment of previously treated follicular lymphoma, in combination with rituximab:
Oral dosage:
Adults: 20 mg orally once daily for 21 days repeated every 28 days for a maximum of 12 cycles; give in combination with rituximab as follows: 375 mg/m2 IV weekly in cycle 1 (on days 1, 8, 15, and 22) and then 375 mg/m2 IV on day 1 of every 28-day cycle on cycles 2, 3, 4 and 5. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. At a median follow-up of 28.3 months, the median progression-free survival (PFS) time was significantly improved in patients (median age, 63; range, 26 to 88 years) with relapsed or refractory grades 1 to 3a follicular lymphoma (n = 295) or marginal zone lymphoma (n = 63) who received lenalidomide plus rituximab compared with placebo plus rituximab (39.4 months vs. 14.1 months; hazard ratio (HR) = 0.46; 95% CI, 0.34 to 0.62) in a multinational, randomized, phase 3 trial (the AUGMENT trial). Patients had received a median of 1 prior regimen (range, 1 to 12 regimens) in this trial. Overall survival (OS) was not significantly different between treatment arms (HR = 0.61; 95% CI, 0.33 to 1.13); however, OS data was not mature at the time of analysis. PFS was also significantly improved with lenalidomide plus rituximab (HR = 0.4; 95% CI, 0.29 to 0.56) in the subgroup of patients with follicular lymphoma.
-for the treatment of previously untreated follicular lymphoma, in combination with rituximab*:
Oral dosage:
Adults: 20 mg orally once daily on days 2 to 22 repeated every 28 days for 6 cycles in combination with rituximab (375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1 and 375 mg/m2 IV on day 1 only of cycles 2 to 6) was evaluated in a multinational, randomized, open-label, phase 3 trial (the RELEVANCE trial; n = 1,030). Patients who had a complete response (CR) after 6 cycles of therapy received lenalidomide 10 mg orally once daily on days 2 to 22 for another 12 cycles of therapy. Patients who had a partial response received lenalidomide 20 mg orally once daily on days 2 to 22 for 3 or 6 additional cycles until a CR was achieved and then lenalidomide 10 mg orally daily on days 2 to 22 for a total of 18 cycles of therapy. Additionally, patients who had a response continued to receive rituximab 375 mg/m2 IV every 8 weeks for 12 cycles. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.
-for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified including DLBCL arising from low grade lymphoma in patients who are ineligible for autologous stem cell transplant (ASCT), in combination with tafasitamab*:
NOTE: Tafasitamab in combination with lenalidomide is is FDA-approved for use for this indication.
Oral dosage:
Adults: 25 mg orally daily on days 1 to 21 for a maximum of 12 cycles in combination with tafasitamab 12 mg/kg (actual body weight) IV on days 1, 4, 8, 15, and 22 of cycle 1; 12 mg/kg IV on days 1, 8, 15, and 22 of cycles 2 and 3; and 12 mg/kg IV on days 1 and 15 of cycle 4 and beyond until disease progression. Treatment cycles are repeated every 28 days. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. After a minimum of 12 months of follow-up (median, 13.2 months), the objective response rate (assessed by an independent review committee) was 60% (95% CI, 48% to 71%) in adult patients with relapsed or refractory DLBCL who received tafasitamab plus lenalidomide in a single-arm, phase 2 trial (the L-MIND trial; n = 80). The complete response rate was 43%. The median duration of response was 21.7 months. At a median follow-up time of 17.3 months, the progression-free survival time was 12.1 months. The median overall survival (OS) time was not reached at a median follow-up time of 19.6 months; the 12-month and 18-month OS rates were 74% and 64%, respectively. In this trial, patients (median age, 72 years) were not candidates for high-dose chemotherapy or ASCT and had a median of 2 prior therapies (range, 1 to 4 therapies) including an anti-CD20 therapy; 11% of patients had received a prior ASCT.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Myelodysplastic Syndrome
Thrombocytopenia (within 4 weeks of starting 10 mg/day)
Baseline platelet count of 100,000 cells/microliter (mcL) or greater and platelet count decline to less than 50,000 cells/mcL: interrupt lenalidomide therapy; when the platelet count returns to 50,000 cells/mcL or greater, resume therapy at 5 mg/day.
Baseline platelet count less than 100,000 cells/mcL and platelet count decline to 50% of baseline: interrupt lenalidomide therapy. If the baseline platelet count was 60,000 cells/mcL or greater, resume therapy at 5 mg/day when the platelet count returns to 50,000 cells/mcL or greater; if the baseline platelet count was less than 60,000 cells/mcL, resume therapy at 5 mg/day when the platelet count returns to 30,000 cells/mcL or greater.
Thrombocytopenia (after 4 weeks of starting 10 mg/day)
Platelet count decline to less than 30,000 cells/mcL or less than 50,000 cells/mcL with platelet transfusions: interrupt lenalidomide therapy; when the platelet count returns to 30,000 cells/mcL or greater without hemostatic failure, resume therapy at 5 mg/day.
Thrombocytopenia (during therapy with 5 mg/day)
Platelet count decline to less than 30,000 cells/mcL or less than 50,000 cells/mcL with platelet transfusions: interrupt lenalidomide therapy; when the platelet count returns to 30,000 cells/mcL or greater without hemostatic failure, resume therapy at 2.5 mg/day.
Neutropenia (within 4 weeks of starting 10 mg/day)
Baseline absolute neutrophil count (ANC) 1,000 cells/mcL or greater and ANC decline to less than 750 cells/mcL: interrupt lenalidomide therapy; when the ANC returns to 1,000 cells/mcL, resume therapy at 5 mg/day.
Baseline ANC less than 1,000 cells/mcL and ANC decline to less than 500 cells/mcL: interrupt lenalidomide therapy; when the ANC returns to 500 cells/mcL or greater, resume therapy at 5 mg/day.
Neutropenia (after 4 weeks of starting 10 mg/day)
ANC decline to less than 500 cells/mcL for 7 or more days OR less than 500 cells/mcL and a temperature of 38.5 degrees Celsius (C) or higher: interrupt lenalidomide therapy; when the ANC returns to 500 cells/mcL or greater, resume therapy at 5 mg/day.
Neutropenia (during therapy with 5 mg/day)
ANC decline to less than 500 cells/mcL for 7 days OR ANC less than 500 cells/mcL and a temperature of 38.5 degrees C or higher: interrupt lenalidomide therapy; when the ANC returns to 500 cells/mcL or greater, resume therapy at 2.5 mg/day.
Other Toxicity
Grade 3 or 4 toxicity: interrupt lenalidomide therapy; when the toxicity resolves to grade 2 or less, may resume therapy at a reduced dose (i.e., next lower dose level).
Multiple Myeloma
Thrombocytopenia
Combination therapy
Platelet count less than 30,000 cells/mcL: interrupt lenalidomide therapy, follow CBC weekly; resume therapy at the next lower dose when the platelet count returns to 30,000 cells/mcL or greater.
Subsequent platelet count declines to less than 30,000 cells/mcL: interrupt lenalidomide therapy; resume therapy at the next lower dose when the platelet count returns to 30,000 cells/mcL or greater; do not dose below 2.5 mg/day.
Maintenance therapy
Platelet count less than 30,000 cells/mcL: interrupt lenalidomide therapy, follow CBC weekly; resume therapy at the next lower dose (e.g., from 15 mg to 10 mg or 10 mg/day to 5 mg/day) when the platelet count returns to 30,000 cells/mcL or greater.
Subsequent platelet count declines to less than 30,000 cells/mcL (at the 5 mg/day dose): interrupt lenalidomide therapy; resume therapy at 5 mg PO daily on days 1 to 21 of a 28-day cycle when the platelet count returns to 30,000 cells/mcL or greater; do not dose below this dosage.
Neutropenia
Combination therapy
ANC less than 1,000 cells/mcL: interrupt lenalidomide therapy, follow CBC weekly; when the ANC returns to 1,000 cells/mcL or greater, resume therapy at the 25-mg dose or the initial starting dose if neutropenia is the only toxicity or resume therapy at the next lower dose if other toxicity has occurred in addition to neutropenia.
Subsequent ANC less than 1,000 cells/mcL: interrupt lenalidomide therapy; resume therapy at the next lower dose when the ANC returns to 1,000 cells/mcL or greater; do not dose below 2.5 mg/day.
Maintenance therapy
ANC less than 500 cells/mcL: interrupt lenalidomide therapy, follow CBC weekly; resume therapy at the next lower dose (e.g., from 15 mg to 10 mg or 10 mg/day to 5 mg/day) when the ANC returns to 500 cells/mcL or greater.
Subsequent ANC less than 500 cells/mcL (at the 5 mg/day dose): interrupt lenalidomide therapy; resume therapy at 5 mg PO daily on days 1 to 21 of a 28-day cycle when the ANC returns to 500 cells/mcL or greater; do not dose below this dosage.
Other Toxicity
Grade 3 or 4 toxicity: interrupt lenalidomide therapy; when the toxicity resolves to grade 2 or less, may resume therapy at the next lower dose.
Mantle Cell Lymphoma
Thrombocytopenia
Platelet count decline to less than 50,000 cells/mcL: interrupt lenalidomide therapy, follow CBC weekly; when the platelet count returns to 50,000 cells/mcL or greater, resume therapy at a reduced dose (i.e., 5 mg less than the previous dose); do not dose below 5 mg/day.
Neutropenia
ANC decline to less than 1,000 cells/mcL for at least 7 days or with an associated temperature of 38.5 degrees C or higher OR ANC decline to less than 500 cells/mcL: interrupt lenalidomide therapy, follow CBC weekly; when the ANC returns to 1,000 cells/mcL or greater, resume therapy at a reduced dose (i.e., 5 mg less than the previous dose); do not dose below 5 mg/day.
Tumor Flare Reaction (TFR)
Grade 1 or 2 TFR: continue lenalidomide therapy.
Grade 3 or 4 TFR: interrupt lenalidomide therapy; resume therapy when symptoms resolve to grade 1 or less.
Other Toxicity
Grade 3 or 4 toxicity: interrupt lenalidomide therapy; when the toxicity resolves to grade 2 or less, may resume therapy at a reduced dose (i.e., next lower dose level).
Follicular Lymphoma or Marginal Zone Lymphoma
Thrombocytopenia
Platelet count decline to less than 50,000 cells/mcL: interrupt lenalidomide therapy, follow CBC weekly; when the platelet count returns to 50,000 cells/mcL or greater, resume therapy at a reduced dose (i.e., 5 mg less than the previous dose); do not dose below 5 mg/day (if starting dose was 20 mg/day) or below 2.5 mg/day (if starting dose was 10 mg/day).
Neutropenia
ANC decline to less than 1,000 cells/mcL for at least 7 days or with an associated temperature of 38.5 degrees C or higher OR ANC decline to less than 500 cells/mcL: interrupt lenalidomide therapy, follow CBC weekly; when the ANC returns to 1,000 cells/mcL or greater, resume therapy at a reduced dose (i.e., 5 mg less than the previous dose); do not dose 5 mg/day (if starting dose was 20 mg/day) or below 2.5 mg/day (if starting dose was 10 mg/day).
Tumor Flare Reaction (TFR)
Grade 1 or 2 TFR: continue lenalidomide therapy.
Grade 3 or 4 TFR: interrupt lenalidomide therapy; resume therapy when symptoms resolve to grade 1 or less.
Other Toxicity
Grade 3 or 4 toxicity: interrupt lenalidomide therapy; when the toxicity resolves to grade 2 or less, may resume therapy at a reduced dose (i.e., next lower dose level).
Maximum Dosage Limits:
-Adults
25 mg/day PO.
-Geriatric
25 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline hepatic impairment: no dosage adjustment is necessary for mild hepatic impairment (defined as total bilirubin level of greater than 1 to 1.5-times upper limit normal (ULN) or any AST level greater than the ULN). Lenalidomide use has not been evaluated in patients with moderate to severe hepatic impairment.
Treatment-related hepatotoxicity: interrupt lenalidomide therapy; when the toxicity resolves to baseline values, may resume therapy at a lower dose.
Patients with Renal Impairment Dosing
Adjust the starting dose of lenalidomide in patients with renal impairment based on baseline creatinine clearance (CrCl) values and indication for use. Subsequent dose adjustments are based on individual patient tolerance.
Mantle cell lymphoma (MCL) and Combination Therapy in Multiple Myeloma
CrCl 30 to 60 mL/min: 10 mg PO once daily; in patients with multiple myeloma, consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10-mg dose without dose-limiting toxicity.
CrCl less than 30 mL/min (not requiring dialysis): 15 mg PO every other day.
CrCl less than 30 mL/min (requiring dialysis): 5 mg PO once daily; administer the dose following dialysis on dialysis days.
Myelodysplastic syndromes (MDS) and Maintenance Therapy in Multiple Myeloma
CrCl 30 to 60 mL/min: 5 mg PO once daily.
CrCl less than 30 mL/min (not requiring dialysis): 2.5 mg PO once daily.
CrCl less than 30 mL/min (requiring dialysis): 2.5 mg PO once daily; administer the dose following dialysis on dialysis days.
Follicular Lymphoma or Marginal Zone Lymphoma
CrCl 30 to 60 mL/min: 10 mg PO once daily; consider escalating the dose to 15 mg/day after 2 cycles if the patient tolerates 10 mg/day.
CrCl less than 30 mL/min (not requiring dialysis): 5 mg PO once daily.
CrCl less than 30 mL/min (requiring dialysis): 5 mg PO once daily; administer the dose following dialysis on dialysis days.
*non-FDA-approved indication
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Chikungunya Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Conjugated Estrogens: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Conjugated Estrogens; Bazedoxifene: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Darbepoetin Alfa: (Moderate) Monitor for signs and symptoms of thromboembolic events if concomitant use of lenalidomide and an erythropoiesis-stimulating agent (ESA) is required. Both medications have been associated with venous thromboembolism and concomitant use may increase the risk of thrombosis.
Denosumab: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
Desogestrel; Ethinyl Estradiol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Dienogest; Estradiol valerate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Digoxin: (Moderate) Concomitant use of lenalidomide and digoxin may result in increased digoxin levels and exposure; use these drugs together with caution. Monitor digoxin levels periodically and as clinically indicated in patients who require both lenalidomide and digoxin. The Cmax and AUC values of digoxin were increased by 14% in patients who received digoxin following multiple oral doses of lenalidomide 10 mg/day.
Drospirenone; Estetrol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Drospirenone; Estradiol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Drospirenone; Ethinyl Estradiol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Epoetin Alfa: (Moderate) Monitor for signs and symptoms of thromboembolic events if concomitant use of lenalidomide and an erythropoiesis-stimulating agent (ESA) is required. Both medications have been associated with venous thromboembolism and concomitant use may increase the risk of thrombosis.
Erythropoiesis-Stimulating Agents: (Moderate) Monitor for signs and symptoms of thromboembolic events if concomitant use of lenalidomide and an erythropoiesis-stimulating agent (ESA) is required. Both medications have been associated with venous thromboembolism and concomitant use may increase the risk of thrombosis.
Esterified Estrogens: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Esterified Estrogens; Methyltestosterone: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Estradiol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Estradiol; Levonorgestrel: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Estradiol; Norethindrone: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Estradiol; Norgestimate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Estradiol; Progesterone: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Estrogens: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Estropipate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Ethinyl Estradiol; Norelgestromin: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Ethinyl Estradiol; Norgestrel: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Etonogestrel; Ethinyl Estradiol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Methoxy polyethylene glycol-epoetin beta: (Moderate) Monitor for signs and symptoms of thromboembolic events if concomitant use of lenalidomide and an erythropoiesis-stimulating agent (ESA) is required. Both medications have been associated with venous thromboembolism and concomitant use may increase the risk of thrombosis.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Norethindrone; Ethinyl Estradiol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Norgestimate; Ethinyl Estradiol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Warfarin: (Minor) Close monitoring of PT levels and INR in patients with multiple myeloma who require both lenalidomide and warfarin is recommended. According to the manufacturer, the use of warfarin in patients with blood dyscrasias is contraindicated. Therefore, to minimize the bleeding risk, warfarin should be used cautiously in patients receiving antineoplastic agents that cause myelosuppression or blood dyscrasias. In addition, effects of antineoplastic agents on protein synthesis as well as protein binding may lead to transient changes in a patient's INR while receiving warfarin. The INR may increase and/or decrease throughout the chemotherapy cycle leading to supra- or sub-therapeutic values; monitor warfarin therapy closely. There was no change in pharmacokinetic parameters for either agent when a single dose of warfarin 25 mg PO was administered following multiple oral doses of lenalidomide 10 mg/day. Expected PT and INR changes from warfarin use occurred.
Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
The mechanism of action of lenalidomide is not completely understood. Lenalidomide possesses immunomodulatory properties. Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells. It inhibited cell proliferation with varying effectiveness (IC50s) in some but not all cell lines. Of cell lines tested, lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) but was much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and other cell lines without chromosome 5 deletions. Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro.
In addition to immunomodulatory properties, lenalidomide possesses antiangiogenic properties. Lenalidomide attenuates growth factor induced angiogenesis and inhibits growth factor induced endothelial cell migration. The antimigratory and thus, antiangiogenic effects of lenalidomide may be a result of Akt phosphorylation inhibition. The inhibition of of growth factor induced Akt phosphorylation correlated with the inhibition of growth factor induced endothelial cell migration. Growth factor induced endothelial cell migration and subsequent tube formation are known to be P13K-Akt-dependent. Activation of the Akt pathway plays a crucial role in malignant transformation, chemoresistance, and invasiveness by inducing angiogenesis and cell survival, growth, and migration. Lenalidomide inhibits the phosphorylation of Akt in response to basic fibroblast growth factor.
Lenalidomide appears to cause cytogenetic changes that correlate with hematologic response in patients with myelodysplastic syndromes. Myelodysplastic syndromes associated with a 5q31.1 deletion appear to be very sensitive to lenalidomide. An absence of the pretreatment cytogenetic abnormality on standard metaphase analysis occurred in 9 of 12 patients with del(5)(q31.1) who received lenalidomide 25 mg daily, 10 mg daily, or 10 mg daily for each 21 of 28 days for 4 months. Eight of the nine patients had an isolated del(5)(q31.1); the other patient also had trisomy 21. The one patient in the study with the chromosomal abnormality t(1;22)(q21p11.2) also had a complete cytogenetic response. In addition to a complete cytogenetic response, an additional patient with del(5)(q31.1) had a reduction in abnormal cells by at least 50%. Thus, 10 of the 12 patients with del(5)(q31.1) had a cytogenetic response, and these 10 patients also had an erythroid response defined as at least a sustained hemoglobin concentration increase of 1 g/dl or at least a 50% reduction in transfusion need. Neither of the 2 patients with del (20)(q11.2) nor any of the 5 patients with other chromosomal abnormalities (+19, t(3;3)(q21;q26.3), +8, -X, and complex) had even a 50% reduction in abnormal cells. Three patients with a 5q31.1 deletion acquired new translocations involving chromosome 7 despite the complete suppression of the initial karyotypic abnormality. An additional patient with a normal karyotype before lenalidomide receipt had deletion 20 (q21q13.1). The clinical significance of the acquired translocations is unknown. Although 3 of the 4 patients remained free from the need for transfusion, one patient had cytogenetic and disease progression.
Lenalidomide is administered orally. Lenalidomide is approximately 30% bound to plasma proteins. It does pass into semen. Metabolism is limited with unchanged lenalidomide representing most of the drug present in circulation; 2 metabolites (hydroxy-lenalidomide and N-acetyl-lenalidomide) represent less than 5% of the parent drug found in circulation. Lenalidomide is primarily eliminated renally; the renal clearance exceeds the glomerular filtration rate. Following a radiolabeled dose of lenalidomide 25 mg in healthy subjects, about 82% of the dose was excreted in the urine within 24 hours, and 90% and 4% of the dose was excreted in the urine and feces, respectively, within 10 days. The metabolites hydroxy-lenalidomide and N-acetyl-lenalidomide accounted for 4.6% and 1.8% of the excreted dose, respectively. The mean elimination half-life is 3 hours in healthy subjects and 3 to 5 hours in patients with multiple myeloma, myelodysplastic syndrome, or mantle cell lymphoma. Multiple dosing at the recommended dose does not result in drug accumulation.
Affected cytochrome P450 (CYP450) isoenzymes or drug transporters: P-gp
Lenalidomide is not metabolized by the CYP450 pathway; therefore, it is not expected to inhibit or induce CYP450 isoenzymes. In vitro, lenalidomide is a P-glycoprotein (P-gp) substrate but not a P-gp inhibitor. However, the pharmacokinetic values (i.e., Cmax, AUC) of lenalidomide were not significantly altered when lenalidomide 25 mg was administered concurrently with multiple doses of the potent P-gp inhibitor quinidine 600 mg twice daily in healthy volunteers. When lenalidomide 25 mg was administered with the P-gp inhibitor/substrate temsirolimus 25 mg, the pharmacokinetic values of lenalidomide, temsirolimus, and the temsirolimus metabolite (i.e., sirolimus) were not significantly changed. Lenalidomide is not a substrate of human breast cancer resistance protein (BCRP); multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3; organic anion transporters (OAT) OAT1 and OAT3; organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2); organic cation transporters (OCT) OCT1 and OCT2; multidrug and toxin extrusion protein (MATE) MATE1; and organic cation transporters novel (OCTN) OCTN1 and OCTN2. Additionally, it is not an inhibitor of bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. Lenalidomide does not inhibit bilirubin glucuronidation formation in human liver microsomes with UGT1A1 genotyped as UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28.
-Route-Specific Pharmacokinetics
Oral Route
Oral lenalidomide is rapidly absorbed with the maximum plasma concentrations occurring 0.5 to 6 hours post-dose following single and multiple doses in patients with multiple myeloma (MM) or myelodysplastic syndromes (MDS). Both the Cmax and AUC values increased proportionally with dose following single and multiple doses. The oral absorption rate in patients with mantle cell lymphoma was similar to that of patients with MM or MDS. In healthy subjects, the administration of a single 25-mg lenalidomide dose with a high-fat meal resulted in a decrease in Cmax by about 20% and a decrease in AUC by about 50%. However, lenalidomide may be taken with or without food.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin level greater than 1 to 1.5-times the upper limit of normal (ULN) or AST level greater than ULN) had no effect on lenalidomide deposition in a population pharmacokinetic analysis of 16 patients. Lenalidomide has not been studied in patients with moderate to severe hepatic impairment.
Renal Impairment
The effect of renal impairment on lenalidomide exposure was evaluated in a pharmacokinetic study in subjects who had mild (n = 8; creatinine clearance (CrCl) of 50 to 79 mL/min), moderate (n = 9; CrCl of 30 to 49 mL/min), and severe (n = 4; CrCl less than 30 mL/min) renal impairment or end-stage renal failure requiring dialysis (n = 6). Compared with healthy subjects of similar age who had normal kidney function (n = 3; CrCl greater than 80 mL/min), the half-life increased 3-fold and clearance decreased by 66% to 75% in patients with moderate and severe renal impairment following a single, lenalidomide 25-mg dose. Additionally, patients on hemodialysis had about a 4.5-fold increase in half-life and an 80% decrease in clearance; about 30% of the lenalidomide dose was removed from the body during a single 4-hour dialysis session.
Geriatric
Age (range, 39 to 85 years) had no clinically significant impact on lenalidomide clearance in adult patients in a population pharmacokinetic analysis.
Gender Differences
Gender had no clinically significant impact on lenalidomide clearance in adult patients in a population pharmacokinetic analysis.
Ethnic Differences
Race had no clinically significant impact on lenalidomide clearance in adult patients in a population pharmacokinetic analysis.
Obesity
Body weight (range, 33 to 135 kg) had no clinically significant impact on lenalidomide clearance in adult patients in a population pharmacokinetic analysis.
Other
Hematologic malignancy
Hematologic malignancy type (e.g., multiple myeloma, myelodysplastic syndrome, mantle cell lymphoma) had no clinically significant impact on lenalidomide clearance in adult patients in a population pharmacokinetic analysis.