Lenalidomide

Hematologic toxicity (neutropenia and thrombocytopenia) occurs in a majority of patients (grade 3/4: 80% in patients with del 5q myelodysplastic syndrome) and may require dose reductions and/or delays; the use of blood product support and/or growth factors may be needed. CBC should be monitored weekly for the first 8 weeks and at least monthly thereafter in patients being treated for del 5q myelodysplastic syndromes. In patients being treated for multiple myeloma, monitor CBC weekly for the first 2 cycles, every 2 weeks during cycle 3, and monthly thereafter. In patients receiving lenalidomide for mantle cell lymphoma (MCL), monitor CBC weekly for the first cycle, every 2 weeks during cycles 2 to 4, and monthly thereafter. Monitor for signs of infection, bleeding, or bruising; may require dosage adjustment.

May cause dizziness or fatigue; caution patients about performing tasks that require mental alertness (eg, operating machinery, driving).

Angioedema and severe cutaneous reactions (eg, Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported; may be fatal. DRESS may manifest as a cutaneous reaction (eg, rash, exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications, which may include hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Consider interrupting or discontinuing treatment with grade 2 or 3 skin rash; discontinue and do not reinitiate treatment with angioedema, grade 4 rash, exfoliative or bullous rash, or for suspected SJS, TEN, or DRESS. Patients with a history of grade 4 rash with thalidomide should not receive lenalidomide.

Hepatic failure, including fatalities, has occurred in patients treated with combination lenalidomide and dexamethasone therapy; may have hepatocellular, cholestatic, or mixed characteristics. Risk factors may include preexisting viral liver disease, elevated liver enzymes at baseline, and concomitant medications. Monitor closely; interrupt therapy in patients with abnormal hepatic function tests. May consider resuming treatment at a lower dose upon return to baseline.

Second primary malignancies (SPMs), including hematologic (primarily AML and MDS) and solid tumor malignancies, and non-melanoma skin cancers, have been reported with lenalidomide when used for the treatment of MDS and multiple myeloma; the incidence may be higher when lenalidomide is used in combination with an alkylating agent. Monitor for development of secondary malignancies.

Lenalidomide has been associated with a significant increase in risk for arterial and venous thromboembolic events in multiple myeloma patients treated with lenalidomide and dexamethasone combination therapy. Deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke have occurred; monitor for signs and symptoms of thromboembolism (shortness of breath, chest pain, or arm or leg swelling) and instruct patients to seek prompt medical attention with development of these symptoms. Thromboprophylaxis is recommended; the choice of regimen should be based on an assessment of the patient's underlying risk factors. The American Society of Clinical Oncology guidelines for VTE prophylaxis and treatment recommend thromboprophylaxis for patients receiving lenalidomide in combination with chemotherapy and/or dexamethasone; either aspirin or low molecular weight heparin (LMWH) is recommended for lower risk patients and LMWH is recommended for higher-risk patients (Lyman 2013; Lyman 2015). Erythropoietin-stimulating agents (ESAs) and estrogens may contribute to thromboembolic risk; use with caution. Patients with a prior history of arterial thromboembolic events may be at greater risk; minimize modifiable factors such as hyperlipidemia, hypertension, and smoking. Anticoagulant prophylaxis should be individualized and selected based on the thromboembolism risk of the combination treatment regimen, using the safest and easiest to administer (Palumbo 2008).

Both hypothyroidism and hyperthyroidism have been reported with lenalidomide use; monitor thyroid function prior to therapy initiation and periodically throughout treatment.

Observed in studies of lenalidomide for the treatment of chronic lymphocytic leukemia (CLL) and lymphoma; clinical presentation includes low grade fever, pain, rash, and tender lymph node swelling. In patients with mantle cell lymphoma (MCL), tumor flare may mimic disease progression; monitor closely. In clinical trials, the majority of tumor flare events occurred in the first cycle of therapy. Treatment with corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be considered; therapy interruption may be necessary as well.

Patients with a high tumor burden may be at risk for tumor lysis syndrome; monitor closely; institute appropriate management for hyperuricemia. Tumor lysis syndrome (with fatalities) has been reported with lenalidomide. Disease-related concerns:

In a scientific statement from the American Heart Association, lenalidomide has been determined to be an agent that may either cause direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).

An increased incidence of early deaths (within 20 weeks) was reported in one study of patients receiving lenalidomide for the treatment of mantle cell lymphoma. Risk factors for early death include high tumor burden, mantle cell lymphoma international prognostic index (MIPI) score at diagnosis, and high WBC count (≥10,000/mm3) at baseline.

An increase in mortality was noted in 2 clinical studies in patients with multiple myeloma who received pembrolizumab in combination with a thalidomide analogue and dexamethasone. Causes of death in the experimental arm (containing pembrolizumab, dexamethasone, and a thalidomide analogue [pomalidomide or lenalidomide]) included myocarditis, Stevens-Johnson syndrome, MI, pericardial hemorrhage, cardiac failure, respiratory tract infection, neutropenic sepsis, sepsis, multiple organ dysfunction, respiratory failure, intestinal ischemia, cardiopulmonary arrest, suicide, pulmonary embolism, cardiac arrest, pneumonia, sudden death, and large intestine perforation. Multiple myeloma is not an approved indication for PD-1 or PD-L1 blocking antibodies; pembrolizumab should not be used to treat multiple myeloma in combination with a thalidomide analogue and dexamethasone unless as part of a clinical trial.

Use with caution in patients with renal impairment; may experience an increased rate of toxicities due to reduced clearance and increased half-life. Initial dosage adjustments are recommended for moderate to severe and dialysis-dependent renal impairment.

Lenalidomide use (≥4 cycles) may decrease the number of CD34+ cells collected for autologous stem cell transplant. Transplant eligible patients receiving lenalidomide should be referred to an appropriate transplant center in order to optimize the timing of stem cell collection. Cyclophosphamide in combination with G-CSF or G-CSF in combination with a CXC chemokine receptor 4 inhibitor (eg, plerixafor) may be considered when CD34+ cell collection is impaired. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Certain adverse reactions (DVT, pulmonary embolism, atrial fibrillation, renal failure) are more likely in elderly patients. Monitor renal function closely, and select dose accordingly.

If used in patients between 12 to 18 years of age, the parent or legal guardian must agree to ensure compliance with the Revlimid REMS program.

Do not use lenalidomide in pregnant women. Lenalidomide is an analogue of thalidomide (a human teratogen) and could potentially cause severe birth defects or embryo-fetal death; use is contraindicated during pregnancy and pregnancy must be avoided while taking lenalidomide. Obtain 2 negative pregnancy tests prior to initiation of treatment; 2 forms of contraception (or abstain from heterosexual intercourse) must be used at least 4 weeks prior to, during and for 4 weeks after lenalidomide treatment (and during treatment interruptions). In order to decrease the risk of embryo-fetal exposure, lenalidomide is available only through a restricted distribution program (Revlimid REMS). Males taking lenalidomide (even those vasectomized) must use a latex or synthetic condom during any sexual contact with women of reproductive potential and for up to 28 days following discontinuation of therapy. Males taking lenalidomide must not donate sperm. Other warnings/precautions:

In a clinical trial comparing lenalidomide versus chlorambucil single agent therapy in patients >65 years of age with chronic lymphocytic leukemia patients (not an FDA-approved indication), increased mortality was observed in the lenalidomide treatment arm. Atrial fibrillation, cardiac failure, and MI were observed more frequently in lenalidomide-treated patients; lenalidomide (alone or in combination) is not currently recommended for first-line treatment of CLL.

Due to the embryo-fetal risk, lenalidomide is only available through a restricted program under the Revlimid REMS program. Prescribers and pharmacies must be certified with the program to prescribe or dispense lenalidomide. Lenalidomide should only be prescribed to patients (male and female) who can understand and comply with the conditions of the Revlimid REMS program.

Patients should be advised not to donate blood during therapy and for 1 month following completion of therapy.

Product may contain lactose; avoid use in patients with Lapp lactase deficiency, glucose-galactose malabsorption, or glucose intolerance.