REMS: FDA approved a REMS for lenalidomide to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of lenalidomide and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page ([Web]). |
Lenalidomide, a thalidomide analog, is an immunomodulatory agent with antineoplastic and antiangiogenic activity.1
Lenalidomide is used in combination with dexamethasone for the treatment of multiple myeloma and as maintenance therapy in patients with multiple myeloma after autologous hematopoietic stem cell transplantation.1 Lenalidomide is designated an orphan drug by the FDA for use in multiple myeloma.8
Newly Diagnosed Multiple Myeloma
Safety and efficacy of lenalidomide in patients with newly diagnosed multiple myeloma who are ineligible for stem-cell transplantation are based principally on the results of a randomized, multicenter, open-label clinical trial (MM-020; FIRST) in 1623 patients.1, 44 Patients were randomized to receive one of the following treatment groups: continuous lenalidomide (25 mg once daily on days 1-21 of a 28-day cycle) in combination with dexamethasone (40 mg once daily on days 1, 8, 15, and 22 of a 28-day cycle; patients older than 75 years of age received reduced doses [i.e., 20 mg] of dexamethasone) until disease progression; the same dosage of lenalidomide and dexamethasone for 72 weeks (eighteen 28-day cycles); or melphalan, prednisone, and thalidomide (MPT) for up to 72 weeks (twelve 42-day cycles).1, 44 All patients received appropriate thromboprophylaxis (e.g., aspirin).1 Median progression-free survival at a median follow-up duration of 45.5 months was 25.5, 20.7, or 21.2 months in patients receiving continuous lenalidomide-dexamethasone, lenalidomide-dexamethasone for 18 cycles, or MPT, respectively.1, 44 Median progression-free survival was significantly prolonged in patients receiving continuous lenalidomide-dexamethasone compared with those receiving MPT (hazard ratio: 0.72 with a 95% confidence interval of 0.61-0.85).1, 44 Median progression-free survival also was prolonged in patients receiving continuous lenalidomide-dexamethasone compared with lenalidomide-dexamethasone for 18 cycles (hazard ratio: 0.70 with a 95% confidence interval of 0.60-0.82); however, statistical significance was not reached.1, 44 Median overall survival was 58.9, 56.7, or 48.5 months in patients receiving continuous lenalidomide-dexamethasone, lenalidomide-dexamethasone for 18 cycles, or MPT, respectively.1, 44 The overall response rate (as assessed by an independent committee) in patients receiving continuous lenalidomide-dexamethasone, lenalidomide-dexamethasone for 18 cycles, or MPT was 75.1, 73.4, or 62.3%, respectively; complete response was achieved in 15.1, 14.2, or 9.3% of patients in the respective groups.1, 44
Previously Treated Multiple Myeloma
Safety and efficacy of lenalidomide in patients with multiple myeloma previously treated with at least 1 prior therapy are based principally on 2 randomized, double-blind, placebo-controlled, multicenter studies (MM-009 and MM-010) involving a total of 704 patients.1, 9, 10, 11 Patients were randomized to receive lenalidomide and placebo (25 mg once daily on days 1-21 of a 28-day cycle and placebo once daily on days 22-28 of each 28-day cycle) or placebo alone (on days 1-28 of each 28-day cycle); all patients received oral dexamethasone 40 mg once daily on days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy, followed by dexamethasone 40 mg once daily on days 1-4 of each subsequent 28-day cycle.1, 9, 10 In both studies, treatment was continued until disease progression.1, 9, 10 Time to progression was substantially longer in patients receiving lenalidomide and dexamethasone compared with those receiving dexamethasone and placebo in both studies (12.1-13.9 months versus 4.7 months).1 Patients receiving lenalidomide and dexamethasone also experienced substantially higher overall (59-61 versus 19-23%), complete (13-15 versus 1-4%), and partial (44-48 versus 19%) response rates compared with those receiving dexamethasone and placebo, respectively.1
Maintenance Therapy Following Autologous Hematopoietic Stem Cell Transplantation
Safety and efficacy of maintenance therapy with lenalidomide in patients with multiple myeloma who have undergone autologous HSCT is based principally on the results of 2 randomized, double-blind, multicenter, placebo-controlled studies (CALGB 100104 and IFM 2005-02).1, 45, 46 In these studies, patients with at least stable disease were randomized to receive lenalidomide (10 mg once daily on days 1-28 of a 28-day cycle; a dosage increase to 15 mg once daily was permitted if dose-limiting toxicities did not occur during the initial 3 months of maintenance therapy) or placebo within 90-100 days of autologous HSCT.1 Treatment was continued until disease progression or withdrawal from the study for other reasons.1 The primary endpoint of progression-free survival was prolonged in patients receiving lenalidomide compared with those receiving placebo in both studies; however, the trials were unblinded at the time of the interim analysis at the request of data monitoring committees after surpassing the threshold for preplanned interim analyses of progression-free survival.1 At the time of analysis, median progression-free survival was significantly prolonged in patients receiving lenalidomide compared with those receiving placebo in both trials (hazard ratio of 0.38 and 0.50).1 Longer-term follow-up data from these studies demonstrated prolonged median progression-free survival in patients receiving lenalidomide; median progression-free survival in patients receiving lenalidomide was 68.6 or 46.3 months in the CALGB 100104 or IFM 2005-02 study, respectively, compared with 22.5 or 23.8 months, respectively, in patients receiving placebo.1
The American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) state that treatment recommendations for patients with multiple myeloma should be individualized based on factors such as stage, cytogenetic abnormalities, age, comorbidities, functional status, frailty status, and patient preferences.47
Newly Diagnosed Multiple Myeloma
Transplant eligible : ASCO and CCO state that the optimal regimen and number of cycles for the treatment of multiple myeloma remain unestablished; however, at least 3-4 cycles of induction therapy including an immunomodulatory drug, proteasome inhibitor, and corticosteroid is advised prior to stem cell collection.47 Drugs associated with stem cell toxicity (e.g., melphalan) and/or prolonged exposure to immunomodulatory drugs (more than four cycles) should be avoided in patients who are potential candidates for SCT.47 Because prolonged exposure to oral melphalan or immunomodulatory drugs (e.g., lenalidomide beyond 4-6 cycles) may compromise stem-cell yield, the manufacturer of lenalidomide states that stem cell mobilization should occur within 4 cycles of lenalidomide-containing therapy in patients who will undergo autologous HSCT.47
Transplant ineligible : ASCO and CCO also state that initial treatment of patients with multiple myeloma who are transplant ineligible should at least include a corticosteroid in combination with an immunomodulatory drug or proteasome inhibitor; however, triplet combination therapy including bortezomib, lenalidomide, and dexamethasone† should be considered.47 Continuous therapy should be offered instead of a fixed duration in patients receiving an immunomodulatory drug or proteasome inhibitor-based regimen.47 Continuous therapy in transplant-ineligible patients generally refers to treatment administered until progression or intolerance occurs or a prolonged but finite time frame (e.g., 2-3 years).47
Previously Treated Multiple Myeloma
ASCO and CCO state that prior therapies should be taken into consideration when selecting the treatment at first relapse.47 Treatment options include triplet combination therapy (two novel agents and a corticosteroid) or doublet combination therapy (one novel agent and a corticosteroid); novel agents include immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies (e.g., daratumumab, elotuzumab).47 For patients who are fit, triplet combination therapy is generally recommended over doublet combination therapy due to improved clinical outcomes.47 In patients with genetic high-risk disease, a triplet combination regimen with a proteasome inhibitor, immunomodulatory drug, and a corticosteroid should be the initial treatment, followed by one or two autologous HSCT, followed by proteasome inhibitor-based maintenance therapy until disease progression occurs.47
Treatment of relapsed multiple myeloma may be continued until disease progression.47 There are not enough data to recommend risk-based versus response-based duration of treatment.47
Maintenance Therapy Following Autologous Hematopoietic Stem Cell Transplantation
ASCO and CCO state that maintenance therapy with lenalidomide should be routinely offered to standard-risk patients starting at approximately day 90-110 following autologous HSCT.47 A minimum of 2 years of maintenance therapy in such patients has been associated with improved survival, and efforts to maintain therapy for at least this duration are recommended by ASCO and CCO.47
Because survival benefit has not been demonstrated in high-risk patients (i.e., ISS stage III disease, adverse cytogenetic features such as t(4;14) or del(17p), elevated lactate dehydrogenase, low creatinine clearance) receiving maintenance therapy with lenalidomide alone, bortezomib-based therapy in high-risk patients may be preferred.47
Lenalidomide is used in the management of transfusion-dependent anemia associated with low-risk or intermediate-1-risk myelodysplastic syndrome (MDS) in individuals with a cytogenetic deletion abnormality involving the long arm of chromosome 5 (a deletion 5q abnormality), with or without additional cytogenetic abnormalities.1, 3, 4, 5, 6, 7 Lenalidomide is designated an orphan drug by FDA for use in MDS.8
The current indication for lenalidomide is based principally on results from an uncontrolled, open-label, multicenter trial (MDS-003) in 148 patients with transfusion-dependent anemia (i.e., requiring at least 2 units of red blood cells within 8 weeks prior to study treatment) secondary to MDS; all patients enrolled in the trial had a cytogenetic abnormality involving a deletion between bands 31 and 33 of the long (q) arm of chromosome 5, designated as del(5)(q31-33), either in isolation or in association with additional cytogenetic abnormalities.1, 4, 5 Most (81%) of the patients in this trial had low-risk or intermediate-1-risk MDS, as determined by the International Prognosis Scoring System (IPSS), a method for evaluating MDS prognosis (i.e., survival and risk of transformation to acute myeloid leukemia [AML]) based on the karyotype, percentage of blast cells in the bone marrow, and number of cytopenias.1, 2, 4 Patients received lenalidomide at a dosage of either 10 mg once daily or 10 mg once daily for 21 days of each 28-day period.1, 5 Sequential dosage reductions (to 5 mg daily or 5 mg every other day) as well as interruptions in the dosage regimen were allowed for management of toxicity.1, 5 Transfusion independence, defined as the absence of red blood cell transfusions during any period of 56 consecutive days (8 weeks) during therapy, was achieved in 67% of patients;1, 4, 5 the transfusion-free period was sustained for a median of 44 weeks (range: 0 to more than 67 weeks) following the end of this 56-day period of transfusion independence.1 Response to lenalidomide was rapid; the median time to response was 4.6 weeks, and 90% of patients who achieved a transfusion benefit with therapy did so within 3 months.1, 5
Lenalidomide also has been studied for the management of transfusion-dependent low-risk or intermediate-1-risk MDS in patients without the deletion 5q (del[5q]) chromosomal abnormality (non-del[5q])†.30, 31 In a multicenter, phase 2, noncomparative clinical trial (MDS-002), 214 patients with transfusion-dependent anemia (i.e., requiring at least 2 units of red blood cells within 8 weeks prior to study treatment) secondary to low-risk or intermediate-1-risk MDS without the deletion 5q chromosomal abnormality received lenalidomide 10 mg once daily on days 1-21 of a 28-day cycle or 10 mg once daily continuously.30 Treatment was administered cyclically upon initiation of the study, but the schedule was amended when data from a prior study in MDS suggested a faster onset of response to lenalidomide, with no apparent increase in toxicity, with continuous administration; patients were permitted to switch from cyclic to continuous treatment.30 Sustained (for at least 8 weeks) hematologic improvement involving the erythroid cell line was reported in 43% of patients in this study, with 26% of patients achieving transfusion independence accompanied by an increase in hemoglobin concentration of at least 1 g/dL after a median of 4.8 weeks of treatment; the median duration of transfusion independence was 41 weeks. 30 An additional 17% of patients had a 50% or greater reduction in transfusions.30 When the study data were analyzed to exclude minor responses and to use a more stringent definition of baseline transfusion dependence (transfusion of 4 or more units of red blood cells in response to a hemoglobin concentration of 9 g/dL or less within 8 weeks prior to study treatment),30, 33, 34 62% of patients had baseline transfusion dependence and 30% of those patients achieved a reduction in transfusion requirements equaling 4 or more units during any 8-week period during therapy.30 In the subset of patients without baseline transfusion dependence, 37% achieved a sustained (for at least 8 weeks) increase in hemoglobin concentration of at least 1.5 g/dL during therapy.30 Overall, 17 or 33% of patients achieved sustained (for at least 8 weeks) transfusion independence or hematologic improvement involving the erythroid cell line.30 Grade 3/4 neutropenia and thrombocytopenia occurred in 30 and 25% of patients, respectively.30, 31 There were no apparent differences in response and few differences in adverse effects between those who initiated therapy with cyclic administration and those who received only continuous daily dosing.30 Efficacy of lenalidomide is being evaluated in a phase 3, placebo-controlled, clinical trial (MDS-005) in patients with low-risk or intermediate-1-risk MDS without the deletion 5q chromosomal abnormality who have transfusion-dependent anemia and are unresponsive to therapy with erythropoiesis-stimulating agents or have endogenous erythropoietin concentrations exceeding 500 mU/mL.32
A post-hoc analysis of the MDS-002 and MDS-003 clinical trials demonstrated a correlation between treatment-related cytopenias and likelihood of achieving transfusion independence in patients with the deletion 5q chromosomal abnormality; however, no relationship between the development of treatment-related cytopenias and response could be established for lower-risk MDS patients without the deletion 5q abnormality.31
Use of lenalidomide for the treatment of transfusion-dependent low-risk or intermediate-1-risk MDS without the deletion 5q chromosomal abnormality is a reasonable choice (accepted, with possible conditions).35 However, randomized controlled studies in adequate numbers of patients are lacking; additional data are needed to further elucidate clinical benefit (i.e., hematologic improvement-erythroid response) and to assess the relevance of prognostic factors (e.g., transfusion requirement, baseline platelet count, duration of MDS, serum lactate dehydrogenase concentration) to lenalidomide response.35
Lenalidomide is used for the treatment of mantle cell lymphoma in patients who have progressed or relapsed after 2 prior therapies including bortezomib.1 Lenalidomide has been designated an orphan drug by the FDA for use in mantle cell lymphoma.8
Safety and efficacy of lenalidomide in patients with mantle cell lymphoma are based principally on the results of an open-label, multicenter, single-arm phase 2 trial (MCL-001; EMERGE).1, 48 In this study, patients received lenalidomide 25 mg once daily for 21 days of each 28-day cycle; therapy was continued until disease progression or unacceptable toxicity occurred.1, 48 Approximately one-third (29%) of patients had undergone autologous stem cell or bone marrow transplantation and 60% of patients had bortezomib-refractory disease.1 The overall response rate in 133 evaluable patients who received at least one dose of lenalidomide was 26% with a duration of response of 16.6 months (range: 7.7-26.7 months); 7% achieved a complete response or unconfirmed complete response.1 The median time to response was 2.2 months (range: 1.8-13 months).1
Use of lenalidomide for the treatment of mantle cell lymphoma also was evaluated in an open-label, randomized phase 2 trial (mantle cell lymphoma-002; SPRINT).49 In this study, 254 patients with relapsed or refractory mantle cell lymphoma who were ineligible for intensive chemotherapy or stem cell transplantation were randomized to receive lenalidomide (25 mg on days 1-21 of a 28-day cycle) or investigator's choice of standard monotherapy (i.e., rituximab, gemcitabine, fludarabine, chlorambucil, cytarabine).49 At a median follow-up duration of 15.9 months, median progression-free survival was prolonged in patients receiving lenalidomide compared with those receiving an investigator's choice of therapy (8.7 versus 5.2 months; hazard ratio of 0.61 with a 95% confidence interval of 0.44-0.84).49
Follicular Lymphoma and Marginal-zone Lymphoma
Lenalidomide is used in combination with rituximab for the treatment of previously treated follicular lymphoma and marginal-zone lymphoma.1 Lenalidomide has been designated an orphan drug by the FDA for these uses.8
The use of lenalidomide with rituximab in patients with previously treated follicular lymphoma or marginal-zone lymphoma is based principally on a randomized, double-blind, multicenter study (AUGMENT) and an open-label, multicenter study (MAGNIFY).1, 50, 51
In the AUGMENT study, 358 patients with relapsed or refractory follicular lymphoma or marginal-zone lymphoma were randomized to receive the combination of lenalidomide (20 mg once daily on days 1-21 for up to 12 cycles or until unacceptable toxicity occurred) and rituximab (375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, followed by 375 mg/m2 on day 1 during cycles 2-5) or the same dosage of rituximab in combination with placebo.1 Treatment cycles were repeated every 28 days.1, 50 At a median follow-up of 28.3 months, median progression-free survival was prolonged in patients receiving lenalidomide in combination with rituximab compared with rituximab and placebo (39.4 versus 14.1 months (hazard ratio: 0.46 with a 95% confidence interval of 0.34-0.62).1, 50 In a subgroup of 295 patients with follicular lymphoma, objective response rate (as assessed by an independent review committee) in patients receiving lenalidomide in combination with rituximab was 80% compared with 55% in those receiving rituximab and placebo.1 In the subgroup of patients with marginal-zone lymphoma, the objective response rate in patients receiving lenalidomide in combination with rituximab was 65% compared with 44% in those receiving rituximab and placebo.1
In the MAGNIFY study, 232 patients with relapsed or refractory follicular lymphoma, marginal-zone lymphoma, or mantle cell lymphoma received lenalidomide (20 mg once daily on days 1-21 of each 28-day cycle for up to 12 cycles or until unacceptable toxicity or disease progression occurred) in combination with rituximab (375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, followed by 375 mg/m2 on day 1 of every other cycle [cycles 3, 5, 7, 9, and 11]).1, 51 In the subgroup of patients with follicular lymphoma or marginal-zone lymphoma, investigator-assessed objective response rate in patients receiving lenalidomide in combination with rituximab was 59 or 51%, respectively.1 At a median follow-up duration of 7.9 or 11.5 months in patients with follicular lymphoma or marginal-zone lymphoma, respectively, median duration of response had not been reached.1
Dispensing and Administration Precautions
Lenalidomide capsules should be administered orally with water, with or without food, once daily.1 The capsules should be swallowed intact and should not be broken, chewed, or opened.1
Combination Therapy for the Treatment of Multiple Myeloma
For the treatment of multiple myeloma in adults, the recommended initial dosage of lenalidomide is 25 mg once daily on days 1-21 of repeated 28-day cycles in combination with dexamethasone.1 Clinicians should consult published protocols for dexamethasone dosing.1 (See Multiple Myeloma under Uses.) In clinical studies, lenalidomide was continued until disease progression or unacceptable toxicity occurred in patients who were not candidates for autologous hematopoietic stem cell transplantation (HSCT).1 In patients who are undergoing autologous HSCT, stem cell mobilization should occur within 4 cycles of lenalidomide-containing therapy.1
Temporary interruption of lenalidomide therapy followed by dosage reduction may be necessary in patients experiencing hematologic adverse effects (see Table 1).1
Adverse Reaction and Severity | Lenalidomide Dosage Modification (Lenalidomide Starting Dosage = 25 mg daily on days 1-21 of each 28-day cycle) |
|---|---|
Thrombocytopenia |
|
Platelet count <30,000/mm3 | First occurrence: Withhold therapy and monitor CBCs weekly; when platelet count ≥30,000/mm3, then resume next lower dosage (do not administer dosages lower than 2.5 mg daily) Subsequent occurrences: Withhold therapy until platelet count ≥30,000/mm3, then resume at next lower dosage (do not administer dosages lower than 2.5 mg daily) |
Neutropenia |
|
Absolute neutrophil count (ANC) <1000/mm3 | First occurrence (neutropenia is only toxicity): Withhold therapy and monitor CBCs weekly; when ANC ≥1000/mm3, then resume at 25 mg daily or initial starting dosage First occurrence (in presence of other toxicity): Withhold therapy and monitor CBCs weekly; when ANC ≥1000/mm3, then resume at next lower dosage (do not administer dosages lower than 2.5 mg daily) Subsequent occurrence: Withhold therapy until ANC ≥1000/mm3, then resume at next lower dosage (do not administer dosages lower than 2.5 mg daily) |
Maintenance Therapy Following Autologous HSCT
In adults who have undergone autologous HSCT, maintenance therapy with lenalidomide at an initial dosage of 10 mg once daily on days 1-28 of a 28-day cycle should be started when the ANC reaches 1000/mm3 or more and/or platelet count reaches 75,000/mm3 or more.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 (See Maintenance Therapy Following Autologous Hematopoietic Stem Cell Transplantation under Uses.) Following 3 cycles of maintenance therapy, the dosage of lenalidomide may be increased to 15 mg once daily, if tolerated.1
Temporary interruption of lenalidomide therapy followed by dosage reduction may be necessary in patients experiencing hematologic adverse effects (see Table 2).1
Adverse Reaction and Severity | Lenalidomide Dosage Modification (Lenalidomide Dosage = 10 or 15 mg daily on days 1-28 of each 28-day cycle) |
|---|---|
Thrombocytopenia |
|
Platelet count <30,000/mm3 | First occurrence: Withhold therapy and monitor CBCs weekly; when platelet count ≥30,000/mm3, resume at next lower dosage and administer continuously (for 28 days of each 28-day cycle) For subsequent occurrences in patients receiving a reduced dosage of 5 mg daily: Withhold therapy; when platelet count ≥30,000/mm3, resume therapy at 5 mg daily on days 1-21 of each 28-day cycle (do not administer dosages lower than 5 mg daily) |
Neutropenia |
|
ANC <500/mm3 | First occurrence: Withhold therapy and monitor CBCs weekly; when ANC ≥500/mm3, resume at next lower dosage and administer continuously (for 28 days of each 28-day cycle) For subsequent occurrences in patients receiving a reduced dosage of 5 mg daily: Withhold therapy; when ANC ≥500/mm3, resume therapy at 5 mg daily on days 1-21 of each 28-day cycle (do not administer dosages lower than 5 mg daily) |
For the management of myelodysplastic syndrome (MDS), the recommended initial dosage in adults is 10 mg once daily.1 Treatment is continued until disease progression or unacceptable toxicity occurs.1 (See Myelodysplastic Syndrome under Uses.)
For the management of transfusion-dependent low-risk or intermediate-1-risk MDS in patients without the deletion 5q (del[5q]) chromosomal abnormality (non-del[5q])†, lenalidomide 10 mg once daily has been used.30
Dosage Modification for Hematologic Toxicity in Patients with Myelodysplastic Syndromes
Temporary interruption of lenalidomide therapy followed by dosage reduction may be necessary in patients experiencing thrombocytopenia (see Table 3) or neutropenia (see Table 4).1
Severity | Lenalidomide Dosage Modification (Lenalidomide Starting Dosage = 10 mg daily) |
|---|---|
Platelet count <50,000/mm3 occurswithin 4 weeks of therapy |
|
Baseline platelet count ≥100,000/mm3 | Withhold therapy until platelet count ≥50,000/mm3, then resume at 5 mg daily |
Platelet count decreases to 50% of baseline value within 4 weeks of therapy |
|
Baseline platelet count ≥60,000/mm3 to <100,000/mm3 | Withhold therapy until platelet count ≥50,000/mm3, then resume at 5 mg daily |
Platelet count decreases to 50% of baseline value within 4 weeks of therapy |
|
Baseline platelet count <60,000/mm3 | Withhold therapy until platelet count ≥30,000/mm3, then resume at 5 mg daily |
Thrombocytopenia occurring after 4 weeks of therapy |
|
Platelet count <30,000/mm3 or <50,000/mm3 and requiring platelet transfusions | Withhold therapy until platelet count ≥30,000/mm3 (without hemostatic failure), then resume at 5 mg daily |
Thrombocytopenia recurs on a reduced dosage of 5 mg daily |
|
Platelet count <30,000/mm3 or <50,000/mm3 and requiring platelet transfusions | Withhold therapy until platelet count ≥30,000/mm3 (without hemostatic failure), then resume at 2.5 mg daily |
Severity | Lenalidomide Dosage Modification (Lenalidomide Starting Dosage = 10 mg daily) |
|---|---|
ANC <750/mm3 occurswithin 4 weeks of therapy |
|
Baseline ANC ≥1,000/mm3 | Withhold therapy until ANC ≥1000/mm3, then resume at 5 mg daily |
ANC <500/mm3 within 4 weeks of therapy |
|
Baseline ANC is <1,000/mm3 | Withhold therapy until ANC ≥500/mm3, then resume at 5 mg daily |
Neutropenia occurring after 4 weeks of therapy |
|
ANC <500/mm3 for ≥7 days or <500/mm3 with fever (≥38.5°C) | Withhold therapy until ANC ≥500/mm3, then resume at 5 mg daily |
Neutropenia recurs on a reduced dosage of 5 mg daily |
|
ANC <500/mm3 for ≥7 days or <500/mm3 with fever (≥38.5°C) on a reduced dosage of 5 mg daily | Withhold therapy until ANC ≥500/mm3, then resume at 2.5 mg daily |
For the treatment of relapsed or refractory mantle cell lymphoma, the recommended initial adult dosage of lenalidomide is 25 mg once daily on days 1-21 of a 28-day cycle until disease progression or unacceptable toxicity occurs.1 (See Mantle Cell Lymphoma under Uses.)
Dosage Modification for Hematologic Toxicity in Patients with Mantle Cell Lymphoma
Temporary interruption of lenalidomide therapy followed by dosage reduction may be necessary in patients experiencing hematologic adverse effects (see Table 5).1
Adverse Reaction and Severity | Lenalidomide Dosage Modification (Lenalidomide Starting Dosage = 25 mg daily) |
|---|---|
Thrombocytopenia |
|
Platelet count <50,000/mm3 | Withhold therapy and monitor CBC weekly; when platelet count ≥50,000/mm3, resume at dosage reduced by 5 mg (do not administer dosages lower than 5 mg daily) |
Neutropenia |
|
ANC <1000/mm3 for ≥7 days, or <1000/mm3 with fever (≥38.5°C), or <500/mm3 | Withhold therapy and monitor CBC weekly; when ANC ≥1000/mm3, resume at dosage reduced by 5 mg (do not administer dosages lower than 5 mg daily) |
Follicular Lymphoma or Marginal-zone Lymphoma
For the treatment of follicular lymphoma or marginal-zone lymphoma, the recommended initial adult dosage of lenalidomide is 20 mg once daily on days 1-21 of a 28-day cycle in combination with rituximab.1 In the AUGMENT and MAGNIFY studies, lenalidomide was administered for up to 12 cycles.1 (See Follicular Lymphoma and Marginal-zone Lymphoma under Uses.)
In the AUGMENT study, rituximab 375 mg/m2 was administered on days 1, 8, 15, and 22 of cycle 1, followed by 375 mg/m2 on day 1 during cycles 2-5.1
Dosage Modification for Hematologic Toxicity in Patients with Follicular Lymphoma or Marginal-zone Lymphoma
Temporary interruption of lenalidomide therapy followed by dosage reduction may be necessary in patients experiencing hematologic adverse effects (see Table 6).1
Adverse Reaction and Severity | Lenalidomide Dosage Modification Lenalidomide Starting Dosage = 20 mg daily) |
|---|---|
Thrombocytopenia |
|
Platelet count <50,000/mm3 | Withhold therapy and monitor CBC weekly; when platelet count ≥50,000/mm3, resume at dosage reduced by 5 mg (do not administer dosages lower than 5 mg daily; if initial dosage was 10 mg daily, do not administer dosages lower than 2.5 mg daily) |
Neutropenia |
|
ANC <1000/mm3 for ≥7 days, or <1000/mm3 with fever (≥38.5°C), or <500/mm3 | Withhold therapy and monitor CBC weekly; when ANC ≥1000/mm3, resume at dosage reduced by 5 mg (do not administer dosages lower than 5 mg daily; if initial dosage was 10 mg daily, do not administer dosages lower than 2.5 mg daily) |
Dosage Modification for Nonhematologic Adverse Reactions
If angioedema, anaphylaxis, grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reaction occurs, lenalidomide therapy should be permanently discontinued.1 (See Hypersensitivity Reactions and also Cutaneous Reactions under Cautions.)
If grade 3 or 4 nonhematologic toxicities occur, temporarily interrupt lenalidomide therapy; when the toxicity resolves or improves to grade 2 or less, lenalidomide therapy may be resumed at the next lower dosage level.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
Initial dosage reduction may be necessary in patients with renal impairment (see Table 7).1
Clcr (mL/minute) | Multiple Myeloma (Combination Therapy with Dexamethasone) | Mantle Cell Lymphoma | Follicular Lymphoma and Marginal-zone Lymphoma (Combination Therapy with Rituximab) | Multiple Myeloma (Maintenance Therapy) and MDS |
|---|---|---|---|---|
30-60 | 10 mg once daily If reduced dosage is tolerated, consider increasing dosage to 15 mg once daily after 2 cycles | 10 mg once dailya | 10 mg once daily If reduced dosage is tolerated, consider increasing dosage to 15 mg once daily after 2 cycles | 5 mg once dailya |
<30 (not requiring dialysis) | 15 mg every other day | 15 mg every other daya | 5 mg once daily | 2.5 mg once dailya |
<30 (requiring dialysis) | 5 mg once dailyb | 5 mg once dailyb | 5 mg once dailyb | 2.5 mg once dailyb |
aSubsequent dosage adjustments should be based on patient tolerance
Because lenalidomide is excreted substantially by the kidneys and geriatric patients are more likely to have decreased renal function,1, 14 careful dosage selection and monitoring of renal function are advised in such patients.1
Fetal/Neonatal Morbidity and Mortality
Lenalidomide may cause fetal toxicity; the drug is a structural analog of thalidomide, a known human teratogen, and teratogenic and other fetotoxic effects have been demonstrated in animals.1
All females of reproductive potential and all sexually mature males receiving lenalidomide must use effective contraceptive measures (which may include abstinence) to help ensure that fetal exposure to lenalidomide does not occur.1, 16 Contraceptive measures are indicated even in females with a history of infertility.1, 16 The only females who do not need to observe mandatory contraceptive measures are those who have undergone hysterectomy, bilateral oophorectomy, or who are postmenopausal and have had no menses for at least 24 consecutive months.1, 16 All female patients of reproductive potential must use 2 reliable forms of contraception simultaneously (unless the patient chooses to remain continuously abstinent from engaging in heterosexual sexual contact) beginning at least 4 weeks prior to initiation of therapy, during therapy or interruptions of therapy, and continue such contraception for at least 4 weeks after lenalidomide therapy is discontinued.1, 16, 43 The patient must use at least 2 birth control methods,1 preferably one should be a highly effective birth control method (intrauterine device [IUD], hormonal contraceptives, tubal ligation, vasectomized partner) and one additional effective barrier method (latex condom, diaphragm, cervical cap).1, 16 Sexually mature males (including those who have successfully undergone vasectomy) receiving lenalidomide must completely avoid unprotected sexual contact with women of reproductive potential because lenalidomide is present in semen.1, 16 While receiving lenalidomide and for at least 4 weeks after discontinuing the drug, sexually mature males must use a latex or synthetic condom each time they have sexual contact with a woman of reproductive potential and must not donate sperm.1, 16 All females of reproductive potential must be tested for pregnancy within 10-14 days prior and again within the 24 hours immediately prior to the first dose of lenalidomide.1, 16, 17
The prescribing clinician should not provide the woman with a prescription for lenalidomide until a written report of the pregnancy test is available indicating that results are negative.1, 16 Pregnancy tests must then be repeated at regular intervals during lenalidomide therapy (i.e., weekly during the first month, then every 2 or 4 weeks in women with irregular or regular menstrual cycles, respectively).1, 16 Pregnancy tests and counseling also should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding.1, 16 The drug should be discontinued during the evaluation period.1, 16 If lenalidomide is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug, lenalidomide should be immediately discontinued and the patient informed of the potential hazard to the fetus; the patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity, and the clinician should notify Bristol Myers Squibb's REMS Call Center (888-423-5436) and the FDA via the MedWatch program (800-FDA-1088). 1 (See REMS under Dosage and Administration..)
Because lenalidomide may cause fetal harm and because of the possibility that the drug may be present in blood and be transfused into a woman who is pregnant, patients receiving lenalidomide must not donate blood during therapy and for at least 1 month following discontinuance of the drug.1
Lenalidomide is associated with substantial neutropenia and thrombocytopenia.1, 3, 5 Periodic monitoring of CBCs is recommended.1 Patients should be monitored for signs or symptoms of neutropenia or thrombocytopenia (e.g., bleeding, bruising, infection).1
In the principal efficacy studies evaluating maintenance therapy with lenalidomide in patients with multiple myeloma, grade 3 or 4 neutropenia or thrombocytopenia occurred in up to 59 or 38% of lenalidomide-treated patients, respectively.1 When lenalidomide is used as maintenance therapy or in combination with dexamethasone in patients with multiple myeloma, CBCs should be monitored weekly for the first 2 cycles, then on days 1 and 15 of cycle 3, and then every 4 weeks thereafter.1 If hematologic toxicity occurs, dosage interruption and/or reduction may be required.1 (See Multiple Myeloma under Dosage and Administration.)
In the principal efficacy study evaluating lenalidomide therapy in patients with MDS, grade 3 or 4 hematologic toxicity was reported in 80% of patients with myelodysplastic syndromes receiving lenalidomide.1 Median time to onset of grade 3 or 4 neutropenia (occurring in 48% of patients) was 42 days (range: 14-411 days), and median time to documented recovery was 17 days (range: 2-170 days).1 Median time to onset of grade 3 or 4 thrombocytopenia (occurring in 54% of patients) was 28 days (range: 8-290 days) and median time to documented recovery was 22 days (range: 5-224 days).1 CBCs should be monitored weekly for the first 8 weeks of therapy and at least monthly thereafter.1 If hematologic toxicity occurs, dosage interruption and/or reduction may be required.1 (See Dosage Modification for Hematologic Toxicity in Patients with Myelodysplastic Syndrome under Dosage and Administration.) 1
In the principal efficacy study evaluating lenalidomide therapy in patients with mantle cell lymphoma, grade 3 or 4 neutropenia or thrombocytopenia was reported in 43 or 28% of patients receiving the drug, respectively.1 CBCs should be monitored weekly for the first cycle, every 2 weeks during cycles 2-4, and then monthly thereafter.1 If hematologic toxicity occurs, dosage interruption and/or reduction may be required.1 (See Dosage Modification for Hematologic Toxicity in Patients with Mantle Cell Lymphoma under Dosage and Administration.)
In the principal efficacy studies evaluating lenalidomide in combination with rituximab in patients with follicular lymphoma or marginal-zone lymphoma, grade 3 or 4 neutropenia occurred in 50% or 33%, respectively, of patients receiving combination therapy.1 Grade 3 or 4 thrombocytopenia was reported in 2% or 8% of lenalidomide-treated patients, respectively.1 CBCs should be monitored weekly for the first 3 weeks of cycle 1 (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. 1 If hematologic toxicity occurs, dosage interruption and/or reduction may be required.1 (See Dosage Modification for Hematologic Toxicity in Patients with Follicular Lymphoma or Marginal-zone Lymphoma.)
Lenalidomide increases the risk of venous and arterial thromboembolic events (e.g., DVT, PE, myocardial infarction, stroke).1 Patients with known risk factors, including prior thrombotic events, may be at greater risk and actions should be taken to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking).1
In clinical trials that did not use concomitant thromboprophylaxis in patients with refractory and relapsed multiple myeloma receiving lenalidomide and dexamethasone, thrombotic events occurred in 21.5% of lenalidomide-treated patients compared with 8.3% of those treated with dexamethasone.1 The median time to first thrombotic event was 2.8 months.1 In the principal efficacy study evaluating lenalidomide in combination with dexamethasone in patients with newly diagnosed multiple myeloma, nearly all patients received thromboprophylaxis; thrombotic events occurred in 17.4% of lenalidomide-treated patients compared with 11.6% of patients receiving melphalan, prednisone, and thalidomide combination therapy.1
In the principal efficacy study evaluating lenalidomide in patients with follicular lymphoma or marginal-zone lymphoma, venous or arterial thromboembolic events occurred in 3.4 or 0.6% of patients receiving lenalidomide in combination with rituximab, respectively.1
The manufacturer recommends thromboprophylaxis; selection of an appropriate prophylactic regimen (e.g., aspirin, anticoagulant) should be based on assessment of patient risk factors.1, 20, 42 The risk of thrombosis may be increased with concomitant use of erythropoietin-stimulating agents or estrogens.1 The International Myeloma Working Group (IMWG) currently recommends thromboprophylaxis with aspirin for multiple myeloma patients receiving lenalidomide with 1 or no underlying individual and/or myeloma-related risk factors for venous thromboembolism and thromboprophylaxis with a low molecular weight heparin for those with 2 or more individual and/or myeloma-related risk factors.20 The IMWG also recommends that thromboprophylaxis with a low molecular weight heparin be considered in lenalidomide-treated patients receiving high-dose dexamethasone, doxorubicin, or multiple antineoplastic agents, independent of additional risk factors.20 The IMWG states that although full-dose warfarin (international normalized ratio [INR] 2-3) is an alternative to low molecular weight heparin, there is limited clinical experience with this approach.20 American Society of Clinical Oncology (ASCO) currently recommends pharmacologic thromboprophylaxis for multiple myeloma patients receiving lenalidomide in conjunction with dexamethasone or antineoplastic agents, and states that those at lower risk for thromboembolism may receive either aspirin or a low molecular weight heparin, while those at higher risk should receive a low molecular weight heparin.42
Other Warnings and Precautions
A prospective clinical trial evaluating single-agent lenalidomide therapy in patients with newly diagnosed chronic lymphocytic leukemia (CLL) was terminated prematurely following revelation of a substantial increase in risk of death in patients receiving lenalidomide compared with those receiving single-agent chlorambucil (hazard ratio of 1.92 with 95% confidence interval 1.08-3.41).1 Serious adverse cardiovascular reactions (e.g., atrial fibrillation, myocardial infarction, cardiac failure) occurred more frequently in patients receiving lenalidomide.1 The manufacturer states that lenalidomide should not be used in patients with CLL outside of a controlled clinical trial.1
Increased mortality also has been reported in clinical trials in patients with multiple myeloma receiving pembrolizumab in combination with a thalidomide analog and dexamethasone.1 The manufacturer of lenalidomide states that an anti-programmed death receptor-1 (anti-PD-1) or anti-programmed-death ligand-1 (anti-PD-L1) antibody should not be used in combination with a thalidomide analog and dexamethasone in patients with multiple myeloma outside of a controlled clinical trial.1 FDA recommends that ongoing clinical trials evaluating an anti-PD-1 or anti-PD-L1 agent in combination with an immunomodulatory agent (e.g., lenalidomide) be evaluated for permanent discontinuance or protocol amendments.52
In patients with mantle cell lymphoma, an increase in early deaths (within 20 weeks) was reported in patients receiving lenalidomide compared with those in the control group (12.9 versus 7.1%) in a clinical trial.1 High tumor burden, baseline mantle cell lymphoma International Prognostic Index (MIPI) score, and high white blood cell count (10,000/mm3 or greater) at baseline were factors associated with early death.1
Development of Second Primary Malignancy
In clinical trials, the risk of hematologic and solid second primary malignancies was increased in patients with multiple myeloma receiving lenalidomide.1 The trials suggested an increased risk of second primary malignancies with lenalidomide compared to other therapies or placebo in patients with newly diagnosed multiple myeloma, those with relapsed or refractory multiple myeloma, and those receiving lenalidomide after autologous hematopoietic stem cell transplantation (HSCT).1 Patients who received lenalidomide therapy until disease progression did not demonstrate an increased risk of invasive second primary malignancy compared with those who received lenalidomide for a fixed duration.1
In patients with newly diagnosed multiple myeloma, 5.3% of patients receiving lenalidomide in combination with oral melphalan developed a hematologic malignancy, including acute myeloid leukemia (AML) and MDS, compared with 1.3% of patients receiving melphalan alone.1 When lenalidomide was used in combination with dexamethasone without melphalan in patients with newly diagnosed multiple myeloma, MDS and AML were reported in 0.4% of patients.1
In patients receiving lenalidomide maintenance therapy after high-dose IV melphalan and autologous HSCT, hematologic second primary malignancy occurred in 7.5% of lenalidomide-treated patients compared with 3.3% of patients receiving placebo.1 Hematologic and solid malignancy (excluding squamous cell carcinoma and basal cell carcinoma) occurred in 14.9% of patients treated with lenalidomide compared with 8.8% of those receiving placebo at a median follow-up duration of 91.5 months.1 Nonmelanoma skin carcinoma, including squamous cell carcinoma and basal cell carcinoma, was reported in 3.9% of patients receiving lenalidomide maintenance therapy compared with 2.6% of those receiving placebo.1
In patients with relapsed or refractory multiple myeloma receiving lenalidomide and dexamethasone, hematologic or solid malignancy (excluding squamous cell carcinoma and basal cell carcinoma) occurred in 2.3% of lenalidomide-treated patients compared with 0.6% of those receiving dexamethasone.1 Nonmelanoma skin carcinoma, including squamous cell carcinoma and basal cell carcinoma, was reported in 3.1% of patients receiving lenalidomide and dexamethasone compared with 0.6% of those treated with dexamethasone alone.1
In patients with follicular lymphoma or marginal-zone lymphoma, AML occurred in 0.6% of patients receiving lenalidomide in combination with rituximab.1 Hematologic or solid malignancy (excluding nonmelanoma skin carcinoma) occurred in 1.7% of patients receiving lenalidomide in combination with rituximab at a median follow-up duration of 29.8 months.1
Patients treated with lenalidomide should be monitored for development of second primary malignancies. The risk of second primary malignancies should be considered along with the potential benefit of lenalidomide.1
Hepatic failure, sometimes fatal, has occurred in patients treated with lenalidomide in combination with dexamethasone.1 The exact mechanism of lenalidomide-induced hepatotoxicity is not known.1 In clinical trials, hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics) occurred in 15% of lenalidomide-treated patients; serious hepatotoxic events occurred in 2 or 1% of patients with multiple myeloma or myelodysplastic syndrome (MDS), respectively.1
Patients with pre-existing liver disease of viral etiology, elevated baseline liver enzymes, and those receiving concomitant medications may be at increased risk.1 Liver function tests should be monitored periodically.1 If elevations in liver enzymes occur, lenalidomide therapy should be interrupted or discontinued.1 When liver enzymes return to baseline values, resumption of lenalidomide therapy may be considered at a reduced dosage.1 (See Dosage Modification for Nonhematologic Adverse Reactions under Dosage and Administration.)
Severe cases of cutaneous reactions (i.e., SJS, TEN, and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported in patients receiving lenalidomide.1 DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis.1 These reactions can be fatal.1 Lenalidomide should not be used in patients with a prior history of grade 4 rash with thalidomide.1 For grade 2 or 3 skin rash, temporary interruption or discontinuance of lenalidomide should be considered.1 If grade 4 rash, exfoliative or bullous rash, or other severe cutaneous reactions (SJS, TEN, or DRESS) occurs, lenalidomide therapy should be permanently discontinued.1
Fatal tumor lysis syndrome has been reported in patients receiving lenalidomide.1 Patients with high tumor burden at baseline are at risk for tumor lysis syndrome, and should be monitored closely; appropriate precautions also should be instituted.1 In the principal efficacy studies in patients with follicular lymphoma or marginal-zone lymphoma, tumor lysis syndrome occurred in 0.5-1.1% of patients receiving lenalidomide in combination with rituximab; serious (grade 3) adverse reactions occurred in 1 patient receiving lenalidomide and rituximab during the induction phase.1
Tumor flare reaction, including fatalities, has been reported in clinical trials in patients with CLL and lymphoma receiving lenalidomide.1 Tumor flare reactions (i.e., tender lymph node swelling, low grade fever, pain, rash) may mimic disease progression.1 The manufacturer states that lenalidomide should not be used in patients with CLL outside of a controlled clinical trial.1
In the principal efficacy study in patients with mantle cell lymphoma (MCL), grade 1 or 2 tumor flare reaction occurred in 10% of patients receiving lenalidomide.1 All reactions occurred during the first cycle; tumor flare reaction recurred in one patient in cycle 11.1 In the principal efficacy studies in patients with follicular lymphoma or marginal-zone lymphoma, tumor flare reaction was reported in 4.1-10.8% of patients receiving lenalidomide in combination with rituximab; 2 events were considered serious.1 In a separate MCL phase 2 trial, one case of tumor flare reaction resulted in a fatal outcome.1
Patients with MCL, follicular lymphoma, or marginal-zone lymphoma should be monitored for signs or symptoms of tumor flare reaction.1 In patients experiencing grade 1 or 2 tumor flare reaction, lenalidomide may be continued without dosage adjustment or interruption of therapy.1 In patients with grade 3 or 4 tumor flare reaction, lenalidomide should be withheld until tumor flare reaction resolves to grade 1 or less.1 Symptomatic treatment for tumor flare reaction may include corticosteroids, non-steroidal anti-inflammatory drugs, and/or opiate analgesics.1
Impaired Stem Cell Mobilization
A decrease in collection of CD34+ peripheral blood progenitor cells (PBPCs) has been reported following lenalidomide therapy for more than 4 cycles.1 (See Multiple Myeloma under Dosage and Administration.) Patients who are eligible for autologous HSCT should be promptly referred to a transplant center to optimize timing of stem cell collection.1 In patients who have received more than 4 cycles of lenalidomide-containing therapy or those who previously failed to achieved adequate PBPC collection following mobilization with a granulocyte-colony stimulating factor (G-CSF) alone, hematopoietic stem cell mobilization combination regimens such as G-CSF and cyclophosphamide or a G-CSF and a CXCR4 chemokine-receptor antagonist may be used.1
Hyperthyroidism and hypothyroidism have been reported in patients receiving lenalidomide.1 Thyroid function should be monitored before initiating lenalidomide and during therapy.1
Hypersensitivity reactions such as angioedema, anaphylaxis, and anaphylactic reactions have been reported in patients receiving lenalidomide.1 If angioedema or anaphylaxis occurs, lenalidomide should be permanently discontinued.1
Lenalidomide is a thalidomide analog and is contraindicated for use during pregnancy.1 (See REMS under Dosage and Administration and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)
Females or Males of Reproductive Potential
Pregnancy must be excluded prior to treatment initiation and throughout therapy.1 Pregnancy must be prevented for ≥4 weeks prior to and during therapy, during dosage interruptions, and for 4 weeks after completion of therapy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Lenalidomide has been shown to be present in semen at 2 and 24 hours following administration of the drug at a dosage of 25 mg daily.1 Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide and for up to 4 weeks after discontinuing therapy, even if they have undergone a successful vasectomy.1 Male patients taking lenalidomide must not donate sperm and for up to 4 weeks after discontinuing the drug.1
Not known whether lenalidomide is distributed into human milk; discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Safety and efficacy of lenalidomide have not been established in pediatric patients.1
In clinical trials of lenalidomide in patients with newly diagnosed multiple myeloma, 94% of patients were 65 years of age or older and 35% of patients were over 75 years of age.1 Overall, patients over 75 years of age experienced more adverse reactions (including serious adverse reactions) than younger adults regardless of treatment arm.1
In clinical trials evaluating maintenance therapy with lenalidomide in patients with multiple myeloma, 10% of patients were 65 years of age or older and no patients were over 75 years of age.1 Grade 3 or 4 adverse reactions occurred more frequently in patients 65 years of age or older receiving lenalidomide maintenance therapy than in younger patients.1 Experience in patients 65 years of age or older receiving lenalidomide maintenance therapy is insufficient to determine whether they respond differently to the drug than younger adults.1
In clinical trials in patients with previously treated multiple myeloma, 45% of patients were 65 years of age or older and 12% patients were over 75 years of age.1 In the studies of previously treated patients, deep-vein thrombosis (DVT), pulmonary embolism (PE), atrial fibrillation, and renal failure were more common in patients over 65 years of age than younger adults treated with lenalidomide.1
In clinical trials in patients with MDS or mantle cell lymphoma, 38 or 63% of patients, respectively, were 65 years of age or older.1 In patients with MDS or mantle cell lymphoma, 33 or 22% of patients, respectively, were 75 years of age or older.1 All patients with MDS experienced an adverse reaction; however, the frequency of serious adverse reactions was higher in patients over 65 years of age (54%) compared with younger adults (33%).1 In patients with mantle cell lymphoma, the frequency of overall adverse events was similar among patients over 65 years of age than in younger patients; however, serious adverse reactions were more common among patients over 65 years than in younger patients (55% versus 41%).1
In clinical trials in patients with follicular lymphoma or marginal-zone lymphoma, 48% of patients were 65 years of age or older and 14% patients were over 75 years of age.1 The overall frequency of adverse reactions was 98% in both patients 65 years of age or older and younger adults.1 Serious adverse reactions were higher among lenalidomide-treated patients 65 years of age or older versus younger adults (37% versus 18%).1
In a single-dose (25-mg) pharmacokinetic study, the elimination half-life of lenalidomide increased and clearance of the drug decreased as creatinine clearance decreased from mild to severe renal impairment.1 Patients with moderate and severe renal impairment had a threefold increase in half-life and a 66-75% decrease in drug clearance compared with healthy individuals.1 In patients on hemodialysis, an approximate 4.5-fold increase in elimination half-life and an 80% decrease in clearance have been observed following single-dose administration of lenalidomide compared with healthy individuals.1 Approximately 30% of an administered dose of the drug was removed during a single hemodialysis session.1, 14
The initial dosage of lenalidomide should be adjusted in patients with renal impairment.1 (See Renal Impairment under Dosage and Administration.)
The pharmacokinetics of lenalidomide were not altered in patients with mild hepatic impairment (total bilirubin exceeding 1-1.5 times the upper limit of normal [ULN] or any aspartate aminotransferase concentration exceeding the ULN).1 Lenalidomide has not been studied in patients with moderate to severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)
Adverse effects reported in at least 20% of patients with multiple myeloma receiving lenalidomide include diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor.1
Adverse effects reported in more than 15% of patients with MDS receiving lenalidomide include thrombocytopenia, neutropenia, diarrhea, pruritus, rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, pharyngitis, and epistaxis.1
Adverse effects reported in at least 15% of patients with mantle cell lymphoma, follicular lymphoma, or marginal-zone lymphoma receiving lenalidomide include neutropenia, thrombocytopenia, anemia, leukopenia, diarrhea, constipation, nausea, fatigue, pyrexia, cough, upper respiratory tract infection, and rash.1
Lenalidomide does not inhibit or induce cytochrome P-450 (CYP) isoenzymes in vitro.1
Lenalidomide does not inhibit P-glycoprotein (P-gp), bile salt export pump (BSEP), breast cancer resistance protein (BCRP), multidrug resistance-associated protein (MRP) 2, organic anion transporter (OAT) 1 or 3, organic anion transport protein (OATP) 1B1 or 1B3, or organic cation transporter (OCT) 2.1
Lenalidomide is a substrate, but not an inhibitor, of P-gp.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
CYP-mediated drug interactions with lenalidomide unlikely.1
Drugs Affecting Efflux Transport Systems
Administration with P-gp inhibitors did not significantly increase the concentration of lenalidomide.1
Drugs Associated with an Increased Risk of Thrombosis
Erythropoietic agents, estrogen-containing therapies, or other agents that increase the risk of thrombosis should be used with caution in patients receiving lenalidomide, only if the potential benefits of concomitant therapy outweigh the risks.1
When digoxin was coadministered with lenalidomide (10 mg daily), the peak plasma concentration and AUC of digoxin increased by 14%.1 Manufacturer recommends periodic monitoring of plasma digoxin concentrations in patients receiving lenalidomide and digoxin concurrently.1
When warfarin was used concomitantly with lenalidomide, the pharmacokinetics of lenalidomide and R - and S -warfarin were unchanged.1 Manufacturer recommends close monitoring of PT and INR in patients with multiple myeloma receiving concomitant lenalidomide and warfarin.1
Lenalidomide, a thalidomide analog, is an immunomodulatory agent with antineoplastic and antiangiogenic activity.1, 3, 4, 5 Cellular activities of lenalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex.1 In vitro, lenalidomide induces direct cytotoxic and immunomodulatory effects following ubiquitination and degradation of substrate proteins such as Aiolos, Ikaros, and CK1α.1 In vitro, lenalidomide also has been shown to inhibit proliferation and induce apoptosis of certain hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, myelodysplastic syndrome (MDS), follicular lymphoma, and marginal-zone lymphoma.1 In vivo, lenalidomide has been shown to delay tumor growth in some nonclinical hematopoietic tumor models including multiple myeloma.1 The drug has been shown to increase count and activation of T cells and natural killer (NK) cells resulting in direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via inhibition of production of proinflammatory cytokines (e.g., tumor necrosis factor [TNF; TNF-α], interleukin-6 [IL-6]), increased secretion of IL-2 and interferon gamma, and increased NK cells.1, 3
Concomitant use of lenalidomide and dexamethasone results in synergistic inhibition of cell proliferation and induction of apoptosis in multiple myeloma cells.1 In vitro, the combination of lenalidomide and rituximab increased ADCC and direct tumor apoptosis in follicular lymphoma cells and increased ADCC in marginal-zone lymphoma cells compared with rituximab alone.1
Lenalidomide is principally eliminated by the kidneys.1 After administration of a single 25-mg radiolabeled dose of lenalidomide, approximately 90 or 4% was eliminated in the urine or feces, respectively, within 10 days, and approximately 82% was excreted as unchanged drug in urine within 24 hours.1 Lenalidomide is rapidly absorbed after oral administration with maximum plasma concentrations occurring between 0.5 and 6 hours post-dose.1 The mean half-life of lenalidomide is 3 hours in healthy subjects and 3-5 hours in patients with multiple myeloma, MDS, or mantle cell lymphoma.1 Lenalidomide is minimally metabolized to 5-hydroxy-lenalidomide and N -acetyl-lenalidomide.1
Clearance of lenalidomide is not affected substantially by age (39-85 years), weight (33-135 kg), sex, race, or type of hematologic malignancy.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Because lenalidomide is an analog of thalidomide (a known human teratogen that can cause severe, life-threatening birth defects if administered during pregnancy), distribution of lenalidomide is restricted.1 (See REMS under Dosage and Administration.)
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 2.5 mg | Bristol Myers Squibb | |
5 mg | Revlimid® | Bristol Myers Squibb | ||
10 mg | Revlimid® | Bristol Myers Squibb | ||
15 mg | Revlimid® | Bristol Myers Squibb | ||
20 mg | Revlimid® | Bristol Myers Squibb | ||
25 mg | Revlimid® | Bristol Myers Squibb |
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15. Bristol Myers Squibb. Welcome to the Lenalidomide REMS program. Lenalidomide REMS. Accessed 7 Apr 2023. [Web]
16. Bristol Myers Squibb. Medication guide: Revlimid®. Princeton, NJ. 2019 Oct.
17. Celegene Corporation, Summit, NJ: Personal communication.
20. Palumbo A, Rajkumar SV, Dimopoulos MA et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia . 2008; 22:414-23. [PubMed 18094721]
30. Raza A, Reeves JA, Feldman EJ et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood . 2008; 111:86-93. [PubMed 17893227]
31. Sekeres MA, Maciejewski JP, Giagounidis AA et al. Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol . 2008; 26:5943-9. [PubMed 19018091]
32. A study of lenalidomide versus placebo in subjects with transfusion dependent anemia in low risk myelodysplastic syndrome (MDS) without Del 5Q. From Clinical Trials (PDQ) database. Accessed 2013 Jan 30. [Web]
33. Cheson BD, Bennett JM, Kantarjian H et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood . 2000; 96:3671-4. [PubMed 11090046]
34. Cheson BD, Greenberg PL, Bennett JM et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood . 2006; 108:419-25. [PubMed 16609072]
35. AHFS off-label determination: Lenalidomide in transfusion-dependent low-risk or intermediate-1 risk myelodysplastic syndrome without the deletion 5q chromosomal abnormality. Published June 2013.
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