Revlimid (lenalidomide) - 4 indications

Scroll down for information on each indication:

• for the treatment of Myelodysplastic Syndromes; approved December 2005
• for use in combination with dexamethasone for the treatment of multiple myeloma; approved June 2006
• for the treatment of mantle cell lymphoma; approved June 2013
• for patients with previously treated follicular lymphoma or marginal zone lymphoma; approved May 2019

General Information

Revlimid (lenalidomide) is an orally available thalidomide analog, exerting both anti-angiogenic and immunomodulatory/anti-inflammatory properties.

Revlimid is specifically indicated for the following conditions:

• in combination with dexamethasone is indicated for the treatment of adult patients with multiple myeloma (MM), and as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT)
• for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities
• for the treatment of adult patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib
• for use in combination with a rituximab product for the treatment of adult patients with previously treated follicular lymphoma or marginal zone lymphoma

Revlimid is supplied as capsules for oral administration. Scroll down for recommended dosing/administration for each indication.

Mechanism of Action

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of lenalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos, Ikaros, and CK1α) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes, follicular lymphoma and marginal zone lymphoma in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM. Immunomodulatory properties of lenalidomide include increased number and activation of T cells and natural killer (NK) cells leading to direct and enhanced antibody dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin-2 and interferon-gamma, increased numbers of NKT cells, and inhibition of proinflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In MM cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis. The combination of lenalidomide and rituximab increases ADCC and direct tumor apoptosis in follicular lymphoma cells and increases ADCC in marginal zone lymphoma cells compared to rituximab alone in vitro.

Side Effects

Adverse effects associated with the use of Revlimid for MM may include, but are not limited to, the following:

• 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
• tremor

Adverse effects associated with the use of Revlimid for MDS may include, but are not limited to, the following:

• thrombocytopenia
• neutropenia
• diarrhea
• pruritus
• rash
• fatigue
• constipation
• nausea
• nasopharyngitis
• arthralgia
• pyrexia
• back pain
• peripheral edema
• cough
• dizziness
• headache
• muscle cramp
• dyspnea
• pharyngitis
• epistaxis

Adverse effects associated with the use of Revlimid for Non-Hodgkin’s Lymphoma (NHL: MCL, FL or MZL) may include, but are not limited to, the following:

• neutropenia
• thrombocytopenia
• anemia
• leukopenia
• diarrhea
• constipation
• nausea
• fatigue
• pyrexia
• cough
• upper respiratory tract infection
• rash

The Revlimid drug label comes with the following Black Box Warning: EMBRYO-FETAL TOXICITY: Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. Revlimid is available only through a restricted distribution program, called the Revlimid REMS program. HEMATOLOGIC TOXICITY: Revlimid can cause significant neutropenia and thrombocytopenia. VENOUS AND ARTERIAL THROMBOEMBOLISM: Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving Revlimid with dexamethasone. Anti-thrombotic prophylaxis is recommended.

Indication 1: Myelodysplastic Syndromes

approved December 2005

Dosing/Administration

The recommended starting dose of Revlimid is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings. Continue treatment until disease progression or unacceptable toxicity. See drug label for dose adjustments for hematologic toxicities during MDS treatment.

Clinical Trial Results

Approval of Revlimid was based on results of an open-label, single arm, multi-center study that enrolled 148 patients with red-blood-cell-transfusion dependent anemia due to low-or intermediate-1- risk MDS associated with a 5 q (q31-33) cytogenetic abnormality in isolation or with additional cytogenetic abnormalities. Subjects received 10 mg Revlimid once daily either continuously or for 21 of every 28 days. Sequential dose reductions, to 5 mg daily and 5 mg every other day, were permitted to mitigate toxicities. The drug was shown to be efficacious in reducing the need for red-blood cell transfusions: 67% (n=99/148) of patients experienced a period of at least 8 weeks during which no transfusion was needed, and the median duration of transfusion independence was maintained for a median 44 weeks. 90% of responders experienced onset of transfusion independence within 3 months. Dose interruption or reduction due to toxicity was necessary in 79.7% of patients (n=118/148).

Indication 2 - for use in combination with dexamethasone for the treatment of multiple myeloma

approved June 2006

Dosing/Administration

Revlimid Combination Therapy

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

Revlimid Maintenance Therapy Following Auto-HSCT

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

See drug label for dose adjustments for hematologic toxicities during MM treatment.

Clinical Trial Results

Randomized, Open-Label Clinical Trial in Patients with Newly Diagnosed MM:

A randomized multicenter, open-label, 3-arm trial of 1,623 patients, was conducted to compare the efficacy and safety of Revlimid and low-dose dexamethasone (Rd) given for 2 different durations of time to that of melphalan, prednisone and thalidomide (MPT) in newly diagnosed MM patients who were not a candidate for stem cell transplant. In the first arm of the study, Rd was given continuously until progressive disease [Arm Rd Continuous]. In the second arm, Rd was given for up to eighteen 28-day cycles [72 weeks, Arm Rd18]). In the third arm, melphalan, prednisone and thalidomide (MPT) was given for a maximum of twelve 42-day cycles (72 weeks). Patients in the Rd Continuous and Rd18 arms received Revlimid 25 mg once daily on Days 1 to 21 of 28-day cycles. Dexamethasone was dosed 40 mg once daily on Days 1, 8, 15, and 22 of each 28-day cycle. For patients over > 75 years old, the starting dose of dexamethasone was 20 mg orally once daily on days 1,8,15, and 22 of repeated 28-day cycles. Initial dose and regimens for Rd Continuous and Rd18 were adjusted according to age and renal function. All patients received prophylactic anticoagulation. The primary efficacy endpoint was progression-free survival. PFS was significantly longer with Rd Continuous than MPT. A lower percentage of subjects in the Rd Continuous arm compared with the MPT arm had PFS events (52% versus 61%, respectively). The improvement in median PFS time in the Rd Continuous arm compared with the MPT arm was 4.3 months. The myeloma response rate was higher with Rd Continuous compared with MPT (75.1% versus 62.3%); with a complete response in 15.1% of Rd Continuous arm patients versus 9.3% in the MPT arm. The median time to first response was 1.8 months in the Rd Continuous arm versus 2.8 months in the MPT arm.

Randomized, Placebo-Controlled Clinical Trials - Maintenance Following Auto-HSCT:

Two multicenter, randomized, double-blind, parallel group, placebo-controlled studies were conducted to evaluate the efficacy and safety of Revlimid maintenance therapy in the treatment of MM patients after auto-HSCT. In Maintenance Study 1, patients between 18 and 70 years of age who had undergone induction therapy followed by auto-HSCT were eligible. Induction therapy must have occurred within 12 months. Within 90-100 days after auto-HSCT, patients with at least a stable disease response were randomized 1:1 to receive either Revlimid or placebo maintenance. In Maintenance Study 2, patients aged < 65 years at diagnosis who had undergone induction therapy followed by auto-HSCT and had achieved at least a stable disease response at the time of hematologic recovery were eligible. Within 6 months after auto-HSCT, patients were randomized 1:1 to receive either Revlimid or placebo maintenance. Patients eligible for both trials had to have CLcr ≥30 mL/minute. In both studies, the Revlimid maintenance dose was 10 mg once daily on days 1-28 of repeated 28-day cycles, could be increased to 15 mg once daily after 3 months in the absence of dose-limiting toxicity, and treatment was to be continued until disease progression or patient withdrawal for another reason. The dose was reduced, or treatment was temporarily interrupted or stopped, as needed to manage toxicity. A dose increase to 15 mg once daily occurred in 135 patients (58%) in Maintenance Study 1, and in 185 patients (60%) in Maintenance Study 2. The major efficacy endpoint of both studies was PFS. In both studies, the primary analysis of PFS at unblinding was significantly longer with Revlimid compared to placebo. With longer follow-up (median 72.4 and 86.0 months, respectively), the updated PFS analyses for both studies continue to show a PFS advantage for Revlimid compared to placebo: Maintenance Study 1 with median PFS of 68.6 months and Maintenance Study 2 with median PFS of 46.3 months.

Indication 3 - for the treatment of mantle cell lymphoma

approved June 2013

Dosing/Administration

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

See drug label for dose adjustments for hematologic toxicities during MCL treatment.

Clinical Trial Results

The FDA approval of Revlimid for mantle cell lymphoma was based on a multicenter, single-arm, open-label trial of single-agent lenalidomide in 134 subjects with mantle cell lymphoma who had relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. Subjects with a creatinine clearance >60 mL/min were given lenalidomide at a dose of 25 mg once daily for 21 days every 28 days. Subjects with a creatinine clearance >30 mL/min and <60 mL/min were given lenalidomide at a dose of 10 mg once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. The endpoints were overall response rate (ORR) and duration of response (DOR). The ORR was 26% and the median DOR was 16.6 months.

Indication 4 - for patients with previously treated follicular lymphoma or marginal zone lymphoma

approved May 2019

Dosing/Administration

The recommended starting dose of Revlimid is 20 mg orally once daily on Days 1-21 of repeated 28-day cycles for up to 12 cycles of treatment in combination with a rituximab-product. For dose adjustments due to toxicity with rituximab, refer to the product prescribing information.

See drug label for dose adjustments for hematologic toxicities during FL and MZL treatment.

Clinical Trial Results

The efficacy of Revlimid with rituximab in patients with relapsed or refractory follicular and marginal zone lymphoma was evaluated in the AUGMENT and MAGNIFY trials.

AUGMENT is a randomized, double-blind, multicenter trial (n=358) in which patients with relapsed or refractory follicular or marginal zone lymphoma were randomized 1:1 to receive Revlimid and rituximab or rituximab and placebo. Revlimid was administered orally 20 mg once daily for Days 1 to 21 of repeating 28-day cycles for a maximum of 12 cycles or until unacceptable toxicity. The dose of rituximab was 375 mg/m2 every week in Cycle 1 (Days 1, 8, 15, and 22) and on Day 1 of every 28-day cycle from Cycles 2 through 5. All dosage calculations for rituximab were based on the patient’s body surface area (BSA), using actual patient weight. Dose adjustments for Revlimid were allowed based on clinical and laboratory findings. A patient with moderate renal insufficiency (≥30 to <60 mL/minute) received a lower Revlimid starting dose of 10 mg daily on the same schedule. After 2 cycles, the Revlimid dose could be increased to 15 mg once daily on Days 1 to 21 of each 28-day cycle if the patient tolerated the medication. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab with a median duration of 39.4 months versus 14.1 months, respectively.

MAGNIFY is an open-label, multicenter trial (n=232) in which patients with relapsed or refractory follicular, marginal zone, or mantle cell lymphoma received 12 induction cycles of Revlimid and rituximab. The information from the subjects who received at least 1 dose of initial therapy in the first 12 induction cycles (n=222) in the MAGNIFY trial was included in the evaluation of the efficacy of Revlimid/rituximab in patients with relapsed or refractory follicular and marginal zone lymphoma. In MAGNIFY, Revlimid 20 mg was given on Days 1-21 of repeated 28-day cycles for up to 12 cycles or until unacceptable toxicity, progression, or withdrawal of consent. The dose of rituximab was 375 mg/m2 every week in Cycle 1 (Days 1, 8, 15, and 22) and on Day 1 of every other 28-day cycle (Cycles 3,5,7,9, and 11) up to 12 cycles therapy. All dosage calculations for rituximab were based on the patient BSA and actual weight. Dose adjustments were allowed based on clinical and laboratory findings. Objective response rates on investigator assessment were 59% in 177 patients with follicular lymphoma (median response duration not reached with median follow-up of 7.9 months) and 51% in 45 patients with marginal zone lymphoma (median response duration not reached with median follow-up of 11.5 months).