Revlimid® (lenalidomide, formerly known as Revimid), is the first of Celgene’s new class of oral cancer drugs called IMiDs®. These immunomodulatory derivatives are chemically similar to thalidomide but are more potent in the laboratory and have a different side effect profile than thalidomide. They have multiple mechanisms of action that affect both the cancer cell and its microenvironment.

On June 29, 2006, Revlimid was approved for use in combination with dexamethasone as a treatment for patients with myeloma who have received at least one prior therapy. Revlimid-dexamethasone is now listed as a recommended option for relapsed and refractory myeloma in the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines for multiple myeloma. Revlimid-dex has also been examined in a number of newly diagnosed patients and, as a result, is also listed in the NCCN guidelines as a recommended option for initial therapy in patients who are candidates for stem cell transplant.

Revlimid has also been evaluated in combination with other novel agents, including bortezomib (Velcade®, Millennium) in relapsed, refractory myeloma. Revlimid is under investigation for use in other hematologic conditions and cancers, as well as solid tumor cancers.

Like thalidomide, IMiDs are immunomodulatory agents (drugs that can modify or regulate the functioning of the immune system). IMiDs appear to have multiple actions, including both anticancer and anti-inflammatory activities.

IMiDs affect the immune system in several ways. They induce immune responses, enhance activity of immune cells, and inhibit inflammation. IMiDs appear to alter the levels of various cytokines (growth factors or factors that inhibit growth) and affect cells of the immune system. Studies show that IMiDs:

• Enhance the activation of T cells
• Enhance the activity of natural killer cells, which help kill cancer cells
• Enhance production of interleukin 2 (IL-2), a growth factor for T cells
• Inhibit inflammatory cytokines including
  

  • Tumor necrosis factor-alpha (TNF-α)
  • Interleukin 1-beta (IL-1β)
• Stimulate the production of interleukin 10 (IL-10), an anti-inflammatory cytokine

IMiDs are thought to affect multiple pathways in myeloma cells.
IMiDs appear to have direct and indirect effects on myeloma cells, including the ability to

• Induce apoptosis (programmed cell death) of myeloma cells
• Inhibit myeloma cell growth
• Inhibit vascular endothelial growth factor (VEGF), thereby inhibiting angiogenesis
• Reduce adhesion of myeloma cells to bone marrow stromal cells

Additionally, in the laboratory, IMiDs appear to act synergistically with other anti-myeloma agents and may kill myeloma cells that are resistant to conventional therapy. For example, in the laboratory, Revlimid augments the cytotoxicity of SGN-40, an anti-CD40 monoclonal antibody, against human myeloma cells. (Tai et al. Cancer Res. 2005;65(24):11712-20.) A trial evaluating this combination is planned.

The figure below illustrates how IMiDs act on myeloma cells.

Revlimid is an oral agent that is available as 5 mg, 10 mg, 15 mg, and 25 mg capsules. The recommended starting dose of Revlimid is 25 mg/day with water administered as a single 25 mg capsule on Days 1 to 21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg/day on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg/day orally on Days 1 to 4 every 28 days. Dosing is continued or modified based upon clinical and laboratory findings.

Dose adjustments may be made during treatment. The guidelines below summarize recommended dose modifications to manage Grade 3 or 4 thrombocytopenia or neutropenia or other Grade 3 or 4 toxicities judged to be related to Revlimid.

For other Grade 3/4 toxicities judged to be related to Revlimid, hold treatment and restart at the next lower dose level when toxicity has resolved to ≤ Grade 2.

In clinical trials conducted to date, the IMiDs appear to have a different safety profile from thalidomide. Significant sleepiness, constipation, or neuropathy—common side effects seen with thalidomide therapy—are much less frequent.

The major potential risks and side effects of Revlimid therapy include low blood cell counts (mainly platelets and neutrophils), blood clots in the veins (deep vein thrombosis, DVT) and in the lungs (pulmonary embolism) when combined with other therapy, and possible birth defects. Although studies are ongoing to determine the risk of birth defects, Revlimid does not appear likely to cause the type of severe birth defects noted in the past with thalidomide. However, because of its similarity to thalidomide, and some evidence of harm in unborn animals in animal testing, female patients who are pregnant or who plan to become pregnant must not take Revlimid. A risk-management plan called RevAssist^SM has been implemented to prevent exposure to Revlimid during pregnancy. Under this program, only prescribers and pharmacists registered with RevAssist are able to prescribe and dispense Revlimid. In addition, Revlimid must only be dispensed to patients who are registered and meet all the conditions of the program.

In the multicenter Phase II trial of Revlimid in relapsed and refractory myeloma (with dexamethasone added if needed in patients with suboptimal response to Revlimid alone), the most common Grade 3 or 4 toxicities were thrombocytopenia and neutropenia. These were noted more frequently in patients receiving 15 mg twice daily than in patients receiving 30 mg once daily. Other Grade 3 side effects were infrequent. Mild side effects included diarrhea, fever, muscle cramps, neuropathy, constipation, rash, and fatigue. DVT was seen in 4% of patients receiving Revlimid in combination with dexamethasone, but not in patients receiving Revlimid alone.

In the Phase III studies of combination Revlimid and dexamethasone in relapsed and refractory myeloma, 151 patients (45%) underwent at least one dose interruption with or without a dose reduction of Revlimid compared to 21% in the placebo/dexamethasone treatment group. Most adverse events and Grade 3 or 4 adverse events were more frequent in patients who received the combination of Revlimid and dexamethasone compared to placebo/dexamethasone. Reported adverse events are shown in the table below.

Grade 3/4 hematologic toxicities included neutropenia, thrombocytopenia, and anemia. Thrombotic events (including DVT and pulmonary embolism) were reported more frequently in patients receiving Revlimid/dex than those receiving placebo/dex (12% vs. 4%). (Note that no prophylactic anticoagulation was administered in these trials.) In a recent trial of Revlimid in previously untreated patients with myeloma, aspirin appeared to be successful as prophylaxis, although further studies in larger numbers of patients are necessary for formal recommendations regarding prophylactic anticoagulation.

A retrospective review of medical records of myeloma patients participating in Revlimid trials at the Mayo Clinic (n=75) was conducted to further examine the dermatologic effects of Revlimid alone and in combination with dexamethasone. (Sviggum et al. Arch Dermatol. 2006;142(10):1298-302.) In this analysis, there was no difference in the incidence of rash in patients receiving Revlimid compared with Revlimid and dexamethasone (both 29%). Most skin eruptions were mild and did not necessitate withdrawal of Revlimid therapy.

On June 29, 2006, Revlimid was approved for use in combination with dexamethasone as a treatment for patients with myeloma who have received at least one prior therapy.

In March 2005, the two ongoing pivotal Phase III clinical trials of Revlimid® and high-dose dexamethasone plus placebo versus high-dose dexamethasone alone in patients with relapsed or refractory myeloma were found to exceed the pre-specified interim efficacy endpoint (p<0.0015) for disease progression. Based on this data, the trials were unblinded many months earlier than anticipated and all patients currently not on Revlimid® had the opportunity to add Revlimid® to their dexamethasone regimen if needed. In December of 2005, Celgene submitted a Supplemental New Drug Application (sNDA) for Revlimid, which was based upon the safety and efficacy results of these two pivotal trials, to the FDA for the treatment of relapsed or refractory myeloma. Just prior to the submission, the FDA had approved Revlimid for the treatment of certain patients with myelodysplastic syndromes (MDS), a group of hematologic malignancies unrelated to myeloma.

The links below summarize results from recent clinical trials regarding the use of Revlimid® in the following settings:

A number of Revlimid® clinical trials are being conducted in patients with relapsed/refractory or newly-diagnosed disease. Revlimid® is also being evaluated for use as maintenance therapy.

In combination with Velcade and dexamethasone. A Phase 2 study of this combination is currently underway in relapsed and/or refractory disease, based on encouraging data from a Phase 1 trial. The combination was shown to be active, with durable responses seen in heavily pretreated patients.

Other combinations. A number of other clinical trials are being conducted in the relapsed/refractory setting, including:

Alone and in combination with dexamethasone. The combination of Revlimid plus dexamethasone has been studied at the Mayo Clinic in 34 patients with newly diagnosed myeloma (see Newly Diagnosed Disease for more information). Ninety-one percent of patients responded to therapy, including 56% who achieved very good partial response or better. Two Phase 3 trials are testing this combination in the United States.

The first trial is being conducted by the Eastern Cooperative Oncology Group (ECOG). The purpose of the study is to evaluate the response rate and toxicity of Revlimid plus dexamethasone versus Revlimid plus low-dose dexamethasone and to determine if Revlimid plus low dose dexamethasone will offer a similar response rate with lower toxicity. All patients receive Revlimid (25 mg/day on days 1-21 of a 28-day cycle) in combination with standard dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20) or low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22) for a total of 4 cycles. Patients must also take prophylactic aspirin to prevent blood clots. The trial is expected to enroll more than 400 patients.

Preliminary safety data from the ECOG trial were reported at ASH in 2006. (Rajkumar et al. Blood. 2006;108(11). Abstract 799.) During the first 4 months of therapy, patients in the Revlimid plus high-dose dexamethasone arm experienced more thrombotic complications (deep-vein thrombosis and pulmonary embolism) than those in the Revlimid plus low-dose dexamethasone arm (18.4% vs. 6.3%, respectively). Revlimid plus high-dose dexamethasone was also associated with significantly higher incidence of infection and grade 4 toxicities.

In March 2007, the data monitoring committee found that overall survival was better in the low-dose dexamethasone arm compared to the high-dose arm (1-year survival of 96.5% versus 86%, respectively). As a result, all patients were asked to switch to Revlimid plus low-dose dexamethasone. Detailed results will be presented at the ASCO meeting in June 2007. Response data has not yet been released.

The Southwest Oncology Group (SWOG) is conducting a large randomized Phase 3 clinical study designed to evaluate the safety and efficacy of dexamethasone versus Revlimid plus dexamethasone in patients with newly diagnosed myeloma who are not candidates for transplant. The trial is expected to enroll approximately 500 patients, but was temporarily closed in April 2007 following the results of the ECOG study to allow an interim analysis to be performed.

In combination with clarithromycin and dexamethasone (BiRD). A Phase I/II study of clarithromycin (Biaxin™), Revlimid, and dexamethasone (BiRD) is being conducted in patients with newly diagnosed disease with poor prognostic features. Preliminary results of this trial reported at ASH in December 2006 suggest that the combination is effective, but myelosuppression and renal dysfunction potentiated the need for dose reductions of Revlimid. (Niesvizky et al. Blood. 2006;108(11). Abstract 3549.)

Of the 58 evaluable patients, 95% had achieved an objective response (PR or better), including 28% achieving a CR and 10% achieving a near-CR. Eighteen percent of patients required dose reductions of Revlimid due to myelosuppression, and creatinine clearance of ≤40 was associated with Revlimid dose reductions. Other toxicities included pulmonary embolism (4%), DVT (9%), heart attack (2%), and sudden death (2%). Other nonhematologic toxicities included muscle disorders (6%), diverticular abscess (10%), hand tremor, weakness, and hyperglycemia.

In combination with Velcade and dexamethasone. A Phase II study evaluating the combination of Revlimid, Velcade, and dexamethasone has been initiated in patients with newly diagnosed disease. In addition, a national study led by ECOG will compare Velcade-Revlimid-dexamethasone to Velcade-dexamethasone in place of transplant following induction therapy for myeloma.

The Cancer and Leukemia Group B (CALGB), in conjunction with the Eastern Cooperative Oncology Group (ECOG), is conducting a Phase III randomized, double blind, placebo-controlled study of maintenance therapy with Revlimid or placebo following autologous stem cell transplantation for myeloma. The trial is expected to enroll approximately 462 patients.

Click here to go to the MMRF’s Clinical Trials Monitor to view a list of ongoing Revlimid clinical trials.