Description

Revlimid, which is a molecular derivative of thalidomide (Thalomid), was introduced in 2004 as a treatment for multiple myeloma. Revlimid in combination with dexamethasone is currently a common therapeutic treatment for multiple myeloma patients. Revlimid is more potent than thalidomide in inhibiting tumor production, and it also produces less severe adverse drug reactions than other drug agents of its kind.

Mechanism of Action

Although the exact mechanism of Revlimid has yet to be fully characterized, it has been shown to possess several properties key to combating tumor production.

Revlimid acts as an antineoplastic agent, a drug that inhibits the development of abnormal tissue masses known as neoplasms. The danger of antineoplastic agents, which includes cancer chemotherapy drugs, is widely acknowledged because they harm both healthy cells and cancerous cells. These drugs are still thought to be beneficial to cancer patients with a life-threatening disease, such as multiple myeloma.

Revlimid is also an immunomodulatory agent, which is a drug that encourages a patient’s immune system to attack and destroy myeloma cells. Immunomodulatory agents are able to induce immune responses and inhibit inflammation. They also enhance the activity of T cells and natural killer cells, which are specialized white blood cells that help kill cancer cells.

Additionally, Revlimid acts on angiogenesis, a process involving the growth of new blood vessels, to restrict the blood vessel growth necessary for the development of tumors.

Revlimid may also alter the production and activity of cytokines, which are involved in the growth and survival of certain cancer cells. It is believed that Revlimid affects the genes that direct the cell's growth and activity, particularly those associated with cytokines, apoptosis (cell death), and metabolism.

History

Revlimid, initially known as CC-5013, is a thalidomide analog that was developed by the biopharmaceutical company Celgene to be more potent and cause fewer side effects than thalidomide.

Celgene initiated a series of clinical trials pairing Revlimid with dexamethasone. These studies revealed that the Revlimid-dexamethasone regimen for patients with relapsed or refractory multiple myeloma was superior to the standard treatment of high-dose dexamethasone. As a result, in June 2006 the FDA granted approval of Revlimid for use in combination with dexamethasone.

Nonetheless, the Revlimid-dexamethasone treatment is complicated by high rates of venous thromboembolism, which is the process by which blood clots occur and travel through the veins. Additional clinical trials are currently underway to prevent the Revlimid-associated venous thromboembolism.

Usage in Multiple Myeloma

For the past 10 years, Revlimid has successfully treated both inflammatory disorders and cancers due to its broad range of activities. Revlimid may be used alone or in combination with dexamethasone for treatment of multiple myeloma. The Revlimid-dexamethasone combination has been shown to be more effective than either drug taken alone. This regimen is currently FDA-approved for the treatment of multiple myeloma patients who have received at least one prior therapeutic treatment.

The National Comprehensive Cancer Network (NCCN), which develops cancer treatment guidelines based on clinical trial results, considers Revlimid an appropriate treatment option for recurrent diseases, including multiple myeloma, that prove unresponsive to other treatments. NCCN guidelines also recommend Revlimid-dexamethasone as a possible primary induction therapy for non-transplant candidates.

Revlimid may also be used with Velcade (bortezomib), with or without dexamethasone, in both relapsed and refractory myeloma and in newly diagnosed patients.

The two-drug combination, known as Rev-Vel, appeared to be very effective in a small clinical trial with patients who had received several prior therapeutic treatments. In this study, 73 percent of patients responded to the therapy, and 36 percent of patients experienced significant reductions in monoclonal (M) protein levels. Multiple myeloma is characterized by increased production of M protein, an abnormal monoclonal serum antibody, and a decline in M protein levels is therefore indicative of a successful treatment. The patients in this trial also showed a prolonged response of 39 weeks to this treatment.

Revlimid is currently being studied in combination with several other cancer drugs: torisel (temsirolimus), HuLuc63, dacetuzumab (with dexamethasone), and LBH-589 (with dexamethasone).

Dosage & Administration

Revlimid, which is administered orally, is available in four capsule strengths: 5 mg, 10 mg, 20 mg, and 25 mg. Physicians typically prescribe a starting dose of 25 mg of Revlimid, in combination with 40 mg of dexamethasone, in treatment cycles of 28 days.

Blood counts should be checked every two weeks for the first 12 weeks of therapy and at least monthly thereafter. Treatment may be interrupted based on the results of the blood tests and on the patient’s general condition.

In standard Revlimid-dexamethasone regimens, patients take Revlimid on days 1-21 of each 28-day treatment cycle, with treatment resuming on day 1 of the next 28-day cycle. Patients take dexamethasone on days 1-4, 9-12, and 17-20 of each 28-day treatment cycle for the first four months. Starting at month five, patients only receive dexamethasone on days 1-4 of each month.

Side Effects

A wide range of side effects is possible with Revlimid treatment. Studies have demonstrated the frequency of side effects usually increases as the Revlimid dose is increased, and higher dosages have been associated with more severe side effects.

Potential side effects associated with Revlimid-dexamethasone treatment are fatigue, muscle cramps, rash, and insomnia.

Patients are recommended to exercise regularly and to eat and drink proper amounts in order to avoid fatigue. It is important to get sufficient rest to build up energy.

Patients may also experience muscle cramps, which are sudden pains that resemble a tightening or hardening in the muscle, and are recommended to speak with a physician immediately.

Another common side effect is rash, which may range in severity from mild irritation to obvious changes in skin color. Several cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients taking Revlimid, though it is not yet clear whether Revlimid is the cause. Because these conditions are life-threatening, patients should contact a physician immediately upon noticing any unusual rash or skin reaction.

Revlimid may also cause chronic sleep disturbances, which may lead to irritability, problems concentrating, depression, and anxiety.

Patients taking Revlimid with dexamethasone may experience gastrointestinal disorders, including constipation and diarrhea. Although the risk of severe constipation is low for these patients, mild constipation may be reduced or eliminated by exercising regularly, drinking plenty of water, and maintaining a high-fiber diet.

Recent studies have indicated that patients taking Revlimid-dexamethasone for an extended period of time (longer than eight months) experience significantly more diarrhea than patients taking dexamethasone alone. For the majority of patients, the diarrhea started after treatment had elapsed for 19 months. Patients experiencing diarrhea should inform their physician as soon as possible so it can be treated. The symptoms of diarrhea may be minimized by eating small, frequent meals and avoiding dairy products, spicy foods, caffeinated and carbonated foods and drinks, and high-fiber and high-fat foods.

More serious side effects associated with Revlimid are low blood counts and deep vein thrombosis.

Patients undergoing Revlimid-dexamethasone treatment may experience a decrease in the production of white blood cells (neutropenia), platelets (thrombocytopenia), or red blood cells (anemia). Blood tests should be administered regularly to monitor blood count levels. For patients experiencing neutropenia, a physician may prescribe a growth factor to increase the white blood cell count.

Deep vein thrombosis (DVT) involves blood clot formation in the deep veins of the body, and if a clot dislodges, it may travel to other areas and block blood flow to vital organs. Researchers estimate that approximately 70 percent of all critical blockages of lung blood vessels originate from DVT in the pelvis or lower extremities.

In initial trials of Revlimid-dexamethasone, 11 percent of patients developed serious blood clots, compared to four percent of patients taking only dexamethasone. Due to this increased risk, it is now recommended that all patients undergoing Revlimid-dexamethasone treatment also take blood thinners to reduce the chance of developing blood clots. The most commonly used blood thinner is aspirin, although Coumadin (warfarin) and heparin may also be prescribed.

The most serious side effect associated with Revlimid is the potential for severe birth defects or fetal death. Revlimid is an analog of thalidomide, a known potent human teratogen. Teratogens significantly disturb the development of an embryo or fetus. Although Revlimid has not been tested in pregnant women, it has harmed unborn animals in animal testing.

When taken immediately prior to conception or during pregnancy, Revlimid can cause severe, life-threatening birth defects or fetal death. As part of a restricted-access program discussed in further detail below, patients must practice abstinence or use contraception in order to receive Revlimid.

Drug Interactions

Revlimid has been reported to interact with digoxin, estrogens and progestins (found in birth control pills and hormone replacement therapies), and Coumadin. Patients taking any of these medications are advised to speak with a physician.

In addition, caffeine, alcohol, cigarettes, and street drugs may affect the action of Revlimid. Patients should speak with a physician if they are using any of these drugs in combination with Revlimid.

Precautions

As a result of its severe effects on unborn fetuses, Revlimid is only available under a restricted distribution program known as RevAssist. RevAssist, which involves physicians, patients, and pharmacists, provides a registry for drug use and mandates that patients undergo education and authorization prior to receiving Revlimid. Females of childbearing potential must also undergo routine pregnancy tests prior to prescription of Revlimid.

All females of childbearing potential taking Revlimid must use two separate forms of effective birth control at the same time. In addition, they must initiate contraception at least four weeks prior to therapy.

Because Revlimid may be present in male ejaculate, all males receiving Revlimid must abstain from heterosexual contact or use a latex condom during sexual contact with a woman who is or could become pregnant. Male patients must not donate sperm while taking Revlimid and for at least four weeks following the end of treatment.

Ongoing Clinical Trials

Open

Phase 2:

• Weill Medical College of Cornell University: Phase 2 Study of Thalidomide, Clarithromycin (Biaxin), Revlimid, and Dexamethasone for Newly Diagnosed Multiple Myeloma (T-BiRD) (NCT00538733)
• New York University School of Medicine: Combination of Revlimid, Melphalan (Alkeran) and Dexamethasone as First Line Treatment for Multiple Myeloma (NCT00843310)

Phase 3:

• National Cancer Institute (NCI): Revlimid and Dexamethasone With or Without Velcade (bortezomib) in Treating Patients With Previously Untreated Multiple Myeloma (NCT00644228)
• Gesellschaft fur Medizinische Innovation: Comparison of 25mg Versus 5 mg Revlimid as Maintenance Therapy in Patients With Multiple Myeloma (NCT00891384)

Closed

Phase 2:

• Weill Medical College of Cornell University: Phase 2 Study of Clarithromycin (Biaxin), Revlimid, and Dexamethasone for Untreated Multiple Myeloma (NCT00151203)
• National Cancer Institute of Canada: Revlimid and Melphalan in Treating Patients With Previously Untreated Multiple Myeloma (NCT00305812)

Phase 3:

• National Cancer Institute (NCI): Revlimid and Dexamethasone With or Without Thalidomide in Treating Patients With Multiple Myeloma (NCT00098475)
• National Cancer Institute (NCI): Dexamethasone With or Without Revlimid in Treating Patients With Previously Untreated Stage I, Stage II, or Stage III Multiple Myeloma (NCT00064038)

For a more detailed listing of clinical trials involving Revlimid, please check the U.S. government’s clinical trials Web site.

Clinical Trial Results

Low-dose Steroid Combined with Revlimid Prolongs Survival Compared with High-dose Steroid for Multiple Myeloma Treatment (2007): Preliminary results from a large, randomized clinical trial for patients with newly diagnosed multiple myeloma has shown that a low dose of the steroid dexamethasone, in combination with Revlimid, is associated with improved survival when compared to a treatment regimen with Revlimid and a higher, standard dose of dexamethasone. More information may be found at the National Cancer Institute’s Clinical Trial Results Web site.

BiRD Combination Therapy Results in High Complete- and Overall-Response Rates in Treatment-Naive Symptomatic Multiple Myeloma (2008): This trial determined the safety and efficacy of the combination regimen clarithromycin (Biaxin)-Revlimid-dexamethasone (BiRD) as first-line therapy for multiple myeloma. A combined complete response rate of 39 percent was achieved, and 74 percent of the patients achieved at least a 90 percent decrease in protein levels. The major adverse events were venous thromboembolism, dexamethasone-related morbidity, and cytopenia, or a reduction in blood cell production. The full description of trial results may be found in the journal Blood.

Revlimid, doxorubicin (Adriamycin), and Dexamethasone (RAD) in Patients with Relapsed and Refractory Multiple Myeloma (2009): Researchers conducted a phase 1-2 trial combining Revlimid with doxorubicin and dexamethasone for relapsed and relapsed-refractory myeloma to determine tolerability and efficacy of this novel regimen, delivered for six 28-day cycles. The overall response rate was 73 percent for the whole study. For participants receiving the highest dose (25 mg Revlimid, 9 mg adriamycin, 40 mg dexamethasone, 6 mg pegfilgrastim),, the overall response rate was 77 percent, with 74 percent attaining a complete response to the treatment. The full description of trial results may be found in the journal Blood.

Patient Assistance Programs

Celgene Product Assistance Program
1-800-931-8691
http://www.celgenepsc.com/pat_medication.aspx

Chronic Disease Fund, Inc.
877-968-7233
www.cdfund.org

HealthWell Foundation
800-675-8416
www.healthwellfoundation.com

Partnership for Prescription Assistance (PPARx)
888-4PPA-NOW (477-2669)
www.pparx.org

Patient Advocate Foundation, Co-Pay Relief
866-512-3861
www.copays.org

RxAssist
401-729-3284
www.rxassist.org

Links of Interest

Revlimid History and Prescribing Information:
http://www.revlimid.com

FDA Questions and Answers on Revlimid:
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm109338.htm

Mechanism of Action of Revlimid in Blood Cancers
http://www.jhoonline.org/content/pdf/1756-8722-2-36.pdf

Blog by Participant in Revlimid Drug Trial
http://www.stewartsrevlimid.blogspot.com/

Revlimid Clinical Trials
http://clinicaltrials.gov/ct2/results?term=revlimid