Description

Thalidomide (news articles, forum discussions) is an immunomodulatory agent (a drug that affects the immune system) that encourages a patient’s immune system to attack and destroy myeloma cells. Thalidomide appears to function through multiple pathways to inhibit myeloma cells’ growth and survival. Additionally, evidence suggests it exerts anti-angiogenesis effects, that is, it helps to restrict tumors’ necessary blood vessel growth.

Mechanism of Action

Currently, thalidomide’s precise mechanism of action remains unknown.

History

Originally developed in the 1950s, thalidomide began as a treatment for insomnia and morning sickness in pregnancy. Researchers soon discovered, however, that the drug could cause severe, life-threatening birth defects if taken immediately prior to conception or during pregnancy. As a result, in 1961 the FDA withdrew thalidomide from the market, but the FDA re-approved it for limited use in 1998. In 1999, researchers published findings that thalidomide was highly effective against multiple myeloma. With these clinical results, thalidomide became the first new therapy in more than 30 years to demonstrate significant myeloma treatment potential.

Usage in Multiple Myeloma

Currently, thalidomide is only FDA-approved for treatment in combination with the corticosteroid dexamethasone (DT) in newly diagnosed multiple myeloma patients. It is neither approved for treatment as a single agent, nor for recurrent disease. Although pharmaceutical companies may not market thalidomide for non-approved uses, physicians remain free to prescribe thalidomide to myeloma patients in any situation or combination they deem appropriate.

The National Comprehensive Cancer Network (NCCN) develops cancer treatment guidelines based on clinical trial results, and it considers thalidomide an appropriate treatment option for recurrent disease as well as myeloma that proves unresponsive to other treatments.

NCCN guidelines also recommend thalidomide as a possible maintenance therapy, either alone or in combination with prednisone (a steroid hormone), which patients begin after remission to reduce the risk of relapse.

In addition to dexamethasone, thalidomide may also be used in combination with melphalan (Alkeran), a chemotherapy agent, and prednisone. This triple-drug combination, known as MPT, is already approved in Europe for treatment of newly diagnosed myeloma.

Although not FDA-approved for use as a single agent, thalidomide alone may be appropriate for patients who relapse after stem cell transplant or for those who cannot tolerate a multiple-drug regimen.

Dosage & Administration

Thalidomide, which is administered orally, is available in capsules of varying dosage between 50-200 mg. Usually, physicians administer thalidomide daily, in combination with 40 mg of dexamethasone, in treatment cycles of 28 days.

Treatment usually continues as long as side effects remain manageable and the myeloma does not progress, thus warranting alternative treatment approaches. If patients achieve remission, their physicians may prescribe continuing with a lower thalidomide dose as a form of remission-maintenance therapy.

The standard thalidomide dose is 200 mg, although physicians may choose to begin patients on lower-dose regimens, gradually increasing dosages to reduce the risk of side effects.

In standard DT regimens, 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.

In other studies with dexamethasone and Revlimid (lenalidomide), researchers have discovered that lower doses of dexamethasone may be equally or more effective. Based on these results, researchers are now investigating the therapeutic potential of pairing a lower dose of once-weekly dexamethasone with thalidomide.

Side Effects

A wide range of side effects are possible with thalidomide treatment, though studies have demonstrated that several side effects may be more likely to occur than others. The frequency of side effects usually increases as the thalidomide dose is increased, and higher dosages have been associated with more severe side effects. However, the overall incidence of severe side effects is low.

The most common reasons that patients discontinue thalidomide treatment are fatigue and peripheral neuropathy. Peripheral neuropathy is a form of nerve damage in the extremities that may cause tingling or burning sensations, as well as decreased sensitivity. While multiple myeloma itself increases the risk of peripheral neuropathy, this nerve damage is also a potential side effect of thalidomide treatment.

Peripheral neuropathy resulting from thalidomide treatment is usually mild to moderate, but more severe forms may result from long-term treatment or high doses. Peripheral neuropathy is not always reversible upon thalidomide discontinuation, and treatment may be altered for a patient who experiences worsening or severe symptoms. Light exercise, as well as wearing loose-fitting shoes and socks, may also help alleviate discomfort.

More serious side effects associated with thalidomide are seizures and deep vein thrombosis (DVT).

An FDA warning recommends that patients with a history of seizures, or their risk factors, undergo careful seizure monitoring while taking thalidomide. It remains unclear, however, whether it is thalidomide specifically, rather than other, co-existing factors, that contributes to seizure activity in susceptible patients.

Deep vein thrombosis, or 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 one trial, DVT developed in 22.5 percent of individuals on a DT regimen, compared to only 5 percent of patients receiving dexamethasone alone. During thalidomide therapy, either alone or in a combination regimen, DVT most often occurs within the first six months of treatment. However, the rates of DVT have decreased significantly with routine preventative treatment with either over-the-counter or prescription blood thinners.

The most serious side effect associated with thalidomide is the potential for severe birth defects or fetal death. Thalidomide is a potent human teratogen, which means that it significantly disturbs the development of an embryo or fetus. When taken immediately prior to conception or during pregnancy, thalidomide 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 thalidomide.

Drug Interactions

Thalidomide has been reported to enhance the sedative activity of alcohol as well as certain sedatives, antipsychotics, and antihypertensive drugs. Medications known to be associated with peripheral neuropathy should also be used with caution in patients receiving thalidomide therapy.

Precautions

Thalidomide is not suggested for patients with a known hypersensitivity, and patients should be warned of the risk of drowsiness and dizziness while taking thalidomide. Thalidomide may also increase the viral load of HIV positive patients.

As a result of thalidomide’s severe teratogenic effects, the FDA has significantly restricted its availability. To receive thalidomide in the United States, patients must participate in the S.T.E.P.S. program: “System for Thalidomide Education and Prescribing Safety.”

The S.T.E.P.S. program, which involves physicians, patients, and pharmacists, provides a registry for drug use and mandates that patients undergo education and authorization prior to receiving thalidomide. Females of childbearing potential must also undergo routine pregnancy tests, and no patient may receive more than a 28-day supply of thalidomide at any one time.

All females of childbearing potential receiving thalidomide must use at least one highly effective form of birth control and one additional method of birth control. In addition, they must initiate contraception at least four weeks prior to therapy. Because thalidomide may be present in male ejaculate, all males receiving thalidomide must abstain from heterosexual contact or use a latex condom during sexual contact with a woman who is or could become pregnant.

Ongoing Clinical Trials

Open:

Phase 2:

• University of Arkansas: Thalidomide, Velcade, melphalan, and dexamethasone (NCT00577668)
• M.D. Anderson Cancer Center: To determine whether cumulative thalidomide dosage is correlated to the frequency and severity of peripheral neuropathy, as well as whether acupuncture may reverse treatment-induced neuropathy (NCT00891618)

Phase 3:

• Nordic Myeloma Study Group: Thalidomide versus Velcade (bortezomib) in melphalan refractory myeloma (NCT00602511)

Closed:

Phase 2:

• Weill Medical College of Cornell University: Thalidomide, dexamethasone, and Revlimid in relapsed or refractory myeloma (NCT00538824)

Phase 3:

• National Cancer Institute (NCI): Revlimid and dexamethasone with/without thalidomide (NCT00098475)
• National Cancer Institute (NCI): Zometa (zoledronate) alone versus Zometa plus thalidomide in early stage myeloma (NCT00432458)

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

Clinical Trial Results

Thalidomide Plus Dexamethasone for Induction Therapy (2006): During induction therapy in preparation for a stem cell transplant, 63 percent of newly diagnosed patients treated with a DT regimen responded to therapy, compared to 41 percent of patients treated with dexamethasone alone. The full trial description and results may be found in the Journal of Clinical Oncology.

Thalidomide Plus Melphalan and Prednisone a Beneficial Option for Elderly Multiple Myeloma Patients (2007): In patients over age 75 years, 62 percent of patients who received thalidomide in addition to melphalan and prednisone (MPT) experienced a partial or better response to treatment. By comparison, only 31 percent of those on melphalan and prednisone alone demonstrated a comparable positive response. The group receiving MPT, however, experienced a higher rate of side effects. More information may be found at the National Cancer Institute’s Clinical Trial Results Web site.

In Elderly, Survival Rates Higher on Melphalan-Prednisone than Thalidomide-Dexamethasone (2009): Elderly multiple myeloma patients undergoing treatment with melphalan and prednisone, known as an MP regimen, enjoyed higher 1-year and overall survival rates than those undergoing treatment with thalidomide and dexamethasone. The combination of thalidomide and dexamethasone resulted in greater tumor reduction, but it did not ultimately translate to better outcome, due to a high rate of fatal toxicities. The full description of trial results, which is still ongoing, may be found in Blood Journal.

Patient Assistance Programs

Celgene Product Assistance Program
1-800-931-8691
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

Thalidomide Package Insert
www.accessdata.fda.gov/drugsatfda_docs/label/2006/021430lbl.pdf

Thalidomide and Pregnancy
www.otispregnancy.org/pdf/thalidomide.pdf

Celgene's Web site for Thalomid
www.thalomid.com/

S.T.E.P.S. Program Information
www.thalomid.com/steps_program.aspx

Thalidomide News, Discussion, and Information
www.topix.com/drug/thalomid