Description

Pomalidomide (new articles ^[1], forum discussions ^[2]) is an immunomodulatory agent (a drug that affects the immune system) that encourages a patient’s immune system to attack and destroy myeloma cells. Pomalidomide is a chemical analogue, or closely related “cousin,” of the drug thalidomide ^[3] (Thalomid), which is already FDA-approved for multiple myeloma treatment. Like thalidomide, pomalidomide appears to function through multiple pathways to inhibit myeloma cells’ growth and survival. Additionally, it helps to restrict tumors’ necessary blood vessel growth.

Compared to thalidomide, pomalidomide has demonstrated enhanced immunological effects in lab testing, including an approximately 500-2,000 times greater potency at stimulating the proliferation of T-cells (an immune system cell).

Mechanism of Action

Pomalidomide appears to combat multiple myeloma through at least three different mechanisms of action, including:

• Angiogenesis, or blood vessel growth, inhibition
• Alteration of the levels of inflammatory and regulatory cytokines (a cell-signaling molecule)
• Stimulation of immune system cells (e.g., T cells, natural killer cells).

History

Pomalidomide was chemically derived from thalidomide as part of Celgene Corporation’s IMiDs research. IMiDs are structural and functional thalidomide analogues, that is, molecules created from and closely related to thalidomide. The IMiD drug class, in addition to pomalidomide, includes the drug Revlimid ^[4] (lenalidomide), which was FDA-approved for myeloma treatment in 2006. Pomalidomide is currently undergoing clinical testing.

Usage in Disease

Currently, pomalidomide is in Phase 1 and 2 clinical testing for multiple myeloma. Past and current trials have tested pomalidomide’s efficacy in treating relapsed or refractory myeloma that is unresponsive to other therapies. An ongoing trial is also comparing pomalidomide alone to pomalidomide in combination with the drug dexamethasone ^[5](Decadron). No clinical trials have evaluated pomalidomide as a front-line therapy for newly diagnosed multiple myeloma.

Dosage & Administration

Pomalidomide, which is administered orally, is available in capsules of varying dosage. In clinical trials thus far, patients have usually received pomalidomide daily for 28-day cycles, with stratified groups receiving different doses to establish optimum pomalidomide dosage. On average, however, administered doses ranged between 2-15 mg – considerably lower than the standard thalidomide dose of 200 mg.

In combination trials of pomalidomide plus dexamethasone, patients have usually received pomalidomide daily, along with 40 mg of dexamethasone on cycle days 1, 8, 15, and 22.

Some clinical trials have evaluated alternate-day, or every other day, pomalidomide dosing and produced promising clinical outcomes. Patients receiving alternate-day dosing generally experienced anti-myeloma activity equivalent to those receiving pomalidomide daily, but they encountered significantly fewer blood clots and other drug side effects.

Side Effects

A wide range of side effects are possible with treatment of pomalidomide, though studies have demonstrated that several side effects may be more likely to occur than others. Based on current studies, the frequency of side effects appears to increase as the pomalidomide dose is increased, and higher dosages have been associated with more severe side effects.

Patients receiving pomalidomide have experienced orthostasis, a condition of low blood pressure that may result in dizziness or imbalance upon standing; skin rash; and constipation. In addition, some patients experience edema, which is swelling due to excess water retention, often under the skin.

Individuals taking pomalidomide may also experience peripheral neuropathy, a condition also associated with thalidomide and Revlimid. 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 pomalidomide treatment.

Peripheral neuropathy resulting from pomalidomide treatment is usually mild to moderate, but more severe forms may result from long-term treatment or high doses, though current studies have not fully evaluated this risk potential. Studies have demonstrated, however, that the risk of peripheral neuropathy appears to be lower with pomalidomide than thalidomide. Peripheral neuropathy is not always reversible upon treatment discontinuation, and therapy may be altered for a patient who experiences worsening or severe symptoms. Light exercise, as well as wearing loose-fitting shoes and socks, may help alleviate discomfort.

More serious side effects associated with pomalidomide, to date, are myelosuppression and deep vein thrombosis. Myelosuppression, or reduced bone marrow activity, results in the production of fewer blood cells – red blood cells, white blood cells, and platelets. Pomalidomide, at higher doses, has been associated with significant myelosuppression, which can increase a patient’s risk for anemia-related fatigue, excess bleeding, and infection. Pomalidomide has been specifically associated with neutropenia, a reduction in a certain type of white blood cell, which can further increase infection risk.

Deep vein thrombosis, or DVT, involves blood clot formation in the deep veins of the body. 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.

Pomalidomide, like thalidomide, has been associated with an increased DVT risk. Current studies, however, suggest that the risk decreases at lower dosages and on alternate-day pomalidomide regimens. DVT risk may be further reduced with routine preventative treatment with either over-the-counter or prescription blood thinners.

The most serious side effect associated with pomalidomide is the potential for severe birth defects or fetal death. Data suggests that pomalidomide, like thalidomide, is a human teratogen, which means that it disturbs the development of an embryo or fetus; studies have not suggested Revlimid, another thalidomide derivative drug, affects fetal development. When taken immediately prior to conception or during pregnancy, pomalidomide may cause severe, life-threatening birth defects or fetal death. Clinical trials to date have required patients to practice abstinence or use contraception while taking pomalidomide.

Drug Interactions

Presently, there have not been a sufficient number of clinical trials to establish pomalidomide drug interactions. Medications known to be associated with peripheral neuropathy, however, should be used with caution in patients receiving pomalidomide therapy.

Precautions

Pomalidomide is contraindicated in patients with a known hypersensitivity; presently, there is too little clinical data to identify and confirm additional pomalidomide precautions.

Due to pomalidomide’s suspected teratogenic effects, however, clinical trials have imposed strict conditions on patients receiving pomalidomide. These requirements parallel S.T.E.P.S. – “System for Thalidomide Education and Prescribing Safety” – which is an FDA program already in place for thalidomide prescription.

The conditions for receiving pomalidomide, like the S.T.E.P.S. program, require that females of childbearing potential undergo routine pregnancy tests, and no patient may receive more than a 28-day supply of pomalidomide at any one time.

Females of childbearing potential receiving pomalidomide 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 pomalidomide may be present in male ejaculate, all males receiving pomalidomide 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 1/2:

• Mayo Clinic, National Cancer Institute: Pomalidomide, Velcade, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma (NCT01212952 ^[6])
• Fondazione Neoplasie Sangue Onlus: Pomalidomide, Cyclophosphamide and Prednisone (PCP) in Patients With Multiple Myeloma Relapsed and/or Refractory to Revlimid (NCT01166113 ^[7])

Phase 2:

• University Hospital, Lille: IFM2009-02-Pomalidomide and Dexamethasone Phase 2 Myeloma (NCT01053949 ^[8])
• University of Arkansas, Celgene: Pomalidomide in Gene Expression Profiling-Defined High-risk Multiple Myeloma (NCT01177735 ^[9])
• Weill Medical College of Cornell University, Celgene: Study of Dexamethasone, Biaxin (clarithromycin), and Pomalidomide in Relapsed/Refractory Myeloma (NCT01159574 ^[10])
• Mayo Clinic, National Cancer Institute: Pomalidomide and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma or Amyloidosis
  (NCT00558896 ^[11])

For a more detailed listing of clinical trials ^[12] involving pomalidomide, please check the U.S. government’s clinical trials Web site.

Clinical Trial Results

Pomalidomide with Low-Dose Dexamethasone for Relapsed/Refractory Multiple Myeloma (2008): According to interim trial results, 76 percent of patients receiving pomalidomide with low-dose dexamethasone experienced disease improvement or stabilization. In addition, of patients who were no longer responsive to Revlimid therapy, 29 percent responded positively to pomalidomide. Investigators concluded that for most patients, pomalidomide was generally well-tolerated with manageable side effects. More information about the clinical trial may be found in the Celgene ^[13] press release.

Alternate-Day Pomalidomide for Relapsed Multiple Myeloma (2007): In 20 patients with relapsed multiple myeloma followed for a median of 14 months, 10 percent achieved complete remission on pomalidomide. More than half of patients experienced at least a 50 percent reduction in M-protein, which can provide a marker for treatment response. In individuals receiving pomalidomide on alternate days, the incidence of side effects, particularly blood clots, dramatically decreased without any compromise of treatment potency. More information about the clinical trial results may be found in the British Journal of Haematology ^[14].

Patient Assistance Programs

Celgene Product Assistance Program
1-800-931-8691
http://www.celgenepsc.com/pat_medication.aspx ^[15]

Chronic Disease Fund, Inc.
877-968-7233
www.cdfund.org ^[16]

HealthWell Foundation
800-675-8416
www.healthwellfoundation.com ^[17]

Links of Interest

Overview of IMiDs
http://www.celgene.com/research/imids-immunomudulators.aspx ^[18]

New Directory Could Assist In Myeloma Treatment
https://myelomabeacon.org/news/2009/10/14/... ^[19]

Combination Pomalidomide And Dexamethasone Regimen Is Promising For Relapsed And Refractory Myeloma Patients
https://myelomabeacon.org/news/2009/09/04/... ^[20]

ASH 2008 – Pomalidomide-Dexamethasone Combination Highly Effective In Treating Relapsed And Refractory Multiple Myeloma
https://myelomabeacon.org/news/2008/12/09/... ^[21]