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Thalomid (thalidomide)
Full Name: Thalomid® (thalidomide)
Other Names: None
Description: Immunomodulatory agent with multiple effects (oral)
Phase: Approved May 2006
Company: Celgene Corporation
www.celgene.com
www.thalomid.com
What It Is
Originally developed as a treatment for insomnia and morning sickness in the 1950s, thalidomide is an oral drug that has been shown to be highly active against myeloma. Many consider thalidomide to be the first new agent with major anti-myeloma activity in more than 30 years.

Thalidomide was approved by the Food and Drug Administration (FDA) in May of 2006 for use in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma.

Click here for product prescribing information.
Effectiveness
The effectiveness of Thalomid was demonstrated by improved response rates and shorter time to response in a randomized, multicenter, open-label study of 207 newly diagnosed patients. To date, there are no placebo-controlled trials demonstrating a clinical benefit, such as improved survival to the addition of Thalomid to therapy.
How It Works
Overview
Thalidomide is an immunomodulatory agent (a drug that affects the immune system). However, its precise mechanism of action is unknown and under investigation. Thalidomide appears to have multiple actions, including the ability to inhibit the growth and survival of myeloma cells in various ways and to inhibit the growth of new blood vessels (angiogenesis).
Details on Thalidomide's Mechanism of Action
Thalidomide appears to have multiple effects that may account for its activity against myeloma. These include: These effects are summarized in the figure below.

Thalidomide's Various Effects in Myeloma
Patient Selection
Thalidomide-based therapy represents an accepted treatment option for patients with myeloma. Recent Clinical Practice Guidelines for Multiple Myeloma developed by the National Comprehensive Cancer Network (NCCN®, 2004) indicate that the use of thalidomide is an appropriate option as salvage therapy for relapsed or refractory disease and in combination with dexamethasone as initial therapy in patients with advanced myeloma (Durie-Salmon Stage II or III).

Single-agent thalidomide may be particularly appropriate for the following patient types:
  • Patients who relapse following transplantation
  • Patients who cannot tolerate steroids
Thalidomide in combination with dexamethasone (thal-dex) is considered an appropriate treatment option for:
  • Patients with more aggressive disease
  • Newly-diagnosed disease (both transplant-eligible and -ineligible)
Dosage and Administration
Thalidomide is a capsule taken orally, usually once a day at bedtime. The daily dose is tailored to the individual patient and is dependent on each patient's tolerance.

In May 2003, a group of leading myeloma investigators convened in Salamanca, Spain, to discuss the current and future role of thalidomide in the management of myeloma. Based on recently reported results and a review of key clinical trials, the panel of investigators developed general dosing and monitoring recommendations to optimize thalidomide therapy, which are summarized in the box below. However, note that there is not uniform consensus on thalidomide dosing and opinions vary among clinicians.


Dosing and Administration Recommendations for Optimizing Thalidomide Therapy
Thalidomide Dose
  • Start at 100-200 mg/day.*
  • In patients with aggressive disease, including those with high tumor burden and high-risk factors, an initial dose of ≥200 mg/day as part of combination therapy (eg, thalidomide plus dexamethasone) is suggested. †
  • Lower starting doses may be employed in elderly patients and those with other conditions
  • Increase dose by 50-100 mg/day every 1-2 weeks
  • Target therapeutic dose: 200 mg/day by 2 weeks, with further dose escalation as tolerated at physician discretion

Managing Toxicities
  • Administer thalidomide earlier in the evening (7-10 PM) to reduce sedation.
  • Dose reduction may be helpful for symptomatic neuropathy. In more severe cases, temporarily stopping the drug may improve symptoms and allow thalidomide to be reinitiated at a lower dose.

Assessing Response and Continuing Therapy
  • Assess response at 1 month.
  • Continue therapy indefinitely as long as:
    • Response (complete, partial, or minor) or stable disease is maintained
    • Thalidomide-related toxicity is manageable
    • There are no uncontrolled disease-related symptoms
  • In cases of disease progression:
    • Continue thalidomide in combination with dexamethasone and/or other treatments
    • Consider alternative therapy

Stewart KA, Berenson J, Borrello I, Hussein M, Mehta J, Prince HM, Rajkumar SV, Siegel D, Singhal S, Vescio R. Maximizing response to thalidomide therapy in multiple myeloma: panel discussion proceedings. September 2003.

*Lower thalidomide doses (ie, 50 mg/day) are commonly used in clinical practice.
†Some clinicians recommend a maximum dose of 200 mg/day when thalidomide is used as part of combination therapy and 400 mg/day when used alone in order to minimize side effects.

Length of Therapy
The optimal duration of therapy with thalidomide is not known. Patients typically stay on thalidomide for as long as treatment is tolerated until they reach their maximal response. Current recommendations are to assess for response after 1 month of treatment. Any sign of clinical response, including partial response, minor response, disease stabilization, or clinical benefit, indicates a potential benefit from thalidomide therapy. (Stewart et al, 2003)

In most cases, benefit is seen within 1 month but maximal response may not be achieved until 2 to 3 months or longer. The majority of patients who respond to therapy do so within 5 months of treatment and responses may improve with continued treatment. Patients who do not respond by 3 months may benefit by an increased dose of thalidomide or by the addition of dexamethasone. Once a good response has been achieved, the thalidomide dose may be reduced for maintenance therapy.

Discontinuing therapy after only a short period, or because of mild side effects, may fail to provide the full therapeutic benefit of thalidomide. As such, increasing the dose slowly and managing side effects may help patients remain on thalidomide.

Potential Side Effects
The side effects to anticancer therapies are well known, and can limit the effectiveness of therapy, prompting investigators to continue seeking new therapies or combinations that can produce a high response (≥50% reduction in serum M protein) while reducing the incidence and severity of side effects.

The most common side effects observed with use of thalidomide in myeloma include drowsiness or fatigue, constipation, dizziness, dry skin or rash, low white blood cell counts, and peripheral neuropathy (a disorder of the nerves that can result in abnormal or decreased sensation, or burning/tingling in the hands and feet). Drowsiness is one of the most commonly reported side effects of thalidomide therapy. Drowsiness and neuropathy are the most common reasons for discontinuation of the drug.

The side effects of thalidomide appear to be dose related. The table below lists the percentage of patients with refractory or relapsed myeloma who experienced side effects with thalidomide alone at doses ranging from 50 to 800 mg/day as part of various clinical trials. These data were from studies published in 2000 to 2004 and not all side effects were reported in every study. The side effects were highly dose dependent, however, and as doses of thalidomide above 400 mg are less frequently used, the incidences of these side effects are generally decreasing.

Common Side Effects of Thalidomide (50 to 800 mg/day) for Refractory or Relapsed Myeloma (Published clinical studies, 2000- 2004)
Side effect Percentage of patients
Drowsiness/Sedation
6% to 77%
Fatigue
25% to 67%
Constipation
18% to 86%
Dizziness
4% to 28%
Dry skin or rash
3% to 35%
Low white blood cell counts
2% to 26%
Peripheral neuropathy
9% to 24%


Not everyone will experience these side effects, and they can range from mild to severe. However, the incidence of severe toxicities is low. In general, these effects can be minimized or controlled with a reduction in dose or by other means. Most side effects are reversible. If side effects are severe, it may be necessary to reduce the dose, or to stop the drug until the side effects resolve and then restart therapy at a lower dose. The table below lists some of the ways side effects can be managed.

The table below lists some of the ways side effects can be managed.


Management of Thalidomide Side Effects
Side effect Management strategy
Drowsiness
May decrease after several weeks of therapy, but may require schedule or dose adjustment. Can be minimized by taking thalidomide between 7:00 and 10:00 in the evening or by twice-daily dosing. If severe, may be treated with dose reduction +/- temporarily stopping thalidomide. Discontinuation of therapy is not normally required.
Constipation
Managed with adequate fluid intake, high fiber intake, daily use of a stool softener, and laxatives, as required
Dizziness
Patients should sit upright for a few minutes, if they have been lying down, before they stand up. If severe, requires dose adjustment
Dry skin/Rash
Dry skin may be confused with a mild rash, but can be relieved with lotion. Rash can range from mild to severe, and stopping therapy usually brings prompt relief. Itching can be managed with antihistamines or topical steroids. After clinical evaluation to rule out serious skin reactions, thalidomide can be restarted at a lower dose, with close monitoring over the first few doses
Peripheral neuropathy
In cancer patients receiving thalidomide, the appearance of neuropathy may be related to long-term use of the drug and/or previous exposure to large doses of chemotherapy drugs, which also cause neuropathy. Symptoms may resolve if therapy is discontinued when they first appear, but neuropathy is often not reversible.

Mild neuropathy is very common; in the absence of progression, the dose of thalidomide should be kept the same. However, for symptomatic neuropathy, a dose reduction may be helpful. In more severe cases, stopping the drug temporarily may improve symptoms and allow thalidomide to be reinitiated at a lower dose.


If thalidomide is taken during pregnancy, it can cause severe birth defects or death to the unborn baby. Therefore, routine pregnancy testing is required, as well as participation in the System for Thalidomide Education and Prescribing Safety (STEPS™) program. In addition, a consent form must be signed before treatment with thalidomide can begin.

Thalidomide has also been reported to slightly depress the activity of the thyroid gland, and cases of hypothyroidism (underactive thyroid) have been reported. Hypothyroidism can result in symptoms such as a low metabolic rate and lack of energy, and other symptoms that may be similar to those seen when taking thalidomide. For this reason, some physicians recommend that thyroid function be monitored during thalidomide therapy. If needed, thyroid hormone replacement therapy can be used to treat an underactive thyroid.

Uncommonly, thalidomide may lead to a slowing of the heart rate (bradycardia), which may result in fainting episodes. Rarely, a pacemaker may be required in symptomatic patients.
Thalidomide as Part of Combination Therapy
When thalidomide is taken in combination with dexamethasone (thal-dex) several serious side effects have been noted in some patients. One of these side effects is a severe skin disorder known as toxic epidermal necrosis (TEN). TEN is a condition where the skin turns very red and peels off, similar to what you would see with a severe burn. If TEN develops, thalidomide therapy is stopped. Another side effect is deep vein thrombosis (DVT), a condition where a blood clot forms in one of the deep veins in the body, usually in the legs or lower abdomen. Less commonly, pulmonary embolism (a condition where clots dislodge from the leg and travel to the lung) has also been described.

In the Phase III Eastern Cooperative Oncology Group (ECOG) study of thal-dex, 18% of patients receiving the combination developed severe (Grade 3 or higher) DVT (Rajkumar et al. Blood (ASH Annual Meeting Abstracts) 2004 104: Abstract 205) It is recommended that patients at high risk for, or with a history of, DVT receive full-dose anticoagulation therapy as a preventive measure. Low-dose anticoagulation should not be used. Some centers routinely administer anticoagulation therapy to all patients receiving this combination. Patients should also receive education about the risks of the condition and its symptoms and close monitoring. If DVT develops, it is treated with full-dose anticoagulation while thal-dex therapy is continued.

Patients receiving thalidomide in combination with doxorubicin are also at increased risk of developing DVT. Because of increased risk of DVT, the use of thalidomide, dexamethasone, and doxorubicin is not recommended.

A recent report on the use of an oral regimen of thalidomide in conjunction with cyclophosphamide and dexamethasone suggest that the incidence of DVT and neuropathy may be reduced when thalidomide is administered on an intermittent basis. (Dimopoulous et al. Hematol J. 2004;5:112-117.) In this Phase II study, 53 patients with previously treated myeloma received cyclophosphamide (150 mg/m2 every 12 hours on days 1-5), thalidomide (400 mg on days 1-5 and 14-18), and dexamethasone (20 mg/m² on days 1-5 and 14-18). The 28-day cycle was repeated 3 times and responding patients received monthly maintenance treatment with the oral regimen for the first 5 days of each month for up to 2 years or longer. The cumulative incidence of DVT and neuropathy were 4% and 2%, respectively, which is lower than expected when thalidomide is administered on a continuous basis.
Clinical Trials
Celgene is seeking FDA approval for use of thalidomide in patients with relapsed and refractory myeloma as well as early stage disease. Phase III trials in both patient populations have been conducted. On February 23, 2004, the U. S. Food and Drug Administration accepted for review Celgene’s Supplemental New Drug Application (sNDA) seeking to market thalidomide for the treatment of myeloma. Celgene received an approvable letter from the FDA and in May 2005 submitted additional data to support the sNDA for thalidomide. In addition, there are a large number of Phase II studies being conducted at academic centers.

Thalidomide has been investigated in numerous trials as a single-agent or as part of combination therapy with chemotherapy and/or dexamethasone in patients with relapsed and refractory myeloma as well as in newly diagnosed patients. It has also recently been evaluated in patients with asymptomatic disease and as maintenance therapy.

The links below summarize results from recent clinical trial regarding the use of thalidomide in the following instances:
Ongoing Clinical Trials
The chart below lists ongoing Phase II and III thalidomide combination clinical trials.

Note: For the latest trials please visit the new MMRF Clinical Trial Matching and Referral Service


Ongoing Phase II and III Thalidomide Combination Trials
as of July 2005
Relapsed and Refractory Myeloma — Thalidomide in combination with:
Newly diagnosed patients — Thalidomide in combination with:
Smoldering/Indolent Myeloma — Thalidomide in combination with:
As Maintenance — Thalidomide in combination with


For More Information on Clinical Trials:
•  Search the MMRF Clinical Trial Matching and Referral Service
www.celgene.com
1-888-771-0141
908-673-9800 (outside U.S.)

Reviewed by:
James R. Berenson Photo
James R. Berenson, MD
Institute for Myeloma & Bone Cancer Research
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