Thalomid is an immunomodulatory agent (a drug that affects the immune system) that was originally developed in the 1950s as a treatment for insomnia and morning sickness. Further research on Thalomid showed it to be highly active against myeloma. When the findings of that research were published in 1999, Thalomid was considered to be the first new agent with major activity against myeloma in more than 30 years. Thalomid is a brand of thalidomide manufactured by Celegene Corporation (www.celgene.com).

To ensure that Thalomid is used safely, Celgene has developed a unique restricted distribution program called S.T.E.P.S. (System for Thalomid Education and Prescribing Safety). Individuals eligible to receive Thalomid must be registered in S.T.E.P.S., and the doctor writing the prescription and the pharmacy filling it must also participate in the program. This program is designed to minimize the chance of fetal exposure to Thalomid.

Thalomid is usually used in combination with another drug or drugs. One combination, Thalomid and dexamethasone (dex), is approved by the US Food and Drug Administration (FDA) for the treatment of newly diagnosed multiple myeloma. The National Comprehensive Cancer Network (NCCN), which develops guidelines for cancer treatments based on evidence from clinical trials, suggests that Thalomid may also be an option for some individuals with relapased/refractory disease or for maintenance therapy (treatment that is started after remission in order to reduce the risk for relapse).

Thalomid may also be used in combination with two other drugs, melphalan and prednisone (MP). This combination, known as MPT, is approved in Europe for the treatment of newly diagnosed disease. The combination of Thalomid and dex (known as Thal-dex) and MPT have been found to be more effective than either Thalomid, dexamethasone, or MP alone.

Thalomid is not FDA approved for use as a single agent. However, it may be an option for individuals who have relapse after transplantation and those who cannot tolerate corticosteroids (such as dexamethasone).

Thalomid, alone and in combination with the corticosteroid prednisone, is recommended by NCCN as an option for maintenance therapy.

The use of Thalomid must be considered carefully for each individual. Thalomid is associated with an increased risk of side effects, and this risk must be balanced with the potential benefit in terms of disease response. Your doctor will determine if Thalomid is the right treatment choice for you.

Thalomid increases the immune system's response against myeloma cells, but its precise mechanism of action is unknown. The drug appears to have multiple actions, including the ability to inhibit the growth and survival of myeloma cells in a variety of ways.

Thalomid is taken orally and is available in 50 mg, 100 mg, 150 mg, and 200 mg dose capsules. The drug is usually given in combination with 40 mg of dexamethasone in 28-day treatment cycles. For best results, Thalomid should be taken once daily with water, preferably at bedtime, and at least 1 hour after the evening meal.

According to the manufacturer's label, the dose of Thalomid is 200 mg. However, your doctor may choose to start treatment at a lower dose to help reduce the likelihood of side effects. When the starting dose is lower, it may be gradually increased by 50 mg or 100 mg to achieve maximum effectiveness, and patients are monitored closely to ensure that side effects remain manageable.

The usual (standard) dose of dexamethasone is 40 mg, taken on days 1-4, 9-12, and 17-20 of each month for the first four months. Starting at month 5, dexamethasone is taken only on days 1-4 of each month. LEARN MORE »

Studies of dexamethasone in combination with Revlimid^® (lenalidomide), a drug chemically related to Thalomid, have shown that lower doses of dexamethasone may be more effective than the so-called standard dose. With a low-dose schedule, dexamethasone (40 mg) is taken one day a week. Based on these findings, the combination of Thalomid and low-dose dexamethasone is now being investigated.

The optimal length of treatment with Thalomid has not been determined. Individuals with multiple myeloma typically continue to take Thalomid as long as the side effects remain manageable and disease does not progress.

Your doctor will evaluate the response to treatment with Thalomid after about 1 month. Some sign of benefit may be seen within this time, but it is usually 2-3 months before response occurs. Because a response can often improve with continued treatment, discontinuing Thalomid therapy after a short period of time may fail to provide the full therapeutic benefit of the drug. Increasing the dose slowly and managing side effects may help individuals continue treatment with Thalomid. Once a good response has been achieved, your doctor may reduce the Thalomid dose for maintenance therapy.

If you do not have a response after 3 months of treatment, your doctor may increase the dose of Thalomid. Another alternative is to add another drug to your treatment regimen if you have no response to Thalomid.

Clinical studies of treatment with Thal-dex (with a dose of Thalomid of 50 to 200 mg per day) have shown that several side effects may occur. The side effects associated with Thalomid can range from mild to severe, and not everyone will experience them. It is important to note that the frequency of side effects usually increases as the dose of Thalomid is increased. The incidence of severe side effects is low, and severe effects appear to be related to higher doses of the drug. Side effects also occur when treatment consists of dexamethasone alone. LEARN MORE »

Fatigue and peripheral neuropathy are usually the most common reasons for discontinuing treatment with Thalomid.

Side effects can usually be minimized or controlled by reducing the dose of Thalomid or by using an appropriate strategy to manage a particular side effect. LEARN MORE »

The most serious side effect associated with Thalomid is its effect on a fetus. If Thalomid is taken immediately prior to conception or at any time during pregnancy, the drug is associated with serious birth defects, including malformed limbs, gastrointestinal disorders, and fetal death. Therefore, routine pregnancy testing and participation in the S.T.E.P.S. program are required. Since the establishment of the S.T.E.P.S. program, no pregnancy has ever been reported among women taking Thalomid.

Seizures (including grand mal seizures) have been reported in association with Thalomid. However, these seizures occurred in individuals who were likely to have other conditions that could cause seizure activity. Because of this, it is unclear whether Thalomid causes seizures directly or triggers an existing predisposition to seizures. An FDA warning recommends that individuals with a history of seizure or risk factors for seizures should be monitored carefully when treated with Thalomid.

Deep-vein thrombosis (DVT), a blood clot that develops and obstructs blood flow in one of the large veins in the legs (or less commonly, the arms), is a side effect that can be serious if not recognized and treated. Signs and symptoms of DVT include an area on one limb that is warm, painful, or tender to the touch; is reddened or discolored; or feels hardened. If you have any of these symptoms, you should contact your doctor immediately.

The prescribing information for Thalomid notes that, in one trial, DVT developed in 22.5% of individuals treated with Thal-dex and in 4.9% of individuals treated with dexamethasone alone. The risk of DVT is also higher when Thalomid is used with some chemotherapy agents, such as doxorubicin. However, these rates of DVT have decreased substantially as prophylactic treatment with an anticoagulant agent has become routine.

Thalomid-based treatment has been shown to be effective in a wide range of individuals with multiple myeloma, including the following.

• Older individuals (65 years or older) as well as younger individuals
  • MPT is considered to be the standard treatment option for older patients, as three studies have demonstrated its effectiveness compared with MP alone or high-dose chemotherapy and stem cell transplantation
• Patients who have had high-dose chemotherapy and stem cell transplantation
  • Two studies have shown that maintenance therapy with Thalomid after transplantation results in better overall survival
• Patients with reduced kidney function (renal impairment)
  • Studies have shown that patients with renal impairment can receive the same dose as patients with normal kidney function without risk of adverse events

• Pregnant or nursing women (male and female individuals of childbearing potential must be willing to take extreme precautions to avoid pregnancy, including registering with the S.T.E.P.S. program)
• Patients with a history of moderate peripheral neuropathy or of DVT, because of the increased risk of these conditions as a side effect

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Adding Thalomid to one or more other drugs to treat newly diagnosed/untreated multiple myeloma has improved response rates and survival time. The combination of Thalomid and another drug or drugs has been effective for both patients who are to have stem cell transplantation and those who are not.

The most common Thalomid-based combination used for induction therapy is melphalan, prednisone, and Thalomid (MPT). Thalomid and dexamethasone (Thal-dex) is also an option for individuals with newly diagnosed myeloma, regardless of their eligibility for transplantation.

Three studies have shown that MPT leads to better outcomes than MP alone. In a study of 447 patients, MPT led to a higher overall survival rate (52%) than MP alone (33%); the rate of partial response was 76% for MPT compared with 35% for MP alone. Two other studies also demonstrated higher response rates among patients treated with MPT. VIEW GRAPH »

Two large studies have shown Thal-dex to be more effective than dexamethasone alone. In a study of 207 patients, the overall response rate was higher for Thal-dex (63%) than for dexamethasone alone (41%). A larger study showed similar rates, as well as a longer 3-year survival rate (80% compared with 64%) and a longer time to disease progression (23 months compared with 7 months). VIEW GRAPH »

Thal-dex has also been compared with the chemotherapy regimen of vincristine, doxorubicin, and dexamethasone in a study of 200 patients. The overall response rate was higher for patients treated with Thal-dex (76%) than for patients treated with chemotherapy (52%).

MPT and Thal-dex are the two most commonly used combinations involving Thalomid, but other combinations have also been evaluated in clinical trials. Thal-dex plus Velcade (bortezomib), was found to be highly effective in a small trial, leading to a response in 33 of 38 patients, with complete remission occurring in six patients.

In a larger study, the combination of Thal-dex plus bortezomib was evaluated in 255 patients who were scheduled to have stem cell transplantation. Thal-dex plus bortezomib led to a complete response (before transplantation) of 36% compared with 9% for Thal-dex alone. The rate of complete response after transplantation was 57% for Thal-dex plus bortezomib and 28% for Thal-dex alone.

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No ideal therapy has been identified or approved by the FDA for patients who do not have a response to standard chemotherapy and/or transplantation. Early studies showed that single-agent Thalomid was effective for relapsed/refractory myeloma. However, the dose needed to produce response was high, leading to a greater likelihood of side effects. Thus, the focus of clinical trials became the use of lower doses of Thalomid in combination with other drugs.

Thal-dex has been shown to be effective for relapsed/refractory myeloma, producing a complete response or near-complete response in some patients who have not had a response to previous treatment. For example, Thal-dex was compared with several conventional chemotherapy options in a study of 240 patients who had been previously treated for myeloma. Thal-dex was most beneficial for patients who had received one prior treatment regimen; among those patients, the estimated 3-year overall survival rate was 60% for patients who received Thal-dex and 26% for patients who received conventional chemotherapy. The rate of near-complete response was 19% for patients treated with Thal-dex compared with 0% for patients treated with conventional chemotherapy. The corresponding rates of partial response were 28% and 16%.

In addition, Thal-dex plus pegylated liposomal doxorubicin (ThaDD) was more effective than Thal-dex alone in a small study of 47 patients with relapsed/refractory disease. The overall response rate was 92% for patients treated with ThaDD and 64% for patients treated with Thal-dex.

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The use of Thalomid for maintenance therapy following stem cell transplantation or conventional chemotherapy is being investigated in several studies. Thalomid alone or in combination with dexamethasone or prednisone has maintained progression-free survival and has improved overall survival. However, the long-term use of Thalomid, especially at higher doses, may cause side effects that necessitate discontinuation of treatment. A dose of 200 mg or less has been found to be tolerable as maintenance therapy. Researchers continue to evaluate various doses of Thalomid and combinations to determine the dose that is effective while not provoking side effects that limit its benefit.

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