What is Thalomid?

Thalomid® is an oral cancer drug 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 part of a class of drugs called Immunomodulatory drugs or IMiDs®. IMiDs work against cancer cells partly by impacting the functioning of the immune system.

Thalomid is a brand of thalidomide manufactured by The Celgene Corporation.

How is Thalomid used in multiple myeloma?

Thalomid® (thalidomide, Celgene) is used in combination with another drug or drugs and is used in several treatment settings. Such settings include newly diagnosed disease (both for individuals who are candidates for stem cell transplantation and for those who are not candidates), relapsed/refractory disease, and maintenance therapy (treatment that is started after remission in order to reduce the risk for relapse).

The combination of Thalomid and dexamethasone (dex), known as Thal-dex, is FDA approved 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 can also be used in combination with melphalan and prednisone (MP) to treat newly diagnosed disease in patients who are not candidates for stem cell transplantation. This combination is known as MPT.

Other combinations recommended as treatment options include Thal-dex with Velcade® (bortezomib, Takeda Oncology) for treatment before transplantation and Thalomid alone or in combination with Velcade or prednisone, a corticosteroid, for maintenance therapy.

How does Thalomid work?

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.

Recently it has been shown in studies the Multiple Myeloma Research Consortium (MMRC) helped to fund that Thalomid and other IMiDs bind a protein in myeloma cells called cereblon. This binding triggers myeloma cell death. In some studies higher levels of cereblon are associated with better outcomes after treatment.

What types of individuals benefit from Thalomid?

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

  • Older individuals (65 years or older) as well as younger individuals
  • 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

Patients who should not take Thalomid include:

  • 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 Thalomid REMS™ program)
  • Patients with a history of moderate peripheral neuropathy or of blood clots (known as deep vein thrombosis or DVT) because of the increased risk of these conditions as a side effect

How is Thalomid administered?

Thalomid® (thalidomide, Celgene) is administered orally and is available in 50 mg, 100 mg, 150 mg, and 200 mg dose capsules. According to the manufacturer’s label, the dose of Thalomid is 200 mg per day. 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. For best results, Thalomid should be taken once daily with water, preferably at bedtime, and at least 1 hour after the evening meal.

When used in combination with dexamethasone, Thalomid is taken in 28-day treatment cycles. 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 4 months. Starting at month 5, dexamethasone is taken only on days 1-4 of each month.

Studies of dexamethasone in combination with Revlimid® (lenalidomide, Celgene), 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 1 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 or may add another drug to your treatment regimen.

What are Thalomid side effects?

Thalomid® (thalidomide, Celgene) side effects have been observed in clinical studies. 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. You should also know that side effects may also occur when treatment consists of dexamethasone alone.

Fatigue and peripheral neuropathy, a disorder of the nerves that can result in abnormal or decreased sensation or burning/tingling in the hands and feet, are usually the most common reasons for discontinuing treatment with Thalomid. Other side effects seen in clinical studies of Thal-dex include:

  • Low blood calcium levels (hypocalcemia)
  • Swelling (edema)
  • Constipation
  • Difficulty breathing
  • Muscle weakness
  • Low white blood cell and neutrophil counts
  • Rash and skin reactions resulting in blistering or peeling

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.

Serious side effects

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. To ensure that Thalomid is used safely, Celgene has developed a unique restricted distribution program called Thalomid REMS™. Individuals eligible to receive Thalomid must be registered in the program.

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 of Thalomid 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 risk of DVT is higher when Thalomid is used with dexamethasone and some chemotherapy agents, such as doxorubicin. However, patients receiving Thalomid will also receive preventative treatment with a blood thinner (anticoagulant). The choice of agent will be based on a patient’s individual risk factors for blood clots and may include aspirin, a low-molecular weight heparin, or warfarin.

Other Thalomid side effects that can be severe at times include peripheral neuropathy, dizziness and sleepiness, heart attack and stroke, increased heart rate, and skin reactions resulting in blistering or peeling.

What have Thalomid clinical studies shown?

Is Thalomid effective in previously untreated myeloma?

Thalomid® (thalidomide, Celgene) clinical studies have shown that adding Thalomid to one or more other drugs to treat newly diagnosed/untreated multiple myeloma has improved response rates and survival time. Combination therapies that include Thalomidhave been shown to be effective for both patients who are to have stem cell transplantation and those who are not.

Three studies have shown that the combination of Thalomid, melphalan, and prednisone (MPT) leads to better outcomes than MP alone in patients not eligible for stem cell transplantation. 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. However, MPT is now being used less frequently for the treatment of myeloma.

Two large studies in patients not eligible for stem cell transplantation 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).

Several studies have shown the combination of Thal-dex plus Velcade® (bortezomib, Takeda Oncology) to be more effective than Thal-dex when given prior to stem cell transplantation. For example, in one study involving 255 patients, 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.

Is Thalomid effective for maintenance therapy?

The use of Thalomid for maintenance therapy following stem cell transplantation or conventional chemotherapy has been 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.

Is Thalomid effective for relapsed/refractory myeloma?

Thalomid is used alone and in combination with a variety of other agents in the treatment of relapsed/refractory myeloma. In clinical studies in previously treated myeloma, Thal-dex has been shown to provide higher response rates compared with Thalomid alone. However, Thalomid alone may be an option for patients who cannot tolerate steroids. Combination therapy that includes Thal-dex and the chemotherapy agents cisplatin, doxorubicin, cyclophosphamide, and etoposide (referred to as DT-PACE), was shown to be an effective treatment for progressive disease. The combination of Thal-dex and Velcade was found to be more effective than Thal-dex in the treatment of patients who had disease progression following a stem cell transplant.