Relapsed/Refractory Patients:

Treatment Options - Thalomid


Thalomid® (thalidomide)

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OVERVIEW

What is Thalomid (thalidomide)?

Thalidomide 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 the drug showed it to be highly active against myeloma. When the findings of that research were published in 1999, thalidomide 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 Celgene 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.

How is Thalomid used for multiple myeloma?

Thalomid is usually used in combination with another drug or drugs and is used to treat relapsed/refractory disease as well as newly diagnosed disease and is also used for maintenance therapy. Thalomid alone or with dexamethasone (Thal-dex) are suggested options for relapsed/refractory disease.

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. You and your doctor will determine if Thalomid is the right treatment choice for you.

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.  

How is Thalomid taken?

Thalomid is taken 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. 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. LEARN MORE »

A lower dose of dexamethasone (40 mg once per week) may be more effective than the standard dose (described above), according to studies of dexamethasone in combination with Revlimid® (lenalidomide), a drug chemically related to Thalomid.

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 or decreasing the dose 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.

What are the possible side effects with 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. You should also know that side effects may 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. LEARN MORE »

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 »

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. 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 preventative treatment with a blood thinner agent has become routine. In a recent study, the rate of DVT ranged from 5% to 8%, depending on which blood thinner agent was used for preventative treatment.

 IMPORTANT SAFETY INFORMATION: Thalomid and Deep-Vein Thrombosis

What is deep-vein thrombosis (DVT)?

DVT is a blood clot that forms in a deep vein in an extremity, usually the calf. The clot can block blood flow and if the clot breaks off the vein, it can travel through the bloodstream to another area of the body, where it can cause more severe problems. Thus, it is important to identify DVT as early as possible. You should tell your doctor immediately if you have any of the following symptoms with your legs (or arms):

  • Warm, painful, or tender area
  • Reddened or discolored area
  • Hardened area

You should also contact your doctor if you have difficulty breathing or chest pain. These symptoms may indicate that a clot has traveled to the lung (known as a pulmonary embolism).

The risk of DVT has been reported to be higher for individuals with myeloma treated with Thalomid than for individuals treated with other drugs. In addition, the risk is even greater when Thalomid is used in combination with dexamethasone or certain chemotherapy drugs (such as doxorubicin). DVT most often occurs within the first 6 months after the start of treatment.

The use of an anticoagulant agent (a drug that thins the blood to prevent the formation of blood clots) has substantially reduced the occurrence of DVT among individuals treated with Thalomid for myeloma, and it is recommended that an anticoagulant agent be used preventively for these individuals.

Anticoagulant agents include warfarin (Coumadin; Bristol-Myers Squibb), low-molecular-weight heparin, and aspirin. Immobility, either through prolonged bedrest or sitting for a long period of time (such as on a long plane or car trip), also increases the risk of DVT. Individuals who take Thalomid should avoid long periods of immobility.

Some individuals may be at greater risk for DVT (aside from the risk associated with Thalomid). Risk factors include

  • Personal or family history of DVT
  • Recent surgery (particularly hip, knee, pelvic, and some gynecologic procedures)
  • Fractures
  • Pacemakers or a catheter in a major vein (used to give some types of anticancer drugs)
  • Pregnancy or childbirth within the past 6 months
  • Horomone-replacement therapy or birth control pills
  • Older age
  • Overweight
  • History of smoking



What types of individuals can take Thalomid?

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
  • 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 S.T.E.P.S. program)
  • Patients with a history of moderate peripheral neuropathy or of DVT, because of worsening of these conditions as a side effect

What studies have proven that Thalomid—alone or in combination—is effective for the treatment of relapsed/refractory myeloma?

No ideal therapy has been identified or approved by the FDA for individuals who do not have a response to primary treatment. Some studies have shown that Thalomid alone is effective for relapsed/refractory myeloma.

In the OPTIMUM study, reported in 2009, Thalomid alone was used to treat 499 patients in whom myeloma had progressed after one to three previous treatment regimens. Three daily doses of Thalomid (100 mg, 200 mg, and 400 mg) were compared with dexamethasone (40 mg) alone. All three doses of Thalomid achieved better outcomes than dexamethasone alone, with longer time to tumor progression, slightly better 1-year survival, and a longer duration of response with some doses.  LEARN MORE »

Side effects must be considered when using Thalomid alone, as they become more common as the dose of the drug increases. Side effects occurred in approximately 60% of patients treated with 400 mg of Thalomid in the OPTIMUM study; this compared with 38% of patients treated with 200 mg and 32% of patients treated with 100 mg.

To help reduce the risk of side effects, researchers have evaluated using lower doses of Thalomid in combination with another drug or drugs. One combination—Thal-dex—has led to a complete response or near-complete response in some individuals who did not have 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%.

To find a clinical trial, call 1-866-603-MMCT (-6628) or click here to go to the MMRF Patient Navigator Program.


For more information on Thalomid, visit www.Thalomid.com

Reviewed by:
Sundar Jagannath, MD  
Chief, Multiple Myeloma Program and Bone Marrow
and Stem Cell Transplantation Program
St. Vincent’s Comprehensive Cancer Center
New York, NY