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Module 2: First-Line Treatment of Multiple Myeloma

Section 3: Thalidomide

View Topic Summary by Seema Singhal, MD

Dr. Seema Singhal: Thalidomide has become one of the promising drugs for the treatment of myeloma. Its role in the treatment of relapsed and refractory disease has been well established, with 2 to 3 years of follow-up with patients who have been receiving it for that purpose. However, for the primary treatment of newly diagnosed myeloma, the role of thalidomide is still a work in progress.

We have used thalidomide as a single agent and in combination with dexamethasone and with other agents such as clarithromycin and dexamethasone. [View Reference] All of these have reportly positive results, but we do not have long-term follow-up.

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Dr. Singhal: I must strike a note of caution here: We do not know the impact of thalidomide on stem cell collection and on subsequent autologous transplant. Therefore, patients who wish to take thalidomide as an alternative to high-dose therapy also should be advised that we do not know the long-term effects of thalidomide as an alternative to transplantation.

Thalidomide has well-known side effects, including drowsiness, peripheral nerve damage, constipation, and skin rashes; different patients have different degrees of tolerance to this drug. The exact dose of this drug has not been well established. Thalidomide is given orally, and the starting dose conventionally ranges between 200 mg and 400 mg per day, although it has been administered in doses as low as 50 mg a day with excellent responses. (Regression of Plasmacytoma Lesions After Thalidomide) The maximal dose that a patient should receive has not been established. The current goal of therapy is to take the patient to the maximal dose tolerated and maintain that level until tolerance declines or the disease progresses. [View Reference]

Thalidomide is usually given as a single dose at night. One of its most common side effects is drowsiness. It is hoped that the patient will sleep through this particular effect and be able to carry on normal activities the next day. Most clinicians recommend giving the drug on a daily basis, but in patients who have tolerance problems, a regimen of 5 days per week or every other day may be appropriate. Dr. Durie has mentioned that he has a patient who receives a dose once per week and is doing well on that regimen. As long as the disease is closely monitored, dosage and dosing frequency can be flexible components of the treatment regimen.

The average time to response with thalidomide in the relapsed refractory setting is 4 weeks to 4 months. [View Reference] Almost 99% of the patients who are going to respond show some evidence of response by around 4 months. If the disease progresses or the patient cannot tolerate the drug, treatment can be discontinued. However, a patient with gradually progressive disease or who has stable disease should undergo an adequate trial of therapy before other agents are considered.

Thalidomide, although it has been used widely for the treatment of myeloma, is still not approved specifically for the treatment of myeloma. Therefore, its use for the treatment of this particular condition should be considered an off-label use. It currently is approved only for the treatment of cutaneous reactions in leprosy.

There has been much publicity about the effectiveness of thalidomide for the treatment of myeloma. Consequently, there is an overwhelming demand from patients and a need for the education of patients as well as physicians about the role of this drug in the treatment of myeloma.

It is well known that in the 1950s, thalidomide was used in women who were pregnant. Given for the treatment of nausea and vomiting in the first trimester of pregnancy, thalidomide caused severe teratogenic effects, particularly the well-described syndrome of limb defects. Therefore, elaborate precautions are in place to ensure that similar tragedies do not occur, including mandatory pregnancy tests before receiving the drug and patient education that this drug can bring about irreversible harm to a fetus.

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Dr. Singhal:
The exact mechanism of action of this drug has not been established. (Potential Mechanisms of Action) It was initially thought that it was going to act through the antiangiogenesis mechanism, but a study of patients who had excellent responses to this drug did not show a corresponding decrease in the angiogenesis in the marrow, and, hence, we were not able to conclude that this is the way the drug acts. [View Reference]

The drug has multiple actions at a cellular and at a molecular level. (Potential Mechanisms of Action) It affects cytokines such as decreasing interleukin-6 levels. It affects other cytokines, affects the T cell and TH1/TH2 response, and, hence, it is possible that any one or more of these actions may be acting together or singly to bring about the response in this disease. Thalidomide also affects adhesion molecule expression.

There is a newer thalidomide analog, called Revimid"! (CC-5013), which is currently in phase 1 trials. (IMiD cc - 5013) Revimid"! appears to have all the efficacy and more of thalidomide without the side effects, so everybody is looking forward to a phase 2 trial of this drug, which should be initiated at the end of this year or early next year.

Use of Thalidomide For Initial Therapy: Faculty Comments

Dr. Robert Kyle: The efficacy of thalidomide for initial therapy depends on the patient. To assure that treatment with thalidomide will not interfere with future collection of stem cells, we collect before starting therapy.

Dr. Seema Singhal:
Are you saying that you stop thalidomide during collection of stem cells?

Dr. Robert Kyle: Yes.

Dr. William Bensinger: How do you collect stem cells? With what mobilization?

Dr. Robert Kyle: We use granulocyte colony-stimulating factor (G-CSF) plus cyclophosphamide.

Dr. William Bensinger: And you have not had any trouble getting cells?

Dr. Robert Kyle: No, and they have engrafted pretty well. We have treated approximately 50 patients with thalidomide in a dosage of 200 mg daily plus dexamethasone as the initial therapy. We have found a response rate of about 65% in these patients, which is at least as good as with VAD. The advantages, of course, are that the dexamethasone and the thalidomide are given orally and one does not need an indwelling catheter.

Dr. William Bensinger: Dr. Kyle, what is your complete response rate in that group?

Dr. Robert Kyle: I cannot provide a precise figure, but it is low.

Dr. William Bensinger: These are mainly partial?

Dr. Robert Kyle: These are partial response. A partial response is characterized as a 50% or greater reduction in M-protein in the serum and urine.

Dr. William Bensinger: Do you think it is time for a phase 3 trial with a direct comparison with VAD?

Dr. Seema Singhal: Or with dexamethasone alone?

Dr. Robert Kyle: Yes.

Dr. Brian Durie: Yes, for dexamethasone alone.

Dr. Robert Kyle: We have proposed a study comparing thalidomide and dexamethasone with dexamethasone for initial therapy.

Dr. Brian Durie: This type of study is terribly important. It could enable us to avoid the potential complications with VAD, which does not seem to confer much additional benefit. We want to avoid the neurotoxicity of vincristine and the infection and blood clotting complications associated with using a catheter or doxorubicin. This is an important step forward: establishing that thalidomide plus dexamethasone could have a magnitude of benefit that could help us to reach the point of stem cell harvesting.

Dr. Robert Kyle: We have had no difficulty in getting an adequate number of hematopoietic stem cells after three or four courses of thalidomide plus dexamethasone.

Dr. Brian Durie: One concern about the combination of thalidomide plus dexamethasone is the thromboembolic complications. What has been your experience with that?

Dr. Robert Kyle: We have had very little trouble with either deep vein thrombosis or pulmonary embolism in these patients. It also is important to point out that the dosage of thalidomide is not increased above 200 mg.

Dr. Brian Durie: Have you used, or do you believe there is, any type of measure that can help prevent thromboembolic complications?

Dr. Robert Kyle: We have not used prophylactic anticoagulants. Some groups do use small doses of warfarin for these patients.

Dr. William Bensinger: Dr. Durie, you were one of the first (or the first) to describe the potential value of clarithromycin. Do you think clarithromycin has an additive role in combination with thalidomide and prednisone or dexamethasone?

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Dr. Brian Durie: There is documentation that thalidomide works, that it works even better with dexamethasone, and that it can work even better still with clarithromycin. The data from Dr. Mort Coleman at Cornell in New York clearly indicate a high response rate with the three-drug combination. It is difficult to compare Coleman s results with the results of thalidomide plus dexamethasone; that is, Coleman has reported an 83% response rate with clarithromycin plus thalidomide plus dexamethasone. [View Reference] Is that better than 77% with thalidomide plus dexamethasone? I think the evidence of synergism is sufficient to justify a trial and a careful study.

The concern about the three-drug combination is the additional toxicity, whether or not there is significant enhancement of thromboembolic risks, and whether there could be possible additional important risks related to infection or other problems.

An important aspect is the dose of thalidomide, which makes a huge impact in terms of the potential side effects, and which could be further exacerbated with combination therapy. Three years ago, I began a phase 2 evaluation of dose of thalidomide in which I initiate a 50-mg dose and only escalate the dose for patients who fail to respond. Of the first 36 patients who were treated in a relapse setting, the response rate to thalidomide alone was 25% to 30%. Of the first group, three patients responded with 50 mg alone. That is an extremely important finding because the side effects associated with that level of dose are considerably fewer than with higher dosage. In this phase 2 study of 36 patients, 80% of the patients who responded required 200 mg or less. Therefore, I believe we need a much closer evaluation of the dose and the schedule. We definitely need comparative studies to assess the efficacy and the toxicity at different dose levels.

One of the problems with thalidomide is that it does not yet have approval from the FDA. It is very disappointing that the kinds of trials that could provide the data necessary for approval by the FDA have not been conducted.

Dr. Robert Kyle: I agree.

Dr. Brian Durie: I have just started to use the thalidomide safety program. It requires a combination of pregnancy tests and commitments from patients to use specific forms of contraception. The program is not easy to implement.

Dr. Seema Singhal: What about thalidomide in patients with dialysis-dependent renal failure?

Dr. Brian Durie: Thalidomide can be used safely in patients with renal failure.

Dr. Seema Singhal: Could it be a drug of choice? (The Place of Thalidomide)

Dr. Brian Durie: Yes, because thalidomide is predominantly metabolized in the tissues, it is safe to use in patients with renal insufficiency and even dialysis-dependent renal failure. I have one patient with complete renal failure who is on dialysis and has had an excellent remission with thalidomide 50 mg daily. This has been extremely well tolerated, and his hemoglobin has improved from 5 grams to 14 grams over a period of a couple of months.

Dr. David Roodman: Is the patient on erythropoietin as well?

Dr. Brian Durie: He has discontinued erythropoietin. Another advantage of thalidomide is that, frequently, patients who have been erythropoietin dependent can finally discontinue erythropoietin.

Dr. Seema Singhal: Do you give the drug immediately after dialysis in these patients every day?

Dr. Brian Durie: Yes. This particular patient takes it in the evening on a regular basis including the days on which he receives dialysis.

Dr. Robert Kyle: Have you observed any improvement in renal function in these patients?

Dr. Brian Durie: I have not. This particular patient has not had any improvement in renal function, nor have I observed such improvement in my other patients.

Faculty Opinions About Thalidomide

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Entire Faculty Discusses Thalidomide:

Dr. David Roodman: It is unclear whether thalidomide should be used as initial therapy outside a trial.Use of thalidomide as up-front therapy in patients who are not going to have immediate transplants is under study; we are awaiting results of those trials before making those types of decisions. For patients who have the potential of getting transplanted later, I would withhold alkylating therapy and consider thalidomide versus dexamethasone versus some other stem-cell sparing therapy as initial therapy.

Dr. William Bensinger: I actually have nothing to add to that statement. I agree completely.

Dr. Seema Singhal: I agree as well. I think that dexamethasone and thalidomide as two separate drugs can be considered as preferable therapeutic alternatives to melphalan and prednisone for a patient who does not want to or cannot have a transplant.

Dr. Brian Durie: I think that I agree. When a new drug is available, and exciting new results are available, timing is extremely important in terms of completing the clinical trial before the evidence of efficacy is so striking that it would be very difficult to implement a clinical trial. Therefore, there is some urgency in going ahead quickly to initiate clinical trials to evaluate the efficacy of thalidomide as a front-line therapy alone or as part of some combination regimen.

Dr. Robert Kyle: I agree.

Overview of Treatment Options | Transplants | VELCADE® |Thalidomide | Radiotherapy, Bisphosphonates, and Other Supportive Therapies for Multiple Myeloma

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