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Maintenance Therapy

Module 3: Post-Treatment Maintenance, Relapsed or Refractory Disease, and Other Issues Related to Multiple Myeloma

Section 1: Maintenance Therapy

What is considered to be the best maintenance therapy?

Dr. Brian Durie: The role of maintenance therapy in multiple myeloma is one of the most difficult issues that physicians address. Over the years, a number of different maintenance strategies have been evaluated without clear benefit for one therapy versus another or, actually, any clear benefit of any specific therapy in terms of prolonging remission or overall survival.

Recently, a study by the Southwest Oncology Group (SWOG) noted that patients receiving prednisone at a starting dose of 50 mg three times a week had excellent remission duration and survival, indicating that this could be a good maintenance strategy. [View Reference] The use of prednisone in this fashion has to be assessed in terms of efficacy and the short- and long-term side effects. However, in terms of all the options that have been tried or are currently available, this use of prednisone seems to be the simplest and perhaps the most widely accepted one.

Dr. William Bensinger: Interferon is one of the more controversial agents used for maintenance therapy. In the 1980s, Franco Mandelli published results suggesting that using interferon could prolong the disease-free interval for patients with multiple myeloma. [View Reference] Subsequent studies have failed to confirm this effect, although not all the studies have been negative. [View Reference] It is difficult to explain the confounding effects of interferon in these various studies.

I think it is important to point out that there is probably a subset of patients with multiple myeloma who have a particular cell type, for example, patients with IgA myeloma who may be more likely to respond positively to interferon treatment. For those patients, maintenance with interferon may be truly beneficial.

Interferon is frequently associated with side effects including myalgias, flu-like syndrome, a general decrease in energy level, and an increase in fatigue. For patients who can tolerate interferon and maintain a good response, I think that it may be an appropriate maintenance option. However, I believe that all of these drugs should be compared in prospective studies.

Dr. David Roodman: Interferon treatment is, as has been stated, very controversial. It is expensive; it has significant side effects; and I believe it has not yet been proven to prolong either remission or survival. Therefore, our practice has been not to put patients on interferon. I agree there may be a subset of patients who will respond to interferon and benefit from treatment, but at this time it is very difficult to identify that subgroup of patients. It could require treating a large group of patients to identify that subset of patients who might benefit. For us, the cost effectiveness of interferon has been questionable, although other centers have found interferon to be a viable maintenance therapy.

Dr. William Bensinger: Although I do not have a strong disagreement with your comments, I would point out that a trial of interferon is generally low risk. If patients do not tolerate the drug after a few weeks at the appropriate dose, the drug can be discontinued, and the symptoms usually resolve fairly rapidly. And so it is very easy to find out whether a patient is going to tolerate the drug and whether it is worth pursuing a longer maintenance interval.

Dr. Robert Kyle: I think that we should discuss the possibility of alfa-2 interferon therapy with the patient. There are some patients who feel very uncomfortable in discontinuing therapy and simply observing the situation after obtaining a response. However, there are patients who are very anxious to complete their chemotherapy and then take nothing afterward.

If the patient is interested in continued therapy, I think that it is very reasonable to use alfa-2 interferon, but it is important to reduce the dosage if the patient has side effects. We must be careful not to reduce the quality of life of patients during their period of response.

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Dr. Robert Kyle: In a meta-analysis, the Oxford Myeloma Trialists Group demonstrated that the response duration was prolonged in patients who had been randomized to alfa-2 interferon when compared with no therapy. In addition, there was also a modest prolongation of survival in these patients. [View Reference]

Thalidomide is a very interesting option for maintenance therapy. However, there are no data to indicate that thalidomide will prolong the patient s response state. I think that we need a prospective study randomizing patients to low-dose thalidomide, alfa-2 interferon, corticosteroids, or to no therapy following response to an autologous stem cell transplant.

Dr. Brian Durie: Another type of maintenance therapy that has been evaluated extensively over the years is the use of vaccines. The major type of vaccine is an idiotypic vaccine: a vaccine directed specifically against the myeloma idiotype. Several approaches to that have been made using protein-based vaccines and, more recently, DNA vaccine approaches.

The problem thus far is that there is really no evidence of clinical benefit. [View Reference] Several studies have shown enhanced idiotypic immune responses following vaccination. However, it has been difficult to sustain these responses, and it has been particularly difficult to show that these vaccines have had an impact on patients duration of remission or survival. [View Reference]

A critical problem underlying this whole range of strategies is whether or not it is possible to trigger an adequate idiotypic immune response without better understanding the reasons for the suppression in the first place.

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Dr. Brian Durie: Because maintenance therapy thus far has failed to show decisive benefit, a critical issue, from the patient s standpoint, is to balance the pros and cons of maintenance therapy with close monitoring alone with a view to initiating treatment for relapse when this might become appropriate. And so one has to balance the potential side effects of ongoing maintenance such as prednisone, alfa interferon, or thalidomide, if that were to be evaluated in a trial to evaluate the benefits and side effects of those therapies versus the risks of problems that might emerge with close monitoring and initiating treatment for relapse at the earliest necessary time. [View Reference]

In general, patients feel very strongly one way or the other. Some patients are often more comfortable being on maintenance, and others are much more comfortable being off treatment entirely. Those patients who are eager to be  finally drug free can be closely monitored and then treated upon relapse.

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Dr. David Roodman: Maintenance therapy with bisphosphonates has not been investigated very carefully. My opinion is that bisphosphonate therapy should not be discontinued in patients with myeloma once it has been initiated for bone disease. Maintaining bone density below the fracture threshold is tremendously important in patients with myeloma. However, some centers will stop bisphosphonate therapy 2 years after transplantation if the patient remains in complete remission.

What is recommended as the ideal monitoring program during the remission phase?

Dr. Robert Kyle: It is difficult to provide a specific monitoring program for patients with multiple myeloma. I think that following an autologous stem cell transplant, the appropriate studies should be performed 3 months after transplant. These tests should include a CBC; chemistry group; serum protein electrophoresis with immunofixation, if necessary; and a 24-hour urine collection if the patient had a monoclonal light chain before transplant.

If the patient remains stable, then, ideally, these tests should be repeated at 3-month intervals. However, if the patient is doing well, 6-month intervals might be sufficient. If the patient has an increase in the M-protein or a reduction in hemoglobin, then he or she needs to be reevaluated sooner. If there are significant changes in the M-protein or in the hemoglobin level, the patient should have a metastatic bone survey and a bone marrow examination to determine whether there is additional evidence of relapse.

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Maintenance Therapy | Relapse | Therapies for Relapsed or Refractory Disease | Complications of Treatment for Disease | Diseases Related to Multiple Myeloma

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