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Therapies for Relapsed or Refractory Disease
08.09.02

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

Section 3: Therapies for Relapsed or Refractory Disease

What treatment options are available at time of relapse, and how do you decide among them?

Dr. Seema Singhal: All the therapies that are available for the initial treatment of newly diagnosed disease are available for reuse in a patient at the time of relapse: dexamethasone; thalidomide; combinations of these two; combination chemotherapy; and high-dose therapy including autologous transplantation, allogeneic transplantation, or even mini-allogeneic transplants.

The selection of a particular therapy depends on the nature or the behavior of the relapsed disease. For example, if a patient has an aggressive, rapid type of relapse, a better choice might be combination therapy, which provides a greater chance that one of the agents might be effective in stopping the progression of the disease. However, if a patient has had a very gradual type of relapse, without significant symptoms, one could even choose to not treat the patient and simply keep the patient under very close observation. Then, when the disease begins to become symptomatic, therapies such as thalidomide or dexamethasone, which are much more easily tolerated by the patient, could be tried.

An important point to consider in the selection of therapy for a patient at the time of relapse is the treatment history of that patient. For example, if a patient at the time of initial therapy had not had a very good response to the induction given using vincristine, doxorubicin, and dexamethasone (VAD) or pulsed dexamethasone, dexamethasone would not be the best choice for the initial therapy of relapsed disease.

Dr. William Bensinger: For patients who relapse after conventional chemotherapy, an autologous transplant is often the best treatment option. These transplants can produce high response rates with subsequently prolonged survival in patients who fail conventional therapy.

The timing of the transplant is somewhat controversial in that patients who have a transplant as salvage therapy as opposed to initial therapy have roughly equivalent outcomes. For patients who have refractory disease either primary refractory or refractory relapse an autologous transplant can still provide higher response rates and significant benefit, although there is some controversy about the relative value of such treatment.

A subsequent autologous transplant for patients who fail an initial autologous transplant can still be beneficial for some patients, especially if a suitable donor is not available to provide an allogeneic transplant. And there are patients who have responded to second transplants and, in rare cases, third transplants using high-dose melphalan, especially when their relapses are several years apart.[View Reference]

Allogeneic transplants are especially attractive for patients who have relapsed because of the well-known immunologic graft-versus-myeloma effect. Standard allogeneic transplants do carry a relatively high morbidity and mortality, especially in patients with advanced refractory disease. It is for this reason that the use of nonablative or so-called minitransplants is now receiving increased interest. [View Reference]

It is important to caution, however, that this type of transplant relies heavily on the immunologic graft-versus-myeloma effect. This effect can often take 2 to 4 months to kick in after a transplant. Patients with rapidly progressive disease or patients with high-volume disease only rarely benefit from these transplants. Before initiating a nonablative allogeneic transplant, it is important to try to provide some cytoreduction to lower the tumor burden of any patient who has relapsed.

For patients who relapse after either a standard allogeneic or a nonablative allogeneic transplant, simple donor lymphocyte infusion (DLI) is often the best treatment option. [View Reference] DLIs are lymphocytes obtained from the original donor and infused into the patient without any additional therapy. Approximately 50% of these patients will achieve a complete response using DLI. [View Reference] However, DLI is often associated with a high incidence of acute or chronic graft-versus-host disease (GVHD).

Dr. Brian Durie: I very much support what Dr. Bensinger has said about the role of second transplant. A helpful way to decide whether to attempt a second autologous transplant is to focus on the length of the first remission with the first transplant. If the first remission has been long for example, beyond 2 years a nonablative or a  mini-allo transplant would be the most appropriate choice, providing that a donor is available.

Dr. William Bensinger: That s a very good point.

Dr. Seema Singhal: In fact, sometimes it may not be possible to offer a second autologous transplant to the patient if you had difficulty in collecting cells for the original autologous transplant. This brings us to the issue of collecting sufficient cells at the time of the initial collection so that we have cells in store at the time of relapse. This would give the patient the option of a second autologous transplant at the time of relapse.

Also, in this time of experimental new designer drugs for the treatment of myeloma, a patient should be offered therapy with one of these drugs as an alternative to continued high-dose therapy. And I think Dr. Durie s point about looking at the duration of remission to the first transplant is very important: If a patient had a very long remission after the first transplant, perhaps a second transplant would be the best option for that patient.

Dr. Brian Durie: I agree on both points. If a patient is a transplant candidate, it is terribly important to harvest enough stem cells for more than one transplant. Then, should the situation arise that warrants a second or even a third transplant, you have the material.

Dr. William Bensinger: My general view in patients with symptomatic multiple myeloma who require treatment is to harvest stem cells relatively early, before patients are heavily treated. This applies even for patients in whom autologous transplant is not part of their initial therapy. The time to collect stem cells is before the patient has had a lot of alkylating agent exposure or had radiation treatments. It is easier before those treatments to harvest stem cells and, as my colleagues have pointed out, it is easier to collect large numbers of cells suitable for more than one transplant.

The only caveats to this are insurance issues. Insurance companies will frequently cover autologous stem cell transplant but are less apt to cover the collection of stem cells and storage for a patient who is not immediately going to transplant. This would need to be negotiated with the patient s insurance company.

How are the decision criteria different for refractory patients? What are the approaches that should be considered? (What are the differences between refractory disease and progressive disease?)

Dr. William Bensinger: Patients who are thought to have refractory disease should be considered for entry into clinical trials. Treating refractory disease is a tricky issue because patients whose diseases have not responded to the induction therapy may also be considered to be refractory, and transplantation would probably be the appropriate treatment in those cases.

Dr. Brian Durie: That is an important point. Patients who have refractory disease, as defined by a lack of sufficient decrease in M component level to qualify as a responder, fall into two categories: patients who continue to have regrowth and true clinical progressive disease, and patients who have residual disease but do not immediately have progressive disease. That second type of refractory patient can be stable or require some ongoing supportive care but may not really need decisive reinduction therapy. Therefore, it is extremely important to distinguish between those two categories in assigning patients to experimental therapy.

Dr. William Bensinger: Would you call those "stable refractory" and "progressive refractory" if you were trying to characterize them?

Dr. Brian Durie: Yes. I think that definitions like those, although they are not routinely used, should be implemented to help sort those patients into discrete groups.

Dr. Seema Singhal: It all boils down to whether the patient has stable disease at a certain point in time and whether or not the disease is troubling the patient physically.

Dr. Brian Durie: Yes.

Dr. Seema Singhal: And if it is, whatever be the circumstances, the patient needs treatment.

Dr. Brian Durie: Right, but I think that for the patient, as well as for the proper evaluation of new drugs, it s important to have that information to assess what happened.

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


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