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Spring 1997 Volume 2, Issue 6:
Transplantation For Multiple Myeloma: The Mayo Clinic Philosophy
By Morie A. Gertz, MD and Martha Q. Lacy, MD

Mayo Clinic, Rochester, Minnesota

The outlook for patients with multiple myeloma continues to improve. Better prognostic factors help individualize therapy for each patient. Of all of the new interventions, however, none has appeared to have such an impact on management as blood stem cell and bone marrow transplantation. This article hopes to deal with issues confronting patients with multiple myeloma facing the decision about treatment options, including transplant.

What are the principles of a transplant? Many believe that the transplant itself is responsible for improved outcomes in patients with myeloma. This is not quite true. In myeloma higher doses of chemotherapy produce greater destruction of myeloma cells. How much chemotherapy can be safely administered is limited by permanent damage to the normal bone marrow cells. Should a very high dose of chemotherapy be administered with no special precautions, the chemotherapy would irreversibly destroy the bone marrow.

In bone marrow and stem cell transplantation the "seeds" that grow into bone marrow are collected and stored frozen. High doses of chemotherapy are administered to destroy as many myeloma cells as possible. After the chemotherapy leaves the body, these "seeds" are returned to the patient to restore bone marrow function. The transplant does not kill any myeloma, but it overcomes the limitation to high dose chemotherapy, that being permanent bone marrow damage.

Who are candidates for bone marrow transplant? Bone marrow transplantation is relatively safe. However, it is impossible to administer high dose chemotherapy completely risk free. After the "seeds" are thawed and returned to the patient, there is a lag of 8-15 days before white cells reappear. During this period of low white cell count there is risk of serious infection. A careful assessment must be made as to which patients benefit the most from a transplant and which would be better served with a conservative approach.

Who represents a good transplant candidate? The patient's activity level is important. Patients who are incapable of being up and about most of the day are at higher risk for complications. Patients should be fully active or have only minimal impairment from their normal routine. Age is a factor, but there is no absolute threshold. We have transplanted patients up to age 74 if his/her clinical condition permits. A patient age 50 is likely to recover from intense treatment much faster than someone age 70. Patients who have significant impairment in heart or in lung function are not good candidates because their risks are increased and could negate any benefit of the procedure. Good kidney function is important. This is not to say that kidney function needs to be normal. The kidney may be functioning at 30% of normal and still be adequate for transplant.

When is the optimal time to transplant? The timing of transplant is currently the subject of a national study. In this protocol comparisons will be made between patients who are transplanted immediately after diagnosis (within 6 months) and those where transplant will be performed at the time of first relapse of the disease. Until the results of this study become available, what is a patient to do? The facts are:

  1. In the study looking at bone marrow transplant versus standard chemotherapy there was a benefit for those patients undergoing bone marrow transplant. Bone marrow or stem cell transplantation (using seeds from the blood stream rather than the bone marrow) should be considered in every newly diagnosed myeloma patient under age 70. This is not to say this is the correct strategy for every patient, but every patient needs to know this option exists.
  2. When a transplant is performed after multiple relapses, the overall duration of response appears to be shorter than patients who are transplanted in the early phase. This addresses only response duration and not overall outcome from diagnosis.
  3. Prior exposure to certain chemotherapy, particularly Alkeran (Melphalan) significantly impairs the ability to collect healthy seeds from the bone marrow or blood stream. The decision regarding transplant should be made prior to the initiation of chemotherapy and not one year later.

What is Mayo's current treatment philosophy? Studies performed by Dr. Philip Greipp of our Institution have demonstrated that there are patients who are destined to do well no matter what form of therapy they receive. Patients who are below age 65, who have a low beta 2 microglobulin (low tumor burden) and low percent plasma cells synthesizing DNA (low labeling index; slow growing cells) have a very favorable outcome. It is not clear that these patients benefit from early intensive therapy. Currently, we have been trying to enroll patients on the national study to answer the question regarding the timing of transplant. However, for those patients who are not eligible or who do not wish to participate in a randomized study, we have been treating with standard VAD (Vincristine, Adriamycin, Dexamethasone). We then collect their stem cells (seed cells) from the blood and store them. If patients have shown an inadequate response at that point, immediate transplantation is recommended. The risk of transplant is justified because the failure to respond to chemotherapy is an adverse predictor of outcome. In patients who are chemotherapy-responsive, the stem cells are stored. Bone marrow transplant will remain an option. We place these patients on conventional chemotherapy and transplant at the first sign of progression. We have patients who have done well for four years and still have stem cells frozen. It is our hope that with sequential chemotherapy followed by transplant the course of the disease can be extended.

Although in one study transplant has been shown to be superior to standard treatment, this does not mean it is a choice for everyone. The collection of the seeds, the transplant and the post-transplant recovery come to approximately six months during which patients are too fatigued to work. For some this is too much of a disruption and they may elect conventional chemotherapy. Another study suggests that patients who would have been eligible for a transplant but were treated with standard therapy had exceptionally good results. Questions that persist include: Are two transplants better than one? If two transplants are performed should they be done back to back or the second one at the time of disease recurrence? Does it help to filter the seeds to eliminate myeloma cells?

The average cost of a transplant is $75,000. This includes the collection of seed cells. These costs also cover hospitalization in a specialized unit staffed by a team of transplant physicians and nurses. Many insurers and Medicare consider transplantation experimental. With privately insured patients there is specific information that needs to be filed with the insurance company before approval. Approval may require a specific protocol for transplant. A system has to be in place for analysis so the insurance company can be certain that the center can do a good job. The transplant center should have experience with myeloma. Between one-third and one-half of patients are denied by insurance carriers.

What should the patient be aware of?: First, transplant can play an important role in management. This is not to say it is required for every patient. Patients should be aware that transplant is an option. Consultation with a specialist that performs the technique is appropriate. The patient can then acquire the information necessary to make an informed decision.

This article is part of an ongoing series on Bone Marrow/Stem Cell Transplantation.

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