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
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
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:
- 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.
- 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
- 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.