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Chris Reynolds, M.D.,
Instructor of Medicine
Joseph Uberti, M.D., Ph.D.,
Associate Professor of Internal Medicine
Clinical Director, Adult BMT Program
Despite advances in the treatment, diagnosis and supportive
care aspects of multiple myeloma, it remains a disease that
is incurable through standard chemotherapy. With chemotherapy,
the median duration of survival is three years. Twenty-five
percent of patients survive longer than five years and only
5% survive longer than 10 years. Initial chemotherapy for
the disease often consists of more complicated and intense
regimens, such as VAD, VMCP or VBAP, which often result in
high complete and objective response rates. However, there
is controversy over whether these more complex regimens substantially
improve the overall survival rates in multiple myeloma when
compared to the more traditional and better-tolerated standard
regimens such as melphalan and prednisone (1). Although conventional
chemotherapy does prolong survival when compared with no treatment,
it ultimately represents palliation for patients due to the
lack of evidence of any curative potential.
High-Dose Chemotherapy and Autologous Transplant
To date there is no convincing evidence that increasing the
complexity and intensity of non-transplant doses of chemotherapy
increases the overall survival in multiple myeloma patients.
However, there is emerging evidence that high-dose chemotherapy
with stem cell support does offer a survival advantage over
standard chemotherapy. A number of phase II studies have shown
that autologous stem cell transplantation is safe and effective
therapy for multiple myeloma with a low transplant-related
toxicity. Thirty to 40% of patients in these trials achieve
complete remissions with overall survivals of 2.7 to 6.7 years
In a recently published trial, patients with myeloma were
randomized to receive either standard chemotherapy or chemotherapy
followed by autologous transplant ( 3). All patients in the
trial received induction chemotherapy with four cycles of
alternating VMCP/VBAP. Patients were then randomized to receive
either further conventional chemotherapy of VMCP/VBAP or high-dose
therapy of melphalan and TBI followed by autologous stem cell
transplant. The study showed a dramatic advantage of transplant
compared to standard chemotherapy. The five-year, event-free
survival (EFS) and overall survival (OS) were 28% and 52%
in the transplant arm compared to 10% and 12% in the chemotherapy
In spite of transplant's advantage over standard chemotherapy,
it is still unclear if autologous BMT is curative for myeloma.
Newer approaches have evolved to enhance the activity of transplants
in an attempt to cure these patients. Approaches include the
use of "tandem transplants" followed by maintenance
interferon (4), as well as "purging" myeloma cells
from the autologous stem cell harvest (5). Although both approaches
offer theoretical advantages over standard transplants, neither
has yet proven to be superior in controlled randomized trials.
Based on the data presented, we believe all patients who undergo
treatment for myeloma should be considered for high-dose therapy
with stem cell rescue. In the absence of HLA-matched donors
and in older patients, we recommend an autologous peripheral
blood stem cell (PBSC) transplant after four courses of induction
therapy with VAD. An interim analysis of 27 consecutive patients
showed that 15 patients were in complete remission, two had
stable disease and 10 had progressed or expired from their
disease. In an attempt to preserve hematopoietic stem cell
function it is helpful to treat patients with regimens that
do not contain alkylating agents. The use of agents such as
melphalan, which is known to be quite toxic to stem cells,
makes collection and use of stem cells difficult.
Allogeneic Transplant for Myeloma
Although most evidence indicates the advantage of high-dose
therapy over conventional therapy, there is little evidence
that this approach will cure a high number of patients. This
limitation has prompted a number of centers to initiate the
use of allogeneic transplantation for patients who have an
HLA-matched donor. Currently we are recommending allogeneic
BMT to patients with myeloma who are young (age < 55) and
have aggressive disease. If an HLA-identical sibling or unrelated
donor is found, we do recommend proceeding to transplant.
A recent interim analysis of 23 patients who have undergone
allogeneic transplant at the University of Michigan demonstrated
an overall survival of 60% (see Figure 1). Fifteen of these
patients entered complete remission after the transplant.
The use of peripheral blood stem cells, as well as better
control of graft-vs.-host disease (GVHD), has contributed
to the initial success of this treatment. Further follow-up
will be needed to assess the relapse rate in these patients.
Despite the high mortality often associated with allogeneic
transplants, there are several potential advantages. The first
is that the allograft provides a stem cell source that is
free from contamination of myeloma cells. The second and perhaps
most promising advantage is the recently documented evidence
of a potent anti-myeloma effect with an allogeneic BMT. Several
centers have shown that myeloma patients who have relapsed
after an allogeneic transplant respond to donor lymphocyte
infusions (6,7). These infusions result in complete or partial
responses in a number of patients who have relapsed after
an allogeneic BMT.
Our current efforts are directed at lessening the transplant-related
toxicity associated with an allogeneic transplant. This includes
the use of allogeneic stem cells instead of marrow as a donor
source (8), the use of new agents for the prevention of GVHD,
such as tacrolimus (9), and the use of a new low-intensity
regimen specifically targeted at older patients with myeloma
(see article on page 6). We feel these new initiatives will
substantially lessen the toxicity of allogeneic transplantation,
which in turn will allow us to harness the potent anti-myeloma
activity of an allogeneic transplant, thus increasing the
cure rate for patients with this otherwise fatal malignancy.
- Gregory WM, Richards MA, Malpas JS. Combination chemotherapy
versus melphalan and prednisolone in the treatment of multiple
myeloma: An overview of published trials. J Clin Oncol.
- Barlogie B. Advances in therapy of multiple myeloma: lessons
from acute leukemia. Clinical Cancer Research. 3:2605, 1997.
- Attal M, Harousseau JL, Stoppa AM, et al. A prospective,
randomized trial of autologous bone marrow transplantation
and chemotherapy in multiple myeloma. NEJM. 335:91, 1996.
- Barlogie B, Jagannath S, Desikan K.R., et al. Total therapy
with tandem transplants for newly diagnosed multiple myeloma.
Blood. 93:55 1999.
- Vescio R, Schiller G, Keith Stewart A, et al. Multicenter
phase III trial to evaluate CD34+ selected versus unselected
autologous peripheral blood progenitor cell transplantation
in multiple myeloma. Blood. 93:1858, 1999.
- Tricot G, Vesole DH, Jagannath S, et al. Graft-vs-myeloma
effect: proof of principle. Blood. 87:1196, 1996.
- Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor
leukocyte infusions are effective in relapsed multiple myeloma
after allogeneic bone marrow transplantation. Blood. 90:4206,
- Uberti JP, Adams PT, Silver SM, et al. Allogeneic peripheral
blood stem cell transplantation (APBSCT) for high-risk hematologic
malignancies: the efficacy of tacrolimus for the prevention
of acute graft-versus-host disease (AGVHD). Blood. 90:393a,
- Uberti JP, Cronin S, Ratanatharathorn V. Optimum use of
tacrolimus in the prophylaxis of graft- versus-host disease.
BioDrugs. 11:5, 1999.
Figure 1. Kaplan-Meier estimate of overall survival following
related, allogeneic one marrow (n=8) or peripheral stem cell
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