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Multiple Myeloma: Role of Allogeneic Transplantation

Multiple Myeloma: Role of Allogeneic Transplantation

Multiple myeloma is a multistep malignancy, starting
with an indolent phase (monoclonal gammopathy of unknown significance [MGUS] or
smoldering myeloma), progressing to overt myeloma (which is typically restricted
to the bone marrow), and terminating with an aggressive transformation
(typically associated with a high lactate dehydrogenase [LDH] level, high plasma
cell labeling index, plasmablastic morphology, and multiple cytogenetic
abnormalities, including deletion of chromosome 13). In the terminal phase, the
disease has extramedullary manifestations, sometimes including disease of the
central nervous system.

Timing of Treatment

In the second phase, the myeloma cells are entirely dependent
on the microenvironment for their survival and growth, and their resistance to
chemotherapy is an epigenetic phenomenon. In the terminal phase, the myeloma
cells have become independent of the microenvironment, and drug resistance is
based on acquired genetic changes. This stage of the disease is completely
refractory to chemotherapy. Although responses can be seen, they are
short-lived.

It is essential to treat myeloma patients in the second phase
of the disease, after minimal and preferentially rotating standard chemotherapy
(to avoid induction of drug resistance), with high-dose chemotherapy to overcome
the epigenetically induced drug resistance. It should be noted that the
epigenetic mechanisms of drug resistance of plasma cells and myeloma cells are
similar to those observed with hematopoietic stem cells, and just as
conventional chemotherapy will not destroy all stem cells, it will not eradicate
all myeloma cells.

Autologous vs
Allogeneic Transplants

The best treatment results in myeloma are obtained with
tandem transplants, as evidenced by the significantly improved long-term outcome
reported in patients undergoing such treatment in a University of Arkansas
study, and by preliminary reports of the randomized IFM-94 study.[1,2] Our Total
Therapy I study shows an overall 10-year survival of 45% in an absence of
cytogenetic abnormalities, and a continuous complete remission (CR) rate of 60%
in patients achieving a CR posttransplantation. It will be very difficult to
improve on these results with any alternative treatment approach, including
allotransplantation, because of its excessive first-year treatment-related
mortality.

In contrast, the survival rate with tandem autologous
transplants at 10 years for patients with cytogenetic abnormalities is less
than 20%. It is in these patients that the role of allotransplantation needs to
be explored, because they are virtually incurable with high-dose chemotherapy
but respond well to a graft-vs-myeloma effect.

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