Haematologica 2003 - Supplements

11. What is the role of allogeneic
transplantation in MM?
Roundtable 1: CONVENTIONAL CONDITIONING
P11.1.1
PROGRESS IN ALLOGENEIC TRANSPLANTATION
WITH ABLATIVE CONDITIONING. USE OF
PROGNOSTIC FACTORS.
G. Gahrton, B.Björkstrand, J.Apperley, A.Bacigalupo,
J.Bladé, M.Cavo, J.Cornelissen, P.Corradini, A.de
Laurenzi, T.Facon, P.Ljungman, M.Michallet,
D.Niederwieser, R.Powles, J.Reiffers, N.H. Russel,
D.Samson, A.Schattenberg, S.Tura, L.F. Verdonck, J.P.
Vernant, R.Willemze, L.Volin, for the European Group for
Blood and Marrow Transplantation ( EBMT )
Department of Medicine, Karolinska Institutet at Huddinge
University Hospital, SE-141 81 Stockholm, Sweden
Allogeneic transplantation has been performed in patients with
multiple myeloma since the early 1980s. 1 During the first ten year
period of transplantation the overall median survival was short
and transplant related mortality high. However, relapse rate after
complete hematologic remission was shown to be lower after
allogeneic transplantation than after autologous transplantation,
although autologous transplantation was associated with better
overall survival due to lower transplant related mortality 2 .
Molecular studies of minimal residual disease have shown that
about half of the 50 % of patients that enter a complete
hematologic response after allogeneic transplantation have no
sign of persistent disease, while only occasional patients are free
of disease following autologous transplantation 3 . Thus the
prospects for cure appear better following allogeneic than
autologous transplantation.
A recent comparison of allogeneic transplantation performed
during the two time periods 1983 – 1993 and 1994 – 1998
showed a significant improvement in survival during the later
time period 4 . The improvement was due to decreased transplant
related mortality. This in turn seemed to be due to many factors,
i.e. earlier transplantation and more effective treatment of
bacterial, fungal and viral infections. No change in relapse rate
was seen. A change to an increasing number of peripheral blood
stem cell ( PBSC ) transplants was not the reason for the
improvement. On the contrary a later update indicates that there
may be a small, but borderline significant disadvantage of using
PBSC, which may be related to a higher risk of chronic GVHD
Despite these improvements in allogeneic transplantation the
transplant related mortality remains high. Selection of patients
based on prognostic parameters could be one way to decrease
overall mortality. Good prognosis parameters for allogeneic
transplantation are female gender, low age, low beta 2 -
microglobulin, stage I at diagnosis, responsiveness to previous
treatment and only one treatment regimen before transplantation.
However most of these parameters also indicate good prognosis
with other treatment modalities such as autologous
transplantation.
Selection of the best donor is important. Matched sibling donor
transplants are associated with better prognosis than unrelated
matched transplants. Also a gender-matched sibling donor is
better than a gender mismatched one. The worst combination
appears to be a female to male transplant.
Procedural factors probably play a role, but documentation is
poor. It has not been possible to show an advantage of any of the
most commonly used high dose conditioning regimens. Until now
the most frequently used regimen has been a combination of
cyclophosphamide 60 mg/kg x 2 plus 10 Gy total body irradiation
with lung shielding to 9 Gy. However, the dose and the way the
total body irradiation is given varies, i.e. fractionated or nonfractionated
etc. Other regimens include melphalan, usually 140 –
200 mg/m 2 .These regimens are considered to be ablative for the
bone marrow. Until now it has not been possible to specify an
ablative regimen that is superior to the most commonly used
ones.
The most common regimen for prophylaxis of GVHD,
methotrexate plus cyclosporine, is standard and other regimens
have not proven to be superior in terms of improving survival.
However, attempts to manipulate the GVHD preventive regimen
have been successful in diminishing GVHD by using various T-
cell depletion regimens. One promising method has been to use
T-cell depletion with later CD4 cell add back in an attempt to
reduce GVHD and still obtain a graft versus myeloma effect 5 .
The use of low intensive (or non-myelablative ) conditioning
methods has increased dramatically. They are usually combined
with later donor lymphocyte infusion. Preliminary results are
encouraging. The rationale for this approach is that the transplant
related mortality can be reduced by the less intensive
pretransplant conditioning while preserving the graft versus
myeloma effect, which may be more important than the
conditioning regimen in preventing relapse. Later donor
lymphocyte infusions directed against the myeloma may
counteract a potentially increased risk of relapse particularly
when T-cell depletion is used.
Many non-myeloablative conditioning regimens have been tried
with initial success. Very promising results have been obtained
with fludarabin 30 mg/m 2 days –4,-3,-2, followed by total body
irradiation 200 cGy on day 0. The initial transplant related
mortality is low and some patients may even be treated as outpatients
6 . The EBMT is presently running a study comparing this
regimen after a previous autologous transplantation compared to
autologous transplantation alone based on the availability of an
HLA matched sibling donor. Post-transplant DLI is included for
all patients except those in complete remission with full donor
chimerism.
In summary allogeneic ablative transplantation may be an option
for patients with stage IIIA disease, preferentially for younger
women that were diagnosed when they had stage I disease and
that have an HLA matched female sibling donor. Patients that
have been responsive to previous conventional treatment and
have received only one treatment regimen before the transplant
are the best candidates. However some patients that have not
responded and are poor candidates for conventional treatment or
autologous transplantation may be offered an allogeneic
transplant if their general condition is otherwise good.
The best offer for a younger myeloma patient may be to enter a
trial of non-myeloablative transplantation following an
autologous transplant and be prepared to later receive donor
lymphocyte transfusions.
1. Gahrton G, Tura S, Ljungman P, et al. Allogeneic bone
marrow transplantation in multiple myeloma. European Group for
Bone Marrow Transplantation [see comments]. N Engl J Med
1991; 325:1267-73.
2. Bjorkstrand BB, Ljungman P, Svensson H, et al.
Allogeneic bone marrow transplantation versus autologous stem
cell transplantation in multiple myeloma: a retrospective case-
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