Haematologica 2003 - Supplements

patients with sensitive disease to reinduction have a high
probability of response to DLI and prolonged remission.
Graft versus Myeloma and deletion of chromosome 13:
We retrospectively evaluated the impact of deletion 13, as
determined by double colour interphase FISH, on the outcome of
myeloablative Allogeneic Stem Cell Transplantation (Allo-SCT)
in 51 patients treated at the department of Haematology,
University Medical Center Utrecht. A del(13) was found in 16
patients (31%). No significant influence of del(13) was found on
post transplant progression free survival (median 32 months
versus 39 months, p=0.36). Overall survival tended to be shorter
in the patients with del(13) (median 16 versus 59 months,
p=0.12), but this difference was partly due to a higher TRM. The
2 longest surviving patients (>10 years), who had a del(13) at
diagnosis, enjoy an extended molecular remission and are
probably cured. 4
Conclusion:
The results of this first prospective evaluation of Upfront Allo-
SCT in MM in comparison with intensive treatment show that
there seems to be no indication for standard Allo-SCT as part of
first line therapy due to a high TRM which is not compensated
for by a GVM effect. In order to make a better use of the GVM
effect of DLI, especially in high risk myeloma like patients with a
deletion 13, this procedure should probably best be applied as
pre-emptive therapy after less toxic transplantation strategies.
Literature:
1. Bjorkstrand BB, Ljungman P, Svensson H, et al. Allogeneic
bone marrow transplantation versus autologous stem cell
transplantation in multiple myeloma: a retrospective casematched
study from the European Group for Blood and Marrow
Transplantation. Blood 1996;88(12):4711-8.
2. Lokhorst HM, Segeren CM, Verdonck LF, et al. Partially T–
cell depleted allogeneic stem cell transplantation for first line
treatment of Multiple Myeloma. A prospective evaluation of
patients treated in the phase III study HOVON 24 MM. J Clin
Oncol: in press.
3. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor
lymphocyte infusions for relapsed multiple myeloma after
allogeneic stem-cell transplantation: predictive factors for
response and long-term outcome. J Clin Oncol 2000;18(16):3031-
7.
4. Laterveer L, Verdonck LF, Peeters T, Borst E, Bloem AC,
Lokhorst HM. Graft versus myeloma may overcome the
unfavorable effect of deletion of chromosome 13 in multiple
myeloma. Blood 2003;101(3):1201
Roundtable 2: DOSE REDUCED INTENSITY
REGIMENS
P11.2.1
Non-Myeloablative Allogeneic Transplant Strategies for
the Treatment of Multiple Myeloma
WI Bensinger, DM Maloney, B Sandmaier, and R Storb
Fred Hutchinson Cancer Research Center (FHCRC), University of
Washington, Seattle, WA, USA
Although high-dose chemoradiotherapy followed by allogeneic
stem cell transplantation (SCT) is capable of producing
remissions and long-term survival for patients with multiple
myeloma, the transplant-related mortality (TRM) of 25-50%,
even in “good-risk” patients, limits the application of this
approach. Furthermore, since the majority of patients who
develop multiple myeloma a
re greater than age 55 years and need closely HLA-matched
family members to serve as donors, less than 10% of patients are
even eligible for allogeneic SCT. Patients who have failed a prior
autologous transplant are generally poor candidates for a fulldose
allogeneic SCT due to treatment related mortality that
exceeds 50%. The high intensity conditioning regimens
customarily used before allogeneic transplants are designed to
produce cytoreduction and immunosuppression sufficient to
allow establishment of the donor graft. The demonstrated efficacy
of donor lymphocyte infusions (DLI) in relapsed allograft
patients, suggests that the allogeneic graft-versus-myeloma
(GVM) effect is a major reason cure can be achieved. This has
led to the exploration of low intensity conditioning regimens,
designed more for immunosuppression rather than cytoreduction,
with the aim of establishing consistent donor engraftment with
while minimizing toxicity and damage to normal host tissues.
Host dendritic cells, which could potentially present myeloma
restricted antigens to donor T cells, should survive and function
after a minimally ablative regimen. Furthermore, low intensity
immunosuppression should minimize or eliminate the period of
severe pancytopenia that always occurs after high intensity
conditioning. This technique could in theory, once donor
engraftment is achieved, allow the GVM effect to operate while
avoiding the high transplant related mortality.
A conditioning regimen developed at the FHCRC was based on
canine transplant studies where it was shown that reliable
allogeneic donor peripheral blood stem cell engraftment could be
achieved with a very low doses of TBI of 200 cGy and a
combination of 2 potent immunosuppressive drugs including
mycophenolic acid and cyclosporine. (1) This strategy was
utilized in 14 patients undergoing allogeneic transplant for
multiple myeloma. These patients generally had very advanced
disease and 50% had failed a prior autograft. Two patients
rejected leading to the addition of fludarabine which provided
additional immunosuppression. (2) Although only 1 patient of 14
died of transplant-related complications, the response rate was
low, suggesting that in myeloma, additional cytoreduction was
needed to improve the ability to achieve responses after an
allograft.
A second strategy was adopted for patients with MM who had not
received a prior high dose regimen using a “tandem” autologous,
non-ablative allogeneic transplant approach. These patients were
treated as part of a cooperative transplant consortium study at the
FHCRC, City of Hope, Stanford University, and the Universities
of Colorado, Leipzig, and Torino. Patients first have autologous
PBSC collected, followed by melphalan 200 mg/m 2 and
reinfusion of PBSC to provide cytoreduction and some
immunosuppression. Two to 4 months' later, patients received the
non-ablative regimen of 200 cGy TBI, MMF and cyclosporine
with allogeneic PBSC. The first 32 patients to receive this have
been preliminarily reported. (3) Currently, 54 patients ages 29-71
years, median age 52 years, received this tandem transplant
strategy with a minimum of 1 year of follow-up. Patients had
mainly stage II (n= 11) or III (n=36) disease and 48% had
refractory or relapsed disease. One patient died of CMV
pneumonia after autograft and 52 received the non-ablative
transplant. One patient did not proceed to allogeneic transplant
due to disease progression. All 52 achieved full donor chimerism,
although one received DLI at day 84 for partial chimerism. With
a follow-up of 18 months after autograft, the survival for all 54
patients on intention to treat was 79%, day 100 transplant-related
mortality was 6%, the CR rate was 57% and the PR rate was
26%. Only 4 patients developed severe GVHD and the overall
TRM was 16%. The rate of chronic GVHD is 54%. Among 28
S68