Haematologica 2003 - Supplements

patients with responsive disease 3 died of transplant
complications, 2 have relapsed, 16 remain in CR, 5 in PR and 2
with stable disease. Among 26 patients with relapsed or
refractory disease, 5 died of transplant complications, 11 remain
in CR, and 4 in PR. Patients with relapsed or refractory disease
had a poorer survival than patients responding to initial
chemotherapy prior to transplant.
Non-ablative or reduced intensity regimens prior to allogeneic
SCT for MM have been reported from other centers. One
promising report utilized melphalan 100 mg/m 2 to prepare 31
patients prior to allografting. These patients had either failed 2 or
3 prior autologous transplants, or received the allograft as part of
a tandem autologous-allogeneic transplant strategy (n=13). The
patients had a median age of 56 years and donors were all HLA
matched; 25 were related. TBI and fludarabine were added to the
regimens of patients receiving transplants from unrelated donors.
The day 100 TRM was 10%, overall TRM 29% and 73%
achieved CR or near CR. There was a significantly better survival
for patients transplanted as part of the planned tandem strategy v.
2 failed autografts, 86% v. 31%, p=0.01. (4) At least 2 other
studies of non-ablative allografts from family or unrelated donors
have confirmed that results are poor when patients have failed a
prior autologous transplant (5) or have chemotherapy resistant
disease.(6)
Thus, non-ablative allogeneic transplant regimens can result in
reliable donor engraftment with relatively low transplant related
mortality compared to high dose regimens. It appears, however,
that substantial cytoreduction pre-allografting is necessary due to
a limited GVM effect. Preliminary results suggest the tandem
auto/min-allogeneic strategy can result in CR’s in at least 50% of
patients with multiple myeloma; similar to what can be achieved
with a single high dose conditioning regimen, yet avoiding the
high early mortality. It will be important, however, to have longer
follow-up of patients transplanted used non-ablative regimens in
order to document the durability of these remissions and to
document the rates and severity of chronic GVHD.
The studies using low intensity, non-ablative regimens appear to
effectively reduce the early complications and mortality of
allogeneic transplants, while retaining GVM effects sufficient to
induce remissions. Such treatments could be combined with
infusions of allogeneic donor lymphocytes or subsets of
lymphocytes in the form of “engineered grafts”, for example CD4
lymphocytes, which may have a GVM effect without increasing
GVHD. Randomized trials will ultimately be required to
determine the relative benefits of tandem autologous/non-ablative
allografting compared to tandem autologous transplantation.
Future studies of allogeneic marrow transplantation in multiple
myeloma should focus on regimens that are less toxic but able to
preserve anti-tumor effects such as radioisotopes linked to bone
seeking chelates(7).
Reference List
1. Storb, R., Yu, C., Sandmaier, B., McSweeney, P., Georges, G.,
Nash, R. , and Woolfrey, A. Mixed Hematopoietic Chimerism
After Hematopoietic Stem Cell Allografts. Transplantation
Proceedings 1999;31:677-8.
2. McSweeney, P. A., Niederwieser, D., Shizuru, J. A.,
Sandmaier, B. M., Molina, A. J., Maloney, D. G., Chauncey, T.
R., Gooley, T. A., Hegenbart, U., Nash, R. A., Radich, J.,
Wagner, J. L., Minor, S., Appelbaum, F. R., Bensinger, W. I.,
Bryant, E., Flowers, M. E. D., Georges, G. E., Grumet, F. C.,
Kiem, H.-P., Torok-Storb, B., Yu, C., Blume, K. G., and Storb,
R. F. Hematopoietic Cell Transplantation in Older Patients With
Hematologic Malignancies: Replacing High-Dose Cytotoxic
Therapy With Graft-Versus-Tumor Effects. Blood 6-1-
2001;97(11):3390-400.
3. Maloney, D. G.; Sahebi, F.; Stockerl-Goldstein, K. E.;
Sandmaier, B. M.; Molina, A. J.; Bensinger, W.; McSweeney, P.
A.; Storer, B. E.; Niederwieser, D.; Chauncey, T.; Appelbaum, F.
R.; Blume, K. G.; Forman, S. J.; Storb, R. Combining an
allogeneic graft-vs-myeloma effect with high-dose autologous
stem cell rescue in the treatment of multiple myeloma. Blood 98
(Part 1)[11], 434a-435a, #1822. 11-16-2001.
4. Badros, A., Barlogie, B., Siegel, E., Cottler-Fox, M., Zangari,
M., Fassas, A., Morris, C., Anaissie, E., van Rhee, F., and Tricot,
G. Improved Outcome of Allogeneic Transplantation in High-
Risk Multiple Myeloma Patients After Nonmyeloablative
Conditioning. Journal of Clinical Oncology 2002;20(5):1295-
303.
5. Hoepfner, S., Probst, S. M., Breitkreutz, I., Moehler, T.,
Benner, A., Goldschmidt, H., Ho, A. D., and Goerner, M. Non-
Myeloablative Allogeneic Transplantation As Part of Salvage
Therapy for Relapse of Multiple Myeloma After Autologous
Transplantation. Blood 11-16-2002;100 (Part 1)(11):859a, #3387.
6. Einsele, H., Schäfer, H. J., Bader, P., Plasswilm, L., Liebisch,
P., Bamberg, M., Faul, C., Hebart, H. , and Kanz, L. Allografts
After Reduced Intensity Conditioning Can Induce Long-Term
Remission in Patients With Chemosensitive Relapsed Multiple
Myeloma (MM). Blood 11-16-2002;100 (Part 1)(11):635a,
#2499.
7. Giralt, S.; Bensinger, W.; Goodman, M.; Champlin, R.; Eary,
J.; Wendt, R. ; Rajendran, J.; Ghalie, R. Long-term follow-up of
83 patients with multiple myeloma (MM) treated on a phase I-II
study of skeletal targeted radiotherapy (STR) using 166 Ho-
DOTMP plus melphalan with or without total body irradiation
(TBI) and autologous hematopoietic stem cell transplant
(AHSCT). Blood 100 (Part 1)[ 11], 179a, #670. 11-16-2002.
P11.2.2
NON-MYELOABLATIVE OR REDUCED INTENSITY
TRANSPLANTATION IN MULTIPLE MYELOMA
Giralt S
Department of Blood and Marrow Transplantation of the University
of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd,
Houston TX 77030
INTRODUCTION: Although the existence of a graft versus
myeloma effect has been well documented, harnessing this effect
has been hampered by the toxicities of standard myeloablative
therapies. Thus any benefits provided by the immune effect were
lost by increases in non relapse mortality.(1-5) Therefore
strategies aimed at reducing the toxicity of allografting in
myeloma are essential to be able to further explore the graft
versus myeloma effect mediated by donor lymphocytes as a
treatment modality.
The reasons for the high rates of non-relapse mortality in
myeloma patients are not well understood. Older age is likely to
contribute in part to the higher mortality rates, since age is a
major risk factor for both regimen related toxicity and graft
versus host disease (GVHD). (6-8) - The existence of a graftversus-tumor
effect mediated by donor lymphocytes independent
of chemotherapy has led to the exploration of less intense
preparative regimens for multiple myeloma. (9-12)
EXPERIENCE WITH NON-ABLATIVE PREPARATIVE
REGIMENS IN MULTIPLE MYELOMA: The first report from
MDACC was presented at ASCO in 1998.(13) In this report, 13
patients with a median age of 50 years (range, 46-55), 10 of
which had refractory disease and 5 had failed prior autologous
transplant. With a combination of fludarabine/melphalan 12
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