Comment on Garban et al, page 3474

In a prospective IFM study in high-risk de novo myeloma, autologous cell transplantation followed by allogeneic transplantation with reduced-intensity conditioning was not superior to tandem autologous stem cell transplantation.

Allogeneic stem cell transplantation (allo-SCT) is probably the only curative option for patients with myeloma. The reduced relapse risk after allo-SCT and the induction of sustained molecular remissions in several patients are likely due to the efficacy of donor lymphocytes to eliminate recipient plasma cells.1,2  The existence of this graft-versus-myeloma (GVM) effect is best illustrated by the response to donor lymphocyte infusion (DLI) in 30% to 40% of patients with relapsed myeloma.3  However, the potential benefit of GVM in myeloablative allo-SCT is probably completely offset by the high transplant-related mortality (TRM). The feasibility of initial studies of allo-SCT after conditioning with a reduced dose and minimal-intensity regimen has led to an enthusiastic revival of allo-SCT in myeloma.4  However, due to the heterogeneity of conditioning regimens and heterogeneity of patients reported, the place of reduced-intensity conditioning (RIC) in myeloma treatment is not established.

The Intergroupe Francophone du Myelome (IFM) is the first group to evaluate in a prospective comparison a new promising treatment modality in myeloma. In this issue, Garban and colleagues report on the outcome of tandem autologous, allogeneic RIC in patients with an HLA-identical sibling donor versus tandem autologous transplantation in patients without a donor. Although the low TRM of 10% following RIC was a major achievement, progression-free survival (PFS) and overall survival (OS) in both arms were comparable.

What are the implications? Should we abandon RIC in (de novo high-risk) myeloma? A probable negative aspect for outcome of the RIC arm was the use of high-dose ATG in the conditioning regimen. The beneficial effect of in vivo T-cell depletion is the low incidence of acute and chronic graft-versus-host disease (GVHD); the detrimental effect is the elimination of the GVM effect. The importance of immune-competent donor T cells for GVM is best illustrated by the absolute correlation between response to DLI and the occurrence of acute and chronic GVHD.3  European study groups, including the Dutch Hemato-Oncology Association (HOVON), Spain's Programa para el estudio y tratamiento de las hemopatias malignas (PETHEMA), and the European Group for Blood and Marrow Transplantation (EBMT), are performing comparable prospective studies, but with a larger number of patients at all risk levels receiving a RIC regimen without T-cell depletion. In anticipation of the results of these studies, it is necessary to begin to explore new strategies. The IFM study shows that by using reduced-intensity conditioning, the first step (ie, the replacement of a deficient autologous immune system by an immune-competent donor system) may be achieved without fatal toxicity. The time has come to focus on strategies after allotransplantation, to redirect the donor T cells toward the residual myeloma cells without enhancing GVHD. The suggestion that the novel anti-myeloma agents such as bortezomib, thalidomide, and revlimid may preferentially stimulate the graft-versus-tumor effect and not GVHD is fascinating.5  One of these observations was a remarkably high response rate (15 of 18 patients, including 3 complete responses) to these agents in DLI refractory multiple myeloma (MM) patients.6 

1
Bjorkstrand B, Ljungman P, Svensson H, et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case matched study from the European Group for Blood and Marrow Transplantation.
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Corradini P, Cavo M, Lokhorst H, et al. Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma.
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Lokhorst HM, Wu K, Verdonck LF, et al. The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma.
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Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma.
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Kröger N, Shimoni A, Zagrivnaja M, et al. Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma.
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6
van de Donk NWCJ, Kröger N, Hegenbart U, et al. Remarkable activity of novel agents bortezomib and thalidomide in patients not responding to donor lymphocyte infusions following nonmyeloablative allogeneic stem cell transplantation in multiple myeloma [letter].
Blood
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