No RIC in high-risk myeloma?

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  ▪