Although allogeneic hematopoietic stem cell transplantation (HSCT) has been performed for the treatment of multiple myeloma since the early 1980s, its place (if any) has been, and is still, highly debated. Conventional allogeneic HSCT following myeloablative conditioning has been associated with cure through a graft-versus-myeloma effect, but its development has been greatly hampered by an unacceptable transplant-related mortality. Recently, non-myeloablative conditioning has led to a resurgence of allogeneic HSCT, and several phase II trials have been associated with more acceptable rates of transplant-related mortality, opening the door for its use in older, mostly relapsed, patients. Thus, the next logical step was to test allogeneic HSCT within the therapeutic schemes of first-line therapy.
The PETHEMA group set up a randomized trial in which 110 patients with multiple myeloma failing to achieve at least near-complete remission after a first autologous HSCT were scheduled to receive a second autologous transplant (85 patients) or an allograft with reduced-intensity-conditioning (Allo-RIC) (25 patients), depending on the HLA-identical sibling donor availability. They reported a higher CR rate (40 percent vs. 11 percent; p=0.001) and a trend toward a longer progression-free survival (PFS) (median 31 months vs. not reached; p=0.08) in favor of Allo-RIC. In contrast, it was associated with a trend toward higher transplant-related mortality (16 percent vs. 5 percent; p=0.07), a 66 percent chronic graft-versus-host disease incidence and no statistical difference in event-free survival and overall survival. They stated that "although the PFS plateau observed with Allo-RIC was encouraging, Allo-RIC is associated with a high morbidity and mortality, and, therefore, it should be still considered investigational and restricted to well-designed prospective clinical trials." Of note, of 752 patients who received a first autologous HSCT, 280 failed to achieve CR or nearly CR, but there was a very high drop-out rate since 170 patients did not undergo the pre-planned second transplant.
Many trials testing the same hypothesis are currently underway, but two major trials asking a similar question as the PETHEMA group have been published and reached different conclusions. The first study, by the Intergroup Français de Myélome (IFM),1 included 65 patients in the autologous/allogeneic group and 219 patients in the autologous/autologous group. Based on an intention-to-treat analysis, there was a significantly better median overall survival in the autologous/ autologous group than in the autologous/allogeneic group. If patients who actually received treatment were analyzed, there was still a significantly superior overall survival in the tandem autologous transplant group over the autologous allogeneic group. This study included only high-risk patients younger than 65, with high serum beta-2 microglobulin and deletion of chromosome 13. The RIC was busulfan plus fludarabine and ATG, and thus some form of T-cell depletion.
The second series by Bruno, et al.2 showed a superior overall survival for patients who underwent autologous-allogeneic transplantation. In this study, 245 patients were included at diagnosis. HLA typing was performed in 162, and 80 of these had an HLA-identical sibling donor while the other 82 patients did not and comprised the control group. However, for various reasons, only 58 patients completed the autologous-allogeneic transplants and 46 patients completed the tandem autologous transplants. Whether analyzed according to the intent-to-treat (i.e., HLA typing had been performed), or based on actual treatment administered, there was a significant advantage of undergoing an auto-allo transplantation. It is interesting to note that the deviation in the survival curves to the advantage of the auto-allo transplantation approach regimen was seen only after about two years of follow-up.
In Brief
Thus, these three trials (although not strictly identical) shared the same problem of significant drop-out with only a portion of the patients receiving the allocated treatment. We still face the unanswered question of the place (if any) of allogeneic HSCT with RIC in the management of newly diagnosed myeloma. Further, during the period when these trials were conducted, significant advances have been made in the treatment of myeloma with better description of the disease severity using cytogenetics and with the advent of new drugs including bortezomib, lenalidomide, and thalidomide.
References
Competing Interests
Dr. Socié indicated no relevant conflicts of interest.
