IMWG Consensus Statement Regarding the Current Status of Allogeneic Stem Cell Transplantation for Multiple Myeloma
There has been much controversy in over two decades about the role of allogeneic stem cell transplant in myeloma. Early studies conducted in Europe and at the Fred Hutchinson Cancer Center in Seattle, WA, consistently demonstrated high treatment-related mortality (TRM) of approximately 45% in heavily patients receiving full myeloablative allogeneic transplant (full allo). Overall survival rates in these studies were generally less than 30% at five years. Full allo in myeloma patients was therefore largely abandoned worldwide in the early 1990s.
There were, however, some long-term remission durations among patients treated within one year of diagnosis, after a single line of therapy, and with chemotherapy-sensitive disease. In fact, there was attainment of sustained CR in a subpopulation of patients. Researchers did not, therefore, give up on the idea of allo transplant.
The Seattle group introduced the strategy of an autologous transplant followed two to four months later by a reduced-intensity conditioning (RIC) allo transplant (subsequently also called "mini allo" transplant), thus reducing TRM among patients whose donor was an HLA-identical sibling. A recent study of 102 patients who had auto/RIC allo from Seattle reports TRM of 18% (i.e. significantly less than 45%), and significantly improved overall survival (OS) and progression-free survival (PFS) at 6.3 years of 64% and 36% respectively. In a similar study in Italy with newly diagnosed patients, follow-up at five years demonstrated event-free survival (EFS) of three years, while median OS was not reached. Unfortunately, neither study has shown a plateau in EFS; that is, patients continued to relapse. The Dutch HOVON group and the European Bone Marrow Transplant (EBMT) groups also conducted trials comparing tandem auto to auto/ RIC allo transplant; both found improved OS in the tandem auto arms of their studies rather than the auto/ RIC allo arms.
Recent data from a very large (710 patients at 43 centers) BMT CTN phase III tandem auto vs. auto/mini allo study presented at the annual American Society of Hematology meeting in December, 2010, demonstrated no difference between the two arms of the study in progression-free or overall survival at three years. Potential benefits of graft-versus-myeloma to reduce disease progression or relapse were offset by increased TRM. The myeloma community interpreted these randomized trial data as definitive evidence that even under the best circumstances, TRM is unacceptably high, without overall survival benefit.
The International Myeloma Working Group therefore recommends that RIC allo transplant should only be performed in the context of clinical trials.
Future studies of allo SCT in myeloma should aim at improving the graft-versus-tumor effect while reducing the morbidity and mortality of allo SCT.