Allogeneic Hematopoietic Stem-Cell Transplantation for Myeloma: It's Time for the Appropriate Studies

Abstract

TO THE EDITOR: The International Myeloma Working Group recently published a consensus statement regarding the use of allogeneic hematopoietic stem-cell transplantation (HSCT) in myeloma. 1 They conclude that new strategies are needed to make allogeneic HSCT safer and recommend reduced intensity conditioning in the context of clinical trials only. The group is to be congratulated for taking up the task for such a consensus statement, and the main conclusions are undoubtedly correct. It is essential to render allogeneic HSCT safer, and further clinical studies are urgently warranted. However, the report misses some important aspects. Some results with allogeneic HSCT for patients with myeloma could be looked at from a different point of view. The conclusions to be drawn and the way forward might then look completely different from the way they are presented in the consensus statement. The authors report that non–relapse mortality is excessively high after allogeneic HSCT for myeloma; they give no explanation for why this is the case. A recent analysis of the European Group for Blood and Marrow Transplantation (EBMT) sheds some light on this erroneous observation. Survival and non–relapse mortality of 1,351 patients with myeloma was not different from survival and non–relapse mortality of patients with any other acquired hematologic disease when risk was adjusted for by the EBMT risk score. 2 In contrast, risk distribution was strikingly different. The risk score includes age, disease stage, time interval from diagnosis, donor type (HLA-identical sibling donor v other), and donor-recipient sex combination (female donor for a male recipient v other). Median age of the patients with myeloma was 46 years, and 60% of them had received transplantations with an EBMT score of 4 or higher. Median age of the 16,000 patients with acute myeloid leukemia was 35 years, and only 24% who had received transplantations had a score of 4 or higher. The sense that there is a higher mortality rate with myeloma is correct. The cause is not the disease but the wrong selection. Recommending allogeneic HSCT to patients for whom autologous HSCT and modern drug therapy have failed will only perpetuate the assumption that allogeneic HSCT is associated with high mortality and is not beneficial. There is no need for novel conditioning regimens. There is an urgent need to investigate standard allogeneic HSCT for the few selected high-risk patients with myeloma who have a donor with a low EBMT risk score. Transplantations should be considered early in the disease course, as soon as remission is reached, when an HLA-identical sibling donor or a fully matched unrelated donor is available for a younger patient with a normal Karnofsky score, and a male recipient should not be given a female donor transplant. Risk of non–relapse mortality will not be higher than that for a comparable patient with leukemia. A randomized study comparing such early HSCT with the current conventional approach could rapidly provide the answer. There is no need to precede the allogeneic HSCT with an autologous transplantation. The tandem approach, autologous HSCT followed by a reduced-intensity conditioning allogeneic transplantation is believed to have improved outcome. This study was reported at a time of general improvement in outcome and provided the impression of early low mortality. 3 No study since has ever confirmed in any disease that separation of cytoreduction and allogeneic HSCT is indeed superior to a direct, full-conditioning allogeneic HSCT. It is an attractive theoretical concept but there are no facts. The authors simply present it as such. There is a more important missing aspect. The authors mention several potential approaches, including reduced-intensity allogeneic HSCT combined with maintenance with one of the novel antimyeloma agents. There are no data, and the authors do not mention costs. Long-term treatment with these novel agents will not be affordable for the vast majority of the global population. An early standard allogeneic HSCT for those few selected patients with high-risk disease and a low-risk transplantation score might provide the most cost-effective approach. Such considerations have been made for patients with chronic myeloid leukemia, and they relate as well to patients with myeloma. 4 Consensus statements should consider global aspects. 5 It is the perfect time to perform the appropriate studies evaluating early allogeneic HSCT for those patients with high-risk disease and a lowrisk donor. The International Myeloma Working Group should be challenged to take on this task.