This consensus statement from the International Myeloma Working Group (IMWG) outlines the current and future roles of allogeneic stem cell transplantation in myeloma. Lokhorst and colleagues describe the high transplant-related morbidity and mortality after full ablative therapy and allografting due to graft-versus-host disease (GVHD), infection, and treatment-related toxicity. Nonetheless, long-term complete responses were observed in patients with responsive disease treated early after diagnosis. In comparative trials of patients undergoing myeloablative allogeneic versus autologous grafting, the early toxicity of the former contrasts with the ongoing risk of relapse in the latter. In an attempt to exploit the allogeneic graft-versus-myeloma (GVM) effect while avoiding the toxicity attendant to myeloablative allotransplantation, reduced-intensity conditioning using chemotherapy and/or low-dose total body irradiation has been broadly studied, either alone or preceded by high-dose therapy and autotransplantation.
These strategies have achieved high frequency and extent of response; however, transplant-related mortality remains at 10 percent to 20 percent, with relapses occurring even in the setting of high rates of chronic GVHD. Indeed, the relapse rate can be higher post reduced-intensity conditioning than after myeloablative allotransplantation, with a resultant similar overall survival. Comparisons of double autologous transplantation versus autologous followed by reduced-intensity conditioning allotransplantation, often predicated upon the availability of an appropriate donor, have shown mixed results; to date, there is no conclusive evidence supporting superiority of incorporating allografting even in genetically defined high-risk groups. Importantly, given that the majority of allotransplantation clinical trials did not include novel agents, the IMWG investigators concluded that future efforts should incorporate novel agents to optimize GVM while minimizing morbidity and mortality.
Unquestionably, there are long-term survivors post allogeneic transplantation for myeloma who remain disease-free in molecular complete response, but sadly they represent a minority of patients and often have chronic GVHD. However, as in myeloma therapeutic management more generally, the incorporation of novel agents offers a unique opportunity to exploit GVM while avoiding attendant toxicity and thereby changing the treatment paradigm of allografting, as has occurred in autotransplantation.
Incorporation of novel therapies, such as bortezomib, into induction therapy increases the extent and frequency of response, with increased very good partial response (VGPR) rates portending improved outcome post autotransplantation. Moreover, the achievement of at least VGPR in the majority of patients after high-dose therapy and a single autotransplant has decreased the use of double autologous grafting.
In Brief
Most recently, the use novel of therapies as induction, as well as to consolidate and maintain response post autologous transplantation, has markedly improved both extent of response and progression-free survival. In fact, the high extent and frequency of response post lenalidomide, bortezomib, and dexamethasone induction therapy now allows for evaluation of the added value of autotransplantation therapy. In a similar vein, studies of reduced-intensity conditioning allotransplantation now should incorporate novel therapies. Lenalidomide, as an immunomodulatory drug, has the capacity to augment GVM. Bortezomib can overcome at least some high-risk features, such as t4:14 translocation, and may also abrogate GVHD and graft rejection. Most importantly, the ability to achieve high frequency and extent of response with lenalidomide, bortezomib, and dexamethasone therapy suggests that reduced-intensity conditioning can now be tested in the setting of minimal residual disease, where maintenance lenalidomide offers the ability to augment donor GVM and achieve long-term disease-free survival.
Competing Interests
Dr. Anderson indicated no relevant conflicts of interest.
