Most studies confirm that event-free survival and overall survival following autologous hematopoietic cell transplantation (HCT) are prolonged when compared to treatment with chemotherapy alone for newly diagnosed patients with myeloma. However, neither chemotherapy nor autologous HCT produces a cure. Conventional myeloablative allografting has the potential for cure because of its ability to produce molecular remissions through a graft-versus-myeloma effect, although its potential benefit is probably completely offset by the high transplant-related mortality rate. With the development of nonmyeloablative regimens, the benefits of allografting may be realized while the toxicity associated with the procedure may be lessened. In this paper, Bruno and colleagues report a comparison of non-myeloablative allografting with autografting for newly diagnosed myeloma.
One hundred and sixty-two consecutive patients with stage II or III newly diagnosed myeloma aged 65 years or younger were enrolled in a clinical trial at five Italian centers. All patients were initially treated with two or three courses of vincristine, adriamycin (doxorubicin), and dexamethasone (VAD). Patients with an HLA-matched sibling were offered a standard autograft using 200 mg of melphalan per square meter and, upon recovery, an allograft using sublethal total-body irradiation (200cGy) on day 0. Patients without an HLA-identical sibling were assigned to receive double autologous transplantation using a preparative regimen of 140 to 200 mg melphalan per square meter for the second transplant. Statistical analysis was performed using the intent-to-treat principle. After a median follow-up of 45 months, the median overall survival and event-free survival were longer in the 80 patients with HLA-identical siblings than in the 82 patients without HLA-matched siblings (80 months versus 54 months, p=0.01; and 35 months versus 29 months, p=0.02, respectively). Among the patients that completed their assigned treatment protocol, the treatment-related mortality did not differ significantly between the double autologous transplant group (2 percent) and the auto-allograft group (10 percent). Yet disease-related mortality was significantly higher in the double autologous transplant group (43 percent) compared with the auto-allograft group (7 percent). According to the authors, among patients with newly diagnosed advanced-stage myeloma, survival in recipients of an autograft followed by an allograft from an HLA-matched sibling is superior to that in recipients of tandem autografts.
In Brief
It is somewhat difficult to develop an algorithm of treatment recommendations for younger patients with newly diagnosed advanced-stage myeloma given the conflicting outcomes with each treatment strategy in the published clinical trials. Questions remain: chemotherapy versus autotransplantation, early versus late transplantation, single versus double transplantation, or autotransplantation followed by maintenance chemotherapy? Bruno and colleagues now advance the case for considering autografting followed by non-myeloablative allografting as a preferred treatment option in suitable patients. Support for graft-versus-myeloma reactions are provided by the fact that with the exception of T-cell depletion studies, relapse rates are consistently lower in virtually every paper published with allografting for myeloma. The use of dendritic cells or vaccination to the idiotype protein may be of benefit following autologous or allogeneic HCT, and this is an area under investigation. Results from the U.S. Clinical Trials Network study comparing tandem autotransplantation with autografting followed by non-myeloablative allografting will be met with much anticipation. For now we must continue to inform our patients of the available treatment options and be content knowing that the path for treating myeloma has many directions.
Competing Interests
Dr. Lowsky indicated no relevant conflicts of interest.
