Newly diagnosed multiple myeloma: allograft or autograft?

Abstract

This study compared autologous peripheral blood stem cell transplantation (ASCT, autograft) followed by reduced intensity allogeneic stem cell transplantation (allograft) from an HLA-identical sibling to the tandem ASCT (double autograft) in newly diagnosed patients of multiple myeloma. Two hundred and forty-five newly diagnosed, consecutive patients (age <65 years) were enrolled into this 5-centre study in Italy. The presence of an HLA-identical sibling was the only criterion for randomization. Among 245 patients, 199 had siblings; and 162 of these 199 underwent HLA typing to determine if they had potential HLA-identical donors. Eighty of 162 patients who had an HLA-identical sibling were assigned to ASCT followed by reduced intensity allogeneic stem cell transplantation (autograft-allograft group). The remaining 82 patients were assigned to double or tandem ASCT (autograft group). All patients initially received induction chemotherapy (vincristine, adriamycin and dexamethasone) and, following recovery from chemotherapy all patients underwent the first ASCT. Following ASCT, patients with an HLA-identical sibling donor (n=80) were advised reduced intensity allogeneic SCT within 1-3 months. Patients with no HLA-identical sibling (n=82) were advised a second ASCT. The overall and event-free survival were primary endpoints and an intention-to-treat analysis was done. Complete (CR) and partial response (PR), and relapse were defined as per standard criteria. Among 80 patients with an HLA-identical sibling, 15 refused allografting as first-line treatment and 5 did not have an eligible donor. Thus, 60 were assigned for the autograft-allograft treatment but only 58 completed treatment. Following recovery from ASCT, patients underwent allografting at a median of 94 days. Post-allograft, 32 (55%) achieved CR and 18 (31%) had PR. Overall, 21 of 58 patients (36%) were in CR after a median follow up of 38 months (range: 10-72 months). The cumulative incidence rates of grades II-III and IV acute graft-versus-host disease (GVHD) were 43% and 4%, respectively. Thirty-seven patients had evidence of chronic GVHD. The cumulative incidence of treatment-related mortality at 2 years was 10%. Of the 82 patients who did not have an HLA-identical sibling, 59 patients were assigned to receive a double autologus transplant. Of these, only 46 patients received a second autotransplant at a median interval of 123 days after the first transplant. Following the second transplant, 12 patients (26%) achieved CR and 29 (63%) had PR. After a median follow up of 36 months from the second transplant, 27 patients had relapsed and only 4 were in CR. The cumulative incidence of transplant-related mortality at 2 years was 2%. The overall response rates after induction chemotherapy and first autograft did not differ significantly between the 2 groups (p=0.74 and p=0.83, respectively). However, CR was significantly higher in the autograft-allograft group than in the double autotransplant group (55% v. 26%, p=0.004). The 2 groups did not differ significantly with respect to treatment-related mortality after a median follow up of 45 months (p=0.09) but disease-related mortality was significantly higher in the double autologous transplant group than in the autograft-allograft group (43% v. 7%, p<0.001). At a median follow up of 46 months (range: 22-88 months) the median overall survival was not reached in the autograft-allograft group and was 58 months in 46 patients who had completed double autografts (hazard ratio 0.46; 95% CI: 0.23-0.93; p=0.03). Multivariate analysis of all 104 patients who completed the assigned treatment revealed that patients in the autograft-allograft group had a significantly longer overall (p<0.01) and event-free survival (p<0.009) compared with those who received a double autograft.