Superiority of Double over Single Autologous Stem-Cell Transplantation for Newly Diagnosed Multiple Myeloma and Prognostic Impact of Complete Response: Final Analysis of “Bologna 96” Study.

We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell (SC) transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma. A total of 321 patients were enrolled in the study and were randomly assigned to receive either a single course of SC-supported melphalan, 200 mg/m² (MEL-200) (n=163 patients) or MEL-200 followed, 3 to 6 months apart, by melphalan, 120 mg/m², and busulfan, 12 mg/kg (n=158 patients). As compared with arm A, randomization to receive double ASCT significantly increased the probability to attain at least a near (n) complete response (CR) (33% vs 47%, respectively; P=0.008). Patients who responded to induction therapy had a CR or nCR rate following either single or double ASCT of 73% and 52%, respectively (P=0.010). Both these values were much higher than those observed among patients who failed to respond to induction therapy, whose posttransplantation ≥ nCR rate was 11% in arm A and 12% in arm B (P=0.20). On multivariate analysis, randomization to double ASCT (P<0.001) and partial response to induction therapy (P<0.001) were independent significant predictors of posttransplantation attainment of CR or nCR. In comparison with a single autotransplantation, double ASCT resulted in a significant prolongation of both relapse-free survival (RFS) (median: 42 vs 23 months, respectively; P<0.001) and event-free survival (EFS) (median: 35 vs 23 months, respectively; P=0.001). The most important and independent variable favorably influencing RFS and EFS in a multivariate model was ≥nCR (P<0.001 for both RFS and EFS). Additional prognostic factors for extended EFS included baseline platelet count greater than 150.000/μL (P=0.004), randomization to double ASCT (P=0.005), hemoglobin level greater than 10 g/dL at diagnosis (P=0.01) and less than 55 years of age (P=0.04). Administration of a second transplantation and of novel agents, including thalidomide or bortezomib, for the treatment of sequential relapses in up to 50% of patients who were randomized to single transplantation likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplant group (43%) (P=0.9). Prolonged OS was significantly related to baseline hemoglobin concentration greater than 10 g/dL (P<0.001), serum creatinine level less than 177 μmol/L at diagnosis (P=0.001) and ≥ nCR (P=0.001). Benefits offered by double ASCT in terms of extended RFS and EFS were particularly evident among patients who failed at least nCR after the first autologous transplantation (P<0.001 for both RFS and EFS). At the opposite, among patients achieving CR or nCR following one transplantation, final outcomes of ASCT(s) were not significantly influenced by study randomization. Because of its potential of inducing long-term EFS and OS in the 30% to 50% range, double ASCT still remains the standard of care for younger patients with newly diagnosed MM. Attainment of CR is a surrogate marker of extended RFS, EFS and OS, and represents an important objective of novel treatment strategies combining high-dose chemotherapy with agents targeting the bone marrow microenvironment.