Incorporation of Thalidomide into Up-Front Double Autologous Stem-Cell Transplantation (ASCT) for Multiple Myeloma Improves the Outcome in Comparison with Double ASCT without Thalidomide. Analysis of Baseline Factors Predicitve of Outcome.

The phase II “Bologna 2002” clinical study incorporated thalidomide-dexamethasone (thal-dex) into double ASCT with melphalan (200 mg/m²) as frontline therapy for patients with symptomatic multiple myeloma (MM) and less than 65 years of age. By study design, thal (200 mg/d) and dex (40 mg/d x 4d every month, with two added courses on the 1^st and 3^rd month of therapy) were administered from the outset until the second ASCT. An analysis was performed on 311 consecutive patients who entered the study from January 2002 to March 2006 and were followed for a median of 32 months. On an intention-to-treat (ITT) basis, the ≥ very good partial response (VGPR) rate increased from 29% after 4 months of primary induction therapy with thal-dex to 63% after the second ASCT. Transplantation-related mortality after first and second ASCT was 1% and 3%, respectively. Median durations of relapse-free survival (RFS) and event-free survival (EFS) were 52 and 42 months, respectively. The 5-year projected overall survival (OS) rate was 70%. A case-match comparison of 135 of these patients with an equal number of pair mates who entered the “Bologna 96” study and were randomly assigned to receive double ASCT without thal showed significant benefit from incorporation of thal into double ASCT in terms of increased ≥VGPR rate (68% vs 49%, respectively; P=0.001) and extended RFS (54% vs 32% at 5 years; P=0.005) and EFS (median: 52 vs 33 months; P=0.01). All 311 patients were screened on purified CD138+ bone marrow plasma cells for the presence at diagnosis of chromosome 13 alterations [del(13)] (47% of cases) and t(4;14) (13% of cases). In a logistic regression analysis, neither del(13) nor t(4;14) adversely influenced response (≥VGPR) to primary induction therapy with thal-dex. At the opposite, both absence of del(13) (P=0.001) and low beta2- microglobulin (beta2-m) levels (P=0.007) were significantly related to attainment of ≥VGPR after the second ASCT. In a multivariate analysis of all 311 patients, the most important variable significantly extending time to progression (TTP), EFS and OS was the absence of del(13) (P=0.001, P=0.001 and P=0.007, respectively), along with attainment of ≥VGPR after the second ASCT. OS was also significantly influenced by both beta2-m (P=0.044) and hemoglobin (Hb) concentration (P=0.05), whereas platelet count was an additional prognostic factor for TTP (P=0.025). In conclusion, in comparison with double ASCT, incorporation of thal into double ASCT as up-front therapy for MM significantly improved the response rate (≥ VGPR), RFS and EFS, without adversely affecting postrelapse OS. The presence of del(13) by FISH analysis was the most important and independent variable adversely influencing attainment of ≥ VGPR, EFS and OS following thal-dex and double ASCT.