ALBERT

Description: Abstract 3562 Aim of the present study was to evaluate the clinical outcome of a large series of younger patients with symptomatic multiple myeloma (MM) who were enrolled in two subsequent clinical trials of thalidomide-dexamethasone (thal-dex) incorporated into double autologous stem-cell transplantation (ASCT) to support high-dose melphalan (200 mg/m2). In both studies, thal (100 mg/day for the first 14 days and then 200 mg/day) and pulsed dex (between 480 and 160 mg per cycle), were administered from the onset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 593 patients who were followed for a median of 36 months. The best VGPR and CR rates were 69% and 35%, respectively. The median duration of CR was 66 months. Median TTP and PFS were 53 and 44 months, respectively. The 5-year projected rates of TTP and PFS were 46% and 38%, respectively, while the corresponding value for OS was 67%. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities by FISH analysis. Forty-five percent of patients had del(13q), while t(4;14) and del(17p) were found in 16 % and 7 % of patients, respectively. The presence of del(17p) and/or t(4;14) was associated with a significantly shorter 5-year projected TTP, PFS and OS in comparison with the absence of these abnormalities, indifferently from the presence or absence of del(13q) (TTP: 30% vs 53%, respectively P=0.0000; PFS: 28% vs 45%, respectively, P=0.0000; OS: 53% vs 69%, respectively, P=0.0000). OS and PFS curves of patients carrying del(13q) alone were almost superimposable to those of patients without cytogenetic abnormalities, while TTP was significantly shorter for patients with del(13q) alone (5-year projected rates: 40% vs 53%, respectively, P=0.04). Patients carrying del(17p) in the absence of t(4;14) had similar 5-year projected TTP and PFS as compared with t(4;14) positive but del(17p) negative patients. However, OS was significantly shorter for the subgroup with del(17p) and absence of t(4;14) in comparison with that of patients carrying t(4;14) without del(17p) (5 year projected rates: 18% vs 70%, respectively, P=0.03). In a multivariate analysis, presence of del(17p) and high beta2-m at baseline were the most important variables adversely influencing TTP (HR: 2.3, P=0.001 and HR: 1.8, P=0.002, respectively), PFS (HR: 2.0, P=0.001 and HR: 1.9, P=0.001, respectively), and OS (HR: 3.9, P=0.000 and HR: 2.0, P=0.005, respectively). Additional variables predicting for shorter TTP and PFS were the presence of t(4;14) (HR: 1.8, P=0.004) and of del(13q) (HR: 1.6, P= 0.009). Also the quality of best response to the overall treatment program influenced clinical outcomes. In particular, patients achieving CR had a significantly longer PFS and OS than those achieving a VGPR (PFS: median 68 vs 40 months, respectively, P=0.007; 5-year projected OS rates: 84% vs 70%, respectively, P=0.01). In conclusion, incorporation of thal-dex into double autotransplantation failed to overcome the poor prognosis conferred by del(13 q), t(4;14) and del(17p). In a multivariate Cox regression analysis, del(17p) and high levels of serum beta2-m at diagnosis were the strongest variables adversely influencing PFS and OS. In comparison with the presence of t(4;14) but absence of del(17p), patients carrying del(17p) without t(4;14) had a significantly shorter OS, possibly due to their worst outcome after relapse. Presence of del(13q) alone conferred a significantly shorter TTP, but did not have an adverse impact on OS due to the favorable role of effective salvage therapies incorporating either bortezomib or lenalidomide. Disclosures: Off Label Use: use of first line thalidomide in preparation for ASCT. Cavo:Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, no; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no.

Description: Background. Array-based technology has been showing a great impact on clinical cancer cytogenetic, especially on genetically heterogeneous disease, such as MM, where relevant lesions might be the hallmarks of different patients’ subgroups, thus becoming of clinical relevance as well. We present herein the results of a molecular sub-study of the EMN02 phase III study (EMN02_HOVON95) which was designed to compare consolidation therapy Bortezomib, Melphalan and Prednisone versus upfront autologous stem cell transplantation, both applied after induction therapy with bortezomib-cyclophosphamide-dexamethasone (VCD). The sub-study was aimed at developing a comprehensive, high throughput genomic profile to be used to stratify uniformly treated MM patients according to their genomic background at baseline and to perform correlations with response to induction therapy. Patients and methods. Data obtained from 170 patients who consecutively entered the study and received three 21-day cycles of VCD induction therapy were analyzed. Baseline patients’ characteristics, including cytogenetic abnormalities, were comparable with those of 717 patients enrolled by participating Italian centres. Highly purified CD138+ bone marrow plasma cells were profiled by SNPs array (Affymetrix 6.0 and CytoScanHD® chip). ChAS (Affymetrix) and Nexus Copy NumberTM 7.5 (Biodiscovery) software were used to perform Copy Number Alterations (CNAs) analyses and clinical correlations, respectively. Results. After induction therapy, 66 out of 170 (38.8%) patients achieved a very good partial response (VGPR) or better, including 15 (8,8%) who attained a complete response (CR). On the contrary, 104/170 (61.1%) patients achieved

Description: Abstract 349 We report here on the final analysis of the multicenter phase II “Bologna 2002” study which incorporated thal-dex into double ASCT with high-dose melphalan (200 mg/m2) as front-line therapy for younger patients with symptomatic multiple myeloma (MM). By study design, thal (200 mg/day) and pulsed low-dose dex (160 mg/month, with two added 4-day courses on the first and third cycle of induction therapy) were administered from the outset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 357 patients who were followed for a median of 43 months. Their median age was 57 years, 86% had advanced disease stage. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities (FISH) on CD138+ bone marrow plasma cells, including del(13q) (45%), t(4;14) (14%) and del(17p) (6%). The rate of at least VGPR increased from 31% after thal-dex induction therapy to 60% after the second ASCT. The final CR rate was 33% for all the patients and 44% for those who actually received pre planned double ASCT. Median TTP and PFS were 68 and 47 months, respectively, with 5-year projected rates of 45% and 33%. The 5-year projected OS rate was 65%. TRM after the first and second ASCT was 0.5% and 2%, respectively. Median OS after relapse or progression was 30 months, suggesting that short-term thal exposure had no adverse influence on response to salvage therapies. The quality of response following ASCT(s) influenced clinical outcomes. In particular, patients achieving CR had significantly longer PFS and OS than patients in VGPR (PFS: median 68 vs 48 months, respectively, P=0.04; 5-year projected OS 84% vs 72%, respectively, P=0.02). Similarly, patients in VGPR had better outcomes compared with patients achieving PR (P=0.02 and 0.04 for PFS and OS comparisons, respectively). In a multivariate analysis, best response (at least VGPR) ever achieved and low beta2-m were the most important variables significantly extending TTP (P=0.04), PFS (P=0.000) and OS (P=0.003). Additional variables predicting for prolonged PFS were the absence of del(13q) (P=0.002) and del(17p) with or without t(4;14)(P=0.03). OS was favourably influenced also by IgG isotype (P=0.04) and absence of high-risk cytogenetic abnormalities [del (17p) +/- t(4;14)(P=0.03)]. A case match comparison of 135 patients enrolled in “Bologna 2002” study with an equal number of pair mates included in the previous “Bologna 96” study of double ASCT without thal confirmed the benefits from the addition of thal-dex to double autotransplantation in terms of rate (P=0.001) and duration (p

Description: Abstract 594 Survival of patients with multiple myeloma (MM) has been extended with the introduction of autologous stem cell transplantation (ASCT). More recently, availability of highly effective novel agents has further improved patient outcomes. However, it is still the matter of debate whether a proportion of patients treated with ASCT can enjoy a long term survival, while sustaining prolonged high quality response. To address this issue and to identify those variables which were related to long-term survival, we performed a post-hoc analysis of two large prospective clinical trials of ASCT in newly diagnosed MM patients, the first one comparing single versus double ASCT and the second one incorporating thalidomide-dexamethasone (TD) into double ASCT. A total of 321 patients were randomly assigned in the first study to receive either a single or double ASCT, as previously described (Cavo M et al, JCO 2007). Three hundred and fifty seven patients were enrolled in the subsequent multicenter phase 2 study incorporating TD from the outset until the second ASCT; details of the protocol were previously reported (Cavo et al, J. Clin. Oncol 2009). Results were updated as of 30 March 2012 and compared with those previously reported. All the analyses were performed on an intention-to-treat basis. After a median follow-up of 61 months for the entire treatment population of the first study, PFS remained significantly longer with tandem versus single ASCT (median 37 vs 25 months, P= 0.012), while OS was similar in the two groups (median 71 vs 67 months). 47% and 33% of the patients in the double and single ASCT group achieved a CR+nCR (P= 0.008). Overall, in 24% and 11% of the patients, CR+nCR was sustained for more than 5 and 10 years, respectively. In a multivariate Cox regression analysis, best response (CR+nCR) ever achieved was the most important variable significantly extending PFS (P= 0.003) and OS (P=0.050); random assignment to double ASCT was an additional variable predicting for prolonged PFS(P= 0.026). After a median follow-up of 84 months from starting TD in the second study, median values of PFS and OS were 47.2 and 109.6 months, respectively. The final rate of CR+nCR was 34%, which was maintained for a median of 53 months. Overall, in 42.1% and 9.1% of the patients CR+nCR was sustained for more than 5 and 8 years, respectively. On multivariate analysis, failure to ever achieve at least CR+nCR, low Hb, high β2-m and t(4;14)±del(17p) were found to be independent variables predicting for poorer outcomes. In particular, a shorter OS was seen for patients ever lacking high-quality responses (HR: 0.35, 0.23–0.54, p

Description: Abstract 317 Introduction: The novel agents bortezomib, thalidomide and lenalidomide have been successfully incorporated into autologous stem-cell transplantation (ASCT) as up-front therapy for newly diagnosed MM. However, several reports have raised concerns about the impact of novel agent-based induction regimens on PBSC collection. Furthermore, the ability to successfully collect PBSCs following initial therapy with two of these newer drugs needs to be confirmed in large phase III clinical trials. Methods: The GIMEMA Italian Myeloma Network designed a phase III study to compare VTD with thalidomide-dexamethasone (TD) as induction therapy prior to double ASCT. Primary study endpoint was the rate of complete or near complete response to each of these two induction regimens, while their toxicity profile – including the impact on PBSC mobilization and collection - was a secondary study endpoint. To address this latter issue, we performed a post-hoc analysis to compare the effect of the triplet VTD induction regimen versus the doublet TD combination on CD34+ cell collection. After three 21-day cycles of VTD or TD induction therapy, patients received intermediate dose cyclophosphamide (CTX 4 g/m2) followed by G-CSF (10 mcg/Kg/die) to mobilize and collect PBSCs. The target threshold to safely perform double ASCT was 4 × 106 CD34+ cells/Kg. Results: Patients evaluable for PBSC collection were 435 out of the 474 who received induction therapy. Of these, 223 were initially randomized to VTD and 212 to TD induction therapy. The median number of collected CD34+ cells was 9.7 × 106/Kg in the VTD arm and 10.7 × 106/Kg in the TD arm (p= n.s.). The planned yield of 4 × 106 CD34+ cells/Kg was achieved with a single harvest in more than 90% of patients in both treatment groups (96% in VTD and 92% in TD, p= n.s.). A yield of CD34+ cells 〉10 × 106 /Kg was reported in 51% and 56% of patients treated with VTD and TD, respectively (p= n.s.). Only 5 patients (2%) in VTD group and 2 patients (1%) in the TD arm failed to collect more than 2 × 106 CD34+ cells/Kg (p= n.s.). The majority of patients (86% in VTD and 82% in TD, p=n.s.) received CTX as an in-patient procedure, the median time of hospitalization being 4 days. Less than 5% of patients developed grade 3–4 infectious complications (2% in the VTD group vs 3% in TD, p=n.s.) which required hospitalization in only 2 patients. Following ASCT, no significant difference was observed between the two treatment arms in terms of hematologic recovery and non hematological toxicity. Kaplan-Meier curves of TTP and PFS were almost superimposable for patients with a CD34+ yield 〉10 × 106/Kg and in the range between 4 and 10 × 106/Kg (group 1). These curves were very similar also for patients who collected between 2 and 4 × 106/Kg CD34+ cells or 10 × 106/Kg CD34+ cells was in the 90% range, a value significantly better than what was seen in the remaining subgroups. In a multivariate Cox regression analysis, yields of CD34+ cells 〉10 × 106/Kg and in the range of 4 to 10 × 106/Kg were independently associated with prolonged PFS (p=0.001 and =0.027, respectively), while CD34+ cells 〉10 × 106/Kg predicted for extended OS (p=0.002). Absence of t(4;14) and/or del(17q), and ISS stage 1 or 2 were additional favorable prognostic factors for both PFS and OS, while randomization to VTD independently predicted for longer PFS. Conclusions: Results of the present analysis showed that both TD and VTD shared the advantage of no adverse impact on PBSC collection and the engraftment potential of collected PBSCs. The target for CD34+ cell collection (〉4 × 106/Kg) was achieved with a single harvest in more than 90% of patients in both treated groups and a collection failure was reported in 1% to 2% of patients. These favorable results are due to early PBSC collection, which was performed after 3 cycles of TD and VTD, and use of CTX plus G-CSF which allows better stem cell collection and less likelihood of a collection failure. Of particular note, both VTD and TD were associated with a 50% to 59% probability to collect 〉10 × 106 CD34+ cells/Kg, a variable independently associated with extended PFS and OS. Disclosures: Off Label Use: bortezomib and thalidomide used as induction therapy for newly diagnosed multiple myeloma patients. Baccarani:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Genzyme: Honoraria.

Description: 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 1st and 3rd 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.

Description: Venous thromboembolism (VTE) has emerged as a major adverse event of primary induction therapy with thalidomide (thal) and dexamethasone (dex) for newly diagnosed multiple myeloma (MM). Aim of the present study was to investigate the relationship between thrombophilic alterations and the risk of VTE in 266 patients who received four months of therapy with thal (200 mg/d) and pulsed high-dose dex in preparation for double autologous transplantation. The rate of VTE in the whole group of patients was 11.6%. The risk of VTE was 26.3% (86.2% patient-years) among the first 19 patients who entered the study and did not received any prophylaxis against thrombosis. The corresponding value among the remaining 247 patients who received thromboprophylaxis with fixed low-dose (1.25 mg/d) warfarin during the four months of thal-dex therapy was 10.6% (35.5% patient-years) (P=0.04). Episodes of VTE occurred at a median of 53 days from the start of thal therapy and, with the exception of 3 patients, were observed after at least a partial response to thal-dex was documented. No VTE events were recorded during the first two months after the end of the induction phase. After VTE occurrence, the majority of patients went on with thal treatment plus full anticoagulation, without evidence of progression of thrombosis. One hundred and ninety patients were evaluated for the presence of thrombophilic alterations at baseline and at the end of thal-dex therapy. The prevalence of factor V Leiden (3.2%) or g20210A prothrombin (2.1%) polymorphism in patients with MM was similar to that observed in 183 healthy controls (3.3%, P= 0.81; 3.8%, P= 0.50, respectively). The relative risk of VTE for patients carrying one of these thrombophilic alterations was 20% compared with 9.4% for patients who lacked both of them (P= 0.58). Reduced protein C and S activities or acquired activated protein C resistance (aAPCR) were recorded at baseline in 11% and 7.4% of MM patients, respectively. Abnormal values at baseline normalized almost completely at the end of treatment. Carriers of aAPCR and/or of reduced levels of natural anticoagulants at baseline did not have a significantly higher risk of VTE compared with normal patients (15.2% vs 9.3%; P=0.49). In conclusion, no significant relationship was found between baseline thrombophilic alterations, including aAPCR, and the risk of thal-related VTE. Prophylaxis with fixed low-dose warfarin was associated with an apparent decrease in the rate of VTE in comparison with a subgroup of patients who did not receive any thromboprophylaxis. A prospective phase III study comparing low molecular weight heparin with fixed low-dose warfarin with aspirin is currently ongoing in Italy to evaluate the best prophylaxis against the risk of thal-related VTE for patients with newly diagnosed MM.