ALBERT

Description: Complete response (CR) is an important objective of autologous stem-cell transplantation (ASCT) in multiple myeloma (MM). In comparison with conventional induction treatments, newer combinations of novel agents may effect increased rates of CR and near CR (nCR), a benefit potentially translating into even higher frequencies of CR/nCR after ASCT and improved clinical outcome. We designed a phase III study to detect an increase in CR+nCR rates from 10–15% with conventional Thalidomide-Dexamethasone (TD) to 20–30% with Velcade added to TD (VTD) in newly diagnosed MM. Both TD and VTD were given as three 21-day cycles in preparation for double ASCT. In the present analysis, CR+nCR rates by the two induction treatments were examined in relationship to baseline prognostic variables in 399 evaluable pts aged ≤65 years, of whom 199 randomized to VTD and 200 to TD. All analyses were intent to treat. In comparison with TD, VTD effected higher rates of CR+nCR (12% vs 33%, P

Description: 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

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: Abstract 5123 Vertebral compression fractures occur in approximately 60% of MM patients and can cause pain, persistent disability and dismail quality of life. Appropriate therapy of MM or radiotherapy can lead to improvement of symptoms in a significant percentage of patients, but these positive effects can take time to be perceived. Vertebral agumentation techniques have been recently proposed as suitable options to relieve bone pain from vertebral compression fractures in patients with benign osteoporosis or neoplastic diseases such as MM. Aim of this study was to analyze the clinical course and outcome of 40 consecutive MM patients (23M, 17F, median age = 67.6yrs) treated in the Centers referring to GER, who underwent percutaneous vertebroplasty from 2006 to 2010. Seventeen patients (43%) were newly diagnosed while 23 patients were relapsed or refractory after 1–3 lines of therapy. All the patients were treated because of severe pain, the extent of vertebral fractures was assessed by nuclear magnetic resonance imaging. Sixty-nine procedures were performed at C2-L5 levels, 51% of the patients were treated at a single level, a maximum of three levels were treated in 6 patients, 13 procedures (32%) were performed at L1 level. Thirty seven patients (92%) experienced reduction of pain, with 55% showing complete disapperance of symptoms prior to any further treatment, 3 patients reported no or little improvement. Responses were durable, after a median follow-up of 14 months no further collapse of the treated vertebrae was observed. After vertebroplasty, first line or salvage therapy was administered to 35 patients, 10 newly diagnosed patients were scheduled to receive autologous stem cell transplant, and peripheral blood stem cell collection was not affected by the procedure. In conclusion, percutaneous vertebroplasty appears to be useful in MM patients with painful vertebral fractures as it allows rapid and durable achievement of pain control, without interfering with further therapeutic programs Work supported in part by RiminiAIL Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 781 Aim of the present study was to evaluate the impact of bortezomib-based induction treatments on clinical outcomes of newly diagnosed multiple myeloma (MM) patients with unfavorable cytogenetic abnormalities. For this purpose, we analyzed 590 bortezomib-treated patients who were screened at diagnosis for the presence of del(13q), t(4;14) and del(17p) by fluorescence in situ hybridization (FISH) on highly purified bone marrow plasma cells. Patients were stratified into the following 3 groups based on 1) the absence of any cytogenetic abnormality (n=261, or 44%) or 2) the presence of del(13q) alone (n=175, or 30%) or 3) positivity for t(4;14) and/or del(17p) (n=154, or 26%). In the great majority of the patients, loss of 17p was detected in more than 70% of bone marrow plasma cells, a finding which precluded a comparison with patients carrying del(17p) in a lower percentage of plasma cells. After diagnosis, 218 patients received induction therapy with bortezomib-thalidomide-dexamethasone (VTD), while the remaining 372 patients were treated with bortezomib-melphalan-prednisone (VMP) (n=181) or VMP plus thalidomide (VMPT) (n=191). The median number of bortezomib infusions (1.3 mg/m2) actually received was 24. Baseline characteristics of the 3 groups of patients were comparable, with the exception of a higher frequency of ISS stage 3 among patients with t(4;14) and/or del(17p) as compared with the cytogenetic-negative group (29% vs 17%, respectively; p=0.003). The rates of absence or presence of del (13q), t(4;14) and/or del(17p) were comparable among patients receiving VTD or VMP or VMPT treatments. Best CR to overall treatment protocols was 39% for the cytogenetic-negative group and 44% for high-risk patients carrying t(4;14) and/or del(17p). With a median follow-up of 27.5 months, median PFS was 40.5 months for patients without cytogenetic abnormalities as compared with 34 months for the high-risk group (p=0.7), while it was not reached after 38 months in the group with del(13q) alone (p not statistically significant for comparison with the other two groups). Overall, the frequency of events was 31% for patients without cytogenetic abnormalities or with del(13q) alone in comparison with 38% for those with high-risk cytogenetic profiles (p=0.15). Median OS was not reached in any of the 3 groups. Forty-month projected OS rates were 89% for the cytogenetic-negative group, 81% for the group with del(13q) alone (p=0.6) and 77% for the high-risk group (p=0.003 for comparison between this latter and the cytogenetic-negative group). Patients with t(4;14) and/or del(17p) had a shorter OS after relapse in comparison with the cytogenetic-negative group (20-month projected rates: 60% vs 76%, respectively; p=0.01). To more carefully evaluate the prognostic relevance of high-risk cytogenetic abnormalities, we stratified patients in the high-risk group into the following 3 subgroups: 1) t(4;14)-positive but del(17p)-negative (84 patients); 2) del(17p)-positive in the absence of t(4;14) (54 patients); t(4;14)-positive and del(17p)-positive (16 patients). Median PFS was not reached after 40 months for patients with t(4;14) alone, while it was 33 months for patients with del(17p) alone (p=0.1) and was 18.5 months for those who carried both these abnormalities (p=0.0008 for comparison between these latter patients and t(4;14)-positive patients). Overall, the frequency of events was 30% and 41% for patients carrying either t(4;14) or del(17p), respectively (p=0.13), while it was as high as 69% for patients with both these abnormalities. The 40-month projected OS rates for these 3 subgroups were 79%, 82% and 64%, respectively (p not significant). In conclusion, the present analysis of a large series of newly diagnosed MM patients receiving bortezomib-based induction treatments showed that: 1) del(13q) alone had no adverse effect on both PFS and OS; 2) the presence of t(4;14) and/or del(17p) did not adversely influence PFS, but was associated with a shorter OS, due at least in part to a worse outcome after relapse; 3) in comparison with t(4;14), del(17p) alone did not predicted for shorter PFS and OS, possibly as a result of the relatively long-term exposure to bortezomib); 4) the presence of both del(17p) and t(4;14) was likely to confer a particularly dismal clinical outlook, a finding which needs to be confirmed in larger series of patients. Disclosures: Cavo: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, 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, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib-based treatment for newly diagnosed multiple myeloma. Petrucci:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Boccadoro:NOVARTIS: Honoraria; CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Palumbo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, no.