ALBERT

Beschreibung: Abstract 492 Background. The risk of venous thromboembolism (VTE) is high in newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens. Anticoagulant prophylaxis is recommended. Controversies exist on the best thromboprophylactic regimen to adopt. Aims. In this prospective, multicenter phase III trial we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) or low-fixed dose warfarin (WAR) as anticoagulant prophylaxis. End-points were incidence of VTE, acute cardiovascular events, sudden death, major and minor bleeding. Methods. In a GIMEMA study, 991 newly diagnosed MM patients were randomized to VTD (Velcade 1.3 mg/m2 d 1,4,8,11; Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or TD (Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or VMPT (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4; Talidomide 50 mg/d) or VMP (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4). In a sub-study, patients treated with VTD or TD or VMPT were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=223) or ASA (Aspirin 100 mg/d, N=227) or WAR (Warfarin 1.25 mg/d, N=223) for the duration of the induction therapy; 61 patients were excluded from sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Patients treated with VMP (N=257) did not receive any prophylaxis and were used as controls. Results. Patient characteristics and distribution of major risk factors were similar in all groups. The incidence of VTE was 5% in the LMWH group, 6% in the ASA group and 8% in the WAR group (p not significant). VTEs were 2% in the VMP group. Median time to onset of VTE for patients who received LMWH or ASA or WAR were 4.7, 2.4 and 2.4 months, respectively. Patients who received higher doses of both steroids and thalidomide (VTD and TD) had a higher VTE incidence (7%) in comparison with those who received lower doses (VMPT, 3%, p=0.06). Patients treated with bortezomib (VTD and VMPT) had a lower VTE incidence (5%) in comparison with patients on TD (8%, p=0.08). The rates of cardiovascular events were 2% in the LMWH group, 1% in the ASA group and 0.5% in the WAR group. The incidence of major and minor bleeding was 2% in the LMWH group, 3% in the ASA group and 1% in the WAR group (p not significant). The incidence of combined thrombosis, bleeding and cardiovascular events was 9% in the LMWH group, 10% in the ASA group and 9% in the WAR group (p not significant). Conclusion. The overall incidence of VTE was less than 10% in all groups and was not superior to that expected during the natural course of MM. The LMWH patients had lower risk of VTE, although no statistical difference was observed. LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens. The final analysis on 991 patients will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: C-KIT gene mutations are not a rare event in Core Binding Factor Leukemia (CBFL). To investigate their prognostic impact in this setting , we attempted at correlating the KIT mutational status with the WBC count, the level of the WBC-index, the presence of extramedullary disease (EMD) and the outcome, in t(8;21)(n=30) and inv(16) (n=20) AML patients. On the basis of genomic DNA analysis of c-KIT gene exons 2, 8, 10, 11, 17 for mutation detection, we categorized 21 patients (42%) in the “KIT mutated group” (KIT+) and 29 patients (58%) in the “KIT unmutated group” (KIT−). The median age at diagnosis was 46.4 and 45.6 years for the KIT(+) and KIT(−) groups, respectively (P=0.872). Among the KIT(+) patients, we found mutations in exon 8 (n = 4), exon 10 (n =1), exon 11 (n = 1) and exon 17 (n = 15). We recorded mean WBC counts of 28.6 x 109/L vs 34.5 x 109/L (P=0.051), and a mean WBC-index, expressed as WBC x (% Bone Marrow blasts/100), of 37.2 vs 15.5 (P=0.0395), for KIT(+) and KIT(−), respectively. Seven out of 50 patients experienced an EMD: in 6 cases (28.57%) this event occurred in the KIT(+) group. 40 patients (age 〈 60 years) were evaluable for clinical response; 18 out of them were KIT mutated. At a median follow-up of 24 months (range 10–107), we recorded for KIT(+) and KIT(−), respectively: CR incidence of 88.8 % (16/18) vs 100% (22/22) (P=0.38); Relapse Incidence 81.3% (13/16) vs 31.81% (7/22), P=0.0072; OS 27.7% (5/18) vs 77.3% (17/22), P=0.0049; DFS 16.7% (3/18) vs 77.3% (17/22), P=0.0005. Using a log-it linear model for univariate and multivariate regression analysis, we found a significant contribution to death (P=0.048) and relapse (P= 0.045) exerted by mutation in the whole group of patients; this effect was more evident when the analysis was restricted to patients

Beschreibung: Abstract 3029 Background. In a recent phase 3 trial, bortezomib–melphalan – prednisone–thalidomide followed by maintenance treatment with bortezomib–thalidomide (VMPT-VT) demonstrated superior efficacy compared with VMP. Peripheral neuropathy (PN) was the most important dose limiting toxicity. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions. This post-hoc analysis assessed the impact of bortezomib dose-modification schedule on clinical outcomes and safety. Methods. Patients (N=511) older than 65 years were randomized to receive nine 6-week cycles of VMPT-VT (N=254; induction:V 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; M 9 mg/m2 d 1–4, P 60 mg/m2, d 1–4, T 50 mg d 1–42; maintenance: V 1.3 mg/m2 every 14 days and T 50 mg/day) or VMP (N=257) alone. In March 2007, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). Patients receiving VMPT-VT and VMP were pooled together and stratified according to the once-weekly or twice-weekly infusion modality; analyses were also conducted for patients receiving VMP only, to eliminate the influence of thalidomide and of maintenance on efficacy and safety. Results. Patients were evaluated in intention-to-treat: 372 patients received once-weekly and 139 twice-weekly bortezomib infusion. Patient characteristics were similar in the two groups, median age was 71 years. The efficacy data did not appear to be affected by the bortezomib schedule. Overall response rates were 85% with once weekly and 86% with twice- weekly schedule (P = .78), including CR rates of 30% and 35% (P = .27).Three-year PFS was 50% in the once-weekly and 47% in the twice-weekly group (P = 1.00), and 3-year OS was 88% and 89%, respectively (P = .54). Similar outcome was seen in the analyses restricted to VMP patients: CR rates were 23% with once-weekly and 27% with twice-weekly schedule (P = .54), 3-years PFS was 46% in once-weekly and 39% (P = .86) in twice-weekly group and 3-years OS was 87% and 89% (P = .47), respectively. The incidence of grade 3/4 hematologic toxicity was similar in the two groups (44% vs 45%, P = .83), but severe thrombocytopenia was slightly less common in the once-weekly patients (19% vs 26%, P = .08).The incidence of non-hematologic grade 3/4 adverse events was significantly reduced in the once-weekly: 35% vs 51% (P = .003). Grade 3/4 gastrointestinal events (6% vs 11%, P = .08), severe systemic events (4% vs 7%, P = .09) and grade 3/4 dermatologic events (2% vs 7%, P = .006) were less frequent in patients receiving once-weekly bortezomib. There was a significantly reduced overall incidence of grade 3/4 PN (8% vs 28%, P 〈 .001) in the once-weekly group. The median time to onset of grade 3/4 sensory PN was 4.3 months in the once-weekly group and 3.2 months in the twice-weekly group (P = .10). The cumulative incidence of sensory PN appeared to plateau after 12 months of therapy in both groups. Rates of discontinuations (5% versus 15%) and dose reductions (15% versus 41%) due to PN were also significantly lower in the once-weekly group (P 〈 .001). These results were reflected in analysis restricted to VMP patients, in which the incidence of grade 3/4 PN (7% vs 29%, P 〈 .001), the discontinuation rate (4% vs 16%, P = 0.002), and the dose reductions rate (15% vs 41% P 〈 0.001) were significantly lower in once-weekly group. Despite the cumulative planned dose being lower in the once-weekly group (46.8 vs 67.6 mg/m2), the delivered cumulative dose of bortezomib was similar in the two groups (39.4 mg/m2 vs 40.1 mg/m2). No association of PN with age or other baseline characteristics was outlined. The only significant factor influencing the incidence of PN was the reduction of bortezomib infusion from twice- to once-weekly (p

Beschreibung: Background: The phase 3 GIMEMA-MMY-3006 study comparing bortezomib-thalidomide-dexamethasone (VTD) vs. thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) provided demonstration of superior CR/nCR rates after induction (the primary study endpoint) and across all subsequent treatment phases, a gain which translated into significantly longer PFS for patients randomized to the VTD arm (Cavo, Lancet 2010; Blood 2012). We herein report an updated analysis of the study with a focus on PFS2, time to second anti-myeloma therapy, treatment-free interval, post-relapse OS and long term outcomes. Methods: Overall, 474 patients were included in the trial. After a median follow up of 65 months, 251 patients (53%) have progressed and of these 221 (88%) had available data on salvage therapy after relapse. Results: On an intention-to-treat basis, median PFS was 57 months for patients randomized to the VTD arm as compared to 42 months for those assigned in the TD arm (HR 0.67; p=0.001). No statistically significant difference in 5-years estimates of OS was observed between VTD and TD groups (80% vs 73%). PFS2, defined as the time from initial randomization to second disease progression or death from any cause, was significantly longer for patients randomised to VTD than for those in the TD group (76% vs. 63% at 5 years, respectively; HR 0.64, p=0.009). Globally, 73% and 83% of patients in the VTD and TD arms required the start of salvage therapy due to symptomatic relapse. Median time to subsequent anti-myeloma therapy (defined as the interval between start of induction treatment and the first dose of second-line therapy) was significantly longer for patients assigned to VTD than for those who experienced relapse in the TD cohort (40 vs 31 months, p=0.014). Similarly, median treatment-free interval (defined as the time between last administration of front-line therapy and start of salvage treatment) was 26 months in VTD group vs 16 months in TD arm (p=0.016). Most of the patients received a novel agent-containing salvage therapy, while 18% was treated with conventional chemotherapy. As expected, a greater percentage of patients in the TD arm were treated with second-line bortezomib-based combinations in comparison with those relapsing in the VTD arm (72% vs 46%, respectively, p=0.001). Within the VTD group, no statistically significant difference in PFS2 was seen regarding the use of bortezomib or an IMiD as (part of) second-line therapy (64 vs 57 months, respectively). Clinical benefit from primary randomization to VTD vs TD was also observed in terms of second PFS (defined as the interval between first and second progression) (HR 0.61, p=0.032). The median OS after relapse was 36 months for both TD and VTD groups. No differences in post relapse OS were observed for patients primarily assigned to VTD or TD who received a subsequent bortezomib-based salvage therapy. Conclusion: With an extended follow-up of approximately 5 years, VTD was superior to TD in terms of extended PFS2, time to subsequent anti-MM therapy and treatment-free interval. PFS2 was significantly longer for patients randomized to VTD, with no difference regardless of the use of bortezomib or an IMiD as part of second-line therapy. This finding, along with similar post-relapse OS values across the two groups, suggest that induction and consolidation therapy with VTD did not select the emergence of bortezomib- resistant clones at the time of relapse. Disclosures Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Array BioPharma: Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Sanofi Aventis: Honoraria. Cavo:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharm.: Consultancy, Honoraria; Bristol-Myers Squib: Consultancy, Honoraria; Onyx: Honoraria.

Beschreibung: INTRODUCTION: A 2-arm Phase I/II trial was initiated to determine activity and toxicities of the VTD combination in patients with advanced and refractory MM. METHODOLOGY: Of 85 patients enrolled, 63 (74%) had abnormal cytogenetics (CA) including 40 patients with deletion of chromosome 13; 71 (84%) had received 1 prior autotransplant, including 56 (66%) with 2 prior autotransplants; 73% had previously received T; none had received prior V. V was given at a starting dose of 1.0 mg/m2 (group A) on days 1, 4, 8, and 11 every 21 days; T was added with the 2nd cycle at dose increments of 50, 100, 150, and 200 mg daily in cohorts of at least 10 patients. In the absence of grade 〉 2 peripheral neuropathy (PN) with V at 1.0 mg/m2 plus T 200mg, V was then increased to 1.3 mg/m2 (group B); T was added in the same incremental dosing schedule as in group A. D was added (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days) with cycle #4 if partial response (PR) or better was not achieved; 34 patients received D, 19 in group A and 15 in group B. PR was defined as ≥ 50% reduction in serum M-protein and/or ≥ 75% reduction of urine M-protein. Responses were computed on an intent-to-treat basis. RESULTS: Median numbers of cycles in group A were 6, 10, 7, 2 per T cohort and 12, 6, 11, 3, respectively, in group B. PR was obtained in 55% of patients, including 16% who achieved ≥ n-CR; an additional 15% had ≥ 25% M-protein reduction. Median EFS/OS for all 85 patients were 9/22 mos. Compared to group A, group B had a superior 12-mo EFS (47% vs. 26%) and OS (79% vs. 57%) (p=0.008/p=0.06); however, the 2 groups were not well balanced with regard to recognized prognostic factors (group A contained more patients with a low albumin level, high B2M, abnormal cytogenetics [CA] and high bone marrow plasmacytosis). No T dose effect on EFS or OS was apparent (≤ 100 mg/d, n=42; 〉 100 mg/d, n=43). Both EFS (p=0.01) and OS (p=0.03) were shorter in the presence of CA. EFS was also inferior in case of prior T (26% vs. 63%, p=0.03). The most common grade 3 or 4 toxicity was myelosuppression (thrombocytopenia and neutropenia). The proportion of patients in group A with PN grade 〉 1 was 41% at study entry and only slightly increased to 50% after cycle 5, with no T dose effect; the corresponding values for group B were 51% at study entry and 56% after cycle 5, with PN reaching grade 3 in 2/6 patients in the T=200 mg cohort. Syncope was observed in 2/6 patients receiving T=200mg in group B. Thus, in group A no T-MTD was reached, whereas it was 150mg in group B. CONCLUSION: VTD is well tolerated at V 1.0 + T 200mg and V 1.3 + T 150mg. Its overall remarkable activity in a high-risk patient population yielded superior EFS/OS in the absence of either CA or prior T. The imbalance of prognostically relevant features, however, precludes a final dose recommendation for V. VTD (V=1.0, T=200mg, D=40mg) has since been combined with PACE combination chemotherapy (VTD-PACE) in Total Therapy 3 (TT3), raising 〉=n-CR rates beyond 80% compared to 65% with TT2+T (ASCO 2005), permitting robust PBSC collection 〉20 million CD34 cells/kg in 〉90% of 〉150 patients enrolled, when performed after the first cycle of VDT-PACE.

Beschreibung: Abstract 1821 Introduction: PN is an important complication of MM and its incidence has been further increased after the introduction of the novel agents thalidomide and bortezomib. In a phase 3 trial comparing TD with VTD as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation for previously untreated MM patients, the VTD arm was significantly superior over TD in terms of improved rates of complete or near-complete response (CR/nCR) (the primary study endpoint) and progression free survival (PFS). Toxicity of VTD and TD regimens, including PN, was a secondary study endpoint. Methods: We performed a subanalysis of the study to assess the frequency, reversibility, risk factors and molecular markers associated with treatment-emergent PN. PN was graded by use of National Cancer Institute's Common Toxicity Criteria (NCI CTCAE) version 3.0. Since grade 1 PN could be misinterpreted and does not interfere with the daily activities, only patients who developed PN of at least grade 2 were evaluated. A total of 474 patients (of whom, 236 randomized to the VTD arm and 238 to TD) were stratified according to the development or not of grade ≥2 neurological adverse events (NAEs). Gene expression profiles (GEP) of pre-treatment CD138+ bone marrow plasma cells (BMPCs) were analyzed in a subset of 127 VTD-treated patients for whom biological samples taken at diagnosis were adequate for genomic analysis. GEP experiments were performed using the Affymetrix HG-U133 Plus 2.0 platform and class comparison of groups of array was done with one-way ANOVA Partek Genomic Suite (version 6.4). Results: Occurrence of PN throughout the entire treatment program was significantly higher in the VTD arm compared with TD. In particular, the rate of grade ≥2 PN was 35% vs 10% (p

Beschreibung: Abstract 1835 Poster Board I-861 Five studies demonstrated the superiority of MPT over MP regimen in elderly patients with MM not eligible for transplantation. In particular, one of these studies, showed this figure in patients aged more than 75 years who represent more than one third of MM patients. Nevertheless, in this latter study 42.5% of patients withdrawn from the MPT protocol because of toxicity. Therefore, there is a wide room of improving these results in this troublesome patient population. Using ThaDD regimen, including liposomal pegylated doxorubicin, we reported low haematological and non-hematological toxicity in elderly and

Beschreibung: Myeloma bone disease is characterized by osteolytic destruction associated with suppressed osteoblastic activity possibly through inhibition of the WNT signaling pathway. We already reported the association between increased alkaline phosphatase (ALP) and B but not dexamethasone response in myeloma patients (Zangari et al., BJH 2005, in press). To extend these observations, using data from the large APEX study, we have attempted to assess the relationship between quantitative alkaline phosphatase (ALP) changes during therapy with B and response and time to progression. We were interested in what threshold of increase in ALP (even within the normal laboratory range) might predict efficacy. Methods: A group of patients with no biochemical evidence of liver disease and creatinine clearances 〉 50 mL/minute treated with bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 for up to eight 3-week cycles followed by bortezomib 1.3 mg/m2 on days 1, 8, 15 and 22 for up to three 5-week cycles were studied. The percentage increase of ALP levels in responders and non-responders was analyzed at different thresholds and time points after baseline. Responses (the sum of CR plus PR) were based on EBMT criteria. The change from baseline ALP during therapy with B was compared in responders and non-responders. Results: There were 229 patients with a median age of 60 years. 59% were male; median B2M was 3.2 mg/L, myeloma subtypes included IgG 64%, IgA 24%; median time from diagnosis was 41 months. The median ALP elevation from baseline for bortezomib responding patients was approximately 25% but even a 10% ALP increment at week 6 from baseline was strongly associated with response (P=0.0001). The most powerful predictor of response was a 25% ALP elevation at week 6. Table 1 Parameter 25% ALP Elevation

Beschreibung: Non factor V Leiden APC resistance (aAPCR) has been described in cancer patients and found to be associated with an increased risk of deep venous thrombosis (DVT). We analyzed the incidence and clinical impact of APC resistance in a large group of multiple myeloma patients. A total of 1178 myeloma patients were tested for APC resistance using an aPTT-based assay in the presence of excess of factor V-deficient plasma and the ratio with or without APC was calculated (≤ 2.00 was considered abnormal). PCR amplification of genomic DNA was used to detect Factor V Leiden. Abnormal APC resistance was found in 109 patients (9.3%), 83 of those were tested for factor V Leiden, 31 had the mutation and 52 (63%) did not have it. Analyzing a subgroup of 254 chemotherapy naïve patients, APC ratio was abnormal in 11% of patients and two third of them were not carriers of factor V Leiden mutation. The presence of aAPC resistance was associated with an increased risk for DVT: 27.9% in patients with aAPCR vs.12.3% in the others (P = 0.008); 22.6% in patients with factor V Leiden mutation. In 32 patients with abnormal aAPCR, the test was repeated: 31/32 patients normalized their APC ratio in sequential testing. Correlation between myeloma baseline markers (serum and urine M-component, beta2-microglobulin, CRP, IL-6), response to treatment and APC activity were studied. In this analysis active disease emerged as the most important factor associated with aAPCR, as 19 patients with normalization of the APC ratio had a concomitant clinical response to therapy. We concluded that aAPCR is a transient finding in myeloma patients that showed a significant correlation with development of DVT.

Beschreibung: Background: A controversy about a possible link between vitamin B12 deficiency and multiple myeloma (MM) has persisted since the 1970s. Vitamin B12 (B12) deficiency can cause anemia, neuropathy and has been associated with osteoporosis and reduced bone density. Therefore, B12 deficiency might worsen some clinical symptoms of MM. Methods: We evaluated serum B12 concentrations in 393 untreated MM patients included in the Myeloma Institute Program (October 1998 to March 2005). Total serum B12 was assessed by using ADVIA Centaur immunoassay with chemiluminescent detection; laboratory B12 deficiency was defined as serum B12 levels 〈 156 mmol/L. Serum alkaline phosphatase (ALP) was determined by a kinetic rate method. Neuropathy was assessed clinically according to NIH guidelines. Correlations of serum B12 concentrations with bone density (radial T- and Z -score) and thalidomide-related neuropathy were investigated. Categorical variables were compared using chi-square and Fisher’s exact test, while correlation coefficient was used for quantitative variables. Results: The sample was 57% male, median age = 58 years, stage III 70%, median creatinine 1.0 mg/dL, IgG 52%, IgA 24%, and light chain disease 19%. Prevalence of laboratory B12 deficiency was 3.5%, prevalence of functional deficiency (B12 〈 241 mmol/L) was 20.4%. No influence of age or MM isotype on B12 levels was observed. Sixty seven percent (264) of the patients received thalidomide in combination with chemotherapy. Levels of B12 did not affect the development of grade ≥ 2 neuropathy after thalidomide treatment (p=0.49). No significant association was observed between serum B12 and the radial T- and Z score at bone densitometry (n= 270). There was a highly significant correlation between serum B-12 and ALP levels (correlation coefficient 0.25, p 〈 0.0001). Conclusions: Laboratory B12 deficiency was not common in our series of newly untreated MM patients. B12 levels did not predict the development of thalidomide-related neuropathy, nor are they associated with reduced bone density. The most striking finding of our study was a highly significant correlation between serum B12 and ALP concentrations; clinical significance of this observation requires further evaluation.