ALBERT

Description: Background: In a phase 1/2 trial of VMP in 60 newly diagnosed MM patients (median age 75 years), the CR/nCR rate was 43%, with 32% CR; the 3-year survival was 85% (Mateos et al, Blood 2006; Mateos et al, EHA/IMW 2007). MMY-3002 is a phase 3 study comparing VMP with standard MP in patients with previously untreated MM who are not candidates for high-dose chemotherapy/stem-cell transplant. Methods: Approximately 680 patients were randomized to VMP or MP and stratified according to baseline β2-microglobulin and albumin, and geographic region. Eligibility criteria required the presence of measurable disease, KPS ≥60% and hematology/chemistry laboratory values meeting predefined criteria. Patients in the VMP arm received intravenous bortezomib 1.3mg/m2 twice weekly (weeks 1, 2, 4, 5) for four 6-week cycles (8 doses per cycle), followed by once weekly (weeks 1, 2, 4, 5) for five 6-week cycles (4 doses per cycle) in combination with oral melphalan 9mg/m2 and prednisone 60mg/m2 once daily on days 1–4 of each cycle. Patients in the MP arm received 9 6-week cycles of MP once daily on days 1–4. For both groups, treatment continued for a maximum of 9 cycles (54 weeks) unless disease progression or unacceptable treatment-related toxicity occurred. The primary endpoint was time to progression (TTP), and secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate, time to and duration of response, and safety. Results: Between December 2004 and September 2006, 682 patients from 151 centers in 22 countries across Europe, North and South America, and Asia were randomized. The median age was 71 years with 30% of patients aged ≥75 years. Fifty percent were male and 88% were of Caucasian origin. Median KPS was 80%, and 34% of patients had KPS ≤70%. Sixty-three percent had IgG myeloma, 25% had IgA myeloma, and 8% had light-chain disease. Bone involvement with 〉10 lytic bone lesions was reported in 27% of patients, 33% had β2-microglobulin 〉5.5mg/L, and 60% had albumin

Description: Renal impairment is a major complication of multiple myeloma (MM) and is associated with poor prognosis. Early effective treatment can lead to improvement in renal function, which is associated with better outcomes. Bortezomib (VELCADE®) is approved by the US FDA for the treatment of MM based on the results of the large, international, phase III VISTA study in previously untreated MM patients ineligible for high-dose therapy, in which bortezomib plus melphalan–prednisone (VMP, N=344) was superior to melphalan–prednisone (MP, N=338) across all efficacy end points, including response rates, time to progression (TTP), and overall survival (OS). Previous studies have shown bortezomib to be active and well tolerated in MM patients with renal impairment, including those requiring dialysis, and bortezomib pharmacokinetics are not influenced by degree of renal impairment (US label). In this analysis we assessed the efficacy and safety of VMP and MP in VISTA in patients with renal impairment. We also evaluated reversal of renal impairment after treatment. Treatment comprised nine 6-week cycles of VMP (bortezomib 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1–4, and days 1, 8, 22, and 29, cycles 5–9, plus melphalan 9 mg/m2 and prednisone 60 mg/m2 on days 1–4, cycles 1–9) or MP alone. Patients with serum creatinine 〉2 mg/dL were excluded. At baseline, 19 (6%), 162 (48%), and 159 (47%) VMP patients, and 15 (4%), 168 (50%), and 154 (46%) MP patients, had creatinine clearance (CrCl) ≤30, 31–60, and 〉60 mL/min, respectively. Efficacy of VMP was not affected by CrCl; complete response rate (28% vs 32%), TTP, and OS were not significantly different among patients with baseline CrCl ≤60 vs 〉60 mL/min. Safety profiles were comparable among patients with CrCl of 31–60 and 〉60 mL/min for both VMP and MP. In the VMP arm, rates of serious adverse events (SAEs; 42% vs 47%), grade 3 (52% vs 55%), 4 (28% vs 27%), and 5 (8% vs 8%) adverse events (AEs), and discontinuations due to AEs (13% vs 17%) were similar between the groups. Rates of SAEs (63%) and grade 4 AEs (42%) appeared somewhat higher in the small group of patients with CrCl ≤30 mL/min, but rate of discontinuations due to AEs (11%) was similar. Similar trends were seen in the MP arm, with rates of grade 4 and 5 AEs and discontinuations due to AEs appearing higher in patients with CrCl ≤30 mL/min, suggesting an effect independent of addition of bortezomib. Reversal of renal impairment, defined as an improvement in CrCl from 60 mL/min on treatment, was seen in 49/111 (44%) VMP patients vs 40/116 (34%) MP patients. Time to reversal in all patients with baseline CrCl

Description: Based on the results of the large, international, phase III VISTA trial in previously untreated MM patients ineligible for high-dose therapy with stem cell transplantation (HDT-SCT), bortezomib (VELCADE®) was approved by the US FDA for the initial treatment of multiple myeloma (MM). Data from VISTA showed that bortezomib plus melphalan–prednisone (VMP) was superior to melphalan–prednisone (MP) across all efficacy end points, including response rates (overall and complete response [CR] rates), time to progression (TTP), time to subsequent therapy (TTNT), and overall survival (OS). Patients (N=682) from 151 centers in 22 countries in Europe, North and South America, and Asia were randomized (1:1) to 54 weeks treatment with VMP (N=344) or MP (N=338). Patients received nine 6-week cycles of bortezomib 1.3 mg/m2 (days 1, 4, 8, 11, 22, 25, 29, 32 in cycles 1–4 and days 1, 8, 22, 29 in cycles 5–9) with melphalan 9 mg/m2 and prednisone 60 mg/m2 (days 1–4 in cycles 1–9), or melphalan plus prednisone, per the dose and schedule described above. The primary end point was TTP, with progression determined using European Group for Blood and Marrow Transplantation (EBMT) criteria. Median age was 71 years; 30% of patients were aged ≥75 years. At baseline, 34% of patients had Karnofsky Performance Status (KPS) ≤70%, 33% had β2-microglobulin 〉5.5 mg/L, and 34% had International Staging System (ISS) Stage III disease. An Independent Data Monitoring Committee recommended the trial be stopped based on a protocol-specified interim analysis as the statistical boundary for the primary end point had been crossed. VMP was well tolerated, with patients remaining on VMP therapy for a median of 46 weeks (8 cycles) versus 39 weeks (7 cycles) with MP; median total dose of bortezomib received was 38.5 mg/m2. Collection of tumor assessment data was stopped after presentation of the positive interim analysis. Collection of survival data, subsequent therapy data and safety/recovery data continued. Updated follow-up through April 25, 2008 confirms a statistically significant survival benefit for VMP versus MP (HR=0.64, P=0.0032) after a median follow-up of 25.9 months. Three-year survival rates were 72% versus 59%, respectively. TTNT and treatment-free interval (TFI) were also significantly longer in the VMP arm (TTNT 28.1 vs 19.2 months, HR=0.53, P

Description: Complete response (CR) has been shown to be prognostic for improved long-term outcomes, including progression-free survival and overall survival (OS), in previously untreated multiple myeloma (MM) patients receiving high-dose therapy and stem cell transplant (SCT; Harousseau et al, IMW 2007; van de Velde et al, Haematologica 2007). However, there is limited evidence of such a correlation in the non-transplant setting. In the large, international phase III VISTA study in previously untreated MM patients ineligible for SCT, bortezomib plus melphalan–prednisone (VMP) demonstrated superiority to MP across all efficacy end points, including response rates, time to progression (TTP), and OS. Here, we assess the differential prognostic impact of best response on time-to-event parameters in VISTA, and evaluate the impact of timing of CR on outcome in patients receiving VMP. A total of 682 patients (median age 71 years) were randomized to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, and days 1, 8, 22, 29, cycles 5–9, plus melphalan 9 mg/m2 and prednisone 60 mg/m2, days 1–4, cycles 1–9) or MP (N=338). The primary end point was TTP. Response and progression were determined using European Group for Blood and Marrow Transplantation (EBMT) criteria; in a post-hoc analysis, response was determined using International Myeloma Working Group (IMWG) uniform criteria. Associations between long-term outcomes and response were examined in the intent-to-treat population by multivariate Cox regression analysis with time-dependent covariates, adjusted for stratification factors (baseline β2-microglobulin and albumin; region), with age, sex, race, MM type, baseline Karnofsky Performance Status, and number of bone lesions as covariates. Among evaluable patients, response rates to VMP vs MP were 71% vs 35%, including 30% vs 4% CR, by EBMT criteria, and 74% vs 39%, including 33% vs 4% CR and 8% vs 4% VGPR, by IMWG criteria. Median TTP was 24.0 vs 16.6 months. CR by EBMT criteria was associated with significantly longer TTP (hazard ratio [HR] 0.45, p=0.004; Figure), time to next therapy (TNT; HR 0.44, p=0.014), and treatment-free interval (TFI; HR 0.37, p=0.004) vs PR, plus improved OS (medians not reached; clear separation between the curves; HR=0.59, p=0.265; statistical significance not seen likely due to a small number of deaths). Significant benefit was seen for CR and PR vs no response by EBMT criteria for all four parameters, including OS. Findings were similar for CR vs VGPR+PR vs no response by IMWG criteria. Importantly, CR was associated with significantly longer TTP (HR 0.45, p=0.019) and TFI (HR 0.39, p=0.026) vs VGPR, with a trend towards longer TNT (HR 0.54, p=0.126); no significant differences for these parameters were seen for VGPR vs PR. However, these findings should be interpreted with caution due to the small number of patients achieving VGPR. Among patients achieving CR (EBMT criteria) with VMP, there were no clear differences in clinical benefit associated with achieving CR early (cycles 1–4, within 24 weeks) vs later (cycle 5 onwards, after 24 weeks), although TTP and overall duration of response appeared slightly longer with later CRs, possibly due to the inherent slightly longer duration of therapy (mean 7.4 vs 8.5 cycles). In conclusion, this analysis demonstrates the prognostic significance of CR on long-term outcomes in the setting of non-intensive therapy. The data show that CR is associated with improved outcomes vs VGPR by IMWG criteria, and indicate that the clinical benefit of CR with VMP is similar regardless of time to achieve CR, supporting continuation of therapy to achieve maximal response. Figure: TTP in patients achieving CR vs PR (EBMT criteria) with VMP Figure:. TTP in patients achieving CR vs PR (EBMT criteria) with VMP

Description: Background : We previously reported a retrospective study suggesting that erythropoietin therapy starting on day 28 after autologous HCT was highly effective to improve Hb levels and that i.v. iron might improve response in patients with low transferrin saturation (Baron et al., Clin Cancer Res 2003). This prompted us to conduct a multicenter prospective randomized study analyzing the impact of darbepoetin alfa with or without i.v. iron on erythroid recovery after autologous HCT. Patients and Methods : 127 autologous HCT recipients with lymphoid malignancies were randomized 1:2:2 between no treatment (group 1, n=25), darbepoetin alfa (Aranesp®) 300 μg QOW starting on day 28 after HCT for a total of 7 doses (group 2, n=52), or the same regimen of darbepoetin alfa plus i.v. iron sucrose (Venofer®) 200 mg on days 28, 42 and 56 after HCT (group 3, n=50). Once the target Hb (13 g/dL) was attained, the dose of darbepoetin alfa was reduced to 150 μg, while it was withheld when Hb was ≥ 14 g/dL. Primary endpoints included proportion of complete correctors (i.e. patients reaching Hb □ 13 g/dL) before day 126 post-transplant and median time to achieve Hb correction in each arm. Data were analyzed following the intention-to-treat principle. The proportion of complete correctors by day 126 in each group was compared using the Fisher’s exact test, and median times to reach 13 g/dL in each group were compared using the logrank test. Results : The proportion of complete correctors was 24% in group 1, 81% in group 2 (P