ALBERT

Description: Abstract 1863 Introduction: Bortezomib is approved for the treatment of MM, and bortezomib-based therapies are a cornerstone of care for both first-line and relapsed and/or refractory MM. As bortezomib is administered for a finite course, as opposed to treatment being continued to disease progression, patients may remain sensitive to bortezomib-based therapy at relapse. A number of prospective and retrospective studies in patients with relapsed and/or refractory MM have demonstrated the efficacy of subsequent retreatment with bortezomib-containing regimens. We report a systematic literature review and meta-analysis to assess the efficacy and safety of bortezomib-based retreatment in relapsed and/or refractory MM. Methods: Using PubMed and major hematology/oncology conference proceedings, a systematic literature review was performed to identify studies from January 2005 to May 2012 of bortezomib-based therapy in patients with relapsed and/or refractory MM. All studies of bortezomib-based retreatment in MM patients with prior exposure to bortezomib were systematically selected. Treatments were classified as bortezomib ± dexamethasone (dex) or bortezomib-based combinations. The proportion of bortezomib-refractory patients was identified for each study where available. Additional prognostic factors, including number of prior therapies, proportion of patients with prior autologous stem cell transplant (ASCT), and time since last bortezomib, were extracted and used in weighted stratified analyses of time to progression (TTP), progression-free survival (PFS), and overall survival (OS). Random-effect pooled estimates (taking into account heterogeneity across studies) were calculated for overall response rate (ORR; partial response or better) and rates of common adverse events (AEs). A meta-regression was conducted to explore the interactive effects of prognostic factors on ORR. Results: Twenty-three studies (N=1051 patients) were identified. Bortezomib was administered IV in all studies. Retreatment comprised bortezomib ± dex in 5 studies and combination therapy in 18. Bortezomib-refractory patients were included in 11 studies (10–100% of patients), 6 studies included only relapsed patients, and data were not available for 6 studies. Across studies in which data were available, the pooled, weighted average ORR was 39% (95% CI: 31–47) and the pooled, weighted average median TTP, PFS, and OS were 7.5, 5.8, and 16.6 months, respectively. Data from stratified univariate analyses are shown in the table. Outcomes appeared generally consistent across groups while patients with fewer prior therapies (≤4) and relapsed (but not refractory) patients achieved higher ORRs of 43% (95% CI: 31–55) and 57% (95% CI: 45–69), respectively. Random-effects meta-regression analysis controlling for number of prior therapies and % prior ASCT confirmed that, compared to refractory patients, relapsed patients were associated with a higher ORR by 28–41 percentage points. In studies of bortezomib ± dex in patients with a median age 〉65 years and with a lower % of patients receiving prior ASCT (≤30%), retreatment remained active (pooled average ORR of 51%, median TTP and OS of 8.4 and 19.2 months). The most common grade 3/4 AEs included thrombocytopenia (35%), neutropenia (15%), anemia (14%), pneumonia (10%), and peripheral neuropathy (3%). Conclusions: Based on these findings, retreatment with bortezomib alone or in combination is efficacious and well tolerated in relapsed patients, with an ORR of 57% and median TTP and OS of 8.5 and 19.7 months. In an era of new and emerging treatment options for relapsed and/or refractory MM, these data indicate bortezomib retreatment remains a highly effective therapeutic option in previously treated patients. Disclosures: Knopf: Millennium Pharmaceuticals, Inc.: Consultancy. Duh:Millennium Pharmaceuticals, Inc.: Research Funding. Lafeuille:Millennium Pharmaceuticals, Inc.: Research Funding. Gravel:Millennium Pharmaceuticals, Inc.: Research Funding. Lefebvre:Millennium Pharmaceuticals, Inc.: Research Funding. Niculescu:Millennium Pharmaceuticals, Inc.: Employment. Ba-Mancini:Millennium Pharmaceuticals, Inc.: Employment. Ma:Millennium Pharmaceuticals, Inc.: Employment. Shi:Millennium Pharmaceuticals, Inc.: Employment. Comenzo:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background In the US and EU, B is approved for the treatment of MM using either SC or IV administration. The MMY-3021 study in relapsed/refractory MM pts demonstrated the non-inferiority of SC vs IV B (in terms of response rate after 4 cycles of treatment) and some improvements in the safety profile of B with SC vs IV administration, including lower rates of peripheral neuropathy (Moreau et al, Lancet Oncol 2011). Therefore, SC administration may improve the tolerability of B, potentially impacting patterns of B treatment. The aim of this non-interventional study was to analyze the impact of initial route of B administration on time to dose reduction and dose intensity delivered to pts. Methods In this retrospective observational cohort study, previously untreated MM pts aged ≥18 yrs who initiated B-based treatment within the McKesson Specialty Health/US Oncology Network between January 1, 2011 and November 30, 2012 and had ≥2 MM-related visits and ≥6 months of follow-up through May 31, 2013 were included. Pts enrolled in randomized clinical trials and/or diagnosed with other cancer were excluded. Data were collected via programmatic data queries of the iKnowMed (iKM) electronic health records (EHR) database. In the base case analysis, the intent-to-treat (ITT) approach was used; baseline pt demographics and disease characteristics, and B dosing patterns (including dose, dose intensity [normalized to dose intensity per month due to asymmetric follow-up periods between groups], rate of dose reduction in the first 16 weeks of treatment, and time to dose reduction) were compared between pts initially receiving SC vs IV B. Some pts switched route of B administration, and sensitivity analyses were conducted using only pts who did not switch. Non-parametric tests were used to test variables described here. Results 1058 MM pts were included, of whom 652 (62%) initially received IV B, and 406 (38%) initially received SC. Baseline characteristics were generally similar between the IV and SC groups: mean (SD) age was 66 (12) yrs and 67 (12) yrs, with 56% and 60% of pts aged ≥65 yrs, 56% and 54% were male, mean (SD) body mass index was 28.6 (7.0) and 28.1 (5.8), and 18%/27%/44% and 22%/25%/42% had ISS stage I/II/III disease, respectively. Karnofsky performance status (KPS) was poorer in the IV vs SC group, with 8%/30%/26%/27% vs 15%/31%/26%/25% having a KPS of 100/90/80/≤70 (p=0.0164), and the rate of general comorbidities (weight loss, anorexia, dehydration, diarrhea, dyspnea, hyper-/hypovolemia, malaise, nausea, pain, sepsis) at baseline was higher in the IV vs SC group (21% vs 15%, p=0.0178). The groups were well balanced in terms of other comorbidities, practice region, payer status (Medicare, private, other), and MM subtypes. Treatment regimens differed between the IV and SC groups (p

Description: Abstract 2563 Background: Results from the phase 3 VISTA trial demonstrated that bortezomib (Velcade®) plus melphalan and prednisone (VMP) has superior efficacy to MP alone in patients with newly diagnosed multiple myeloma (MM) ineligible for ASCT. In a similar patient population, the three-arm phase 3 MM-015 trial compared lenalidomide (Revlimid®) plus MP with or without continuous lenalidomide maintenance treatment after cycle 9 (MPR-R vs MPR) with MP alone. There was no difference in progression-free (PFS) or overall survival (OS) between patients who received MPR or MP during the 9-cycle induction period; MPR-R was associated with superior PFS vs MP during the R maintenance period. To assess the value of R in combination with MP followed by R maintenance therapy we indirectly estimated the incremental cost-effectiveness of VMP vs MPR-R as therapy for MM patients ineligible for ASCT. Methods: An Excel-based Markov model from the US payer's perspective was developed. Simulations were performed for hypothetical cohorts of newly diagnosed MM patients ineligible for ASCT with an average age of 70 years at treatment initiation. The model includes seven health states representing periods of treatment response (stable disease/minimal response, partial response, and complete response), treatment-free interval/maintenance treatment, progressive disease, second-line treatment, and death. Monthly transition probabilities were estimated from patient-level data for VISTA for VMP and MP (data cut-off June 15 2007; San Miguel et al NEJM 2008) and published results for MM-015 for MPR-R (data cut-off April 15 2009; Palumbo et al ASH 2009). As previously reported (Wang et al ASH 2009), costs included per-protocol drug and medical costs, treatment-related adverse event costs, second-line treatment costs, and resource utilization during the treatment-free interval and progressive disease; all costs were adjusted to 2010 US dollars. State-specific utility estimates were derived from patient-level EQ-5D data from the VISTA trial using US-specific weights. Health outcomes (as indicators of the effectiveness of therapy) were expressed in life years (LYs) and quality-adjusted LYs (QALYs). Costs and health outcomes were discounted at 3%. Incremental cost-effectiveness ratios (ICERs) were calculated for VMP vs MPR-R over a lifetime horizon (20 years). In the base case, the MPR-R vs MP hazard ratio (HR) for PFS was set to 0.499 and that for OS was set to 1, due to a lack of survival benefit with MPR-R vs MP observed in MM-015. One-way sensitivity analyses were conducted by running the model with upper and lower values of key parameters to assess the general robustness of model findings and identify key drivers. Results: Model base case results for the incremental cost-effectiveness of VMP relative to MPR-R are shown in the Table. Estimated OS was 4.187 years with VMP vs 3.409 years with MPR-R over a lifetime horizon. Lifetime direct medical costs were $119,102 with VMP vs $241,247 with MPR-R; the lifetime cost of R maintenance was $107,047. Thus, VMP appears associated with reduced costs and better outcomes vs MPR-R; VMP costs approximately 50% less than MPR-R and seems to provide slightly more QALYs (0.567) on average. One-way sensitivity analyses supported the general robustness of model findings and identified the MPR-R vs MP HR for OS as a key driver; only when this HR was set to ≤0.25 did MPR-R become cost-effective vs VMP at $100,000 per QALY. Conclusions: In newly diagnosed MM patients ineligible for ASCT, VMP appears to be associated with lower costs and better health outcomes vs MPR-R. From a cost-effectiveness perspective, R maintenance therapy therefore seems to have little benefit in this patient population. The current comparison was based on published results for MPR-R from MM-015 after a median follow-up of 9.4 months (vs 16.3 months for VMP vs MP in VISTA), at which time no survival benefit was observed for MPR-R vs MP. If longer follow-up in MM-015 indicates a survival benefit for MPR-R vs MP, a re-estimation of the incremental cost-effectiveness of VMP vs MPR-R using the present Markov model would be warranted; however, updated data (Palumbo et al EHA 2010) show no significant difference in OS between the MPR-R and MP arms at a median follow-up of 21 months. Disclosure: Wang: Millennium Pharmaceuticals: Consultancy, Research Funding. Huang:Millennium Pharmaceuticals, Inc: Employment. Ba-Mancini:Millennium Pharmaceuticals, Inc.: Employment. Shi:Millennium Pharmaceuticals, Inc: Employment. Chen:Millennium Pharmaceuticals: Consultancy, Research Funding. Korves:Millennium Pharmaceuticals, Inc: Research Funding. Dhawan:Johnson & Johnson: Employment, Equity Ownership. Cakana:Johnson & Johnson: Employment, Equity Ownership. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Duh:Millennium Pharmaceuticals, Inc: Consultancy, Research Funding.

Description: Introduction The UPFRONT trial compared the efficacy and safety of three bortezomib (V)-based induction regimens – VD (V-dexamethasone), VTD (V-thalidomide-dexamethasone), and VMP (V-melphalan-prednisone) – followed by weekly V maintenance, in previously untreated, transplant-ineligible MM pts, and was the first to prospectively evaluate VD and VTD in this population. The trial was designed to best resemble ‘real-life' treatment practice in the US community oncology setting. Methods Pts with symptomatic, measurable MM were randomized 1:1:1 to receive eight 21-day cycles of VD, VTD, or VMP induction (VD: V 1.3 mg/m2, d 1, 4, 8, 11; D 20 mg, d 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), d 1, 2, 4, 5 [cycles 5–8]); VTD: V as before; T 100 mg/day, d 1–21; D as before); VMP: V as before; M 9 mg/m2 and P 60 mg/m2, d 1–4 every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with weekly V 1.6 mg/m2, d 1, 8, 15, 22. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), overall response rate (ORR, partial response or better [≥PR]), complete response (CR), near-CR (nCR), and very good partial response or better (≥VGPR) rates, duration of response (DOR), time to next therapy (TTNT), safety, and quality of life (QoL). Best confirmed responses were investigator-assessed per modified IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v3.0. Kaplan-Meier methodology was used for time-to-event analyses; hazard ratios (HR) and 95% confidence intervals (CI) are reported. QoL was assessed using the EORTC-QLQ-C30 questionnaire via a hand-held personal device. A linear mixed effect model was used to assess QoL changes over time within and between treatment arms; sensitivity analyses were conducted to test the robustness of the primary analysis. Here we report final results from the study, including updated PFS and OS, and previously unreported DOR and TTNT data for all 502 pts (VD, n=168; VTD, n=167; VMP, n=167) after a median follow-up of 42.7 months. Results Baseline characteristics were generally well balanced across arms. Pts median (range) age was 73 (38–91) years; 42% of pts were aged ≥75 years. 74%/17%/9% of pts were White/Black/Other and 73% had ISS stage II/III disease. 48% of pts had baseline comorbidities and 19% had a Charlson comorbidity index of ≥2; the most common comorbidities were diabetes mellitus (21%), renal disease (15%), and chronic pulmonary disease (8%). In the VD, VTD, and VMP arms, pts received a median (range) of 8 (1–13), 6 (1–13), and 7 (1–13) cycles, respectively; 50%, 38%, and 42% of pts received V maintenance. The mean V dose intensity (number of V doses received/number of V doses planned) for VD, VTD, and VMP was 72%, 63%, and 68% during induction and 75%, 81%, and 87% during maintenance. Median PFS was 14.7 (VD), 15.4 (VTD), and 17.3 (VMP) months, respectively, with no significant difference between arms (Figure). Median OS was 49.8 (VD), 51.5 (VTD), and 53.1 (VMP) months, respectively, with no significant difference between arms (VD–VTD: HR=1.03 [95% CI: 0.73, 1.46]; VD–VMP: HR=1.12 [95% CI: 0.80, 1.58]; VTD–VMP: HR=1.09 [95% CI: 0.77, 1.54]). For VD, VTD, and VMP, best confirmed ORRs during treatment were 73%, 80%, and 70%, including 30%, 40%, and 32% CR/nCR, and 37%, 51%, and 41% ≥VGPR, respectively. Median DOR was 18.3, 22.4, and 19.8 months, and median TTNT was 19.7, 24.5, and 19.0 months, respectively. Over 13 cycles, grade ≥3 AE rates were 78%, 87%, 83%; serious AE rates were 53%, 58%, 51%; and discontinuation rates due to AEs were 29%, 38%, 34%, respectively. Across arms, the most common grade ≥3 AEs were peripheral neuropathy (23%), fatigue (10%), and diarrhea (9%). V maintenance was associated with limited additional toxicity compared with induction. For QoL, the observed data, linear mixed model estimates, and sensitivity analyses all showed a common trend for decreasing mean global health status score during V-based induction (most notably for VTD), followed by a trend to stabilizing/improving score during single-agent V maintenance. Conclusions All three V-based regimens showed substantial activity in this community-based, elderly, comorbid pt population. PFS and OS were similar between the arms. Toxicities and QoL appeared less favorable with the triplet regimens, particularly VTD, than with the doublet. These data highlight the importance of V as a backbone of therapy and the need to adapt treatment for elderly pts. Disclosures: Niesvizky: Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Flinn:Millennium: The Takeda Oncology Company: Research Funding; Celgene: Research Funding. Rifkin:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Neuwirth:Millennium: The Takeda Oncology Company: Employment. Ba-Mancini:Millennium: The Takeda Oncology Company: Employment. Zhu:Millennium: The Takeda Oncology Company: Employment. Niculescu:Millennium: The Takeda Oncology Company: Employment.