ALBERT

Description: Abstract 2790 Background: The development of more effective front-line regimens for lymphoma (e.g. R-CHOP, BEACOPP) has resulted in lower response rates to salvage regimens such as Ifosphamide, Carboplatin, Etoposide +/− Rituximab (RICE/ICE) and improved strategies are needed. Vorinostat (V) is a well-tolerated, oral pan-HDAC inhibitor approved for the treatment of cutaneous T cell lymphoma. In vitro data indicate that combinations of V at 〉2-5μM plus etoposide or platinum analogs yield synergistic anti-tumor activity, but these concentrations are not typically attained with standard dose regimens. We hypothesized that pulse high-dose V could safely augment the anti-tumor activity of ICE/RICE for patients with relapsed lymphoma. Here we present the final results of a multi-center Phase I trial defining the maximally tolerated dose (MTD) and pharmacokinetics of V that can be given with RICE or ICE. Methods: Eligibility included: relapsed/refractory lymphoma (untreated T-NHL or mantle cell lymphoma [MCL] allowed), age ≥18 years, performance status of 0–2, measurable disease, no active CNS involvement, ANC ≥ 1,500/μL, plts ≥ 100,000/μL, adequate hepatic/renal function, no known HIV. The primary objective was to define a maximally tolerated dose associated with a dose limiting toxicity (DLT) rate of ≤ 25%. DLT = gastrointestinal grade 3 NCI-CTCAE adverse event (AE) 〉7 days, any related non-hematologic grade ≥4 AE, inability to complete one full cycle of therapy due to toxicity, or any significant medical event at the discretion of the PI. Interpatient dose escalation was implemented using a “two stage” design (Storer et al) with single patient cohorts until a DLT was observed, followed by cohorts of 4 patients. Therapy consisted of V ranging from 400 mg daily to 700 mg BID days 1 to 5 in combination with standard ICE or RICE (CD20+ only) delivered on days 3 to 5 every 21 days for up to 2 cycles using G-CSF support. Results: Twenty-nine patients were treated, 9 in stage 1, 20 in stage 2. Baseline features: median age = 56 (range 23 to 69), median prior therapies 2 (range 0 – 7), refractory to last regimen = 14 (of 27 evaluable, 52%), and prior transplant 2 (7%). Histologies: Hodgkin Lymphoma (8), Diffuse large B-cell (7), MCL (5), T-NHL (4), Follicular (3), Marginal Zone (1), and Small Lymphocytic lymphoma (1). Fifteen patients received 2 cycles and 14 received 1 cycle due to a DLT (8), patient/MD choice (4), insurance denial (1), or progressive disease (1). Non-hematologic AEs ≥ grade 3 were observed in 25 patients with 14 experiencing grade 3 nausea, vomiting, diarrhea, and/or anorexia. The most common DLTs were infection (n=2), hypokalemia (n=2), transaminitis (n=2) (Table). The MTD was estimated to be 500mg BID × 5 days with full dose ICE/RICE. Responses were observed in 19 of 27 evaluable patients (70%) including 8 CR/CRU and 11 PR. Mobilization of peripheral blood stem cells was successful in 4 of 9 patients immediately following VICE/VRICE (median 5.52×106 CD34/kg), in all 4 attempting after prior unsuccessful VICE/VRICE mobilization (median 4.4 × 106 CD34/kg), and in all 12 others attempting after a subsequent regimen (median 7.5 × 106 CD34/kg). 25 (86%) patients are alive and 15 (52%) are progression-free with a median follow up of 5 months (range 1 – 23 months). Pharmacokinetic data indicated that the median peak V concentration day 3 was 4.5μM (range 4.2–6.0μM). Studies are underway evaluating the impact of high-dose V on histone acetylation patterns, BCL-2 family proteins, and gene expression profiles of patient-derived normal and tumor cells and will be reported. Conclusions: High-dose V can safely be delivered with ICE/RICE, achieves potentially synergistic drug levels, and responses are encouraging, though adequate prophylaxis and treatment of GI toxicity is required. The Phase II dose of V with ICE/RICE is defined as 500mg BID × 5 days and warrants further study. Disclosures: Budde: Merck: Research Funding. Off Label Use: Off label use of vorinostat. Shustov:Merck: Research Funding. Pagel:Merck: Research Funding. Gopal:Merck: Research Funding.

Description: Abstract 478 Background: The US community-based, phase 3b randomized, open-label, multicenter UPFRONT trial compares the efficacy and safety of three bortezomib (VELCADE®, Vc)-based regimens, VcD (Vc-dexamethasone), VcTD (Vc-thalidomide-dexamethasone), and VcMP (Vc-melphalan-prednisone), followed by weekly Vc maintenance, in elderly, newly diagnosed, transplant-ineligible multiple myeloma (MM) patients. This is the first phase 3 study of VcD and VcTD in this patient population. Methods: Patients with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD, VcTD, or VcMP (VcD: Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcTD: Vc as before; T 100 mg/day, days 1–21; D as before); VcMP: Vc as before; M 9 mg/m2 and P 60 mg/m2, days 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with weekly Vc 1.6 mg/m2, days 1, 8, 15, 22. Patients in the VcTD arm received concomitant prophylaxis with aspirin, full-dose warfarin, or low-molecular weight heparin unless medically contraindicated. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), complete response (CR)/near CR (nCR) and very good partial response (VGPR) rates, overall survival (OS), and safety. Best confirmed responses were assessed by investigators per modified International Myeloma Working Group (IMWG) criteria. Adverse events (AEs) were graded by NCI-CTCAE v3.0. PFS and OS were estimated by Kaplan–Meier methodology. For the first time, we report results from the entire cohort of 502 randomized patients (VcD, n=168; VcTD, n=167; VcMP, n=167), who completed up to a maximum of 13 cycles of treatment. Results: Patients in the VcD, VcTD, and VcMP arms had a median age of 74.5, 73.0, and 72.0 years, respectively, and 71%, 62%, and 72% had ISS stage II/III disease. Patients received a median of 8 (VcD), 6 (VcTD), and 7 (VcMP) treatment cycles; 50%, 38%, and 42% of patients, respectively, received Vc maintenance. Response and safety data are summarized in the table. All three Vc-based induction regimens exhibited substantial activity, with ORR of 73% (VcD), 80% (VcTD), and 69% (VcMP) during the treatment period. After a median follow-up of 21.8 months, no significant difference in PFS was observed between the treatment arms; median PFS was 13.8 months (VcD), 14.7 months (VcTD), and 17.3 months (VcMP), respectively (Figure). 1-year OS estimates were 87.4% (VcD), 86.1% (VcTD), and 88.9% (VcMP). Rates of grade ≥3 AEs, serious AEs (SAEs), and discontinuations due to AEs during the treatment period were highest for the VcTD arm. The most common grade ≥3 AEs across all three arms during the treatment period were neuropathy peripheral (23%), fatigue (10%), and diarrhea (9%). Grade ≥3 pneumonia was reported in 10% (VcD), 6% (VcTD), and 6% (VcMP) of patients. AEs of deep vein thrombosis/pulmonary embolism were reported in 8% (VcD), 7% (VcTD), and 2% (VcMP) of patients. Compared with rates during induction, Vc maintenance produced little additional toxicity; across all three treatment arms, only 5% of patients experienced grade ≥3 peripheral neuropathy during cycles 9–13. One second primary malignancy (lung neoplasm) was reported in the VcMP arm. Conclusions: VcD, VcTD, and VcMP induction followed by weekly Vc maintenance produced similar activity in elderly, newly diagnosed, transplant-ineligible MM patients. Patients in the VcD doublet arm appear to have similar long-term outcomes to patients in the VcTD and VcMP triplet arms. Disclosures: Niesvizky: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Rifkin:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Charu:GSK: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Equity Ownership; Pfizer: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Corzo:Millennium Pharmaceuticals, Inc.: Employment.

Description: Abstract 129 In this US community-based, randomized, open-label, multicenter phase 3b study, we compare the safety and efficacy of three highly active bortezomib (Velcade®, Vc)-based regimens for multiple myeloma (MM), Vc–thalidomide–dexamethasone (VcTD), Vc–dexamethasone (VcD), and Vc–melphalan–prednisone (VcMP), in previously untreated MM patients (pts) ineligible for high-dose therapy and autologous stem cell transplantation. Use of these regimens is supported by data from phase 3 studies; only VcMP has been investigated specifically in elderly pts. Here we present data from a pre-specified interim analysis (IA) of 210 pts performed after the first 70 pts in each arm had the opportunity to complete four cycles of therapy. Pts with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD (Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [Cycles 1–4)], days 1, 2, 4, 5 [Cycles 5–8]), VcTD (Vc 1.3 mg/m2, days 1, 4, 8, 11; T 100 mg/d, d1-21; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [Cycles 1–4), days 1, 2, 4, 5 [Cycles 5–8]) or VcMP (Vc 1.3 mg/m2, days 1, 4, 8, 11; M 9 mg/m2 and P 60 mg/m2, day 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with Vc alone (1.6 mg/m2, days 1, 8, 15, 22). Prophylactic aspirin, full dose warfarin, or low molecular weight heparin was administered to the VcTD arm unless medically contraindicated.The primary endpoint is progression-free survival; secondary endpoints include overall survival, duration of response, time to next therapy, quality of life (QoL) using the EORTC QLQ-C30 questionnaire, safety and tolerability, and efficacy (CR/nCR, VGPR, PR, and ORR). Responses were assessed by investigators using central laboratory data, applying the International Myeloma Working Group uniform criteria. An Independent Data Monitoring Committee (IDMC) assessed safety, tolerability, response rates and QoL data to determine which two of the three arms should continue enrolling pts. Pts in the VcD, VcTD, and VcMP arms had median ages of 74, 73, and 72 years, respectively; 83%, 58%, and 73% had ISS stage ll/lll and 21%, 22% and 32%, respectively, were non-Caucasian. In the VcD, VcTD, and VcMP arms, mean number of treatment cycles (for the first four cycles) and total Vc doses (16 doses for the first four cycles) were similar: 3.8, 3.6, and 3.7 cycles and 14.5, 13 and 13.8 Vc doses, respectively. The VcD arm had the lowest rate of adverse events (AEs) grade ≥3 (58% vs 71% each in the VcTD and VcMP arms, respectively), as well as the lowest rate of discontinuations due to AEs (10% vs 18% and 16% in the VcTD and VcMP arms, respectively). The VcTD arm had the highest rate of serious AEs (50% vs 39% and 36% in the VcD and VcMP arms, respectively), as well as peripheral neuropathy (PN) of any grade (48% vs 29% and 30% in the VcD and VcMP arms, respectively). PN grade ≥3 was 6%, 12% and 13% in the VcD, VcTD, and VcMP arms, respectively. The VcTD arm had higher rates of serious embolism/thrombosis (8% vs 6% and 3%) than in the VcD and VcMP arms, respectively. All three regimens demonstrated substantial activity. The overall response rate was 60%, 70%, and 52% in the VcD, VcTD, and VcMP arms, respectively (complete response (CR)/near CR: 13%, 18% and 15%; ≥very good partial response 15%, 23% and 24%, respectively). QoL functional scores improved in all arms, except for physical, role function and global health status, which worsened in the VcTD arm only. At a preplanned IA, the three Vc-based regimens were evaluated as having similar risk/benefit considerations after four cycles. The regimens were active with well-characterized and predictable toxicities. The study continues to enroll in all three arms as recommended by the IDMC. The UPFRONT trial demonstrates the feasibility of conducting a large, randomized, outpatient, phase 3b trial in community-based oncology centers in the United States. Disclosures: Niesvizky: Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Gabrail:Millennium Pharmaceuticals, Inc: Research Funding. Phooshkooru:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria. Charu:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria, Research Funding. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Neuwirth:Millennium Pharmaceuticals, Inc: Employment.

Description: Abstract 3696 Poster Board III-632 Platinum based regimens such as ICE with or without Rituximab (RICE) have been widely used to treat relapsed or refractory lymphoid malignancies prior to transplantation. However, a significant portion of patients do not respond to treatment, and improved therapies are needed. Vorinostat (V) is an oral HDAC inhibitor with moderate toxicity and has clinical activity against a variety of tumors including cutaneous T cell lymphoma. Preclinical data demonstrated marked anti-tumor synergism between V and platinum analogues as well as etoposide. We present data from a phase I, open-label, multicenter, dose escalation study estimating the maximally tolerated dose of V that can be combined with RICE or ICE (V-RICE or VICE) in patients with relapsed or refractory lymphoid malignancies or untreated T- or Mantle Cell Lymphoma. Other endpoints include tolerability, exploratory anti-tumor activity and impact of above regimen on stem cell reserve. Patients (aged ≥18 years, an ECOG performance status of 0-2, measurable disease, no active central nervous system involvement, adequate bone marrow, hepatic and renal function, no active arrhythmias on EKG) were sequentially enrolled on escalating doses of V combination therapy using the “two stage” design introduced by Storer with single patient cohorts until a dose limiting toxicity (DLT) is observed, followed by cohorts of 4 patients. A DLT was defined as any gastrointestinal grade 3 NCI-CTCAE adverse event (AE) lasting longer than 7 days, or any related non-hematologic grade 4 or 5 AE; any event that prevents the completion of one full cycle of therapy (5 days of V) due to toxicity from V; or any AE at the discretion of the principal investigator. Therapy consisted of V ranging from 400 mg daily to 700 mg BID days 1 to 5 in combination with standard RICE or ICE on days 3 to 5 every 21 days. A total of 18 patients have been enrolled on this study thus far (9 in stage 1, 9 in stage 2) and 14are fully evaluable to date, including: Hodgkin lymphoma (4), T-cell lymphoma (3); mantle cell lymphoma (2); diffuse large B cell lymphoma (2); follicular lymphoma (2), and chronic lymphocytic leukemia (1). Baseline characteristics (n=14) included: median age 55 (range: 33-67), male 10 (71%), stage III/IV 14 (100%), median number of prior therapies 2 (range: 0-6), elevated LDH 5 (35%), prior anthracycline 13 (93%), prior platinum 2 (14%), refractory diseases 5 (36%), relapsed diseases 8 (57%), untreated disease 1 (7%). A maximum V dose of 700 mg BID was attained in stage I (Table). The dose adjustment schema of stage II has ranged from 600 mg BID to 400 mg BID currently. Among the 14 evaluable patients, six received only1 cycle of treatment (3/5 patients declined the second cycle; 2/5 patients developed DLT), 8 completed 2 cycles. Eight of 14 (57%) patients experienced non-hematologic AEs≥ grade 3 with most common being nausea, vomiting, or diarrhea seen in 6 and grade 4 hypokalemia in 2. Twelve patients (86%) responded including 1 with complete remission (CR), 2 with unconfirmed CR, and 9 with partial responses. One patient had stable disease and one had disease progression. Nine of 12 patients (75%) who attempted peripheral blood stem cell collection following VICE/V-RICE were successful (〉5×106 CD34+/kg) Collectively, these findings indicate that the combination of vorinostat with RICE or ICE, is feasible and active in patients with lymphoid malignancies. Special attention should be given to the management of the frequent gastrointestinal AEs. Pending identification of the MTD, phase II evaluation of VICE or V-RICE regimen will be designed to formally define its efficacy. Table Summary of DLTs and responses at various dose levels Stage Dose level Dose n DLTs responses I 1 400 mg QD 2 0 PR(1); SD (1) 2 300 mg BID 1 0 PR (1) 3 400 mg BID 1 0 PD (1) 4 500 mg BID 2 0 PR (1); CR (1) 5 600 mg BID 1 0 PR (1) 6 700 mg BID 2 1 PR (2) II 5 600 mg BID 4 3 PR (1); CRu (3) 4 500 mg BID 1 1 PR (1) Total - - 14 5 12 (86%) Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1864 Background: In addition to determining the efficacy and safety of different treatment options for MM, the impact of treatment and associated toxicities on patient-reported QoL should be evaluated. The US community-based phase 3b UPFRONT study compares the efficacy and safety of three bortezomib (VELCADE®, Vc)-based regimens, Vc-dexamethasone (VcD), Vc-thalidomide-dexamethasone (VcTD), and Vc-melphalan-prednisone (VcMP), followed by weekly Vc maintenance, in elderly, newly diagnosed, transplant-ineligible MM patients. Updated efficacy and safety data are reported elsewhere at this meeting; here we present patient-reported QoL results – a secondary endpoint of the trial – from all 502 randomized patients, who received up to a maximum of 13 treatment cycles. Methods: Patients with symptomatic MM were randomized (1:1:1) to receive eight 21-day cycles of VcD (Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]), VcTD (Vc as before; T 100 mg/day, days 1–21; D as before), or VcMP (Vc as before; M 9 mg/m2, and P 60 mg/m2, days 1–4, every other cycle) induction, followed by five 35-day cycles of maintenance with Vc 1.6 mg/m2, days 1, 8, 15, 22. QoL was assessed using the EORTC QLQ-C30 questionnaire, which includes global health status, physical, role, cognitive, emotional, and social functioning, and symptom scales of fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Global health status scores combine overall health and QoL scores, with higher scores reflecting better health status. Questionnaires were completed prior to dosing on day 1 of cycle 1 (baseline), prior to dosing on day 1 of every odd-numbered cycle, at the end-of-treatment visit, and every 12 weeks until progressive disease. Patient-reported QoL scores presented herein represent data collected within 1 year of randomization regardless of discontinuation status; for patients who died, missing assessments were assigned the worst possible score of 0. A linear mixed effect model was used to assess QoL changes over time, both within and between treatment arms. Sensitivity analyses were conducted to test the robustness of the primary analysis. Results: Patient baseline characteristics were well balanced across the VcD (n=168), VcTD (n=167), and VcMP (n=167) arms as reported previously (Niesvizky et al, EHA 2011). Median age was 74.5 (VcD), 73.0 (VcTD), and 72.0 (VcMP) years, and 71%, 62%, and 72% of patients had ISS stage II/III disease. QoL assessments were available at baseline and ≥1 post-baseline time point for 78% (VcD), 69% (VcTD), and 78% (VcMP) of patients. Observed data showed a downward trend in mean global health status score until cycle 7 (VcD, VcMP) or 9 (VcTD), followed by a trend to stabilizing/improving score thereafter (Figure). Symptom scores changed very little during induction in all arms, except for nausea/vomiting and diarrhea, with moderate improvements seen during maintenance. After fitting observed data with a linear mixed effect model, a significant decrease in mean global health status score from baseline to cycle 7 (induction period) was evident in all arms (VcD, p=0.0127; VcTD, p

Description: Abstract 3026 Background: UPFRONT is an ongoing US community-based phase 3b study designed to compare the safety and efficacy of three bortezomib (Velcade®, Vc)-based regimens, Vc-dexamethasone (VcD), Vc-thalidomide-dexamethasone (VcTD), and Vc-melphalan-prednisone (VcMP), followed by Vc maintenance therapy, in previously untreated multiple myeloma (MM) patients who were ineligible for high-dose therapy and autologous stem cell transplantation (HDT-SCT). Efficacy data have been presented elsewhere; here we present patient-reported quality of life (QoL) data after 300 patients had the opportunity to undergo the entire 13-cycle treatment period (8 Vc-based induction cycles and 5 Vc maintenance cycles). Methods: Patients with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD, VcTD, or VcMP (VcD: Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcTD: Vc 1.3 mg/m2, days 1, 4, 8, 11; T 100 mg/d, d1–21; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcMP: Vc 1.3 mg/m2, days 1, 4, 8, 11; M 9 mg/m2, and P 60 mg/m2, day 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with Vc alone (1.6 mg/m2, days 1, 8, 15, 22). Patient-reported QoL was recorded using the EORTC QLQ-C30 questionnaire, which assesses global health status, physical, role, cognitive, emotional, and social functions, fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Patients completed the questionnaire prior to dosing on cycle 1, day 1 (baseline), prior to dosing on day 1 of every odd cycle, at the end of treatment visit, and every 12 weeks thereafter. Here we present updated study results after 300 patients had the opportunity to undergo the entire 13-cycle treatment period, focusing on change in global health status score over time; no adjustment was made for missing cases or patient deaths. Results: Patient baseline characteristics were well balanced across the three treatment arms. Patients in the VcD, VcTD, and VcMP arms had median ages of 73.5, 73.0, and 72.0 years, respectively; 85%, 64%, and 74% had ISS stage II/III; 22%, 27%, and 28% were non-Caucasian; and 51%/25%/24%, 55%/30%/14%, and 62%/24%/15% had Charlson comorbidity index 0/1/≥2 in the VcD, VcTD, and VcMP arms, respectively. Patients received a median of 9 (VcD), 6 (VcTD), and 7 (VcMP) treatment cycles (induction + maintenance); 56%, 33%, and 43% of patients, respectively, received Vc maintenance. In the VcD, VcTD, and VcMP arms, Vc dose intensity (mean ratio of doses received/doses planned) was 76%, 63%, and 69% during induction, and 73%, 77%, and 85% during maintenance, respectively. After 13 treatment cycles, the rates of grade ≥3 adverse events (AEs) were 74%, 86%, and 80% in the VcD, VcTD, and VcMP arms. The incidence of serious AEs was highest in the VcTD arm (61%, vs 57% and 51% with VcD and VcMP), as was the rate of study drug discontinuation due to AEs (41%, vs 29% and 35% with VcD and VcMP). Global health status score by cycle is shown in the Figure, with number of patients with available QoL data in each arm indicated below. In all three arms, for those patients with available QoL data, global health status score at the end of cycle 12 was greater than at baseline and at the end of cycle 8 (end of Vc-based induction therapy). In the induction phase, global health status score remained stable in the VcD arm and transiently decreased in the VcMP arm at cycle 4, before increasing to above baseline levels. A similar trend was seen for the VcTD arm; global health status score started decreasing at cycle 2 but took slightly longer to increase, possibly due to the increased incidence of AEs in the VcTD arm. Similar trends were seen for other EORTC QLQ-C30 function and symptom scores. Conclusions: Although there was some variability during the study, by the end of the treatment period patients who received one of the three Vc-based regimens reported improvements in QoL compared with baseline values. The study is ongoing and patients continue to be followed for assessment of patient-reported QoL and long-term outcomes. Updated QoL data, including the correlation between change in QoL and best response achieved, will be presented. Disclosures: Niesvizky: Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Off Label Use: Discussion of Velcade in a novel combination in frontline myeloma is included. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Gabrail:Millennium Pharmaceuticals, Inc.: Research Funding. Charu:Amgen: Equity Ownership, Research Funding; Pfizer: Equity Ownership; GSK: Equity Ownership, Research Funding; Lilly: Equity Ownership, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Reeves:Celgene: Equity Ownership.

Description: Abstract 619 The UPFRONT study is a US community-based, randomized, open-label, multicenter phase 3b trial comparing the safety and efficacy of three bortezomib (Velcade®, Vc)-based regimens, VcD (Vc-dexamethasone), VcTD (Vc-thalidomide-dexamethasone), and VcMP (Vc-melphalan-prednisone), followed by Vc maintenance, in newly diagnosed multiple myeloma (MM) patients ineligible for high-dose therapy and stem cell transplantation. Patients with previously untreated, symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD, VcTD, or VcMP (VcD: Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcTD: Vc 1.3 mg/m2, days 1, 4, 8, 11; T 100 mg/d, d1–21; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcMP: Vc 1.3 mg/m2, days 1, 4, 8, 11; M 9 mg/m2 and P 60 mg/m2, day 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with weekly Vc (1.6 mg/m2, days 1, 8, 15, 22). Here we present updated results after 300 patients had the opportunity to undergo the entire 13-cycle treatment period (8 induction + 5 maintenance cycles). The primary study endpoint is progression-free survival (PFS); secondary endpoints include efficacy (overall response rate [ORR], complete response [CR]/near-CR [nCR] and very good partial response [≥VGPR] rates), safety and tolerability, and response duration. Responses were assessed by investigators using central laboratory data, applying modified International Myeloma Working Group (IMWG) criteria. Patients in the VcD, VcTD, and VcMP arms had median ages of 73.5, 73.0, and 72.0 years, respectively; 85%, 64%, and 74% had ISS stage II/III, and 22%, 27%, and 28% were non-Caucasian. Patients received a median of 9 (VcD), 6 (VcTD), and 7 (VcMP) treatment cycles (induction + maintenance); 56%, 33%, and 43% of patients, respectively, received Vc maintenance. In the VcD, VcTD, and VcMP arms, Vc dose intensity (mean ratio of doses received/doses planned) was 76%, 63%, and 69% during induction, and 73%, 77%, and 85% during maintenance, respectively. All three Vc-based induction regimens exhibited substantial efficacy after 8 cycles, with ORRs (≥PR; best confirmed response) of 68%, 78%, and 71% for VcD, VcTD, and VcMP, respectively. After 5 cycles of Vc maintenance, the ORR was increased to 71%, 79%, and 73% in the VcD, VcTD, and VcMP arms, respectively. Similar trends were seen in CR+nCR and ≥VGPR rates after Vc maintenance in the VcD, VcTD, and VcMP arms: CR+nCR rates were 24%, 36%, and 31% after induction versus 31%, 38%, and 34% after Vc maintenance, and ≥VGPR rates were 36%, 44%, and 40% after induction versus 39%, 47%, and 44% after Vc maintenance, respectively (Table). After 13 treatment cycles, the rates of grade ≥3 adverse events (AEs) were 74%, 86%, and 80% for patients in the VcD, VcTD, and VcMP arms, respectively; similar to the rates reported after 8 cycles, 70%, 84%, and 79%, respectively. After 13 cycles, the five most common grade ≥3 AEs were peripheral neuropathy (PN) (18%, 28%, and 21% for VcD, VcTD, and VcMP, respectively), fatigue (10%, 15%, 8%), diarrhea (11%, 5%, 10%), neutropenia (1%, 3%, 21%), and pneumonia (11%, 6%, 6%). The incidence of serious AEs was highest in the VcTD arm (61%, vs 57% with VcD and 51% with VcMP). All-grade PN was most frequently reported in the VcTD arm (61%), versus the VcD (49%) and VcMP (45%) arms; these rates are similar to those reported after 8 induction cycles (59%, 45%, and 43% for the VcTD, VcD, and VcMP arms). Rates of deep vein thrombosis and pulmonary embolism were 7%, 4%, and 2%, and 4%, 3%, and 1%, respectively, in the VcD, VcTD, and VcMP arms. Study drug discontinuation due to AEs was highest in the VcTD arm (41%, vs 29% with VcD and 35% with VcMP). In conclusion, maintenance with Vc monotherapy is well tolerated when administered after VcD, VcTD, and VcMP induction regimens. Response rates, including CR and ≥VGPR, improved after Vc maintenance with no concomitant increase in the incidence of PN. Patients continue to be monitored for PFS and response duration. Disclosures: Niesvizky: Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Off Label Use: Discussion of Velcade in a novel combination in frontline myeloma is included. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Gabrail:Millennium Pharmaceuticals, Inc.: Research Funding. Charu:Amgen: Equity Ownership, Research Funding; Pfizer: Equity Ownership; GSK: Equity Ownership, Research Funding; Lilly: Equity Ownership, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Reeves:Celgene: Common stock in Celgene.