ALBERT

Description: Key Points Weekly oral proteasome inhibitor ixazomib appears generally well tolerated with manageable toxicity, limited grade 1/2 neuropathy. Data show that more than 25% of 30 evaluable relapsed/refractory myeloma patients who received the MTD had clinically meaningful responses.

Description: Abstract 4002 African-Americans (AA) have a 2–3-fold higher risk of multiple myeloma (MM) relative to Whites (Gebregziabher, 2006). We have formed a consortium and are conducting a multi-center study with 9 clinical centers and 4 NCI Surveillance, Epidemiology and End-Results (SEER) Program population-based cancer registries to determine the causes of the disease in this population and explain the excess risk (Myeloma in African-American Patients, MAP). Participation involves providing a blood or saliva specimen for DNA and answering a lifestyle and medical history questionnaire. At the end of the data collection period, a genome-wide scan will be performed and our results compared to those from 2,000 African-American controls participating in cohort studies. Patients with African ancestry (predominantly African-Americans) are identified from outpatient clinic rosters or from population-based cancer registries. For patients recruited at clinics, information on subtype, cytogenetics, FISH and lytic bone lesions is abstracted from medical records. To date, 601 patients have agreed to be in the study and we have received DNA samples from 592 patients; 54.6% are female and 45.4% are male. The mean age at diagnosis is 57 years (SD =11.2) with a median age at diagnosis of 58 years (range 27 to 90 years of age). Of the 514 subjects who completed a questionnaire, 7.8% were obese at age 20 (body mass index 〉 30) and 39% were obese 5 years prior to diagnosis. A first-degree relative with MM was reported by 17 cases (3%), 74% higher than the lifetime risk of 1.7% in the general population based on SEER data. In addition, cases reported 21 first-degree relatives with leukemia (4%), 7 with non-Hodgkin lymphoma (1%) and 14 with Hodgkin lymphoma (3%). To date, clinical information has been abstracted for 351 patients. Of these, 207 (58%) have active disease with the following distribution: stage I (30%), stage II (27%) and stage III (43%). The remainder have relapsed (13%), refractory (1%), relapsed and refractory (4%), or smoldering myeloma (6%), or are in remission (18%). The subtype distribution is: IgG (74%), IgA (11.4%), IgD (0.9%) and IgM (0.3%), and light chain only (13.5%); a distribution significantly different from that observed in a predominantly White population (P

Description: INTRODUCTION: Perifosine (Peri) a novel, oral signal transduction modulator with multiple effects including inhibition of Akt and activation of JNK, has demonstrated clinical activity when combined with dexamethasone (Dex) in patients (pts) with relapsed/refractory MM (ASH 2007 #1164). Lenalidomide (Revlimid®, Rev) a novel, oral immunomodulatory drug has single-agent activity against MM and additive effects when combined with Dex. We previously reported encouraging safety data and observed clinical activity of the oral triplet combination in the first 12 pts (ASH 2007 # 1169). We now report the phase I results of this study which aimed to determine the MTD and activity of Peri + Rev + Dex, as an oral combination in pts with relapsed or refractory MM. METHODS: Four cohorts (≥6 pts each) were planned, dosing Peri at 50 or 100mg (daily), Rev 15 or 25mg (d 1–21) and Dex 20mg (d 1–4, 9–12 and 17–20 for 4 cycles, then 20 mg d 1–4) in 28-d cycles. To limit dex-related toxicities, the protocol was amended to use weekly dex (40 mg), applying to cohorts 3, 4, and the MTD cohort. Toxicity was assessed using NCI CTCAE v3.0; DLT was defined as grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets 1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Pts had to have received at least 1 prior therapy and no more than 4. Pts refractory to Rev/Dex were excluded. RESULTS: 32 pts (17 men and 15 women, median age 61 y, range 37 – 80) were enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg); 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg); 8 pts in cohort 3 (Peri 100mg, Rev 15mg, Dex 40mg/wk); 6 pts in cohort 4 (Peri 100mg, Rev 25mg, Dex 40mg/wk) and 6 pts at MTD (Cohort 4). Median prior lines of treatment was 2 (range 1–4). Prior therapy included dex (94%), thalidomide (83%), bortezomib (47%), and stem cell transplant (47%). 37% of pts had progressed on prior Thal/Dex. Two pts did not complete one full cycle (noncompliance and adverse event not related to study drugs – both in cohort 3) and were not included in the safety and efficacy analysis. Of the 30 pts evaluable for safety, the most common (≥ 10%) grade 1/2 events included nausea (13%); diarrhea (17%); weight loss (17%); upper respiratory infection (23%); fatigue (30%); thrombocytopenia (20%); neutropenia (20%); hypophosphatemia (23%); increased creatinine (23%); anemia (36%); hypercalcemia (47%). Grade 3/4 adverse events ≥ 5% included neutropenia (20%); hypophosphatemia (17%); thrombocytopenia (13%); anemia (10%), fatigue (7%). There was one reported DLT in cohort 3 (Nausea). Rev was reduced in 8 pts, Peri reduced in 8 pts and Dex reduced in 6 pts. All 30 pts in the analysis are evaluable for response, with best response as follows: Response: N = 30 N (%) Duration (wks) ORR (≥PR) stable disease: 〈 25% reduction in M-protein Near Complete Response (nCR) 2 (7%) 79+, 15+ Very Good Partial Response (VGPR) 3 (10%) 62+, 34, 17 15 (50%) Partial Response (PR) 10 (33%) 26+ (range 11 – 54+) Minimal Response (MR) 6 (20%) 17+ (range 9 – 30+) Stable Disease (SD) 7 (23%) 14+ (range 8 – 19) Progression (PD) 2 (7%) 8, 4 As of August 2008, the median time to progression (TTP) for pts achieving ≥ PR is 31 wks (range 11–79), and the median TTP for all 30 pts is 23 wks (range 4 – 79). The median TTP has not been met with 11/30 pts continuing on active treatment. Survival for all study pts remains at 90%. CONCLUSIONS: Patients have tolerated Peri + Rev + Dex well with manageable toxicity, and with encouraging clinical activity demonstrated by an ORR (≥ PR) of 50%. Accrual is complete and the final analysis for all pts will be presented at the meeting.

Description: Fludarabine melphalan conditioning has been used widely for conditioning of pts with hematologic malignancies. When combined with in vivo alemtuzumab, this regimen leads to reliable engraftment, minimal acute and chronic GVHD, and low early transplant-related mortality (TRM). Between 2002 and 2004, we conducted a prospective study in hematologic malignancies. Here we report outcomes in 55 patients with high-risk myeloid malignancies. Median age was 54 (range 17–71); 17 were 60 and older. 28 had HLA-identical related donors, 23 had MUD donors, and 4 had 1 Ag-MM related donors. 32 pts had high leukemia burden at transplant (24 active AML, 6 MDS with 〉5% blasts, 1 CML-BC, 1 myelofibrosis in transformation). 23 pts had low leukemia burden at transplant (4 AML in CR1 with adverse cytogenetics, 2 AML CR1 with WBC〉100K, 1 AML CR1 requiring 2 inductions, 6 AML CR2, 1 AML CR3, 4 MDS 0 in 20 pts. Many had other high risk features including 15 with prior transplant and 10 with secondary leukemia. Conditioning consisted of fludarabine-melphalan-alemtuzumab (as per Smith, Blood 2002, abstract 5292), with tacrolimus for GVHD prophylaxis until day 100. Stringent CMV prophylaxis with high dose valacyclovir was given for 180 days. There were two early graft rejections (both from1 Ag-MM related donors) and both pts died of aplasia. There were also 2 deaths during conditioning. Including these 4 pts, cumulative day 100 TRM is 17% (95% CI 7–27). Median follow-up for survivors is 14 months (range 2–30). Estimated one year survival is 53% (95% CI 39–67) and one year PFS is 44% (95% CI 30–68). Donor type did not affect survival. Age 〉 55 (HR 2; p= 0.04), PS 〉 0 (HR 2.4; p= 0.001) and high leukemia burden (HR 7.7; p=0.0001) were associated with decreased survival in univariate analysis. 20 of 23 pts with low leukemia burden remain alive, 18 in ongoing remission. By contrast, one year survival for pts with high leukemia burden is 35 % (figure). Only 1 case of grade III–IV acute GVHD was observed and extensive chronic GVHD occurred in 3 pts. CMV reactivation was common, but documented CMV pneumonia occurred in only one patient. Fludarabine melphalan alemtuzumab conditioning results in excellent long-term outcome for patients with high-risk myeloid malignancies and low leukemia burden, with a very low incidence of acute and chronic GVHD. In these disorders, GVHD is not a prerequisite for achievement of durable CR. For pts with high leukemia burden, therapy provided mainly palliative responses with a low incidence of GVHD. Further improvements are needed to reduce recurrence rate for pts with high leukemia burden. Figure Figure

Description: Abstract 3064 Introduction: Perifosine (Peri) a novel, oral signal transduction modulator with multiple effects including inhibition of Akt and activation of JNK, has demonstrated clinical activity when combined with dexamethasone (Dex) in patients (pts) with relapsed/refractory MM (ASH 2007 #1164). Lenalidomide (Revlimid , Rev) a novel, oral immunomodulatory drug has activity against MM when combined with Dex. We previously reported encouraging safety data and observed clinical activity of the oral triplet combination (ASH 2008 # 3691). We now report the final phase I results of this study which aimed to determine the MTD and to evaluate activity of Peri + Rev + Dex, as an oral combination in pts with relapsed or refractory MM. Methods: Four cohorts ( 6 pts each) were planned, dosing Peri at 50 or 100mg (daily), Rev 15 or 25mg (d 1–21) and Dex 20mg (d 1–4, 9–12 and 17–20 for 4 cycles, then 20 mg d 1–4) in 28-d cycles. To limit dex-related toxicities, the protocol was amended to use weekly dex (40 mg), applying to cohorts 3, 4, and the MTD cohort. Toxicity was assessed using NCI CTCAE v3.0; DLT was defined as grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets 1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Pts had to have received at least 1 prior therapy and no more than 4. Pts refractory to Rev/Dex were excluded. Results: 32 pts (17M/15F, median age 64 y, range 37 – 79) were enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg); 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg); 8 pts in cohort 3 (Peri 100mg, Rev 15mg, Dex 40mg/wk); 6 pts in cohort 4 (Peri 100mg, Rev 25mg, Dex 40mg/wk) and 6 pts at MTD (Cohort 4). Median prior lines of treatment was 2 (range 1–4) with a median PS of 1. Relapsed (53%), Refractory to last therapy prior to study entry (47%). Prior therapy included dex (94%), thalidomide (75%), bortezomib (44%), and stem cell transplant (72%). Two pts (6%) were previously treated with Rev. 63% (15/24) of the prior thalidomide + dex (Thal/Dex) treated pts had progressed on a Thal/Dex regimen while 43% (6/14) of the prior bortezomib (Vel) treated pts had progressed on a prior Vel based regimen. Two pts did not complete one full cycle (non-compliance and adverse event not related to study drugs – both in cohort 3) and were not included in the efficacy analysis. 31/32 pts were evaluable for safety (non-compliant patient never took study drug and was excluded). The most common grade 1/2 events (any causality) included fatigue (48%), diarrhea (45%), upper respiratory infection (35%), nausea (32%) and hyperglycemia (32%). Grade 3/4 events 〉 10% included neutropenia (26%); hypophosphatemia (23%); thrombocytopenia (16%) and leucopenia (13%). There was one reported DLT in cohort 3 (Nausea). No grade 3/4 events of peripheral neuropathy or DVT were reported. Rev dose was reduced in 11 pts, Peri reduced in 9 pts and Dex reduced in 7 pts: 30 pts are evaluable for response, with best response as follows: Median progression-free survival (PFS) for all pts was 10.8 mos (CI: 4.6, 27.7) and 7 pts have not progressed. The median overall survival (OS) was 30.6 mos (CI: 16.7, NR) with 15/30 pts still alive. Of the 8 thalidomide naïve pts, 4 have progressed with a median projected PFS of 30 mos and all 8 pts remain alive (range 28 – 43 mos). Conclusions: Pts have tolerated Peri + Rev + Dex well with manageable toxicity, and with promising clinical activity demonstrated by an ORR (≥ PR) of 50%, an extended PFS and OS. Given that most pts were exposed to Thal/Dex with more than half refractory to a prior Thal/Dex regimen, the encouraging response rates and survival appear to suggest benefit with the addition of perifosine to Rev/Dex. This data thus warrants further study, including a potential randomized trial to confirm the activity of perifosine added to Rev/Dex. A randomized phase III trial of Peri/Vel/Dex vs. Vel/Dex is underway for previously Vel exposed MM patients. Disclosures: Jakubowiak: Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson Ortho-Centocor: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor-Ortho Biotech: Speakers Bureau. Off Label Use: Perifosine in combination with Lenalidomide and Dexamethasone. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Millennium, Celgene: Speakers Bureau. Alsina:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding. Kaufman:Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Description: Abstract 2972 Introduction Siltuximab is a chimeric monoclonal antibody that binds human interleukin (IL)-6 with high affinity. Formal assessments of siltuximab's effects on cardiac repolarization using triplicate electrocardiograms (ECGs) have not yet been performed in clinical studies. A phase 1 study was conducted to evaluate the effect of siltuximab, administered at the highest dose level used in clinical studies, on the QT interval in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or indolent multiple myeloma (IMM, i.e., asymptomatic MM with ≤3 lytic bone lesions but no other end organ damage). Methods Thirty patients with MGUS, SMM, or IMM who met the following criteria on ECG at screening: pulse 45−90 bpm, QTcF and QTcB ≤500 ms, QRS

Description: Abstract 2965 Background: Alkylating agents have been the mainstay of multiple myeloma (MM) therapy for decades and despite introduction of several new therapies, it continues to play a significant role in its management as part of various drug combinations. While melphalan has been the most commonly used alkylator in MM, recent studies have suggested significant activity for bendamustine, a bifunctional alkylator. The combination of lenalidomide and melphalan has been associated with high response rates in relapse and newly diagnosed MM. Based on these promising results we designed a trial to evaluate the maximally tolerated dose of lenalidomide and bendamustine when used in combination as well as the efficacy of the combination in relapsed disease. Patients and Methods: Patients with relapsed MM and measurable disease were enrolled on this phase 1/2 trial provided they had not more than 4 prior lines of therapy for MM, had adequate performance status and organ and hematological function. Patients refractory to lenalidomide were allowed to enroll. The primary objectives were to (i) to determine the MTD of bendamustine and lenalidomide in combination with dexamethasone in subjects with relapsed MM (phase 1) and (ii) to evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in patients with relapsed MM (phase 2). Bendamustine (B) was administered on days 1 and 2 of a 28-day cycle at doses of 50–100 mg/m2. Lenalidomide (R) was given days 1–21 at doses of 15–25 mg daily. Dexamethasone (D) was administered at 40 mg weekly. Dose escalation was done using a 3+3 design and MTD was defined as one dose level below that resulted in 〉=2 DLTS among 6 patients. The primary end point for this trial was the proportion of patients with confirmed hematologic response (sCR, CR, VGPR, or PR) over the first 6 cycles of treatment. Results: A total of 72 patients were accrued to this study from March 2010 to May 2012: 21 patients in phase 1 and 51 in phase 2. The 6 patients from the MTD dose level of phase 1 were also included in phase 2. The median age of all 72 patients was 62.1 (range, 40–86) and 57% were male. Majority (75%) of patients had previously been exposed to lenalidomide and 69% had prior exposure to bortezomib. Median # of prior therapies was 3 (range, 1–5) and 74% of patients had a prior autologous stem cell transplant. Patients have received a median of 4 cycles (range, 1–25), with 27 patients still continuing on active treatment. Disease progression led to study discontinuation in 22 (49%) and adverse events were the reason for discontinuation in 14 (31%). In phase I, two DLTs (Grade (Gr) 2 neuropathy and Gr 4 neutropenia) were seen at the highest dose level (100 mg/m2 B, 25 mg R), and the MTD was determined as 75 mg/m2 of B given days 1 and 2 and 25 mg of R days 1–21, along with D 40 mg weekly. Overall patients, 12/21 (57%) had a PR or better. In phase 2, 17 (40%) confirmed responses (〉=PR) were seen among the 43 patients evaluable for response (received at least 6 cycles of treatment or have gone off study prior to 6 cycles); including 9 (21%) VGPR and 8 (19%) PR. An additional 5 patients had a minor response. Over all dose levels, a gr 3 or higher adverse event at least possibly attributed to the study was seen in 75% of patients. The most common toxicities were all hematological (thrombocytopenia and leukopenia), and most common non-hematological toxicity was infection. Prolonged time to recovery of blood counts was seen in a few patients, but majority of patients were able to tolerate the regimen with adequate dose reductions. Conclusion: The recommended dose of the combination for further studies is bendamustine at 75 mg/m2 days 1 and 2, lenalidomide 25 mg daily on days 1–21 and dexamethasone days 1, 8, 15, 22; with cycles repeated every 28 days. The regimen is well tolerated with hematological toxicity being the most common and manageable with dose reductions. The regimen is effective with high response rates and durable responses seen. Updated results with response rates and time to event analyses will be available for the entire cohort at the time of meeting. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Krishnan:celgene: Consultancy, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Novartis: Expert Testimony, Expert Testimony Other. Vij:Teva: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Honoraria, Research Funding.

Description: Abstract 816 Background: Proteasome inhibition is a very effective therapeutic strategy in multiple myeloma (MM). The investigational agent MLN9708 is an oral, specific, reversible inhibitor of the 20S proteasome that has shown antitumor activity in solid tumor and hematologic malignancy xenograft models. Phase 1 trials are evaluating both intravenous and oral formulations using different dosing schedules in a variety of tumor types. Here we report the findings from the dose-escalation portion of a phase 1 trial of once-weekly, orally administered MLN9708 in patients with relapsed and/or refractory MM (NCT00963820). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of MLN9708. Secondary objectives included determination of response rate, and characterization of the pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (PD, 20S proteasome inhibition in blood) of once-weekly oral MLN9708. Patients with MM who had received ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. Treatment consisted of MLN9708 administered orally on days 1, 8, and 15 of a 28-day cycle. Dose-escalation proceeded from 0.24 mg/m2 using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded by NCI-CTCAE v3. Response was assessed by modified EBMT/IMWG criteria. Blood samples were collected after dosing on days 1 and 15 of cycle 1 for PK and PD analyses; parameters were calculated using noncompartmental methods (WinNonlin software v5.3). Results: A total of 28 patients have been enrolled to date (data cut-off: June 29, 2011), including 3 each at dose levels of 0.24, 0.48, 0.80, and 1.20, 4 at 1.68, 3 at 2.23, 4 at 2.97, and 5 at 3.95 mg/m2. The median age was 63.5 years (range 40–76); 54% were male. The median number of prior regimens was 5 (range 2–15), and median time from diagnosis was 4.6 years. Nineteen (68%) patients had prior stem cell transplant, and 16 (59%) were refractory to their last prior therapy, including 7 (26%) to bortezomib and 11 (41%) to lenalidomide or thalidomide. The MTD has not been reached; the current cohort is receiving 3.95 mg/m2. No DLTs have been observed among 21 DLT-evaluable patients. Patients have received a median of 2 treatment cycles (range 1–11; mean 2.8). Four patients remain on treatment; discontinuation was mainly due to progressive disease (71%). All 28 patients are evaluable for toxicity; 26 (93%) experienced at least one AE, including 22 (79%) who experienced at least one drug-related AE. Drug-related AEs occurring in 〉20% of patients included fatigue (39%), thrombocytopenia (36%), nausea (32%), and diarrhea (29%). Two (7%) patients had drug-related peripheral neuropathy (PN, both grade 2); both had grade 1 PN at baseline. Ten (36%) patients experienced grade ≥3 AEs, 4 (14%) had AEs resulting in MLN9708 dose reductions, and 3 (11%) discontinued due to AEs. No on-study deaths have occurred. In 16 response-evaluable patients, one partial response has been seen, in a patient treated at 2.97 mg/m2 (who had three prior lines of therapy, thalidomide–dexamethasone, lenalidomide–dexamethasone –perifosine, and bortezomib–dexamethasone, to which the patient responded and relapsed); duration of response is 3.7 months, and the patient remains in response at cycle 8. A further five patients had a best response of stable disease, durable for up to 9.5 months. PK analyses showed that MLN9708 was rapidly absorbed, with MLN2238 Tmax of 0.5–2.0 hours and a terminal half-life after multiple dosing of approximately 7 days based on limited data (n=5). MLN2238 exposure appeared to increase proportionally with increasing MLN9708 dose over the range 0.8–2.97 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent. Conclusions: Current data suggest that MLN9708 on a once-weekly schedule is generally well tolerated and has early signs of anti-tumor activity in this heavily pre-treated population with prior exposure to lenalidomide/thalidomide and bortezomib. To date, toxicity has been manageable, and no significant neuropathy signal has been observed. Updated data will be presented, with the MTD anticipated to be reached. Data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708 will also be presented. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Bensinger:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding; Array: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding. Reeder:Celgene: Institutional research funding; Millennium Pharmaceuticals, Inc.: Institutional research funding; Novartis: Institutional research funding. Zimmerman:Novartis: Expert witness; Celgene: Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc: Honoraria, Speakers Bureau. Berenson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Niesvizky:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Research Funding.

Description: Abstract 3876 Poster Board III-812 Background Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). In mouse xenograft models of MM, elotuzumab demonstrated significantly enhanced anti-tumor activity when combined with bortezomib compared to bortezomib alone (Van Rhee et al., Mol. Cancer Ther., in press, 2009). This phase 1/2 trial will determine the maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK) and clinical response of elotuzumab in combination with bortezomib in patients with relapsed MM following 1-3 prior therapies. Methods The study consists of 4 escalating cohorts of elotuzumab (2.5 mg/kg to 20 mg/kg) administered on Days 1 and 11 and bortezomib (1.3 mg/m2) administered on Days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease at the end of Cycle 2 or 3 also receive oral dexamethasone (20 mg) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each subsequent cycle. Patients with stable disease or better at the end of 4 cycles will continue treatment for 6 or more cycles unless withdrawn earlier due to unexpected toxicity or disease progression. Key entry criteria: age ≥ 18 years; confirmed diagnosis of MM and documentation of 1 to 3 prior therapies; measurable disease M-protein component in serum and/or in urine; and no prior bortezomib treatment within 2 weeks of first dose. Results To date, a total of 16 MM patients with a median age of 64 years have been enrolled in the study. The median time from initial diagnosis of MM was 3.5 years and patients had received a median of 2 prior MM treatments. Patients have been treated in four cohorts; 3 each in 2.5, 5 and 10 mg/kg elotuzumab cohorts, and 7 in the 20 mg/kg elotuzumab cohort. No dose limiting toxicity (DLT) was observed during the first cycle of the study and the MTD was not established. Five SAEs have been reported in four patients in later treatment cycles; two events, chest pain and gastroenteritis, occurring in one patient, were considered elotuzumab-related. Other SAEs include grade 3 sepsis, vomiting, pneumonia and grade 2 dehydration. The most common AEs reported include Grade 1-3 diarrhea, constipation, nausea, fatigue, thrombocytopenia, neutropenia, anemia and peripheral neuropathy. The best clinical response (EBMT criteria) for the 16 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis suggests a serum half-life of 10-11 days at higher doses (10 and 20 mg/kg). Preliminary analysis of peripheral blood mononuclear cells and bone marrow of patients on study indicates that objective responses in the study correlate well with complete saturation of CS1 sites by elotuzumab on bone marrow plasma and NK cells. Conclusions The combination of elotuzumab with bortezomib has a manageable adverse event profile and shows promising preliminary efficacy with ≥PR in 44% and ≥MR in 75% of all enrolled patients. Accrual is ongoing in the expanded 20 mg/kg cohort. Updated safety, efficacy, and PK data will be presented at the meeting. Disclosures: Jakubowiak: Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor Ortho Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bortezomib in combination with elotuzumab for the treatment of relapsed/refractory multiple myeloma. Bensinger:Millennium: Membership on an entity's Board of Directors or advisory committees. Siegel:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Zimmerman:Millennium: Speakers Bureau; Centecor: Speakers Bureau. Van Tornout:BMS: Employment. Zhao:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 132 Background: The RVD combination of Lenalidomide (Revlimid®, Len), Bortezomib, (Velcade®, Bz), and Dexamethasone (Dex) and the VDD combination of Bz, pegylated liposomal doxorubicin (Doxil®, PLD), and Dex are among the most active in newly diagnosed multiple myeloma (MM). Pre-clinical studies suggest that combining 4 drugs from RVD and VDD into RVDD may produce even higher activity. The aims of this Phase I/II trial were to determine the maximum tolerated dose (MTD) of the RVDD regimen and to assess its safety and evaluate efficacy in newly diagnosed MM. Methods: Patients (Pts) received Len 15–25 mg (days 1–14), Bz 1.3 mg/m2 (days 1, 4, 8, 11), Dex 20/10 mg (cycles 1–4/5–8; days of and after Bz), PLD 20 or 30 mg/m2 (day 4) at 4 dose levels for up to eight 21-day cycles. In the Phase I portion of the study, pts were assigned to dose levels 1-4 according to the TITE-CRM algorithm. Responses were assessed by modified European Group for Blood and Marrow Transplantation (EBMT) and Uniform Criteria. Pts who achieved at least partial response (PR) could proceed to autologus stem cell transplant (ASCT) after ≥ 4 cycles. After 8 cycles, pts could continue treatment using 21-day maintenance cycles with Len (days 1–14), Bz (day 1 and 8), and Dex (days of and after Bz) at the doses tolerated by the end of initial treatment. Results: The study has enrolled 68 pts to date (median age 61; 52% ISS II/III), 42 pts in phase I (including 6 pts treated at the MTD) and 26 pts in phase II, for a total of 32 of 38 planned pts at the MTD. Pts received a median of 4 cycles (range 1–16); 48 completed at least 4 cycles, 11 completed all 8 cycles, and 34 have discontinued/completed therapy. Seven patients remain on maintenance therapy. Toxicity data are available for 55 pts. In the phase I, 4 pts were assigned to level 1 (Len/PLD 15/20), 11 to level 2 (Len/PLD 20/20, 21 to level 3 (Len/PLD 25/20), and 6 to level 4 (Len/PLD 25/30). Two pts were not evaluable for DLT per protocol criteria and were replaced; 1 at level 2 and 1 at level 3, leaving 40 pts evaluable for DLTs. There were no DLTs at level 1, 2 at level 2, 3 at level 3, consisting of 2 grade (G) 3 asymptomatic neutropenia on day 1 cycle 2, 1 G3 elevation of transaminases, 1 G3 drug fever, and 1 grade 3 hypophosphatemia and none at level 4. Based on the pre-determined definition of maximum tolerated dose (MTD) and probability estimates of DLTs of 4.7% for level 1, 9.7% for level 2, 13.7% for level 3, and 17.9% for level 4, the maximum planned dose level 4 was selected as the MTD for the phase II portion of the study as the closest to, but not exceeding, a target rate of 20% of DLTs. Overall, toxicities have been manageable with G3/4 toxicities in 3–18% of all pts including neutropenia (18%), thrombocytopenia (7%) , infections (16 %) , DVT (2%). There was 4% G3 and no G4 peripheral neuropathy reported, 24% G 1/2 palmar-plantar erythrodysesthesia, and no treatment-related mortality. Response rates in 57 pts evaluable for response were as follows: 96% ≥ PR, 58% ≥ VGPR, and 30% CR/nCR. In 48 pts who completed 4 cycles, defined in the protocol for efficacy assessment, response rates were: 98% ≥ PR, 58% ≥ VGPR and 29% CR/nCR; at MTD ≥PR is 100%. Response rates were not statistically different in a subset of pts (24) with 13q deletion or t(4;14) or t(14;16) or 17p del, with PR, VGPR, and CR/nCR rates 92%, 67%, and 33%, respectively. Twenty four pts proceeded to stem cell collection with 7.5 × 106 CD34+ cells/kg collected after a median of 4 cycles of RVDD (range 3–10). After a median of 6 months of follow-up, median progresssion-free survival and overall survival have not been reached. Conclusion: RVDD is well tolerated in newly diagnosed MM and appears highly active with ≥ PR of 96%, including 58% ≥VGPR, which is unaffected by adverse cytogenetic status. Pts treated at the MTD ,which was determined as Len 25 mg, Bz 1.3 mg/m2, Dex 20 mg, and PLD 30 mg/m2, and completed at least 4 cycles, show 100% ≥PR. Stem cell mobilization and collection was successful in all pts, with unremarkable transplant course reported to date. Updated toxicity and efficacy data will be presented at the meeting. Disclosures: Jakubowiak: Bristol Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Reece:Ortho Biotech: Honoraria, Research Funding. Lonial:Novartis: Consultancy; Gloucester: Research Funding; Bristol Myers - Squibb : Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy. Zimmerman:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Centocor: Speakers Bureau. Schlossman:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Laubach:Novartis: Advisory Board. Raje:Celgene, Norvartis, Astrazeneca: Research Funding. Anderson:Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Barrickman:Celgene: Employment, Equity Ownership. Tendler:Johnson and Johnson: Employment, Equity Ownership. Esseltine:Johnson and Johnson: Equity Ownership; Milllennium: Employment, Equity Ownership. Kelley:Bristol-Myers Squibb: Equity Ownership. Anderson:Millennium: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Richardson:Bristol Myers-Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.