ALBERT

Description: Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) after myeloablative AuSCT in pts with MM. Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAM F7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of MM pts who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report updated results of the primary (PFS) and secondary (overall survival [OS] and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 27 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2, q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=57 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until disease progression (PD). LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity 〉 grade 1 and significant cytopenias (ANC 〈 1000/mL, platelet count 〈 100,000/ml). For the 1st 8 weeks, pts

Description: Abstract 336 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate (Richardson et al, Blood 2010; Kumar et al, Blood 2012). The addition of a novel targeted agent to RVD may improve depth of response as reflected by an increase in complete remission (CR) rate. Preclinical studies have demonstrated that vorinostat (Vor), a histone deacetylase inhibitor, is synergistic with bortezomib, immunomodulatory compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study was to determine the tolerability and activity of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (pts) received the classical RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5–8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. Dose limiting toxicity (DLT) (Grade (G) 3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of neutrophils to 1,000/μL or platelets to 50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified European Group for Blood and Marrow Transplantation and Uniform Criteria. Pts with partial remission (PR) or better could proceed to autologous transplant after 4 cycles. After completion of 8 cycles, patients could continue maintenance with lenalidomide +/− bortezomib, with Vor not administered during maintenance therapy. Results: Thirty pts (median age 56 years [range 40–76], 63% men) were enrolled with 4 pts in cohort 1 (Vor 100mg), 15 pts in cohort 2 (Vor 200mg), 8 pts in cohort 3 (Vor 300 mg) and 3 pts in cohort 4 (Vor 400mg). The maximum tolerated dose was determined to be 200 mg Vor with RVD. Including maintenance, the median number of cycles completed was 4 (range

Description: Introduction The advent of new therapies for the treatment of multiple myeloma (MM) has resulted in improved clinical outcomes and patient (pt) survival. However, the best combination of agents from different drug classes and subsequent therapeutic strategies for pts with newly diagnosed MM (NDMM), while investigated, has not yet been established. The goal of the Connect(R) MM registry is to provide insight into the disease and explore the management and outcomes of pts with NDMM who are treated at community and academic sites in the United States. This analysis aims to describe the combinations used in NDMM outside the interventional clinical trial setting and the activity and outcome response to different regimens by class of therapeutic agents in clinical practice. Methods Connect MM is an ongoing prospective, longitudinal, observational registry of NDMM pts. This multicenter US pt registry was initiated in 2009. Pts who were newly diagnosed with symptomatic MM within 2 months of enrollment were eligible to participate. Data were collected at baseline and every 3 months. Pts who had response data 12 months after enrollment, met CRAB criteria, and received treatment were eligible for this analysis. Treated pts were stratified according to SCT status. Data on baseline demographic and clinical characteristics, and initial therapies (proteasome inhibitors [PI], IMiD(R) immunomodulating agents, alkylating agents [AA], corticosteroids, and combinations) were collected. The overall response rate (ORR), as assessed by the site investigator, was defined as the best response during the course of initial therapy and is presented as cumulative ORR over 3, 6, and 12 months. Results As of the data cutoff (April 15, 2013), 1494 pts were enrolled in the registry; 1312 pts met CRAB criteria and received treatment. Of these, 439 received SCT or were anticipated to receive (had undergone a stem cell harvest) SCT and 873 would not receive SCT (non-SCT). Mean (SD) age for SCT and non-SCT pts was 58.9 years (8.7) and 69.8 years (10.7), respectively. Majority of pts in both groups were male (62.0% vs 56.5%) and Caucasian (85.4% vs 81.4%). Among SCT pts, ISS stages were: I/II (55.1%), III (25.3%), and unknown (19.6%) and ECOG performance status (PS) was 0/1 (63.1.%), 2/3 (7.1%), and unknown (29.8%). Among non-SCT pts, ISS stages were: I/II (42.0.%), III (32.2%), and unknown (25.8%) and ECOG PS was 0/1 (56.6%), 2/3/4 (14.7%), and unknown (28.8%). ORR to initial therapy and 1-year survival for the 5 most commonly used regimens are presented in the Table. A triplet regimen is 2 times more likely to be selected for SCT pts than for non-SCT pts, suggesting investigator bias in selecting more aggressive therapy for younger pts. For the 5 most commonly used regimens, 1-year survival was 97.9% for SCT pts and 83.3% for non-SCT pts. Conclusion Outside an interventional clinical trial setting, the most commonly used initial treatment regimens for NDMM were IMiD + PI + steroid for SCT pts and PI + steroid for non-SCT pts. Response rates were higher among SCT pts regardless of regimen. The investigator-assessed response rates were similar across the various combinations including 2 vs 3 drug combinations in SCT pts. Disclosures: Abonour: Celgene: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding. Off Label Use: This abstract will report on an observational study. There is no pre-specified use of drugs; treating physicians determined what drugs to use and some could be off-label. Shah:Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Durie:Celgene: Consultancy; Millennium: Consultancy; Onyx: Consultancy. Terebelo:Amgen: Honoraria; Millennium: Honoraria. Gasparetto:Celgene ( 2012): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium (2012): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Narang:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Consultancy. Sullivan:Celgene: Employment. Srinivasan:Celgene: Employment. Nagarwala:Celgene: Employment. Rifkin:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Description: Introduction Plasmablastic lymphoma (PBL) is a rare, aggressive subtype of non-Hodgkin lymphoma. Published data are predominantly in the form of case reports and small retrospective case series. Initial reports of PBL were described in HIV positive patients (pts) with disease in the oral cavity, and in pts after organ transplantation on immunosuppressive therapy. The natural history may have evolved recently, with case reports of PBL in immunocompetent patients. There is no established standard of care therapy, though HIV positive pts benefit from initiation of anti-retroviral therapy, tend to respond to chemotherapy, have historically been associated with CD20 expression, and have increased overall survival rates compared with HIV negative pts with PBL. We now describe our experience in pts with PBL who received treatment at the University of Texas MD Anderson Cancer Center (UTMDACC). Methods We conducted a retrospective analysis of pts diagnosed with PBL between August 2000 and August 2012. We evaluated the baseline demographics, stage, therapy, response rate, progression-free survival (PFS) and overall survival (OS). Results 28 pts (males n=23) with PBL were identified, with a median age of 51 (range 26-81). 10 patients had a diagnosis of HIV, and 15 were EBV positive. 7 pts had stage I disease, 2 had stage II, 1 had stage III and 18 had stage IV disease. The primary site of disease in the 7 pts with stage I disease was: 2 in the maxillary sinus, 2 in the nasal cavity, and 1 each in the colon, testicle, and lower jaw. 2 pts with stage II disease had primary sites in bowel and tonsils. 7/17 (41%) of HIV negative pts and 2/10 (20%) of HIV positive pts had stage I/II disease. The median LDH was 492 IU/L (313-618), median Ki-67 proliferation index was 85%, and all pathological samples were CD20 negative. Median follow up was 16 months (1-120). 27 pts received systemic therapy (1 pt elected hospice care). PBL was an initial cancer diagnosis for 25 pts who received the following as first line therapy: Hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone alternating with methotrexate and cytarabine) (n=10), CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) (n=7), modified CVAD, 2 with EPOCH (etoposide, vincristine, cyclophosphamide, Adriamycin, prednisone) (n=4), bortezomib/dexamethasone (n=1), and the DeAngelis protocol (methotrexate, vincristine, procarbazine, with intrathecal methotrexate) (n=1) for CNS involvement. 2 pts had prior therapy for diagnosis of diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) prior to diagnosis of PBL. The first pt with DLBCL was treated with Rituximab-hyper-CVAD 6 years earlier, and gemcitabine/oxaliplatin for the diagnosis of PBL. The second pt had CLL which underwent Richter's transformation to PBL, and was treated with hyper-CVXD (cyclophosphamide, vincristine, liposomal daunorubicin and dexamethasone). 1 pt underwent auto-stem cell transplant, while 8 pts received localized radiation (5 for consolidation and 3 for palliative therapy); 5/7 pts with stage I disease received consolidation with involved field radiation. After first line therapy, 20/27 patients (74%) achieved complete response, 5/27 (19%) partial response, and 2/27 (7%) stable disease. Median PFS and OS were 24.1 and 28.8 months, respectively. 5 year PFS and OS were 40% and 38%, respectively. Early stage disease (stage I or II) and younger age at diagnosis (less than 40 years old) were associated with improved survival. 5 year PFS for stage I/II pts was 90%. Conclusion 41% of HIV negative pts had stage I/II disease. Early stage PBL pts who received combined chemotherapy followed by radiotherapy achieved a good PFS of 90% at 5 years. PBL consistently lacked CD20 expression irrespective of HIV status. PBL can be seen in both HIV+ and HIV– patients with overall 40% long term survival. Disclosures: Qazilbash: Otsuka Pharmaceuticals: Research Funding. Fanale:Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Consultancy, Honoraria, Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees.

Description: Abstract 1860 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY-520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design. Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43–79) and a median of 6 prior regimens (range 2–16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant. The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G-CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G-CSF support was conducted and the MTD for ARRY-520 with G-CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed. ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY-520 has been dosed over extended periods of time (to date, median 7 cycles [range 1–44]), with no evidence of cumulative toxicity. The plasma concentrations of ARRY-520 were determined over a 7-day period during Cycle 1 following the Day 1 and 2 infusions of ARRY-520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going. ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2–8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY-520 was prolonged, with a median time to PR of 3.7 mos (range 3.7–8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs. Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY-520 at 1.5 mg/m2/day with G-CSF support. Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Litwiler:Array BioPharma: Employment. Karan:Array BioPharma: Employment. Hilder:a: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

Description: Abstract 74 Background: Carfilzomib, a novel proteasome inhibitor (PI), and pomalidomide, an immunomodulatory agent (IMiD), have both demonstrated promising activity as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma. IMiD+PI combinations including lenalidomide, bortezomib, dexamethasone and lenalidomide, carfilzomib, dexamethasone have had high response rates and good tolerability. We aimed to combine carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) for the first time and hypothesized that this regimen would be highly active in patients with relapsed/refractory multiple myeloma. Here, we report the first findings from the Phase I dose-escalation and expansion portions of the first phase I/II trial of Car-Pom-d in patients with relapsed/refractory multiple myeloma (NCT01464034). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of Car-Pom-d. Secondary objectives included determination of overall response rate, time to progression, progression free survival, and time to next therapy. All patients had to be refractory to prior lenalidomide, and must have been relapsed/refractory to their most recent therapy. Treatment consisted of 28-day cycles of oral pomalidomide once daily on days 1–21, intravenous (IV) carfilzomib over 30 minutes on days 1, 2, 8, 9, 15, and 16, and oral or IV dexamethasone 40 mg on days 1, 8, 15, and 22. Dose-escalation of carfilzomib started with 27mg/m2 carfilzomib/4mg pomalidomide/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Carfilzomib was initiated at 20 mg/m2for Cycle 1, days 1–2 at all dose levels. Investigators were permitted to adjust the dose of dexamethasone at any point based on their discretion. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results: In the Phase I dose-escalation portion of the trial, a total of 12 patients were enrolled from 6 centers. The median age was 61 years (range 44–78), 67% were male. The median number of prior regimens was 6 (range 2–15), and median time from diagnosis was 5.1 years. Four (33%) patients had prior stem cell transplant, 11 (92%) had prior bortezomib, and all were lenalidomide-refractory. Cytogenetic abnormalities included 5 patients with del(17p), 2 patients with t(4;14), and 1 patient each with del(13), t(11;14), and t(14;16). In these first 12 patients, drug-related AEs occurring in 〉20% of patients included fatigue (42%), anemia (33%), pneumonia (33%), dyspnea (25%), and thrombocytopenia (25%). Six (50%) patients experienced grade ≥3 AEs including 2 incidence each of neutropenia and febrile neutropenia. The MTD was established as the starting dose level (carfilzomib 20/27 mg/m2, pomalidomide 4mg, dexamethasone 40 mg). At this dose, 1 of 6 patients experienced a protocol-defined DLT of febrile neutropenia. At dose level 2 (carfilzomib 20/36 mg/m2, pomalidomide 4 mg, dexamethasone 40 mg), 2 of 6 patients experienced DLTs, consisting of grade 4 thrombocytopenia and grade 3 rash. All 12 patients were response evaluable with 2 very good partial response (VGPR), 4 partial response (PR), 2 minor response (MR), 2 stable disease (SD), and 2 progressive disease (PD) for a ≥ MR rate of 67%. The 6 month progression free survival was 70% (95% CI: 37 to 90%). Of the 5 patients with del(17p), 1 achieved VGPR, 2 achieved PR, 1 achieved SD. We then enrolled an expansion cohort of 20 patients from 8 centers resulting in a total study population of 32 patients, with 25 still receiving treatment. Three patients have died, all from progressive multiple myeloma. Early response assessments in 27 out of 32 patients show 2 VGPR, 7 PR, 6 MR, 8 SD, and 4 PD for a ≥MR rate of 56%. Conclusions: The Car-Pom-d regimen is well tolerated and achieves a high response rate in a heavily pre-treated, lenalidomide-refractory population with prior bortezomib exposure. Importantly, we have seen responses in patients with poor risk cytogenetics, specifically del (17p). We are beginning enrollment in a larger phase 2 cohort, and updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Array: Consultancy. Stadtmauer:Celgene: Consultancy, Speakers Bureau; Millennium: Consultancy, Speakers Bureau. Abonour:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau. Cohen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:Onyx: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Gasparetto:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Lentzsch:Celgene: Consultancy, Research Funding. Vogl:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Research Funding; Otsuka: Consultancy; Acetylon: Research Funding. Orlowski:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Durie:Onyx: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Amgen: Consultancy.

Description: Abstract 3034 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate. The goal of the current trial is to improve on the CR rate compared with RVD by adding a novel targeted agent. Preclinical studies have demonstrated that vorinostat (Vor), an HDAC inhibitor, is synergistic with bortezomib, immunomodulatory (IMiD®) compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study is to determine the tolerability and preliminary efficacy of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (Pts) received the current standard RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5-8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. DLT (≥ G3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of ANC to ≥1,000/μL or platelets to ≥50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified EBMT and Uniform criteria. Pts with PR or better could proceed to autologous transplant after ≥ 4 cycles. Results: Eleven pts (median age 54, 82% men, 54.5% ISS Stage II/III) have been enrolled to date with n=4 pts each in cohorts 1 (Vor 100mg) and 2 (Vor 200mg), and 3 pts in cohort 3 (Vor 300 mg). One patient has completed 8 cycles, 1 pt completed 4 cycles and proceeded to transplant, 6 pts remain on study treatment and 3 pts have discontinued therapy (1 for significant peripheral neuropathy {grade 3}, 1 for patient choice unrelated to toxicity and 1 for non adherence). Two DLTs have occurred: syncope (cohort 1) and asymptomatic grade 3 elevation of ALT (cohort 2) with none in cohort 3.The episode of syncope was not related to cardiac arrhythmia. One study related SAE has occurred (syncope). One other episode of grade 3 elevation of ALT occurred in a pt in cycle 3 in cohort 1. Both episodes of increased ALT resolved and patients remained on study with dose modification. One patient developed grade 3 diarrhea in cohort 1. No patients have developed a grade 4 toxicity. Treatment emergent peripheral neuropathy occurred in 6 patients (4 grade 1, 1 grade 2 and 1 grade 3). No episodes of study related grade 3 fatigue, nausea, or vomiting have occurred. The MTD has not been reached. Eight patients are evaluable for response. All have responded to study therapy with 3 CRs, 1 VGPR and 4 PRs. Three patients went on to stem cell collection after 4 cycles and all collected an adequate dose for transplant of 〉5 ×106 CD34+ cells/kg. Conclusion: The combination of RVD with vorinostat has been generally well tolerated to date. No unexpected toxicity has been noted with side effects commensurate with prior experience with each of the drugs and no additive toxicity seen to date. While asymptomatic elevation of ALT has been seen and will require ongoing monitoring, grade 3 ALT elevation was a DLT in the original RVD study and related to dexamethasone, so may not be related to the addition of vorinostat. Early efficacy data is promising with 50% of patients achieving a VGPR or higher. Accrual is ongoing to determine the MTD. Disclosures: Kaufman: Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Off Label Use: Use of lenalidomide as upfront therapy. Use of vorinostat as upfront therapy. Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Novartis: Research Funding. Heffner:Millenium: Consultancy, Honoraria, Research Funding. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Orlowski:Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau.

Description: The decision to provide prophylactic platelet transfusions to patients with hematologic malignancy and chemotherapy induced thrombocytopenia (CIT) is often based solely on the platelet count being below a somewhat arbitrary threshold. The ability to rapidly assess the overall (net) coagulation status (thrombotic and hemorrhagic tendencies) of these patients may help limit transfusion to those with a measurable bleeding tendency and reduce overall platelet product consumption. We performed pre- and post-platelet transfusion whole blood thromboelastography (TEG) in 20 pts with leukemia (16) or lymphoma (4) and CIT. Citrated venous blood was obtained prior to and 1 hour after single transfusions of 5 units of random donor platelets. Normal ranges were derived from TEG evaluation of 18 normal controls. Correlation between absolute and % changes in maximum TEG amplitude (MA, mm) and time to initial clot formation (R, min) and absolute and % changes in platelet count was assessed. Pts were defined as normal if MA = 45.7 to 64.9 and R = 8.3 to 19.9; hypocoagulable if MA19.9; hypercoagulable if MA〉64.9 and/or R

Description: Abstract 2976 Background: c-Met receptor tyrosine kinase (RTK) activity has been implicated in establishing the oncogenic phenotype across several human cancers with high levels of the activating c-Met ligand, hepatocyte growth factor (HGF). Malignant plasma cells secrete HGF-activator (HGFA), which converts HGF to its active form, and high HGF levels are correlated with a poor prognosis in multiple myeloma (MM). Syndecan 1 (CD138) on malignant plasma cells binds HGF and potentiates interleukin-6-induced growth and migration. HGF stimulation of myeloma cells also activates autophosphorylation of c-Met and other critical downstream signaling pathways promoting oncogenesis. Finally, pre-clinical studies have shown that suppression of c-Met signaling with a number of small molecules, including ARQ 197, induced myeloma cell apoptosis. Tevantinib-mediated cytotoxic response was observed at concentrations of less than 5 μM, which are achievable in the clinic. These findings supported the hypothesis that suppression of the HGF/c-Met signaling axis could be a rational strategy against relapsed multiple myeloma. Methods: In this phase II study, the efficacy and safety of ARQ 197, a non-competitive and highly selective inhibitor of the c-Met RTK, is being studied in patients with relapsed multiple myeloma. Primary objectives were to determine the overall response rate (ORR) to single-agent tivantinib in patients with relapsed multiple myeloma who had received one to four prior lines of therapy, and to define the toxicities in this population. ARQ 197 was administered at a starting oral dose of 360 mg twice daily with meals for each day of every 4-week treatment cycle. This dose was selected from prior phase I investigations in solid tumors, and at this dose level, steady-state plasma level sof ARQ-197 were 7 μM. Treatment could continue providing that patients did not experience undue toxicities, or disease progression. Tivantinib is provided through the Cancer Therapy Evaluation Program (CTEP), and this study is supported by CTEP, as well as the M. D. Anderson Cancer Center SPORE in Multiple Myeloma. Results: A total of 10 patients have been enrolled and treated to date, all of whom were evaluable for toxicity, with 8 evaluable for response based on having completed two treatment cycles. Patients had received from 1–3 prior lines of therapy for their disease, and 7/10 (70%) had presented with International Staging System stage I disease at diagnosis. All patients on study had an ECOG performance status of 1 or better, and received a median of 3.5 cycles of tivantinib (range 1–7). The most common adverse events (AEs) of any grade seen in at least 30% of patients included diarrhea (30%), dizziness (30%), dry eyes (30%), shortness of breath (30%), memory change (30%), myalgias (40%), fatigue (60%), and neutropenia (60%). Serious AEs (SAEs) occurred in 2 patients, including one patient with grade 3 syncope, and another with grade 4 neutropenia and a grade 3 anal fissure. Stable disease (SD) has been seen as the best response in 5/7 (71%) evaluable patients, which was maintained for up to 7 cycles, while the remaining patients showed evidence of disease progression. Conclusion: Enrollment is continuing to this first study of any c-Met inhibitor in patients with relapsed multiple myeloma to better define the role of single-agent tivantinib in this setting. To date, tivantinib has been tolerated well, and some evidence of activity has been seen, with stable disease in 63% of patients, all of whom were progressing at the time of enrollment. Updated toxicity and efficacy data will be presented at the time of the Annual Meeting. Correlative studies are also underway with the goal of identifying potential predictive biomarkers. Disclosures: Off Label Use: Tivantinib is being evaluated for patients with relapsed myeloma, but is not yet approved in this setting.

Description: Abstract 3828 Introduction: Attention is being paid to HRQOL when monitoring hematologic disorders or the impact of treatments on those disorders. Minimal HRQOL data have been published on multiple myeloma (MM) patients (pts) in the United States (US). This analysis characterizes variation in the HRQOL of pts with active, symptomatic MM by International Staging System (ISS) stage and ECOG status. Methods: Data were collected as part of Connect MM®, a prospective observational registry initiated in September 2009 involving centers in the US. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was reported by pts in the clinic at enrollment, within two months of diagnosis. Pts completed 3 psychometrically validated instruments: EQ-5D, Brief Pain Inventory (BPI), and Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM). Standard analyses were conducted of each instrument given clinical characteristics at that time. Reported mean BPI, EQ-5D and FACT-MM scores were analyzed by ISS and ECOG status. Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results: HRQOL data were reported by 328 pts, enrolled from 135 centers. Pts were predominantly male (60%) and white (79%) with mean age at 67.3 (standard deviation [SD] 11.6) yrs. HRQOL scores by evaluable ISS stage (n=236) and ECOG status (n=258) are presented. BPI data (on a scale of 0 [no pain] to 10 [worst pain]) indicate that average reported pain worsens by ISS and ECOG severity. Mean EQ-5D scores (on a scale of 1 [no problem] to 2 [some problems] to 3 [incapacity]) indicate that pain/discomfort, and usual activities are most compromised, and with self care increase in severity as ISS and ECOG worsen. Anxiety/depression level is associated with ECOG, but not with ISS. FACT-MM results indicate that ISS and ECOG severity is associated with greater decrement in physical and functional domains. The associations of HRQOL with ECOG status were stronger than with ISS stage. Specifically, scores on the BPI, all EQ-5D domains, and all FACT-MM domains (except the social/family domain) were statistically significantly associated with more severe ECOG status. Conclusions: Initial results from the Connect MM® Registry indicate that HRQOL worsens with worsening ISS stage and ECOG status, especially in physical and functioning domains, pain/discomfort, and ability to conduct usual activities and to provide self care. These areas should receive attention at diagnosis. Future analyses should be conducted on: (1) more newly diagnosed patients; (2) how HRQOL may be affected over time with changes in disease; and, (3) how HRQOL may be influenced by alternative therapies. Results reported here should serve as useful baseline reference. Disclosures: Pashos: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: CONNECT is a disease registry and includes data on off-label use of anti-myeloma agents. Durie:Celgene & Millennium: Consultancy. Rifkin:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Street:Celgene: Employment. Sullivan:Celgene: Employment, Equity Ownership. Khan:Celgene Corporation: Employment.