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This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1–4 mg days 1–14), bortezomib (1–1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1–8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.

PMCID: PMC4112539.-- International Myeloma Working Group: et al., Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥20%) and absolute number (≥2 × 10 9/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL., This work has been supported in part by “Josep Font” Grant from Hospital Clínic de Barcelona and RD06/0020/0005 from Instituto de Salud Carlos III, Spain.

Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma

e78 BP-055 Subgroup Analysis by Prior Treatment of the Efficacy and Safety of Panobinostat Plus Bortezomib and Dexamethasone in Patients With Relapsed or Relapsed and Refractory Multiple Myeloma in the PANORAMA 1 Study P.G. Richardson, V.T.M. Hungria, S.-S. Yoon, M. Beksac, M.A. Dimopoulos, A. Elghandour, W.W. Jedrzejczak, A. Guenther, T.N. Nakorn, N. Siritanaratkul, R.L. Schlossman, J. Hou, P. Moreau, S. Lonial, J.H. Lee, H. Einsele, M. Sopala, B.R. Bengoudifa, C. Corrado, J.F. San-Miguel Dana-Farber Cancer Institute, Boston, MA, USA; Irmandade da Santa Casa de Misericordia de Sao Paulo, Sao Paulo, Brazil; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Ankara University School of Medicine, Ankara, Turkey; Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; Alexandria University, Alexandria, Egypt; Medical University of Warsaw, Warsaw, Poland; Division of Stem Cell Transplantation and Immunotherapy, 2 Department of Medicine, University Hospital SchleswigHolstein and University of Kiel, Kiel, Germany; King Chulalongkorn Memorial Hospital and Chulalongkorn University, Bangkok, Thailand; Siriraj Hospital, Bangkok, Thailand; Chang Zheng Hospital, Shanghai, China; University Hospital of Nantes, Nantes, France; Winship Cancer Institute, Atlanta, GA, USA; Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea; Medizinische Klinik und Poliklinik II, University of Wurzburg, Wurzburg, Germany; Novartis Pharma AG, Basel, Switzerland; Clinica Universidad de Navarra, Pamplona, Spain Introduction: Panobinostat (PAN), a potent pan-deacetylase inhibitor, affects processes integral to growth and survival of multiple myeloma (MM) cells through alteration of protein metabolism and epigenetic mechanisms. In the PANORAMA 1 phase 3 trial, combination of PAN with bortezomib (BTZ) and dexamethasone (Dex; PAN-BTZ-Dex) led to a clinically significant increase in progression-free survival (PFS) of z4 mo vs placebo plus BTZ and Dex (Pbo-BTZ-Dex). This analysis examined efficacy and safety of PAN-BTZ-Dex based on prior treatment. Therapeutic options for patients (pts) who have received immunomodulatory agents (IMIDs) and protease inhibitors are limited, and with each relapse these options become progressively restricted by drug resistance or intolerance. Methods: The study design was described previously (San-Miguel JF, Lancet Oncol. 2014). A subanalysis assessed efficacy and safety of PAN-BTZ-Dex in pts based on prior treatment characteristics, including receipt of prior IMiDs, BTZ + IMiDs, and BTZ + IMiDs and 2 prior lines of therapy. Here, we focus on efficacy and safety of PAN-BTZ-Dex in pts with relapsed or relapsed and refractory MM who received 2 prior regimens, including BTZ and an IMiD (n1⁄4147). Results: Pts in the PAN-BTZ-Dex arm (n1⁄473) had improved efficacy compared with those receiving Pbo-BTZ-Dex (n1⁄474). Of note, in the studied subgroup, pts in the PAN arm had Clinical Lymphoma, Myeloma & Leukemia September 2015 a longer median PFS (12.5 mo) than those in the Pbo arm (4.7 mo, HR: 0.47 [95% CI, 0.31-0.72]; Figure). Pts in the PAN arm vs Pbo arm also showed improvements in overall response rate (ORR; 58.9% [95% CI, 46.8%-70.3%] vs 39.2% [28.0%-51.2%]) and complete response/near-complete response (CR/nCR) rate (21.9% [95% CI, 13.1%-33.1%] vs 8.1% [3.0%-16.8%]). Common grade 3/4 adverse events and laboratory abnormalities in the PAN arm vs Pbo arm included thrombocytopenia (68.1% vs 44.4%), neutropenia (40.3% vs 16.4%), diarrhea (33.3% vs 15.1%), and asthenia/fatigue (26.4% vs 13.7%). Importantly, incidence of ontreatment deaths was nearly identical in both arms (n1⁄45 [6.9%] vs n1⁄45 [6.8%]). Conclusion: This analysis identified a subpopulation of pts in whom PAN-BTZ-Dex more than doubled the PFS vs PboBTZ-Dex, with marked improvements in CR/nCR rate and ORR. The safety profile was similar to the overall population. Together, these findings support the approval of PAN-BTZ-Dex by the US FDA in pts with relapsed or relapsed and refractory MM with 2 prior regimens, including BTZ and an IMiD. BP-056 Safety Profile of Oral Ixazomib: Experience from 761 Patients (Pts) Across 14 Phase 1 or Phase 1/2 Clinical Studies S. Lonial, K. Colson, R.D. Harvey, S. Kumar, A.-M. Hui, G. Liu, D. Berg, P. Richardson Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Division of Hematology, Mayo Clinic, Rochester, MN, USA; Millennium Pharmaceuticals, Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company

When considering possible implementations of space-time adaptive processing (STAP) techniques, it is apparent that there are two principal approaches; STAP before Doppler filtering (pre-Doppler STAP) and STAP after Doppler filtering (post-Doppler STAP). The two approaches are founded on very different and partly contradicting arguments. This paper tries to collect all these viewpoints. The aim is to give the application engineer, who is not familiar with the details of STAP, a guideline of the basic problem and criteria of choice between pre and post Doppler STAP architectures. (21 pages)

The control of spurious signals, caused by cross modulation of two or more strong signals, is a demanding driver on the linearity of transmit/receive modules and subarray channel receivers in active electronically scanned array (AESA) antennas used with airborne radars. This paper proposes a method for the suppression of the spurious signals caused by cross modulation and presents simulation results to quantify its performance. The effects of potential errors on the suppression achieved are considered and a method is proposed for reducing these effects. With adaptive equalisation filtering, suppression of up to 30 dB can be achieved in the presence of realistic errors. (4 pages)

Subarrays constitute a step in the direction towards full digitisation of array antennas. An overview of the problems of digital processing with subarray outputs and a description of several mitigation techniques is given. We present rules for designing subarrays, for forming sum and difference beams, clusters of scanned beams at subarray level, and for forming a guard channel. The grating effects of subarrays on adaptive beamforming and STAP are described and demonstrated by examples. Finally we describe the problems of applying superresolution methods with subarrays. (5 pages)

e174 PO-162 Four phase 3 studies of the oral proteasome inhibitor (PI) ixazomib for multiple myeloma in the newly-diagnosed, relapsed/refractory, and maintenance settings: TOURMALINE-MM1, -MM2, -MM3, and -MM4 J. San Miguel, P. Moreau, V. Rajkumar, A. Palumbo, T. Facon, G. Morgan, R. Orlowski, M. Cavo, H. Einsele, F. Neumann, R. Labotka, S. Lonial, P. Richardson Clinica Universidad de Navarra, Centro Investigacion Medica Aplicada (CIMA) Pamplona, Spain; University Hospital Hotel Dieu, Nantes, France; Division of Hematology, Mayo Clinic, Rochester, MN, USA; Azienda Ospedaliero-Universitaria (AOU), University of Torino, Torino, Italy; Hopital Claude-Huriez, Lille, France; University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA; MD Anderson Cancer Center, Houston, TX, USA; Seragnoli Institute of Haematology, University School of Medicine, Bologna, Italy; Medizinische Klinik und Poliklinik II, Julius Maximilians Universitat Wurzburg, Wurzburg, Germany; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Winship Cancer Institute of Emory University, Atlanta, GA, USA; Dana-Farber Cancer Institute, Boston, MA, USA Background: Triplet regimens combining a PI with an immunomodulatory drug (IMiD) plus dexamethasone (dex) have been shown to be highly effective for the treatment of multiple myeloma (MM), resulting in improved long-term outcomes. These improved outcomes have increased the focus on extended treatment, including maintenance therapy; however, the feasibility of long-term treatment with current regimens is limited due to toxicities or the need for regular clinic visits. Ixazomib is the first oral PI to be studied in the clinic, with encouraging early-phase data. A phase 1 study showed weekly administration of single-agent ixazomib to be TOURMALINE-MM1 TOURMALINE-MM Setting Relapsed/refractory MM Newly diagnosed MM Regimen Ixazomib plus Iendex vs Iendex Ixazomib plus Iendex vs Dosing Ixazomib 4 mg or placebo on days 1 ,8, and 15 Ixazomib 4 mg or plac on days 1, 8, and 1 Len 25 mg on days 1e21 Dex. 40 mg on days 1, 3, 15, and 22 Len 25 mg on days 1 Dex. 40 mg on day 1, 8,15, and 22 28-day cycles 28-day cycles Enrollment 722 patients Estimated 701 Primary end point PFS PFS Main secondary end points OS, OS in del17p, response rate, DOR, TTP, safety, PFS and OS in patients with high-risk cytogenetics OS, response rate, DOR, TTP, safety, PFS and O patients with high-ris cytogenetics Abbreviations: ASCT, autologous stem cell transplantation; dex, dexamethasone; DOR, duration of r survival; TTP, time to progression: TTR, time to response. 15th International Myeloma Workshop, September 23-26, 2015 generally well tolerated in patients with relapsed/refractory MM, with a low incidence of peripheral neuropathy (PN) (20% overall, only 1 case of grade 3 PN), and encouraging preliminary efficacy (Kumar et al Blood 2014). The feasibility of the all-oral combination of ixazomib plus lenalidomide (len) and dex has also been demonstrated, with a 90% overall response rate (including 62% VGPR) and a manageable safety profile with limited PN (6% grade 3) reported in patients with newly diagnosed MM (Kumar et al Lancet Oncol 2014). These studies, together with population pharmacokinetic results, identified the recommended ixazomib phase 3 dose as 4 mg weekly for patients with relapsed/refractory or newly diagnosed MM (Gupta et al Br J Clin Pharmacol 2015). The recommended phase 3 dose for ixazomib maintenance therapy was identified as 3 mg, increasing to 4 mg after 4 cycles if tolerated, using an exposure-safety-efficacy analysis approach (Gupta et al EHA 2014). On the basis of these preliminary data, 4 phase 3 trials of ixazomib are ongoing in the following settings: relapsed and/or refractory MM (TOURMALINE-MM1, NCT01564537), newly diagnosed MM (NDMM) (TOURMALINE-MM2, NCT01850524), MM maintenance therapy following autologous stem cell transplantation (ASCT) (TOURMALINE-MM3, NCT02181413), MM maintenance therapy after initial therapy without ASCT (TOURMALINE-MM4, NCT02312258). Methods: The four trials are shown in the Table. All are randomized, placebo-controlled, double-blind, multicenter studies. Patients in the TOURMALINE-MM1 and -MM2 studies will receive the all-oral combination of ixazomib plus len-dex, while those in the TOURMALINE-MM3 and -MM4 maintenance trials will receive single-agent ixazomib. Progression-free survival is the primary endpoint for all four trials. Recruitment for TOURMALINEMM2, -MM3, and -MM4 is ongoing The authors would like to thank Jane Saunders of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this abstract, which was funded by Millennium Pharmaceuticals, Inc. 2 TOURMALINE-MM3 TOURMALINE-MM4 MM maintenance post-ASCT MM maintenance without ASCT Iendex Ixazomib maintenance vs placebo Ixazomib maintenance vs placebo ebo 5 Ixazomib 3 mg or placebo on days 1, 8, and 15 for cycles 1e4 Ixazomib 3 mg or placebo on days 1, 8, and 15 for cycles 1e4 -21 s Ixazomib 4 mg or placebo on days 1, 8, and 15 for cycles 5e26 Ixazomib 3 or 4 mg, or placebo on days 1 , 8, and 15 for cycles 5e26 28-day cycles 28-day cycles Estimated 652 Estimated 761

In a phase 2 open-label study of the novel proteasome inhibitor bortezomib, 54 patients with multiple myeloma who had relapsed after or were refractory to frontline therapy were randomized to receive intravenous 1.0 or 1.3 mg/m(2) bortezomib twice weekly for 2 weeks, every 3 weeks for a maximum of eight cycles. Dexamethasone was permitted in patients with progressive or stable disease after two or four cycles respectively. Responses were determined using modified European Group for Blood and Marrow Transplantation criteria. The complete response (CR) + partial response (PR) rate for bortezomib alone was 30% [90% confidence interval (CI), 15.7-47.1] and 38% (90% CI, 22.6-56.4) in the 1.0 mg/m(2) (8 of 27 patients) and 1.3 mg/m(2) (10 of 26 patients) groups respectively. The CR + PR rate for patients who received bortezomib alone or in combination with dexamethasone was 37% and 50% for the 1.0 and 1.3 mg/m(2) cohorts respectively. The most common grade 3 adverse events were thrombocytopenia (24%), neutropenia (17%), lymphopenia (11%) and peripheral neuropathy (9%). Grade 4 events were observed in 9% (five of 54 patients). Bortezomib alone or in combination with dexamethasone demonstrated therapeutic activity in patients with multiple myeloma who relapsed after frontline therapy.

Objectives and Backgrounds What counts as quality or performance in the modern emergency department has changed since the inception of the Australasian College for Emergency Medicine (ACEM). Most if not all modern Emergency Physicians already know, that in addition to service provision, they are active and performing a number of other important domains: education and teaching research administration tasks crossing safety, risk management and continuity domains Professional development These other activities have previously not been formally recognised as valid performance measures. Methods Emergency physicians at the Royal Brisbane and Women9s Hospital in Australia embarked on a process to develop a national template to facilitate individual emergency department quality and performance and have this adopted by the ACEM RBWH is the largest adult emergency department in Australasia with 75 000 attendances and staffed by 18 FTE FACEMs. In 2009 a modified Delphi was undertaken following a review of the current literature to identify what could be considered important quality and performance indicators of a highly functioning emergency department. This led to the development of a unifying template the identified all the core areas where emergency physicians are active and are required to show performance in for continuing professional development compliance. These domains can no longer be considered incidental to service provision. Results A template was developed with five core domains for emergency departments to show activity in: Quality and Performance Template (Figure 1) . Conclusions The template was adopted by the ACEM Quality Sub Committee in September 2010 for further development as a standardised tool and template for promoting quality and performance in Australasian ED9s. It will further be developed and enhanced by further research nationally and internationally as to its effectiveness and utility.

Basilar artery thrombosis is an infrequent but important neurological emergency requiring early diagnosis and treatment. Of particular relevance to emergency medicine is the recognition and consideration of the unusual signs that may be present in an often previously well patient. It is therefore crucial to expedite investigations, confirm the diagnosis and commence life-saving treatment through the early involvement of a number of disciplines including neurology, radiology and intensive care. This paper confirms the use of magnetic resonance imaging and angiography as the preferred investigative mode and microcatheter directed intra-arterial thrombolysis as the treatment strategy of choice.

A246 VMP Results in Fewer Bone Events and Greater ALP Increases Versus MP in the VISTA Study in Front-Line MM M Delforge,1 M Kropff,1 I Spicka,2 M Petrucci,3 PG Richardson,4 R Schlag,5 N Khuageva,6 MA Dimopoulos,7 O Shpilberg,8 O Samoilova,9 MV Mateos,10 K Liu,11 W Deraedt,12 H van de Velde,13 J San Miguel14 1University of Munster, Germany; 2University Hospital, Prague, Czech Republic; 3University La Sapienza, Rome, Italy; 4Dana-Farber Cancer Institute, Boston, MA; 5Praxisklinik Dr. Schlag, Wurzburg, Germany; 6SP Botkin Moscow City Clinical Hospital, Russian Federation; 7University of Athens, School of Medicine, Athens, Greece; 8Rabin Medical Center, Petah-Tiqva, Israel; 9Nizhnii Novgorod Region Clinical Hospital, Russian Federation; 10Hospital Universitario Salamanca, CIC, IBMCC (USAL-CSIC), Spain; 11Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan; 12Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; 13Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; 14Hospital Universitario Salamanca. CIC, IBMCC (USAL-CSIC), Salamanca, Spain

TPS227 Background: The development of novel agents, including the proteasome inhibitor bortezomib (BTZ), has resulted in significant improvements in survival for patients (pts) with multiple myelom...

8014 Background: Elotuzumab is a humanized monoclonal IgG1 antibody targeting human CS1, a cell surface glycoprotein. CS1 is highly and uniformly expressed on multiple myeloma (MM) cells, with limi...

8016 Background: Bortezomib (VELCADE, Bz) or lenalidomide (REVLIMID, Len) plus dexamethasone (dex) demonstrate substantial activity in front-line MM; the three-drug combination has shown efficacy in the relapsed setting. This was the first prospective study of the three-drug regimen in front-line MM. Methods: Patients (pts) received eight 3-wk cycles of Bz 1.0–1.3 mg/m2 (d 1, 4, 8, 11), Len 15–25 mg (d 1–14), and dex 40 or 20 mg (d 1, 2, 4, 5, 8, 9, 11, 12) at 5 dose levels (phase I) and the maximum tolerated/planned dose (MTD; phase II). Responding pts could receive maintenance therapy or ASCT. Pts received prophylactic anticoagulants and anti-viral therapy. Primary endpoints were MTD and response rate. Results: 66 pts were treated (35 in phase II). Median age was 58 (range 22–86); 55% were men; 44%/47%/9% had ISS stage I/II/III MM; 68%/23%/9% had IgG/IgA /light chain MM; 57% had any of del 13q, del 17p, t(4;14), and t(11;14). Pts received a median of 10 cycles, including medians of 8, 10, and 8 cycles o...

TPS308 Background: BTZ, a backbone of novel therapy for patients (pts) with MM, is an effective agent but pts will relapse and ultimately become refractory to BTZ-based therapy as well as other novel agents, thereby constituting a high unmet medical need. Panobinostat (PAN; LBH589) is a potent pan-deacetylase inhibitor (pan-DACi) that targets HDAC6, disrupts aggresome and HSP90 activity, and promotes MM cell death. Combination with BTZ has shown synergistic cytotoxicity in preclinical studies. In a phase Ib MM study, combination of oral PAN with iv BTZ displayed a predictable and manageable safety profile with limited neurotoxicity and clinical efficacy seen with CR + PR + MR in 68% of pts, including 8 of 13 (62%) BTZ-refractory pts. Hence this combination is to be further evaluated in the PANORAMA program (PANobinostat ORAl in Multiple myelomA) Phase III (PANORAMA 1) and Phase II (PANORAMA 2) studies. PANORAMA 2is a U.S.-based, multicenter, single-arm study to evaluate the efficacy of PAN + BTZ + DEX in ...

8032 Background: Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (MM) patients following ≥1 prior therapy. RAD001, an m...

8140 Background: Aminobisphosphonates (aBP) are standard of care for myeloma related bone disease and are recommended every 3-4 weeks. Our previous data suggests altered bone remodeling in osteonec...

8003 Background: Elotuzumab is a humanized antibody against a cell surface glycoprotein, CS1, which is highly expressed in multiple myeloma (MM). This phase I study was designed to determine MTD, safety, PK and response of elotuzumab in combination with bortezomib in relapsed/refractory MM patients (pts) following 1-3 prior therapies. Methods: Four escalating doses of elotuzumab (2.5 mg/kg to 20 mg/kg) were administered on D 1 and 11 and bortezomib (1.3 mg/m2) on D 1, 4, 8 and 11 of a 21-day cycle. Pts with ≥ stable disease after 4 cycles continued treatment until progression. Key entry criteria included age ≥ 18 years; confirmed MM diagnosis with 1 to 3 prior therapies including prior bortezomib and refractory MM; measurable M-protein in serum and/or urine. Results: In this fully enrolled study, 28 MM pts were treated; 3 each at 2.5, 5 and 10 mg/kg and 19 at 20 mg/kg elotuzumab. The 26 pts with completed analysis had a median of 3.4 years from initial MM diagnosis and a median of 2 prior lines of therapy...

8125 Background: Outcome of patients (pts) with multiple myeloma (MM) has improved with the introduction of the immunomodulatory drugs (IMiD; thalidomide, lenalidomide) and the proteasome inhibitor...

8031 Background: MM remains incurable despite recent therapeutic advances. Although novel treatment combinations have improved outcome, new combinations are urgently needed. V, an oral histone deac...

8110 Background: Bortezomib is an effective treatment for both multiple myeloma (MM) and Waldenstrom Macroglobulinemia (WM), whose activity is attributed to blocking elimination of ubiquitin tagged...