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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...

8503 Background: Tanespimycin (Tan) disrupts HSP90, a key molecular chaperone for signal transduction proteins critical to myeloma (MM) growth, survival and drug resistance. Preclinical data show anti-tumor synergy between Tan and bortezomib (Bz) and suggest Tan may be neuroprotective, including reversibility of Bz-induced peripheral neuropathy (PN). A phase I study of single agent Tan in advanced MM showed favorable tolerability and modest activity. Methods: 72 patients (pts) with relapsed/refractory MM received 0.7 - 1.3 mg/m2 Bz as IVB followed by 1-hr infusion of 100 -340 mg/m2 Tan on days 1, 4, 8,11 q 21d, with 42 pts receiving the highest dose of both drugs as part of a phase II expansion. Toxicities were assessed by CTCAE v3 and response by modified EBMT criteria. Results: Of 72 pts, 72% had IgG subtype with a median age of 60 yo. Median time since MM diagnosis was 50 mos with median of 5 (1–15) prior regimens. Prior treatments included stem cell transplant (69%), thalidomide (74%), Bz (69%), lenalidomide (28%) and Hsp90 inhibitors (13%). 58 pts with measurable disease were treated at 1 or 1.3 mg/m2 Bz. Response rates (≥ MR) were 41%, 20% and 14% in the Bz-naive, -pretreated and -refractory pts respectively. In the subgroup with 1–3 prior therapies and who were Bz-naive, the response rate was 56%. Median duration of response (DOR) for all pts with response (n=14) was 10.7 mos, including 3 Bz-refractory pts who had durable PR through mos 12, 22 and 28. 3 other pts remain in response through 24 mos. Of the 72 pts, the most frequent AEs were diarrhea (60%), nausea (49%), fatigue (49%), thrombocytopenia (40%) and AST elevation (28%), which proved manageable with dose reduction and supportive care. Most frequent G3–4 AEs included thrombocytopenia (25%), diarrhea, anemia and fatigue (7% each), as well as back pain and AST elevation (4% each). Only 21% of pts had G1–2 PN; no G3–4 PN was seen. Conclusions: Tan + Bz is active and well tolerated in relapsed/refractory MM, with durable responses in Bz-naive, -pretreated and -refractory pts. Median DOR for the combination compares favorably to Bz monotherapy. Final PFS data will be presented. No severe PN has been observed, consistent with Tan's neuroprotective effect in pre-clinical models. A phase III study of Tan + Bz vs Bz is ongoing. [Table: see text]

8517 Background: Three-drug combinations with lenalidomide (Revlimid, Rev) and bortezomib (Velcade, Vel) are highly active in previously untreated multiple myeloma (MM). Among the most active are RVD (Revlimid, Velcade, Dexamethasone) and VDD (Velcade, Doxil, Dexamethasone) with ≥ PR rate of 100% and 93%, and a CR/nCR rate of 44% and 40%, respectively. Pre-clinical evaluations suggest that adding pegylated liposomal doxorubicin hydrochloride (Doxil, Dox) to RVD (RVDD) may have higher activity. This phase I/II study was designed to determine the maximum tolerated dose (MTD) of RVDD, assess safety and evaluate efficacy of this 4-drug regimen in newly diagnosed MM. Methods: Four dose levels are being evaluated: Rev 15–25 mg (days 1–14), Vel 1.3 mg/m2 (days 1, 4, 8, 11), dexamethasone (Dex) 20/10 mg (cycles 1–4/5–8; days of and after Vel), Dox 20 and 30 mg/m2 (day 4), with dose assignment for patients (pts) according to the TITE-CRM algorithm. Eight 21-day cycles are planned with 38 pts to be treated at the MTD in phase II. Pts who achieve ≥ PR can proceed to autologus stem cell transplant (ASCT) after ≥ 4 cycles, while all others receive 21-day maintenance cycles with Rev (days 1–14), Vel (day 1 and 8), and Dex (days of and after Vel) at the doses tolerated by the end of initial treatment. Results: The study has enrolled 23 pts to date. Four pts received level 1 (Rev/Dox 15/20), 11 pts level 2 (Rev/Dox 20/20, and 8 pts level 3 (Rev/Dox 25/20). Nineteen pts are evaluable for toxicity after completion of a median of 4 cycles (range 1–8). Two pts developed DLT at dose level 2, consisting of grade (G) 3 asymptomatic neutropenia and G3 elevation of transaminase. The MTD has not been reached. Overall, toxicities have been manageable with no additional G3 hematologic events. There have been 4 additional G3 non-hematologic events including one case each of pneumonia, DVT, fatigue, and hypotension. After a median of 12 (range 3–24) weeks of treatment, preliminary response rates by modified EBMT/UC in 19 evaluable pts are: 95% ≥ PR, 47% ≥ VGPR, 26% CR/nCR. Conclusions: RVDD is well tolerated in newly diagnosed MM and appears highly active with an overall response (≥ PR) of 95%. Accrual is ongoing, with updated toxicity and efficacy data to be presented at the meeting. [Table: see text]

8505 Background: NPI-0052 produces rapid, broad and prolonged inhibition of all 3 catalytic activities of the 20S proteasome. NPI-0052 has a non-peptide based structure that appears to result in a unique proteasome inhibition (PI), signal transduction and safety profile. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with significant activity in hematologic and solid tumor malignancies including MM resistant to bortezomib (BZ) and other agents. Methods: This phase I dose escalation study of NPI-0052 was conducted in patients (pts) with r/r MM, including after BZ and/or lenalidomide. Pts were treated with NPI-0052 IV weekly for 3 weeks in 4-week cycles. The dose of NPI-0052 was escalated utilizing a combination of accelerated titration and 3+3 designs. PI and PK were assayed after the 1st and 3rd doses. Results: 17 patients have been treated at doses ranging from 0.025 mg/m2 to 0.6 mg/m2 without reaching a MTD. One patient experienced reversible creatinine elevation associated with progression of light chain nephropathy at 0.075 mg/m2. Drug- related adverse events have consisted principally of mild-to-moderate fatigue, nausea and diarrhea. In this study at dose levels 0.75 and 0.15 mg/m2, the half-life = 0.5 - 5.0 min; clearance = 4.8 ± 5.2 L/min and Vz = 22.6 ± 44.2 L. PI in whole blood demonstrates dose-dependent chymotrypsin-like inhibition up to 26% at 0.075 mg/m2. Of note, 2 patients remained on study for over 6 months and one year with stable disease and no significant toxicity. Importantly, NPI-0052 does not appear to induce peripheral neuropathy or myelosuppression. Conclusions: NPI-0052 was well tolerated in this study with escalation continuing to a recommended phase II dose (RP2D) for r/r MM. The RP2D (0.7 - 0.8 mg/m2), PI and safety profiles of NPI-0052 have been defined in other diagnoses, and appear unique from BZ in spite of up to 100% proteasome inhibition. In this study, NPI-0052 has effects on PD, PK and may potentially confer clinical benefit at doses which are well below the MTD determined in the other trials. Additional trials in MM are being initiated, including with lenalidomide. [Table: see text]

Introduction and Aims: In the international, phase III VISTA trial, bortezomib (velcade) plus melphalan/prednisone (VMP) was superior to MP across all efficacy end points, including response rate, time to progression (TTP), time to subsequent therapy (TTNT), and overall survival (OS; San Miguel et al, N Eng J Med 2008). Here we present updated survival data after prolonged follow-up, and data on use of subsequent therapy. Methods: Patients were randomized to VMP (n = 344) or MP (n = 338). Patients received nine 6-week cycles of bortezomib 1.3 mg/m2 (days 1, 4, 8, 11, 22, 25, 29, 32 in cycles 1-4 and days 1, 8, 22, 29 in cycles 5-9); melphalan 9 mg/m2 and prednisone 60 mg/m2 (days 1-4 in cycles 1-9), or MP alone. Results and Conclusion: VMP offered a significant survival benefit over MP (HR = 0.64; P = .0032); median follow-up, 25.9 months. Three-year OS was 72% versus 59%, respectively. OS was not substantially affected by baseline creatinine clearance. TTNT and treatment-free interval (TFI) were also significantly longer with VMP (TTNT 28.1 months vs. 19.2 months; HR = 0.53; P < .000001; TFI 16.6 months vs. 8.4 months; HR = 0.54; P < .00001). Clinical benefits appeared greater with VMP in patients achieving a complete response versus partial response versus no response. Fewer patients in the VMP versus MP arm (38% vs. 57%, respectively) required subsequent therapy; 16% and 43% received bortezomib, 49% and 44% received thalidomide, and 19% and 6% received lenalidomide, respectively. Bortezomib re-treatment was feasible in the VMP arm (6% CR; Table 1); a 10% CR rate was observed in patients who received bortezomib after MP. Peripheral neuropathy in the VMP arm improved in 79% of events (median, 1.9 months); 60% resolved completely (median, 5.7 months).

A224 Lenalidomide, Bortezomib, and Dexamethasone Has Notable Activity in High-Risk First-Line Myeloma PG Richardson,1 S Lonial,1 A Jakubowiak,2 S Jagannath,3 N Raje,4 D Avigan,5 IM Ghobrial,6 R Schlossman,6 A Mazumder,3 NC Munshi,6 D Vesole,7 R Joyce,5 D Doss,6 D Warren,6 L Lunde,6 R Lukas,6 S Kaster,4 K Shea,4 C Delaney,5 M Lauria,5 C Mitsiades,6 T Hideshima,6 R Knight,8 DL Esseltine,9 KC Anderson6 1Winship Cancer Institute, Atlanta, GA; 2University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; 3St. Vincent’s Comprehensive Cancer Center, New York, NY; 4Massachusetts General Hospital, Boston, MA; 5Beth Israel Deaconess Medical Center, Boston, MA; 6Dana-Farber Cancer Institute, Boston, MA; 7Division of Hematology/Oncology, Loyola University Medical Center, Maywood, IL; 8Celgene, Inc., Summit, NJ; 9Millennium: The Takeda Oncology Company, Cambridge, MA, USA

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

A166 VMP in Renally Impaired Newly Diagnosed MM Patients: Cohort Analysis of the VISTA Study MA Dimopoulos,1 PG Richardson,1 R Schlag,2 NK Khuageva,3 O Shpilberg,4 E Kastritis,5 M Kropff,6 M Petruci,7 M Delforge,8 J Alexeeva,9 R Schots,8 T Masszi,10 MV Mateos,11 V Deraedt,12 K Liu,13 A Cakana,14 H van de Velde,12 J San Miguel11 1Dana-Farber Cancer Institute, Boston, MA; 2Praxisklinik Dr. Schlag, Wurzburg, Germany; 3SP Botkin Moscow City Clinical Hospital, Russian Federation; 4Rabin Medical Center, Petah-Tiqva, Israel; 5Alexandra Hospital, University of Athens, School of Medicine, Athens, Greece; 6University of Munster, Germany; 7University La Sapienza, Rome, Italy; 8Myeloma Study Group, Belgian Hematological Society, Belgium; 9St Petersburg, Russia; 10St. Istvan and St. Laszlo Hospital of Budapest, Budapest, Hungary; 11Hospital Universitario Salamanca. CIC, IBMCC (USAL-CSIC), Salamanca, Spain; 12Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; 13Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ; 14Johnson & Johnson Pharmaceutical Research & Development, High Wycombe, UK

A224 Lenalidomide, Bortezomib, and Dexamethasone Has Notable Activity in High-Risk First-Line Myeloma PG Richardson,1 S Lonial,1 A Jakubowiak,2 S Jagannath,3 N Raje,4 D Avigan,5 IM Ghobrial,6 R Schlossman,6 A Mazumder,3 NC Munshi,6 D Vesole,7 R Joyce,5 D Doss,6 D Warren,6 L Lunde,6 R Lukas,6 S Kaster,4 K Shea,4 C Delaney,5 M Lauria,5 C Mitsiades,6 T Hideshima,6 R Knight,8 DL Esseltine,9 KC Anderson6 1Winship Cancer Institute, Atlanta, GA; 2University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; 3St. Vincent’s Comprehensive Cancer Center, New York, NY; 4Massachusetts General Hospital, Boston, MA; 5Beth Israel Deaconess Medical Center, Boston, MA; 6Dana-Farber Cancer Institute, Boston, MA; 7Division of Hematology/Oncology, Loyola University Medical Center, Maywood, IL; 8Celgene, Inc., Summit, NJ; 9Millennium: The Takeda Oncology Company, Cambridge, MA, USA

A084 Similar Benefit in Patients Aged 75 Years Versus < 75 Years with VMP in First-Line MM and Bortezomib in Relapsed MM M Kropff,1 PG Richardson,1 R Schlag,2 N Khuageva,3 MA Dimopoulos,4 O Shpilberg,5 R Schots,6 M Petrucci,7 R Neuwirth,8 A Boral,8 A Cakana,9 K Liu,10 W Deraedt,11 H Van de Velde,11 J San Miguel12 1Dana-Farber Cancer Institute, Boston, MA; 2Praxisklinik Dr. Schlag, Wurzburg, Germany; 3SP Botkin Moscow City Clinical Hospital, Russian Federation; 4University of Athens School of Medicine, Greece; 5Rabin Medical Center, Petah-Tiqva, Israel; 6Myeloma Study Group Belgian Hematological Society, Belgium; 7University La Sapienza, Rome, Italy; 8Millennium: The Takeda Oncology Company, Cambridge, MA; 9Johnson & Johnson Pharmaceutical Research & Development, High Wycombe, UK; 10Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, USA; 11Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; 12Hospital Universitario Salamanca. CIC, IBMCC (USAL-CSIC), Salamanca, Spain

8525 Background: Lenalidomide is a potent immunomodulatory drug and long-term administration in responding patients may have clinical benefit to patients. Early results from this phase II study previously determined that Len was active and well-tolerated in pts with relapsed/refractory MM (Richardson Blood 2006). Here, we present long-term follow-up results of pts that remained on therapy. Methods: Len (30 mg qd or 15 mg bid on days 1–21 every 28 days) was given to pts with relapsed/refractory MM in a multi-center, open-label, randomized phase II study. Concomitant Dex was permitted in pts with disease progression or stable disease. Treatment was continued as tolerated until disease progression. Response was assessed monthly using modified EBMT criteria and toxicity using NCI-CTCv2. No follow-up was done for pts who came off study drug. Overall survival was not included in follow-up. Results: From May 2002 to July 2003 102 were enrolled on the study, and 15 were still on therapy (11 on 30 mg qd and 4 on 1...

8524 Background: Lenalidomide (Len) in combination with high-dose dexamethasone (Dex) is approved for previously treated patients (pts) with multiple myeloma (MM). This study determined the efficac...

Background: In a phase 1/2 trial of VMP in 60 newly diagnosed MM patients (median age 75 years), the CR/nCR rate was 43%, with 32% CR; the 3-year survival was 85% (Mateos et al, Blood 2006; Mateos et al, EHA/IMW 2007). MMY-3002 is a phase 3 study comparing VMP with standard MP in patients with previously untreated MM who are not candidates for high-dose chemotherapy/stem-cell transplant. Methods: Approximately 680 patients were randomized to VMP or MP and stratified according to baseline β2-microglobulin and albumin, and geographic region. Eligibility criteria required the presence of measurable disease, KPS ≥60% and hematology/chemistry laboratory values meeting predefined criteria. Patients in the VMP arm received intravenous bortezomib 1.3mg/m2 twice weekly (weeks 1, 2, 4, 5) for four 6-week cycles (8 doses per cycle), followed by once weekly (weeks 1, 2, 4, 5) for five 6-week cycles (4 doses per cycle) in combination with oral melphalan 9mg/m2 and prednisone 60mg/m2 once daily on days 1–4 of each cycle. Patients in the MP arm received 9 6-week cycles of MP once daily on days 1–4. For both groups, treatment continued for a maximum of 9 cycles (54 weeks) unless disease progression or unacceptable treatment-related toxicity occurred. The primary endpoint was time to progression (TTP), and secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate, time to and duration of response, and safety. Results: Between December 2004 and September 2006, 682 patients from 151 centers in 22 countries across Europe, North and South America, and Asia were randomized. The median age was 71 years with 30% of patients aged ≥75 years. Fifty percent were male and 88% were of Caucasian origin. Median KPS was 80%, and 34% of patients had KPS ≤70%. Sixty-three percent had IgG myeloma, 25% had IgA myeloma, and 8% had light-chain disease. Bone involvement with >10 lytic bone lesions was reported in 27% of patients, 33% had β2-microglobulin >5.5mg/L, and 60% had albumin Conclusion: Efficacy and safety analyses will be reported at the meeting.

3532 Background: Tanespimycin (17-AAG/KOS 953) disrupts Hsp90, a molecular chaperone of MM client proteins including IL-6 and IGF-1R that are key to MM growth, survival and drug resistance. Single agent T was well tolerated with modest anti- MM activity. Preclinical studies suggest potential synergy with BZ. Methods: Pts received BZ as IVB followed by 1-hr infusion of T on D1,4,8,11 q 21d. Results: 49 pts were enrolled in 7 cohorts (T 100- 340 mg/m2; BZ 0.7 - 1.3 mg/m2). PK of T was similar with or without BZ. Inhibition of 20S proteasome with T+BZ was not different vs. historical BZ single agent data. PBLs showed induction of Hsp70 4h post-infusion with maintenance of induction prior to T infusion across the dosing interval; pAKT plus total AKT were also reduced 4 and 72h following infusion. CD138 but not CD4 or CD8 cells from serial BM aspirates showed induction of apoptosis by flow cytometry. In addition, ↓expression of IGR-1R and IL-6R client proteins was seen after treatment. Safety: In Cohort 7, 19 pts received T 340 / BZ 1.3 mg/m2. Common all-grade (G) drug-related toxicity (n=19) included diarrhea (42%), nausea (32%), vomiting (26%), ↑ AST/ALT/Alk Phos (26%/21%/21%), myalgias (16%), and dizziness (16%). G3 thrombocytopenia was noted in 16% with no other G3 toxicity observed in more than 1 pt. DLT was seen in 2 pts: G3 myalgias/cramps and dehydration (reversible in both). G1–2 only treatment-emergent peripheral neuropathy was recorded in 15%. Activity: Responses have been seen across dose levels in BZ-naïve, pre-treated and ref pts (“ref” defined as no response to or disease progression within 60d of last dose of BZ-containing regimen). Specifically, 1 BZ-ref pt with 3 prior regimens had confirmed PR after 2 cycles and continues in Cycle 9 (M-spike ↓92%); a 2nd pt with 2 prior regimens achieved PR after 2 cycles and continues in Cycle 7; a 3rd pt with 7 prior regimens with confirmed PR after 3 cycles continues in Cycle 6. Conclusions: Treatment with T 340/ BZ 1.3 combination had generally manageable toxicity. Durable Hsp90 inhibition and similar proteasome inhibition (vs single-agent BZ) was seen. Importantly, anti-MM activity in BZ-ref pts was observed and further investigation of this combination in rel/ref MM is therefore warranted. No significant financial relationships to disclose.

8108 Background: 2-methoxyestradiol (2ME2) is a natural endogenous product of estradiol metabolism with anti-angiogenic and anti-neoplastic properties that has demonstrated activity against multiple myeloma cell lines and xenografts in immunocompromised mice. We report results of the first phase II clinical trial of 2ME2 in pts with relapsed and plateau phase myeloma. Methods: This trial was designed with a one-stage design to accrue 60 pts in the setting of relapsed and plateau phase myeloma. 2ME2 was administered orally at a dose of 1000 mg daily. After the first 39 pts were accrued, based on the results of ongoing phase I trials, the dose of 2ME2 was increased to 800 mg twice daily for the remaining patients. Pts who were already on study at that point were also allowed to escalate their dose to 800 mg twice daily. The primary endpoint was overall response rate. Responses were assessed using Eastern Cooperative Oncology Group criteria. Results: Sixty patients were treated at Mayo Clinic and Dana Farber Cancer Institute. Median age was 60 years (range, 28–99). Thirty-one patients had relapsed/refractory myeloma and 29 patients had plateau phase myeloma. Median number of prior therapies was 4 including stem cell transplant (48%), thalidomide (62%), bortezomib (6%) and lenalidomide (3%). Therapy was well tolerated. Adverse events were anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flashes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most toxicities were mild (grade 1–2). Estimated progression-free survival rates for all pts at one, two, and three years are 24%, 16%, and 9% respectively. Three pts with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months. Response assessment is ongoing; so far, whilst no partial responses have been seen, prolonged stable disease has been observed in 3 pts (5%). Conclusions: 2ME2 is a novel agent that appears to be safe and well tolerated. Although no responses have been seen, prolonged stable disease in some pts is promising. Preliminary pharmacokinetic data indicate that the dose of 2ME2 used in this study may be inadequate, and a new formulation with significantly better bioavailability will be tested soon in this patient population. No significant financial relationships to disclose.

14144 Background: Defibrotide (DF) is a mixture of polydeoxyribonucleotides with anti-thrombotic activity. Next to endothelium stabilization, recent data suggest anti-neoplastic properties of DF modulating interactions of tumor cells with their microenvironment. We investigated whether DF regulates expression and activity of heparanase, an enzyme critically involved in breaking down extracellular barriers and releasing growth factors linked to tumor invasion and angiogenesis. Methods: Heparanase expression was tested by RT-PCR and flow cytometry with multiple myeloma (MM) and microvascular endothelial cells. Heparanase activity was measured in cellular extracts with a heparan-degrading enzymatic assay. Serum degradation products of DF were identified by SEC-HPLC. The anti-angiogenic potential of DF was tested in vitro using a kit with human microvascular endothelial cells forming tubes across a layer of fibroblasts. In vivo, DF was tested in the dorsal skin-fold chamber assay in mice after inoculation of human gastric cancer cells. Proliferation was assessed by trypan blue exclusion. Results: We demonstrate a striking downregulation of expression and enzymatic activity of heparanase in endothelial as well as MM cells. In contrast, the degradation products of DF failed to exert any biological activity, suggesting that the intact mixture of deoxyoligonucleotides is responsible for the anti-tumor effect. We could also show that DF prevents (tumor) angiogenesis in vitro and in vivo. Western blots suggest that DF reduces phosphorylation-activation of p70S6 kinase, a key target in the mTOR pathway linked to angiogenesis. In addition, DF does not influence proliferation of vascular or tumor cells, rather acts via selective inhibition of tube formation of endothelial cells. Conclusion: In the present report we provide evidence for an anti-tumor activity of DF. DF inhibits (tumor) vessel formation and heparanase activity, and thus should be considered as an anti-cancer agent. [Table: see text]

Correction to: Leukemia (2006) 20, 1467–1473. doi:10.1038/sj.leu.2404284 It has been identified by the authors that there are three errors in this paper. Table 4: Criteria listed under subheading ‘Definitions for measurable disease’ should also include: ‘Bone marrow plasma cells ⩾30%. Table 5: Bone marrow criteria for CR should be ‘

BACKGROUND: The phase 2 SUMMIT trial of patients (pts) with relapsed and refractory MM showed that btz (VELCADE®) is active, with a response rate of 27% (CR/PR) as a single agent, median TTP of 7 months, and median OS of 17 months. The phase 3 APEX trial in pts with relapsed MM following 1–3 prior therapies showed btz to be superior to high-dose dexamethasone (dex) in terms of response rate, TTP, and OS. Updated APEX data show a CR/PR rate of 43%, median TTP of 6.2 months, and median OS of 29.8 months. This analysis evaluated the relationship between quality of response to btz (CR/nCR versus PR; PR does not include nCR in this analysis) in these trials and clinical benefit, as defined by treatment-free interval and time-to-alternative-therapy (TFI and TTAT; time from last and first dose of btz, respectively, to first dose of alternative antineoplastic therapy), OS, and TTP. METHODS: In SUMMIT, 202 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for up to eight 21-day cycles (median # of cycles: 6). Dex 20mg was added on the day of and day after each btz dose in pts with suboptimal responses to btz alone. In one arm of APEX, 333 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for eight 3-week cycles and then on days 1, 8, 15, and 22 for three 5-week maintenance cycles (median # of cycles: 6). Responses in both trials were assessed according to EBMT criteria (modified to include nCR, a CR with positive immunofixation test). RESULTS: Data are shown in the Table. Median TFI appeared longer in pts with CR/nCR vs PR (SUMMIT, 9.8 vs 3.1 months; APEX, 17.5 vs 6.7 months). Similarly, TTAT appeared longer in pts with CR/nCR vs PR (SUMMIT, 15.4 vs 8.5; APEX, 21.2 vs 14.0). Median OS in all response groups has not yet been reached after a median follow-up of 22 months. TTP tended to be longer with CR/nCR vs PR in both studies (SUMMIT, 16.4 vs 9.2; APEX, 12.2 vs 8.3). CONCLUSIONS: Increasing quality of response to btz is associated with greater clinical benefit assessed by extended TFI ,TTAT, and TTP. Long un-maintained remissions can be attained with btz by achieving maximum tumor mass reduction (CR/nCR), even in pts with relapsed/refractory MM. Updated APEX data show that despite rapid initial response, many pts showed continued improvement in terms of M-protein reduction, and an increasing proportion of pts achieved CR with continued therapy. These data, together with the findings of this analysis, support maximizing tumor mass reduction to CR/nCR with btz to achieve greater clinical benefit. Clinical benefit of btz by response Kaplan-Meier median (95% CI) CR/nCR PR* *PR does not include nCR in this analysis; †Includes 8 cycles of protocol-specified therapy plus maintenance cycles SUMMIT, n 19 34 TFI, mo 9.8 (2.7,14.3) 3.1 (2.0,8.7) TTAT, mo 15.4 (7.9,17.6) 8.5 (7.3,14.0) TTP, mo 16.4 (10.6,NE) 9.2 (7.2,NE) Median cycles, n 8 8 APEX, n 48 87 TFI, mo 17.5 (6.7,24.1) 6.7(4.4,10.0) TTAT, mo 21.2 (14.0,27.1) 14.0 (12.6,16.1) TTP, mo 12.2 (8.8,NE) 8.3 (7.6,10.3) Median cycles,† n 9 10