Platelet Doubling After the First Azacitidine Cycle Is a Promising Predictor for Response in MDS, CMML and AML Patients in the Dutch Azacitidine Compassionate Patient Named Program,

Abstract 3841 The efficacy of azacitidine in the treatment of high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) (20–30% blasts) has been demonstrated. To investigate the efficacy of azacitidine in daily clinical practice and to identify predictors for response, we analyzed a cohort of 90 MDS, CMML and AML patients who have been treated in a Dutch compassionate patient named program. Patients received azacitidine for a median of 5 cycles (range 1–19). The overall response rate (CR/PR/HI) was 57% in low risk MDS, 53% in high risk MDS, 50% in CMML, and 39% in AML patients. Median overall survival (OS) was 13.0 (9.8–16.2) months. In multivariate analysis we confirmed that circulating blasts (HR 0.48, 95% CI 0.24–0.99; p=.05) and poor risk cytogenetics (HR 0.45, 95% CI 0.22–0.91; p=.03) are independent predictors for OS. Interestingly, in this analysis we also identified platelet doubling after the first cycle of azacitidine as a simple and independent positive predictor for OS (HR 5.4, 95% CI 0.73–39.9; p=.10). Of the 90 treated patients, 14 (16%) had an at least two-fold increase in platelet count after the first cycle of azacitidine, which was associated with significant better OS (p=.01, according to logrank test) (figure). Of these 14 patients 13 could be classified according the azacitidine prognostic scoring system for OS as recently proposed by Itzykson et al. (Blood:2011;117:403); 6 patients belonged to the low risk and 7 to the intermediate risk group. Median baseline platelet count of these patients was 35 x109/L (range 2–290 x109/L). Characteristics of this subgroup of patients were not significantly different from the patients without platelet doubling. Interestingly, platelet doubling was observed in all cytogenetic risk groups, in patients with and without circulating blasts, and in patients who are transfusion dependent and independent. In conclusion, routine administration of azacitidine to patients with variable risk groups of MDS, CMML and AML is feasible and subgroups with distinct efficacy of azacitidine treatment can be identified. Disclosures: Wijermans: Centocor Ortho Biotech Research & Development: Research Funding.

A Phase 2 Multicenter Study of Siltuximab, An Anti-IL-6 Monoclonal Antibody, in Patients with Relapsed or Refractory Multiple Myeloma,

Abstract 3971 Background: Although outcomes have improved for patients (pts) with multiple myeloma (MM), relapsed/refractory MM remains associated with short survival and constitutes an unmet medical need. Glucocorticoids (GCs) are an important component of MM therapy; however, resistance is common. In preclinical models, interleukin-6 (IL-6) promotes the proliferation and survival of MM cells in the context of the bone marrow microenvironment and protects these cells from GC-induced apoptosis. Therefore, blocking IL-6 may disrupt resistance and restore sensitivity to GCs. Here, we report the final results from a Phase 2 open-label, non-randomized study that evaluated the safety and efficacy of siltuximab (S), a monoclonal antibody targeting soluble human IL-6, in combination with high-dose dexamethasone (D) in pts with relapsed and relapsed/refractory MM. Methods: Pts with measurable, secretory disease who had received at least 2 prior lines of therapy, one of which contained bortezomib, and progressed during or after their last line of treatment were eligible. Other key eligibility criteria included a creatinine clearance ≥20 mL/min, platelets ≥50,000/mm3, and neutrophils ≥1,000/mm3. S was administered 6 mg/kg IV on days 1 and 15 of a 28-day cycle and oral D 40mg once daily, on days 1–4, 9–12, and 17–20 for a max of 4 cycles; days 1–4 for subsequent cycles. The first 14 pts received S alone for the initial 1 to 2 cycles; 10 pts had D added for progressive disease post-Cycle 1 or suboptimal response post-Cycle 2. 39 subsequent pts received S+D concurrently as none of the first 14 pts achieved ≥PR while on S monotherapy. The primary endpoint was overall response rate (ORR, CR+PR) using EBMT criteria. Secondary endpoints were time to progression (TTP), progression-free survival (PFS), overall survival (OS), and incidence of AEs and SAEs. Results: Forty-nine pts received S+D. The median age was 65 yrs (range 43–89) and 43% of pts were female. The median disease duration was 4 yrs (range 0.7–13.2). Pts were heavily pretreated, having received prior bortezomib (100%), steroids (100%), IMIDs (90%), alkylating agents (91%) and ASCT (65%). The median number of prior lines of therapy was 4 (range 2–9); 86% had disease that was refractory to the last prior line. Of the 44 pts with prior D exposure, 32 (73%) were refractory to the last D-containing regimen. The median duration of therapy was 4 cycles (99 days). Of the 47 pts evaluable for response, the ORR by EBMT criteria was 17% (0 CRs, 8 PRs); the ORR + minimal response (MR) rate was 23.4% (N=11). Using IMWG criteria, the ORR + MR rate was 27.7% (9 PRs, 4 MRs). Of the 11 pts with at least MR by EBMT criteria, 5 pts were refractory to the last D-containing regimen and 7 experienced less than MR on a prior D-containing regimen. The median duration of response was 5.9 months (181 days, 95% CI: 147, 365). Three pts had a long-lasting response of 9 months or more. For all 49 pts, the median PFS was 3.7 months (114 days, 95% CI: 84, 148) and median OS was 20.4 months (621 days, 95% CI: 347,984). AEs occurring in ≥25% of pts were thrombocytopenia, fatigue, anemia, abnormal hepatic function, neutropenia, diarrhea, peripheral edema, dyspnea and dizziness. 74% of pts experienced a grade ≥3 AE; the most frequent non-hematologic grade ≥3 AEs were fatigue (8%), abnormal hepatic function (8%), and pneumonia (6%). Grade 4 hematologic toxicities were thrombocytopenia (12%), neutropenia (4%) and anemia (2%). 25% of pts discontinued treatment due to an AE. Twenty (41%) of the 49 pts experienced ≥1 SAE. The most frequently occurring SAEs were pneumonia (8%), thrombocytopenia (6%), septic shock, anemia, and hemolytic anemia (4% each). Five pts died during the study; 3 due to progressive disease, 2 due to infection (nosocomial infection, septic shock). Conclusions: The combination of siltuximab with dexamethasone was well tolerated. Although the ORR was modest in this relapsed/refractory patient population, responses were seen in pts with MM refractory to prior dexamethasone-containing therapy, suggesting that siltuximab may be able to at least partially overcome dexamethasone resistance in some cases. Overall, these results provide a rationale for further studies of siltuximab in combination with dexamethasone-based MM therapy. Disclosures: Voorhees: MedImmune: Consultancy; Pfizer: Research Funding; Centocor Ortho Biotech: Research Funding; Celgene: Research Funding; Merck: Research Funding. Off Label Use: Siltuximab for the treatment of multiple myeloma. Manges:Centocor Ortho Biotech: Research Funding. Sonneveld:Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jagannath:Merck: Honoraria; Millennium Pharmaceuticals: Honoraria; Johnson and Johnson Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Research Funding. Somlo:Onyx: Consultancy; Millennium: Consultancy; Celgene: Consultancy, Speakers Bureau; Centocor Ortho Biotech: Research Funding. Krishnan:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau; Centocor Ortho Biotech: Research Funding. Lentzsch:Celgene: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; Centocor Ortho Biotech: Research Funding. Frank:Centocor Ortho Biotech: Research Funding. Zweegman:Centocor Ortho Biotech: Research Funding. Wijermans:Centocor Ortho Biotech Research & Development: Research Funding. Rijnbeek:Ortho Biotech Oncology Research and Development: Employment. Qin:Johnson & Johnson Pharmaceutical Research & Development, LLC: Employment. Cornfeld:Ortho Biotech Oncology Research and Development: Employment. Xie:Ortho Biotech Oncology Research & Development: Employment. Thomas:Centocor Ortho Biotech: Research Funding; Millennium Pharmaceuticals: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding.

Primary Therapy of Waldenström's Macroglobulinemia (WM) with Weekly Bortezomib, Low-Dose Dexamethasone and Rituximab (BDR): A Phase II Study of the European Myeloma Network

Abstract 1941 Rituximab and bortezomib are active agents in the treatment of WM. Based on preclinical studies which indicated synergism between bortezomib and rituximab, in 2006 we designed a large phase II multicenter trial to evaluate the combination of these agents in previously untreated patients with WM requiring therapy based on consensus recommendations (Kyle et al, Sem Oncol 2003;30:116). This trial was conducted by the European Myeloma Network in 10 centers. In order to prevent the “IgM flare effect” seen with rituximab-based regimens, one course of single agent bortezomib was first administered at a standard dose of 1.3 mg/m2 IV on days 1, 4, 8 and 11. Ten days later, the patients received four courses of 35 days duration each. In courses 2 to 5, bortezomib was administered weekly at a dose of 1.6 mg/m2 on days 1, 8, 15 and 22. During courses 2 and 5, immediately after the administration of bortezomib, patients received dexamethasone 40 mg IV followed by rituximab 375 mg/m2 IV. Patients received a total of 8 infusions of rituximab. Bortezomib was administered weekly in order to reduce the incidence of neurotoxicity which can be significant in WM patients treated with standard schedule bortezomib (Treon et al, Clin Cancer Res 2007;13:3320). A single dose of dexamethasone was given before each dose or rituximab in order to take advantage of potential synergism with rituximab and to reduce allergic reactions but to avoid steroid-induced complications. During treatment, valacyclovir prophylaxis for herpes zoster was prescribed. After completion of treatment, patients with CR, PR, MR or SD according to consensus criteria (Kimby et al, CLM 2006;3:380) were followed without further therapy until there was evidence of progressive disease. Dose modifications for toxicity were allowed and bortezomib could be reduced from 1.6 mg/m2 to 1.3 mg/m2 to 1.0 mg/m2. The trial was initiated in March 2007, 61 patients were scheduled to be enrolled and the study completed accrual in June 2010. Patients characteristics included: age >65 years in 60% of patients, hemoglobin <11.5 g/dL in 82%, platelet count <100×109/L in 17%, β2-microglobulin >3 mg/dL in 63%, serum monoclonal protein >7 g/dL in 3.4%, lymphadenopathy in 42%, splenomegaly in 29%, and B-symptoms in 42% of patients. According to IPSS for WM, 18% of patients were rated as low risk, 23% as intermediate risk and 59% as high risk. The main reasons to start treatment included cytopenias in 43% of patients, hyperviscosity in 22%, presence of B-symptoms in 18% and lymphadenopathy in 8%. So far, 54 patients are evaluable for response. On an intent to treat, response rating include CR in 2 (4%), PR in 33 (61%), MR in 8 (15%), SD in 5 (9%) and PD in 6 (11%) patients. In responding patients, at least MR occurred within 2.3 months of treatment and the median time to best response is 4.8 months. Plasmapheresis was not required in any patient before or after treatment with BDR. An “IgM flare phenomenon” was not seen and this was attributed to the initial course of single agent bortezomib. Median follow up for all patients is 12 months, and so far 10 patients have progressed. Eight patients have died, 5 due to causes unrelated to WM or complications of treatment. Toxicities include: neutropenia (grade ≥3) in 13% of patients; thrombocytopenia (grade ≥3) in 5%; peripheral sensory neuropathy, grade 1,2 in 30%, but grade ≥3 in only 5%; neuropathic pain in 17%, but grade ≥3 in only 2%, gastrointestinal toxicity, grade 3 in 7%; and infections in 17% (grade ≥3 in 7%). One patient died of septic shock in absence of neutropenia. Three patients (5%) experienced pulmonary toxicity (grade 3/4) which was attributed to bortezomib and consisted of dyspnea, decrease of O2 saturation and diffuse pulmonary infiltrates on chest CT scan. This toxicity resolved completely after administration of steroids and 2 of 3 patients continued treatment as per protocol. Only one patient (who had discontinued valacylovir prophylaxis) developed herpes zoster. The dose of bortezomib was reduced in 30% of patients primarily because of peripheral neuropathy. This is the largest trial that has evaluated the role of a bortezomib-containing regimen in the frontline setting of symptomatic patients with WM, most of whom were rated as high risk according to IPSS. We conclude that the BDR regimen is active. An update on response, toxicity and time to progression will be performed in November 2010. Disclosures: Dimopoulos: Ortho-Biotech: Honoraria; Millennium: Honoraria. Off Label Use: Bortezomib for Waldenstrom's Macroglobulinemia. García-Sanz:Ortho-Biotech: Honoraria; Millennium: Honoraria; Celgene: Honoraria. Merlini:Millennium: Honoraria; Ortho-Biotech: Honoraria. Sonneveld:Ortho-Biotech: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Vorinostat Combined with Bortezomib In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Update on the Vantage Study Program

Abstract 1952 Background: Initial clinical response rates have improved significantly with current treatments for multiple myeloma (MM). However, most patients eventually relapse or become refractory to approved agents, prompting the development of additional targeted agents and combination regimens. Vorinostat is a first-in-class oral histone deacetylase inhibitor that regulates the expression of genes and proteins involved in tumor growth and survival, and is approved in the United States for the treatment of patients with advanced cutaneous T-cell lymphoma in whom prior therapies have failed. Bortezomib, a reversible proteasome inhibitor, is approved for the treatment of patients with MM who have received at least 1 prior therapy. The synergistic effects of vorinostat and bortezomib have been shown in preclinical studies and confirmed in Phase I trials in patients with relapsed/refractory (RR) MM, producing objective response rates (ORRs; partial response or better) of up to 42% in all patients (including those with bortezomib-refractory disease) and overall clinical benefit of up to 90%. Methods: Vantage 088 is a global, Phase III, randomized, double-blind study to investigate the safety and efficacy of vorinostat vs placebo in combination with bortezomib in patients with relapsed MM and progressive disease after 1–3 prior antimyeloma regimens. The primary objective is to determine the duration of progression-free survival, with a planned enrollment of 742 patients. Overall survival, time to progression, ORR, tolerability, and patient-reported outcomes (PROs) will be included as secondary and exploratory outcomes. A distinctive aspect of this study design involves the evaluation of PROs using validated instruments, including quality-of-life (QoL) questionnaires for cancer patients (EORTC QLQ-C30) and myeloma patients (EORTC QLQ-MY20) and the EuroQoL-5D, presenting an opportunity to correlate PROs with efficacy and safety data. Interim analysis will take place when at least 126 events have occurred. Vantage 095 is a Phase IIB open-label study to investigate the efficacy and tolerability of vorinostat combined with bortezomib in patients with RR MM who had received ≥2 prior antimyeloma regimens; were refractory to bortezomib; and were relapsed, refractory to, intolerant of, or ineligible for other MM therapies, including immunomodulatory drugs (IMiDs). The primary objective is to determine the ORR, with a planned enrollment of 142 patients. In both studies, patients receive 21-day cycles of intravenous bortezomib (1.3 mg/m2; days 1, 4, 8, and 11) combined with oral vorinostat 400 mg (or matching placebo in Vantage 088) once daily on days 1–14. Efficacy is assessed using European Bone and Marrow Transplantation Group criteria. Adverse events (AEs; including clinical and laboratory events) are assessed and recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Results: Vantage 088: As of June 11, 2010, 349 patients (range, 1–17 cycles) were randomized. Patients received a median of 2 prior regimens (range, 1–3 regimens; 25% prior bortezomib, 48% prior thalidomide, and 12% prior lenalidomide). Vantage 095: As of June 11, 2010, 108 patients were enrolled. Patients (median age, 62 y; 57% men; 67% with Eastern Cooperative Oncology Group performance status 1) were heavily pretreated (median prior regimens, 5 [range, 2–17]). Interim efficacy data were reviewed in January 2010 by an independent data monitoring committee (DMC) for the first 43 patients enrolled; the futility threshold was passed, and final results are expected to be available 2Q2011. Conclusion: 2 ongoing global, multicenter, investigational trials are evaluating the efficacy and safety of combined vorinostat and bortezomib in patients with RR MM and are rapidly accruing patients. The Vantage 088 trial has passed the initial safety evaluations by the DMC, while interim results from Vantage 095 suggest that combined vorinostat and bortezomib may have clinical activity in patients with RR MM who are refractory to bortezomib and IMiDs and ineligible for other regimens. Disclosures: Siegel: Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board, Consultancy. Off Label Use: Vorinostat Combined with Bortezomib for treatment in Multiple Myeloma. Jagannath:Celgene: Honoraria; Millenium: Honoraria; Ortho Biotech: Honoraria; Onyx Pharma: Honoraria; Merck: Honoraria; Proteolix: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Hajek:Janssen-Cilag: Honoraria; Celgene: Honoraria; Merck, Sharp, and Dohme: Honoraria. Dimopoulos:MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Graef:Merck Research Laboratories: Employment. Pietrangelo:Merck Research Laboratories: Employment. Lupinacci:Merck Research Laboratories: Employment. Reiser:Merck Research Laboratories: Employment. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Elotuzumab In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma: Updated Results of a Phase 1 Study

Abstract 3023 Background: Elotuzumab is a humanized monoclonal IgG1 antibody directed against a cell surface glycoprotein, CS1, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against MM cell lines. In vitro pretreatment with bortezomib enhanced elotuzumab-mediated autologous ADCC, and in a murine xenograft model of MM the combination of elotuzumab and bortezomib exhibited synergistic antimyeloma activity. We present updated results of a phase 1 study that evaluated the maximum tolerated dose (MTD) of elotuzumab and the overall safety and clinical responses of the combination of elotuzumab and bortezomib in patients with relapsed/refractory MM. Methods: The study enrolled patients with MM and measurable serum and/or urinary M protein who had received 1 to 3 prior therapies. A 3+3 dose escalation design evaluated 4 escalating doses of elotuzumab (2.5, 5, 10, and 20 mg/kg IV) administered on days 1 and 11 in combination with bortezomib (1.3 mg/m2 IV) administered on days 1, 4, 8, and 11 of a 21-day cycle. Dexamethasone 20 mg PO was added for patients with disease progression after cycle 2 or 3 on days 1, 2, 4, 5, 8, 9, 11, and 12 of subsequent cycles. Patients with stable disease or better after 4 cycles continued treatment until disease progression or unexpected toxicity. Dose-limiting toxicities (DLTs) were assessed during cycle 1, and responses were assessed during each cycle using European Group for Bone Marrow Transplantation (EBMT) criteria. Results: The 28 enrolled patients had a median time since MM diagnosis of 3.5 years and had received a median of 2 prior therapies; 11 patients (39%) had received prior bortezomib, 4 (14%) were refractory to bortezomib, and 12 (43%) were refractory to their last therapy. Three patients each received the 2.5, 5, and 10 mg/kg doses of elotuzumab and 19 received 20 mg/kg. No DLTs were observed during cycle 1 and the MTD was not reached. After a median of 6 cycles of therapy (range, 1–25 cycles), 2 patients remain on therapy. Serious adverse events related to elotuzumab were 1 grade 3 chest pain and 1 grade 3 gastroenteritis. The most frequent grade 3/4 AEs were lymphopenia (25%), fatigue (14%), thrombocytopenia, neutropenia, hyperglycemia, peripheral neuropathy, and pneumonia (11%), and leukopenia and anemia (7%). Twenty-seven patients completed at least 2 cycles of therapy or progressed earlier and were therefore evaluable for response (Table). An objective response (≥ PR) was observed in 13/27 (48%) evaluable patients, including 7% CR and 41% PR. A clinical response (≥ MR) was seen in 17/27 (63%) evaluable patients. Notably, a partial response was seen in 2 (50%) of 4 patients refractory to prior bortezomib. The objective response rate (ORR) was 60% (6/10), 50% (6/12), and 20% (1/5) in patients who had received 1, 2, or 3 previous lines of therapy, respectively. Analysis of bone marrow plasma cells indicated that 10 and 20 mg/kg elotuzumab doses resulted in complete or near complete saturation of CS1 sites by elotuzumab. Median time to progression was 9.46 months in the overall population as well as in the bortezomib-naïve population. Conclusions: The combination of elotuzumab and bortezomib had a manageable safety profile. Key toxicities attributable to elotuzumab appeared to be related to infusion reactions. The combination showed promising efficacy with an ORR of 48% and a clinical response rate of 63%. Notably, activity was seen in bortezomib-refractory patients (ORR = 50%). The median time to progression was 9.46 months for both the overall and the bortezomib-naïve populations. Disclosures: Jakubowiak: Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson, Centocor Ortho Biotech: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor Ortho Biotech: Speakers Bureau. Off Label Use: Elotuzumab In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma: Updated Results of a Phase 1 Study. Bensinger:Millennium Pharmaceuticals, Celgene Corp., Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board. Zimmerman:Millennium, Celgene: Speakers Bureau. Mohrbacher:Millennium: Speakers Bureau. Richardson:Millennium, Celgene, Johnson & Johnson, Novartis: Membership on an entity's Board of Directors or advisory committees. Afar:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Millennium, Celgene, Novartis, Onyx, Merck, Bristol-Myers Squibb: Consultancy; Acetylon: Stock Options; Acetylon: Membership on an entity's Board of Directors or advisory committees.

Final Phase I Results of Perifosine In Combination with Lenalidomide and Dexamethasone In Patients with Relapsed or Refractory Multiple Myeloma (MM)

Abstract 3064 Introduction: Perifosine (Peri) a novel, oral signal transduction modulator with multiple effects including inhibition of Akt and activation of JNK, has demonstrated clinical activity when combined with dexamethasone (Dex) in patients (pts) with relapsed/refractory MM (ASH 2007 #1164). Lenalidomide (Revlimid , Rev) a novel, oral immunomodulatory drug has activity against MM when combined with Dex. We previously reported encouraging safety data and observed clinical activity of the oral triplet combination (ASH 2008 # 3691). We now report the final phase I results of this study which aimed to determine the MTD and to evaluate activity of Peri + Rev + Dex, as an oral combination in pts with relapsed or refractory MM. Methods: Four cohorts ( 6 pts each) were planned, dosing Peri at 50 or 100mg (daily), Rev 15 or 25mg (d 1–21) and Dex 20mg (d 1–4, 9–12 and 17–20 for 4 cycles, then 20 mg d 1–4) in 28-d cycles. To limit dex-related toxicities, the protocol was amended to use weekly dex (40 mg), applying to cohorts 3, 4, and the MTD cohort. Toxicity was assessed using NCI CTCAE v3.0; DLT was defined as grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <25,000/mm3 on >1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Pts had to have received at least 1 prior therapy and no more than 4. Pts refractory to Rev/Dex were excluded. Results: 32 pts (17M/15F, median age 64 y, range 37 – 79) were enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg); 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg); 8 pts in cohort 3 (Peri 100mg, Rev 15mg, Dex 40mg/wk); 6 pts in cohort 4 (Peri 100mg, Rev 25mg, Dex 40mg/wk) and 6 pts at MTD (Cohort 4). Median prior lines of treatment was 2 (range 1–4) with a median PS of 1. Relapsed (53%), Refractory to last therapy prior to study entry (47%). Prior therapy included dex (94%), thalidomide (75%), bortezomib (44%), and stem cell transplant (72%). Two pts (6%) were previously treated with Rev. 63% (15/24) of the prior thalidomide + dex (Thal/Dex) treated pts had progressed on a Thal/Dex regimen while 43% (6/14) of the prior bortezomib (Vel) treated pts had progressed on a prior Vel based regimen. Two pts did not complete one full cycle (non-compliance and adverse event not related to study drugs – both in cohort 3) and were not included in the efficacy analysis. 31/32 pts were evaluable for safety (non-compliant patient never took study drug and was excluded). The most common grade 1/2 events (any causality) included fatigue (48%), diarrhea (45%), upper respiratory infection (35%), nausea (32%) and hyperglycemia (32%). Grade 3/4 events > 10% included neutropenia (26%); hypophosphatemia (23%); thrombocytopenia (16%) and leucopenia (13%). There was one reported DLT in cohort 3 (Nausea). No grade 3/4 events of peripheral neuropathy or DVT were reported. Rev dose was reduced in 11 pts, Peri reduced in 9 pts and Dex reduced in 7 pts: 30 pts are evaluable for response, with best response as follows: Median progression-free survival (PFS) for all pts was 10.8 mos (CI: 4.6, 27.7) and 7 pts have not progressed. The median overall survival (OS) was 30.6 mos (CI: 16.7, NR) with 15/30 pts still alive. Of the 8 thalidomide naïve pts, 4 have progressed with a median projected PFS of 30 mos and all 8 pts remain alive (range 28 – 43 mos). Conclusions: Pts have tolerated Peri + Rev + Dex well with manageable toxicity, and with promising clinical activity demonstrated by an ORR (≥ PR) of 50%, an extended PFS and OS. Given that most pts were exposed to Thal/Dex with more than half refractory to a prior Thal/Dex regimen, the encouraging response rates and survival appear to suggest benefit with the addition of perifosine to Rev/Dex. This data thus warrants further study, including a potential randomized trial to confirm the activity of perifosine added to Rev/Dex. A randomized phase III trial of Peri/Vel/Dex vs. Vel/Dex is underway for previously Vel exposed MM patients. Disclosures: Jakubowiak: Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson Ortho-Centocor: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor-Ortho Biotech: Speakers Bureau. Off Label Use: Perifosine in combination with Lenalidomide and Dexamethasone. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Millennium, Celgene: Speakers Bureau. Alsina:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding. Kaufman:Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Transfusion and Post-Hospital Discharge Outcomes In Elective Total Hip Replacement (THR) or Total Knee Replacement (TKR) Surgery Among Adults <65 Years of Age.

Abstract 3814 Introduction: This retrospective claims analysis describes transfusion use and outcomes following discharge from elective THR/TKR surgery in patients <65 years of age. Methods: Patients aged 18 to 64 years with a THR/TKR surgery claim (index) between 1/1/06 and 12/31/08 were identified in the Thomson Reuters MarketScan® Commercial and Medicare Supplemental Databases. Eligible patients had continuous health plan enrollment for ≥6 months before the surgery admission and ≥6 months following surgery discharge. Patients were excluded if their surgery was associated with multiple joint procedures, revision surgery, or trauma diagnosis. Inpatient joint revision surgeries were excluded from readmission analyses. Patients with a claim for myelosdysplastic syndrome, chronic kidney disease, renal dialysis, human immunodeficiency virus infection, cancer, chemotherapy, sickle cell anemia, or a hospitalization or emergency room visit 6 months before surgery were excluded. Patients were categorized into 2 groups based on transfusion status during index surgery stay. The transfused (T) group had a blood transfusion claim while the non-transfused (NT) did not. Outcomes evaluated included the proportion of patients with an infection claim (wound site infection, pneumonia, urinary tract infection, Clostridium difficile, septicemia, or other) within 30 days of discharge, proportion of patients readmitted within 180 days of discharge, time to first readmission, readmission length of stay (rLOS), and readmission cost. Descriptive statistics included mean, median, and standard deviation (SD). Differences between the T and NT groups were assessed by chi-square or two-sample t-tests. Results: A total of 64,014 patients met the inclusion criteria. Mean age of the population was 56.1 ± 6.1 years, 57% were female, and 99% were insured. A transfusion claim was found for 8.3% of patients during index admission. Within 180 days after surgery discharge, 12.6% of patients were readmitted; mean time to first readmission was 79 days. Approximately 57% of first readmissions occurred ≤ 90 days after discharge while 43% occurred 90 to 180 days after discharge. The average rLOS for all readmissions was 5.3 days and median cost was $18,917. A claim for infection within 30 days of THR/TKR discharge was noted for 1.9% of patients. As reported in the table below, 2.6% in the T group had a claim for infection within 30 days of discharge versus 1.9% in the NT group (p<0.001). The proportion of patients readmitted after THR/TKR discharge was similar for T and NT groups, as was the rLOS (p=NS for both). On average, readmission occurred about 5 days earlier in the T versus NT group (p<0.001). Median readmission costs were $19,816 in the T group and $18,877 in the NT group. Conclusions: The proportion of THR/TKR patients with a readmission and rLOS did not differ between T and NT groups in this claims-based analysis. However, this study observed a higher proportion of patients with a transfusion claim during THR/TKR surgery having an infection within 30 days after surgery, a shorter time to readmission and higher readmission costs as compared to patients without a transfusion claim. Further research is needed to confirm these observations in other data sources. Disclosures: Ellis: Centocor Ortho Biotech Services, LLC: Employment. Bailey:Centocor Ortho Biotech Services, LLC: Employment. Forlenza:Centocor Ortho Biotech Services, LLC: Employment. Senbetta:Centocor Ortho Biotech Services, LLC: Employment. Landsman-Blumberg:Centocor Ortho Biotech Services, LLC: Consultancy, Research Funding.