This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047.

Background: AML and MDS are distinct, though largely overlapping, diseases, especially in older patients (pts) (Vardiman, Blood, 2008). Injectable AZA is the reference first-line treatment (Tx) for pts with higher-risk (HR) MDS ineligible for alloSCT (NCCN guidelines, v1.2016), as it improved overall survival in this population in the phase 3 AZA-001 (AZA-MDS) trial (Fenaux, Lancet Oncol, 2009). The safety profile of AZA in pts with MDS is well-established from clinical trials and post-marketing reporting (Santini, Eur J Haematol, 2010; Vidaza Package Insert, 2014). Recently, the safety and efficacy of AZA in older pts (≥65 years [yrs]) with AML and >30% marrow blasts were evaluated in the phase 3 AZA-AML-001 (AZA-AML) study (Dombret, Blood, 2015).

Background: Overall survival (OS) in older patients (pts) with AML and poor-risk cytogenetics is only ~2-3 months (mos) (Burnett, Cancer, 2007). Often these pts receive only palliative treatment (Tx) with best supportive care (BSC). Low-dose Ara-C (LDAC) provides no OS benefit in pts with poor cytogenetics (Döhner, Blood, 2010). Typically, intensive chemotherapy (IC) is either not suitable for older AML pts with poor cytogenetics or, when it is used, provides no OS benefit (Kantarjian, Blood, 2010). The phase 3, multicenter, randomized, open-label AZA-AML-001 trial showed azacitidine (AZA) Tx in older pts with newly diagnosed AML (>30% bone marrow [BM] blasts) prolonged median OS by ~4 mos vs conventional care regimens (CCR) (10.4 vs 6.5 mos; p=0.1009) and improved 1-year survival (46.5% vs 34.2%) (Dombret, EHA, 2014). Cytogenetic risk is a prognostic indicator in elderly AML and a frequent determinant of Tx approach and outcomes.

Abstract Background: AML is characterized by molecular heterogeneity; morphology and genetic alterations are important prognostic factors (Weinberg, 2009). In the large, phase 3, multicenter, randomized AZA-AML-001 study, AZA treatment (Tx) prolonged median overall survival (OS) vs CCR by ~4 months (10.4 vs 6.5 mo; p=0.1009) in older pts with newly diagnosed AML (>30% BM blasts). About 33% of patients (pts) in AZA-AML-001 had AML with morphologic dysplastic changes (AML-MDC). Aim: Determine effects of AZA vs CCR on OS, response, and safety in the subset of pts with AML-MDC in the AZA-AML-001 trial; and further analyze OS in AML-MDC pts who had been preselected to receive low-dose cytarabine (LDAC) before randomization to AZA or CCR. Methods: Eligible pts were age ≥65 years (yrs), had AML with >30% BM blasts, ECOG performance status (PS) 0-2, WBC count ≤15x109/L, and intermediate- or poor-risk cytogenetics. This analysis includes pts who, based on local assessment, had AML-MDC.Before randomization, investigators preselected the preferred Tx option for each pt from 3 CCR: intensive chemotherapy (IC; standard 7 + 3 regimen), LDAC (20mg SC BID x 10 days [d]/28d cycle), or best supportive care (BSC) only. Pts were then randomized to AZA (75mg/m2/d x 7 d/28d cycle) or CCR, and then received the preselected CCR. Median OS (Kaplan-Meier method) and percent of pts alive at 1 yr were compared between AZA vs CCR for all pts with AML-MDC, and between AZA vs LDAC specifically in pts with AML-MDC preselected to LDAC before randomization. Response was assessed by IWG AML criteria (Cheson, 2003). Transfusion independence (TI) was defined as no transfusion for 56 consecutive days for transfusion dependent (TD) pts at baseline (ie, ≥1 transfusion in 56d before randomization). Overall response was defined as complete remission (CR) + morphologic CR with incomplete blood count recovery (CRi). Adverse events (AEs) were graded by NCI-CTCAE v4. Hazard ratios (HR) and 95% confidence intervals (95%CI) were determined by unstratified Cox proportional hazards model and p values from log-rank or Fisher's exact test. Results: Of 488 pts in AZA-AML-001, 158 (32.4%) had AML-MDC and are included in these analyses. Baseline characteristics were generally balanced between Tx arms (AZA n=75, CCR n=83 [IC n=13, LDAC n=50, and BSC n=20]). Median (range) ages were 76 (65, 86) and 74 (66, 87) yrs in the AZA and CCR groups, respectively. Higher proportions of pts in the AZA arm were age ≥75 yrs (59% vs 48% of CCR) and had prior MDS (47% vs 37%). In the AZA and CCR arms, 43% and 47% of pts had poor-risk cytogenetics, and 24% and 25% had ECOG PS score of 2. Median (range) %BM blasts (central review) in the AZA and CCR arms was 67% (4, 99) and 73% (9, 100). Mediannumber of Tx cycles with AZA, IC, and LDAC were 6 (1, 28), 1 (1, 3), and 3 (1, 23). Median exposure to BSC was 79 d (8, 535). Median OS in pts with AML-MDC was prolonged 2-fold with AZA vs CCR: 12.7 mo (95%CI 7.2, 14.1) vs 6.3 mo (4.3, 9.6); HR=0.69 (0.48, 0.98), p=0.0357 (Figure). Similarly, 1-yr survival was greater with AZA: 50.7% vs 33.8% with CCR (16.9% difference [95%CI 1.5, 32.2]). Rates of CR+CRi were 26.7% with AZA vs 19.3% with CCR (Table). Most pts with AML-MDC (n=99, 63%) were preselected to receive LDAC (AZA n=49, LDAC n=50). Median OS in the preselected LDAC group with AZA vs LDAC, respectively, was 13.2 mo vs 6.3 mo, a 6.8-mo improvement with AZA (HR=0.76 [95%CI 0.49, 1.19], p=0.23). Further, 1-yr survival with AZA vs LDAC was 55% vs 31% (24% difference [95%CI 5.0, 43.0]). In the overall AML-MDC group with baseline-TD, 16/51 (31%) and 14/58 (24%) attained RBC TI in the AZA and CCR groups, and 10/26 (39%) and 12/33 (36%) attained platelet TI. Grade 3-4 anemia, neutropenia, febrile neutropenia, and thrombocytopenia rates, respectively, were: AZA 12%, 30%, 30%, 28%; IC 15%, 46%, 39%, 31%; LDAC 16%, 29%, 35%, 27%; and BSC 6%, 11%, 44%, 11%. Conclusions: AZA prolonged median OS 2-fold to >1 yr in this older, poor-risk subgroup of pts with AML-MDC. More than one-half of AZA-treated pts with AML-MDC remained alive at 1 yr. Notably, median OS in pts preselected to LDAC, but who were randomized to AZA, was more than doubled vs pts who did receive LDAC. AZA safety profile was consistent with that seen in the entire AZA-AML-001 population (Dombret, 2014). Compared with commonly used CCR, AZA was safe, effective and well- tolerated in this subset of pts with AML. These data suggest AZA may be a beneficial initial Tx as an alternative to LDAC in pts with AML-MDC. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Seymour: Celgene: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Use of azacitidine in AML with blast count >30%. Döhner:Celgene: Consultancy. Wierzbowska:Celgene: Honoraria, Speakers Bureau. Selleslag:Celgene: Consultancy, Research Funding, Speakers Bureau. Cavenagh:Celgene: Honoraria. Kumar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schuh:Celgene: Membership on an entity's Board of Directors or advisory committees. Candoni:Celgene: Consultancy, Speakers Bureau. Récher:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sandhu:Celgene: Honoraria. Bernal del Castillo:Celgene: Consultancy. Al-Ali:Celgene: Honoraria, Research Funding. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy. Falantes:Celgene: Consultancy. Stone:Agios: Consultancy; AbbVie: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Minden:Celgene: Honoraria. McIntyre:Celgene: Employment. Songer:Celgene: Employment, Equity Ownership. Lucy:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Dombret:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma.Design and Methods We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression.Results In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide.Conclusions Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (Clinical trial registration number: NCT00452569)

Abstract Abstract 3815 Background: Azacitidine (AZA) is approved for the treatment of patients with higher-risk myelodysplastic syndromes (MDS) and increases median overall survival (OS) by 9.5 months compared with conventional care regimens (CCR). However, the median OS for AZA-treated patients in this population is only two years (Fenaux, 2009, Lancet Oncol). Biomarkers predictive of maximal clinical benefit with AZA would allow identification of those patients ideally suited for AZA therapy. One of the molecular mechanisms of AZA activity is hypomethylation of DNA. Previous evaluation of DNA methylation of 5 genes (CDKN2B [p15], SOCS1, CDH1 [E-cadherin], TP73, and CTNNA1 [α-catenin]) in baseline bone marrow (BM) samples of MDS patients in the Phase 3 AZA-001 trial demonstrated that increased DNA methylation in pre-treatment baseline BM was associated with worse OS, and patients with lower levels of methylation derived the best OS benefit from AZA therapy (Herman, 2009, AACR). Methods: In the present study, we expanded our evaluation of DNA methylation patterns in the baseline BM of MDS patients from the AZA-001 trial to identify a DNA methylation-based predictive signature of OS in AZA-treated patients. DNA methylation levels of 27,578 genomic loci were determined in pre-treatment unpurified BM aspirates of 129 patients (AZA [n=59] and CCR [n=70]) using Illumina Infinium Methylation27 Beadarray. The data were randomly divided into a training data set (n=95: AZA [n=38] and CCR [n=57]) and a validation data set (n=34: AZA [n=21] and CCR [n=13]). A DNA methylation signature predictive of OS in AZA-treated patients was identified using uniCox algorithm (Tibshirani, 2009, Stat Appl Genet Mol Biol) first in the training data and then re-evaluated in the validation data. The influence of the signature on OS was assessed using Cox proportional hazards models. All statistical analyses were carried out in R (R Foundation for Statistical Computing, Vienna, Austria, http://www.R-project.org). Results: A baseline DNA methylation signature predictive of OS was identified based on the training set of 38 AZA-treated patients and re-evaluated in the validation set of 21 AZA-treated patients. The signature contains 214 genomic loci representing 187 genes, including WT1, CDH1, and CDKN2B. A DNA methylation score was calculated for each patient as the weighted average of the DNA methylation levels of these 214 genomic loci, with weights optimized in the training data set. As expected, in the training data set, the DNA methylation score was significantly (hazard ratio [HR]=2.34 [95% confidence interval: 1.54, 3.54]; p=5.8E-5) associated with OS and remained significant (HR=3.25 [1.65, 6.38]; p=0.00062) in a multivariate analysis, adjusting for the clinical co-variates: sex, cytogenetic score, ECOG grade, and baseline RBC transfusion status. The DNA methylation score was not predictive of OS in patients treated with conventional care (p=0.81), demonstrating the specificity of this marker to AZA therapy. When applied to the validation data set, the association of the DNA methylation score with OS remained marginally significant (HR=1.66 [0.99, 2.79]; p=0.053) in a univariate analysis, but became non-significant (p=0.52) in a multivariate analysis. For the majority of the loci in the signature, lower DNA methylation correlated with better OS. Interestingly, DNA methylation of WT1 loci alone was predictive of OS in both univariate (HR=1.47 [1.00, 2.16]; p=0.048) and multivariate (HR=2.04 [1.14, 3.64]; p=0.016) analyses of AZA-treated patients in the training data set. DNA methylation of WT1 loci remained a significant (HR=2.87 [1.24, 6.64]; p=0.014) predictor of OS in the validation data set in a univariate analysis, but became non-significant (p=0.35) in a multivariate analysis. As with the signature containing 214 loci, DNA methylation of WT1 loci was not predictive of OS in patients treated with conventional care (p=0.64). All performance results are summarized in Table 1. Conclusion: We have identified a DNA methylation signature that correlates with OS in the unpurified pre-treatment BM aspirate samples of AZA-treated higher-risk MDS patients. We have also demonstrated that DNA methylation of WT1 loci alone was predictive of OS. As these markers could be used to make therapeutic choices for patients with MDS, their predictive values warrant further validation in a larger independent data set. Disclosures: Shi: Celgene Corporation: Employment, Equity Ownership. Luo:Celgene Corporation: Employment, Equity Ownership. Lucy:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership.

Abstract Abstract 4031 Introduction: Because MDS are clinically heterogenous, classification and prognostic tools are essential to guide disease management decisions. The international, multicenter, phase 3 trial (AZA-001) enrolled 358 pts with higher-risk MDS as defined by French-American-British (FAB) criteria and International Prognostic Scoring System (IPSS) (Lancet Oncol 2009;10:223). The recent World Health Organization (WHO) classification of hematologic malignancies criteria (JCO 1999;17:3835) and the WHO Classification–Based Prognostic Scoring System (WPSS) (JCO 2007;25:3503) are increasingly being used in clinical practice. Aim: To evaluate whether overall survival (OS), hematologic improvement (HI), and transfusion independence (TI) in the subgroup of patients (pts) from AZA-001 who met WHO classification and WPSS criteria for higher-risk MDS are consistent with overall findings from AZA-001. Methods: According to protocol, AZA-001 enrolled pts with FAB-defined RAEB, RAEB-t, or CMML with more than 10% blasts, and IPSS Int-2 or High risk (Lancet Oncol 2009;10:223). Pts were randomized to AZA 75 mg/m2/d SC × 7d q 28d (n=179) or to a conventional care regimen (CCR; n=179), which included supportive care, low-dose ara-C, or intensive chemotherapy. This analysis included pts with WHO-defined RAEB-1 or RAEB-2 (pts with WHO-AML, CMML-1, CMML-2, or indeterminate classification were excluded) who had baseline WPSS risk of intermediate, high, or very high. Kaplan-Meier methods were used to estimate median OS and 95% CIs. HI and TI were defined by IWG-2000 criteria and results for AZA vs CCR were compared by Fisher's exact test. P values can only be used as a reference because these analyses were performed post hoc on a selected pt population that met WPSS criteria (40% of all AZA-001 pts did not meet these criteria and were excluded from analyses). Results: Overall, 215 pts in AZA-001 (106 AZA, 109 CCR) met a WHO classification for higher-risk MDS (RAEB-1: 13 AZA, 16 CCR; RAEB-2: 93 AZA, 93 CCR). Baseline WPSS risk was intermediate (1 AZA pt), high (66 AZA, 59 CCR), or very high (39 AZA, 50 CCR), with proportionately more CCR pts at very high risk than AZA pts (46% vs 37%, respectively). Median age was 68 years (range 42 – 83) in the AZA group and 70 years (range 38 – 88) in the CCR group. At baseline, 63% of both the AZA and CCR cohorts were RBC transfusion-dependent and 19% and 15%, respectively, were platelet transfusion dependent. Median OS was 26.3 months (95%CI: 17.2, not reached) with AZA vs 13.9 months (95%CI: 8.9, 18.8) with CCR, (log-rank p=0.016) (Figure). Rates of any HI and major erythroid and platelet lineage responses were better with AZA vs CCR (Table). RBC TI was also more frequent with AZA than with CCR (Table), but the platelet TI rate did not differ between treatment groups. Conclusion: These results are highly consistent with reported OS and hematological response outcomes for the entire AZA-001 population of higher-risk MDS pts classified by FAB and IPSS risk. The efficacy of AZA is consistently superior to CCR in pts with higher-risk MDS, irrespective of the classification and prognostic criteria used to describe them. Disclosures: Gattermann: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Giagounidis:Celgene: Consultancy, Honoraria. Seymour:Celgene: Honoraria, Speakers Bureau. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria; J&J: Honoraria. Santini:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ramos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lucy:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment. Silverman:Celgene: Honoraria.

Abstract Abstract 1856 Background: Sixty to 80% of patients (pts) with higher-risk myelodysplastic syndromes (MDS) require RBC transfusions to manage symptoms of anemia. Transfusion-associated complications include iron overload, transmitted infections, alloimmunization, and decreased overall survival (OS) (Cancer 2006;106:2087; JCO 2005;23:7594). The phase 3 AZA-001 study compared azacitidine (AZA) with conventional care regimens (CCR) in pts with higher-risk MDS (Lancet Oncol 2009;10:223). For all pts randomized to AZA, the reported median number of RBC transfusion events in the 56-day pre-randomization baseline (BL) period was relatively low (1.0, range 0 – 10), since 68/179 (38%) AZA-treated pts required no RBC transfusions (Haematologica 2009:Abstract 0813). However, pretreatment transfusion burden in the 111 RBC transfusion-dependent (TD) pts treated with AZA was substantial in many cases. It is unknown to what extent pts with higher RBC transfusion requirements at BL achieve transfusion independence (TI) and derive an OS benefit from AZA treatment. Aim: To assess OS in pts with higher-risk MDS treated with AZA in the AZA-001 study who were RBC TD at BL, based on pretreatment transfusion needs and posttreatment transfusion status. Methods: In AZA-001, 179 pts with higher-risk MDS (FAB-defined RAEB, RAEB-t, or CMML with >10% blasts, and IPSS risk Int-2 or High) were randomized to AZA (75 mg/m2/d SC × 7d q 28d). Of these pts, 111 (62%) were RBC TD at BL and 50 pts (45%) achieved TI during AZA treatment (Lancet Oncol, 2009;10:223). (Because so few pts who received CCR became TI on treatment [13/114, 11%], this analysis included only AZA-treated pts.) Erythropoietic stimulating agents were not permitted on study. BL RBC TD was defined as receiving ≥1 transfusion during the 56-day pre-randomization BL period, and per IWG 2000 criteria, TI on treatment required an RBC transfusion-free period ≥56 consecutive days. BL characteristics of pts who remained TD and of pts who achieved TI were evaluated and compared descriptively. Median OS was estimated using Kaplan-Meier (KM) methods for pts with pretreatment RBC transfusion burden of ≥1 (ie, all pts in the analysis), 1, or ≥2 transfusions (similar to IWG 2006 criteria for TD). The KM OS distributions for the on-treatment TI and TD groups were compared within in each cohort defined by pre-treatment RBC transfusion burden using the log-rank test. Results: Among the 111 AZA-treated pts who were RBC TD at BL, median age was 70 yrs (range 42 – 83), 77% were male, and 91% had ECOG performance scores of 0–1. Most pts (84/111, 76%) required ≥2 RBC transfusions in the 56-day pre-randomization BL period (Table). Median number of RBC transfusions at BL was 2 (range 1 – 10) in pts who achieved TI, and 3 (range 1 – 9) in pts who remained TD. Of pts who required ≥2 RBC transfusions at BL, 35 (42%) achieved TI. One-third (7/21) of pts with the highest RBC transfusion requirements at BL (≥5 transfusions) achieved TI during AZA treatment. Median OS was improved 3-fold for all cohorts of pts who achieved RBC TI with AZA, regardless of RBC transfusion burden at BL, compared with median OS in pts who remained TD (log-rank p<0.0001, all comparisons). Similarly, OS at 2 years in pts who achieved RBC TI during AZA treatment was 60–75% greater than OS at 2 years in pts who remained TD (Table). Of pts with the highest RBC transfusion needs at BL, 73% who achieved TI were alive at 2 years compared with only 12% of pts who remained TD. Generally, pts who remained TD on AZA were more likely to have WHO AML (20-30% blasts), higher LDH, and require platelet transfusions at BL than pts who achieved TI. However, pts who achieved TI on AZA more often had IPSS poor cytogenetics and 3 cytopenias at BL than pts who remained TD. Conclusion: A substantial proportion of pts with higher-risk MDS who required ≥2 RBC transfusions pretreatment achieved TI with AZA. TI in this analysis was associated with a marked improvement in OS. Disclosures: Seymour: Celgene: Honoraria, Speakers Bureau. Santini:Celgene: Honoraria. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria; J&J: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Finelli:Celgene: Consultancy. Lucy:Celgene: Employment, Equity Ownership. Backstrom:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership.

Abstract Abstract 959 Introduction: The OPTIMUM trial was designed to compare the efficacy of single-agent Thalidomide (THAL) with high-dose Dexamethasone (DEX) in patients with relapsed refractory (RR) multiple Myeloma (MM) and to determine the optimal dose of THAL in these patients. Methods: Patients with RRMM who had progressed after 1-3 lines of prior therapy were eligible for this multinational, randomized, open label phase III study. Patients were randomized to either daily THAL 100mg (THAL 100), 200mg (THAL 200) or 400mg (THAL 400), or DEX (40mg daily on days 1-4, 9-12 and 17-20 of each 28 day cycle for four cycles. From cycle 5 onwards, the dosing schedule was reduced to 40mg daily on days 1-4 of each cycle). All patients received study medication until disease progression or for a maximum of 12 cycles. Anticoagulant prophylaxis was not given routinely. Stratification factors included number of prior lines of therapy (1 versus > 1), prior autologous stem cell transplantation (ASCT) and International Staging System (ISS) score (Stage I+II versus III). The primary endpoint was time-to-progression (TTP) validated by an Independent Review Committee (IRC). Secondary endpoints included response rate, clinical benefit, survival, quality of life and safety. Planned accrual was 496 patients in order to detect a significant difference of 3 months in median TTP between the arms with 82% power at a two-sided significance level of 0.05. Results: Between Apr 2006 and Feb 2008, 499 patients were randomized by 68 sites in 15 countries from Europe, Asia and South Africa. Median age was 64 years (range 33-86); 73% of patients had ISS Stage I+II; 56.7% had received one prior therapy, 29.7% had received 2 and 12.8% had received 3 prior lines; 14.4% of patients had received prior bortezomib. Patients who had received prior thalidomide or lenalidomide were not included in this trial. Based on IRC-confirmed disease progressions during the treatment phase of the study, median TTP in the THAL 400 and in the DEX groups were 9.9 versus 6.0 months (hazard ratio, 0.64; p=0.017). Median TTP of the THAL 100 and THAL 200 arms were 6.7 and 7.3 months, respectively. IRC-validated complete and partial response rates according to EBMT criteria were 20.7% with THAL 100, 18.0% with THAL 200, 21.5% with THAL 400, and 24.6% with DEX. However, duration of response (DOR) showed a clear benefit for patients responding to THAL in comparison to DEX (median DOR in months: THAL 100: 12.7, p=0.046; THAL 200: 13.1, p=0.005; THAL 400: 11.6, p=0.016; DEX: 6.5). There was no difference in one year overall survival between the groups (80%, 83%, 82% and 80% for THAL 100, THAL 200, THAL 400 and DEX, respectively). During the study treatment period, the median of average daily drug dose in the THAL 100, THAL 200, THAL 400 and DEX groups were 99.5 mg, 198.2 mg, 255.5 mg and 40 mg, and the median treatment duration was 185, 179, 195, and 144 days, respectively. 60.2% of patients treated with THAL 400 had at least one treatment emergent AE (TEAE) ≥ Grade 3 compared to 39.5% with DEX. Thalidomide caused more frequent nervous system events (16.4 versus 2.4%), ≥ Grade 3 blood and lymphatic system disorders (14.8 versus 4.8%) and general disorders (12.5 versus 8.1%). Infections ≥ Grade 3 were more frequent with DEX (10.5% versus 8.6%). However, since TEAE of Grade 4 or higher were similar between both groups (12.5 versus 11.3%), the higher number of grade 3/4 events in the THAL 400 arm is due to an increase in grade 3 but not grade 4 TEAE with THAL 400 versus DEX. Venous thromboembolic events were uncommon in both groups (1.6% with DEX versus none with THAL 400). Patients treated with lower doses of THAL showed a more favorable safety profile. TEAEs of grade 3 or higher occurred in only 38.2 and 32.0% of the patients treated in the THAL 200 and 100 arms, respectively. Conclusion: This study is the first trial to evaluate the single agent activity of THAL in RRMM patients in a randomized controlled setting. Patients treated with THAL showed longer disease control in terms of TTP and DOR compared to high-dose DEX. The results confirm that THAL is a good treatment option for these patients with a dose dependent safety profile. Disclosures: Kropff: Celgene, ORTHO BIOTECH: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: In Europe, thalidomide is not approved for the treatment of relapsed multiple myeloma. . Robak:Celgene: Consultancy, Research Funding. Hajek:Janssen-Cilag: Honoraria. Liebisch:Celgene, ORTHO BIOTECH: Honoraria. Blade:Janssen-Cilag: Honoraria; Celgene: Honoraria. Caravita:Celgene: Honoraria. Pattou:Celgene: Employment. Lucy:Celgene: Employment, Equity Ownership. Kueenburg:Celgene: Employment. Glasmacher:Celgene: Employment, Equity Ownership. Zerbib:Celgene: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

PURPOSE:The long-term impact of thalidomide plus dexamethasone (thal/dex) as primary therapy for newly diagnosed multiple myeloma (MM) is unknown. The goal of this study was to compare thalidomide plus dexamethasone versus placebo plus dexamethasone (placebo/dex)as primary therapy for newly diagnosed MM.PATIENTS AND METHODS:In this double-blind, placebo-controlled trial, patients with untreated symptomatic MM were randomized to thal/dex (arm A) or to placebo plus dexamethasone (dex) (arm B). Patients in arm A received oral thalidomide 50 mg daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2 (28-day cycles). Oral dex 40 mg was administered on days 1 through 4, 9 through 12, and 17 through 20 during cycles 1 through 4 and on days 1 through 4 only from cycle 5 onwards. Patients in arm B received placebo and dex, administered as in arm A. The primary end point of the study was time to progression. This study is registered at http://ClinicalTrials.gov (NCT00057564).RESULTS:A total of 470 patients were enrolled (235 randomly assigned to thal/dex and 235 to placebo/dex). The overall response rate was significantly higher with thal/dex compared with placebo/dex (63% v 46%), P < .001. Time to progression (TTP) was significantly longer with thal/dex compared with placebo/dex (median, 22.6 v 6.5 months, P < .001). Grade 4 adverse events were more frequent with thal/dex than with placebo/dex (30.3% v 22.8%).CONCLUSION:Thal/dex results in significantly higher response rates and significantly prolongs TTP compared with dexamethasone alone in patients with newly diagnosed MM.