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Abstract 3010FN2 Background: There is a need to improve the conditioning regimens for allogeneic HSCT, both reducing the regimen related toxicity and improving the anti-leukemic effect. The myeloablative (MA) regimen consisting in intravenous (iv) busulfan (BU) with fludarabine (F) might be a better option than the conventional BU-CY (Cyclophosphamide) combination, since BU and F act synergistically against leukemia cell lines and previous studies with iv BU-F conditioning have reported an improved safety profile over BU-CY. Objective: We aimed to evaluate the efficacy and safety of the MA BU-F regimen, delivering iv BU in a one-daily dose after F infusion, since previous pharmacologic and clinical data supported its safety compared with the standard four-daily doses in the HLA identical sibling allogeneic HSCT setting. Patients: One hundred thirty seven consecutive adult patients with myeloid malignancies from nine Spanish institutions were recruited from 2005 to 2011. They had a median age of 47 years (range 19–74) and 60% were males. Diagnosis were AML: 80 (58.4%), AML secondary to MDS: 24 (17.5%), MDS: 23 (16.8%) and MPD: 10 (7.3%). At HSCT, the disease stage was 1st CR or untreated in 85 (62%) and more advanced stage in 52 (38%) cases. Patients having Karnofsky < 90% and Sorror CI >1 accounted for 11.7% and 38.3%. The conditioning regimen consisted in F, 40 mg/m2 daily for 4 days (total dose 160 mg/m2) followed by BU, one-daily IV 3.2 mg/kg infusion (total dose 12.8 mg/kg). GVHD prophylaxis consisted in cyclosporine and methotrexate. HSC infusion and post-transplant supportive measures and follow-up were made according each institution policies. Results: Donor graft source was peripheral blood (PB) in 93 (67.9%) and bone marrow (BM) in 44 (32.1%) cases. Median CD34+ cells infused were 4.5 millions/kg (range 0.6–17.8). All but one patient engrafted, with a median of 15 days (range 8–49) to >0.5 ×10E9 PMN/L and 13 days (range 7–149) to >20 ×10E9 platelets/L. The most frequent toxicity was mucositis, which was grade >1, in 68.8% cases. Three patients had hepatic SOS grade >1, and all of them resolved. Median hospitalization time was 30 days (range 17–114). Acute GVHD grade 2–4 incidence was 25% with a median of 32 days (range 12–87) to GVHD onset. The day-100 mortality was 4.8%. The chronic GVHD incidence in 114 patients at risk is 61.4%, with 37.7% of cases in extended form. At the time of this analysis, the median follow-up is 12 months (range 1–74). Crude survival data showed 106 (77.4%) patients remaining alive and 106 (77.4%) relapse free. Overall, 31 patients have died, 19 relapse-related (13.9%) and 12 (8.8%) due to transplant related mortality. Actuarial survival at 12 months is 79.4% and disease free survival is 71.3% in the whole series. Kaplan-Meier analysis showed that advanced age, comorbidities or advanced disease status at HSCT did not predict an inferior outcome. In conclusion, in the HLA identical sibling allogeneic HSCT setting, the BU-F regimen provides an adequate control of myeloid malignancies, with low regimen related toxicity and both reduced day-100 and non-relapse related mortality. Disclosures: Lahuerta: Janssen: Honoraria; Celgene: Honoraria.

Minimal residual disease (MRD) assessment is standard in many hematologic malignancies but is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol (VBMCP/VBAD induction plus autologous stem cell transplant [ASCT]). MRD status by MFC was determined at day 100 post-ASCT. Persistent myelomatous plasma cells (MM-PCs) were detected by MFC in 170 patients (58%), who were considered MRD-positive. Progression-free survival (PFS; median 71 vs 37 months, P < .0001) and overall survival (OS; median not reached vs 89 months, P = .002) were longer in patients who were MRD-negative versus MRD-positive at day 100 post-ASCT, with a 5-year PFS rate of 60% and 22% (P < .0001), respectively. Similar prognostic differentiation was seen in 147 patients who achieved immunofixation (IFx) negative complete response post-ASCT. The 5-year PFS rate was 62% in MRD-negative patients (n=94) versus 30% in MRD-positive patients (n=53; P < .0001), and the respective 5-year OS rates were 87% versus 59% (P = .009). Moreover, MRD− IFx− and MRD− IFx+ patients had significantly longer PFS than MRD+ IFx− patients (median 71, 65, and 37 months, respectively, P = .0002). By multivariate analysis, only MRD status by MFC at day 100 post-ASCT and FISH cytogenetics were identified as independent prognostic factors for PFS, and only MRD status by MFC and age were identified for OS. The relative risks of progression and death among MRD-positive versus MRD-negative patients were 3.64 (P = .002) and 2.02 (P = .02), respectively. Finally, a subgroup of 157 patients in which MRD information was available both pre- and post-ASCT were analyzed. Patients who were MRD-positive both pre- and post-transplant (n=93) had the worst prognosis; patients who were MRD-positive pre-ASCT but improved to MRD-negative post-ASCT (n=48) had an intermediate prognosis, and patients who were MRD-negative both pre- and post-transplant (n=16) had the best prognosis. The 5-year PFS and OS rates in these three prognostic subgroups were 25%, 57%, and 80%, respectively (P = .0001), and 59%, 78%, and 100%, respectively (P = .06). In summary, our results show that MRD evaluation by MFC is a very useful technique to identify patients at different risk of progression. This type of analysis, particularly when performed post-ASCT, may contribute to the design of patient-specific maintenance treatment approaches, as well as the evaluation of the potential benefits of consolidation therapies.

Background: MRD is an established biomarker to evaluate treatment efficacy, define patients at risk based on persistent MRD, and eventually, act as surrogate for prolonged survival based on sensitive MRD-negative definitions. Accordingly, the IMWG has developed criteria for MRD-negativity defined by next-generation sequencing, NGF or PET/CT, and has recommended their inclusion in clinical trials. Notwithstanding, most flow cytometry results have been obtained using less sensitive methods and in fact, there is no data about the impact of NGF-based MRD assessment in clinical trials. Aim: To define the feasibility, sensitivity and clinical impact of NGF-based MRD assessment in the phase III PETHEMA/GEM2012 trial. Methods: A total of 458 patients were enrolled into the PETHEMA/GEM2012 trial. MRD was predefined to be prospectively assessed at three time-points: after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), after HDT/ASCT, and after two courses of consolidation with VRD. MRD monitoring was performed blinded for clinical outcomes in four PETHEMA/GEM laboratory cores, and data was centralized for MRD analyses. MRD assessment was performed following EuroFlow SOPs in a total of 1,134 bone marrow (BM) samples from 419 patients. The 39 cases without MRD assessment had suboptimal response to induction and were thus considered as MRD+ for intention-to-treat analyses. Noteworthy, in 14 BM samples with undetectable MRD, B-cell precursors, erythroblasts and mast cells represented Results: Overall, 225/458 (49%) patients had undetectable MRD at the latest time-point in which MRD was assessed and were thus classified as MRD-. Conversely, 233/458 (51%) cases remained MRD+: 28% with ≥10-4 MRD, 12% with 10-5 MRD, and 11% with 10-6 MRD. Detailed analyses of MRD kinetics in 320 patients with available MRD results at all three time-points, showed that the percentage of MRD- patients increased from 35% into 54% and 58% after induction, HDT/ASCT and consolidation, respectively. Furthermore, a restricted analysis among MRD+ patients showed that whereas after induction only 8% of them had MRD levels as low as 10-6, subsequent intensification with HDT/ASCT and consolidation could reduce MRD levels down to 10-6 in 32% of MRD+ cases. Progression-free survival (PFS) rates at 3-years were of 92%, 70%, 54% and 44% for patients being MRD-negative, MRD+ 10-6, 10-5 and ≥10-4, respectively (P Conclusions: This is the largest study of MRD monitoring in MM based on the total number of samples analyzed (n=1,134). Our results show that NGF-based MRD assessment is feasible in large multicenter clinical trials, is highly-sensitive, and allows the identification of hemodiluted BM samples inadequate for MRD assessment. Risk of relapse among MRD-negative patients was remarkably reduced (3%), and was particularly related to the reappearance of extramedullary plasmacytomas, which urges the need for combined cellular and imaging MRD monitoring in these patients; by contrast, even MRD levels as low as 10-5 and 10-6 conferred significantly inferior PFS. Overall, this study defines MRD-negativity as the most relevant clinical endpoint for both standard- and high-risk transplant-eligible MM patients. Figure Figure. Disclosures Paiva: Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria; Merck: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; EngMab: Research Funding. Oriol: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia; Celgene: Speakers Bureau. de la Rubia: Janssen: Other: Honoraria; Amgen: Other: Honoraria; Celgene: Other: Honoraria. Rosinol: Celgene: Honoraria; Janssen: Honoraria. Mateos: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. San Miguel: Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

From 1985 to 2006, 71 patients with primary mediastinal large B-cell lymphoma receiving induction doxorubicine-based chemotherapy followed by ASCT as front-line therapy were registered in the GEL-TAMO (Spanish Group for Lymphoma and Autologous Transplantation). Median age was 28 years, 56% of patients were female, 40% presented with an ECOG ≥ 2; B-symptoms at diagnosis were present in 25% of the patients. Most patients presented with high-risk clinical features: bulky tumours defined as ≥10 cms of diameter were observed in most patients (87%), high LDH in 72% and, as previously reported (Rodriguez et al, Ann Oncol, 1994), β2m was elevated only in 7% of the cases. Forty-seven percent of patients presented 2–3 risk factors of the a-IPI. At transplant, thirty-five patients (49%) in first complete remission (CR), 23 (33%) in partial response and 13 patients (18%) failing the first induction therapy were transplanted, respectively. Conditioning regimens were BEAM or BEAC in 90% of the patients. 39 patients received Radiotherapy: 19 prior and 20 after the transplant. Most patients (91%) received peripheral stem cells. Only a patient failed to engraft after the transplant. After the transplant 73% of the patients achieved a CR and 17 patients were refractory. With a median follow-up from transplantation of 46,5 months the OS, PFS and DFS are 68%, 59% and 81% respectively. Progression of the disease was the main cause of death (78%). A patient died of a second neoplasia and 3 patients died of sepsis. There were no deaths related to transplant toxicity. By multivariate survival analysis both status of the disease at transplant (CR vs PR vs failure) and the Tumor score (Rodriguez et al, Ann Oncol,1992 ) were the only independent variables associated with the OS and PFS, respectively. In conclusion our experience, with a prolonged follow-up, shows that patients with primary mediastinal large B-cell lymphoma presenting at diagnosis with high-risk features have an encouraging survival and PFS with front-line ASCT. However, patients who received the transplant having failed the induction regimen have a very poor prognosis and should be tested with another innovative approach.

Multiple myeloma (MM) is a heterogeneous disease. Evaluation of prognostic factors and risk stratification at diagnosis is necessary to compare outcome. Attempts have been made to apply a comorbidity score in the clinical sitting, but a standardized general approach is still lacking. We hypothesized that a comprehensive examination of every associated disease in a large cohort of patients could better highlight the prognostic impact of comorbidity in MM. All consecutive patients diagnosed in our institution, from 1993 to 2013, with symptomatic MM according to IMWG criteria were included in our population-based MM registry. Patients with plasma cell leukemia or with palliative management were excluded. Clinical variables analyzed were: age, sex, Durie-Salmon, International Scoring System (ISS), percentage of plasma cell in bone marrow by morphology (PC), serum creatinine (Cr) and estimated glomerular filtration rate according with Modification of Diet in Renal Disease (eGFR-MDRD). The following comorbodities were analysed: hypertension (HTA), diabetes (DM), obesity (OB) (body mass index > 30 Kg/m2), hyperlipaemia (HL), prior malignancy (PM), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), peptic ulcer (PU), thromboembolism (TE), renal transplant (RT), splenectomy (S), cutaneous disease (CD), amyloidosis (AM), heart disease (HD) (arrhythmia, congestive heart failure, coronary artery disease, other), lung disease (LD) (chronic obstructive pulmonary disease, asthma, other), liver disease (HE) (cirrhosis, non-alcoholic fatty liver disease, other), neurological disorder (ND), psychiatric disorder (PD) and rheumatologic disorder (RD). Kaplan-Meier method was used to estimate OS curves. Cox regression was used to determine the prognostic impact of each comorbidity in a univariate and multivariate model. 311 patients were eligible. Median age was 66 years (12-91), 148 men (47.6 %) and 163 women. Percentage of comorbidities was: HTA 45; OB 32.5; DM 20.4; HD 20.4; LD 15.2; PU 10; HL 9.7; ND 8; PM 7.8; PD 6.5; HBV 3.9; HE 3.9; TE 3.6; RD 3,5; AM 2.3; HCV 1.9; CD 1.6; S 1; RT 0.6; HIV 0.3. 63 patients (20.4 %) showed no comorbidities. Univariate analysis (table 1) demonstrated that AM (P=0.022), HCV (0.038), HIV (0.022), PD (0.015) and ND (0.05) were significantly associated with shorter OS. The variables associated with mortality in the multivariate analysis were age (p=0.002), ISS (III vs I: p=0.01), PC (p=0.05) and Cr (p=0.02). Results will be validated in another MM series and presented during the meeting. The overall prognosis of MM depends on a variety of host and disease-related characteristics. We confirm age, ISS, PC and Cr as robust and independent prognostic factors. Adjusting for these factors, no isolated comorbidity reach statistical significance; however, comorbidity seems to have a role in MM prognosis. More studies are warranted to define the prognostic impact of comorbidities in MM. Disclosures: No relevant conflicts of interest to declare.

Background: Renal failure (RF) is present in about 20% of patients with newly diagnosed multiple myeloma (MM) and is associated with a poor outcome. Bortezomib-based therapy has shown significant activity in patients with RF, including a higher rate of renal recovery when compared with previous regimens. We report the results of a prospective phase II trial for patients with newly diagnosed MM and RF treated with bortezomib and dexamethasone (VD) (RENVEL: www.clinicaltrials.gov NCT 01084837). Aim: The primary end-point was efficacy in terms of response rate and secondary end-points were recovery of RF, PFS and OS. Patients and Methods: Patients with newly diagnosed MM and renal failure from 11 PETHEMA institutions were included. RF was defined as an estimated filtration glomerular rate (eFGR) < 50 ml/min calculated by the MDRD formula. Patients Results: Between April 9, 2010 and September 13, 2012, 60 patients (42 M, 18F, median age 72 years) were enrolled. The M-protein type was IgG in 14 patients, IgA in 22, light-chain only (Bence-Jones) in 22 and IgD in 2. 85% of the patients had ISS 3 and 19% had high-risk cytogenetics. The median baseline eFGR was 17 ml/min and 40 patients had severe RF defined as eFGR Eighteen patients (30%) were initially considered candidates to receive ASCT. The overall response rate after 4 induction cycles was 77% (28% CR, 23% VGPR, 28% PR, 5% MR, 16% refractory disease). Seven patients did not proceed to ASCT because of progressive disease (4), renal impairment with poor PS (2) and lost of follow-up (1). The response rate of the 11 patients who underwent to ASCT was CR in 8 patients (73%), VGPR in 1 (9%), PR in 1 (9%) and early death (sepsis) in 1 (9%). Grade 3 toxicity was only observed in 3 patients. No patient developed grade 3-4 neurological toxicity and only 2 patients had grade 2 peripheral neuropathy. Forty-two patients (70%) were not candidates to receive ASCT. The median number of cycles administered was 7.5. The overall response rate was 71% (29% CR, 29% VGPR, 14% PR, 2% MR, 17% refractory disease, 7% early death, 2% non-evaluable). 15 patients discontinued therapy because of bortezomib-related toxicity and seven were discontinued due to infectious complications. One patient developed grade 3 thrombocytopenia and grade 3 extrahematological toxicity was observed in 4 patients (gastrointestinal, asthenia, Wernicke-Korsakoff and rash one patient each). Peripheral neuropathy was observed in 18 patients (grade 2: 13 patients, grade 3: 5 patients). Renal response was achieved in 66% of the patients (29% CR, 14% PR, 23% MR). The median time to renal respose was 1.6 months (0.8-2.7). Therteen patients out of 17 (76%) could have been discontinued from dyalisis. The renal response rate was similar in the two groups. After a median follow-up of 26.7 months, the median PFS in ASCT and no-ASCT groups was 33.3 and 16.3 months, respectively. The estimated OS at 36 months were 82% and 72%, respectively. In both groups the PFS was not significantly different among patients achieving renal response vs. those not achieving renal response. In no-ASCT group the OS was significantly longer in patients achieving renal response compared with patients not achieving renal response (not reached vs. 35.3 months, p=0.03). Conclusions: VD is a highly effective regimen in patients with newly diagnosed multiple myeloma and severe renal failure, resulting in a high quality tumor responser and a renal response rate of 66% including a 76% of dialysis discontinuation. Disclosures Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Oriol:Celgene Corporation: Consultancy. Mateos:Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Jiménez:Janssen: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade:Janssen: Honoraria; Celgene: Honoraria.

Abstract 334 Introduction: The Spanish Myeloma Group (PETHEMA/GEM) conducted a randomized phase III trial comparing induction with thalidomide/dexamethasone (TD) vs. bortezomib/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM and ASCT with MEL-200 followed by maintenance with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN). The induction part of the study has been recently published and the maintenance results are reported here. End-points: The primary end-point was progression-free survival (PFS) and the secondary end-points were increase of response rate, overall survival (OS) and safety. Patients and Methods: The maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (single agent thalidomide at a dose of 100 mg daily) versus alfa2-IFN (subcutaneous alfa2b-IFN at a dose of 3 MU three times per week). The planned maintenance duration was three years or until disease progression or toxicity. From February 1, 2007 to January 27, 2011 266 patients were randomized to maintenance therapy (TV: 89; T: 87, alfa2-IFN: 90). Response and survival were evaluated on an intention-to-treat basis. Responses, relapses and progressions (EBMT criteria) were monitored by an external contract research organization and centrally reassessed. Results: Patient's characteristics at diagnosis such as age, M-protein type, ISS stage, cytogenetics and presence of extramedullary plasmacytomas as well as induction regimen (VTD, TD and VBMCP/VBAD/Bortezomib) and diagnosis-randomization interval were similarly distributed among the 3 arms. The response status at the time of randomization for maintenance after ASCT was CR: 51%, nCR: 12%, PR: 34%, MR 2% and SD: 1% and was well balanced in the three groups. The CR rate with maintenance was improved by 19% with TV, 15% with T and 17% with alfa2-IFN (p=NS). After a median follow-up of 34.9 months, the PFS was significantly longer with TV compared with T and alfa2-IFN (figure 1, p=0.0009). However, OS was not significantly different among the 3 arms. Grade 3 and 4 hematological toxicity was similar (22.2% vs. 16% vs. 21.8%). No peripheral neuropathy (PN) was observed with alfa2-IFN being its frequency similar with TV (12.2%) and T (10.1%). No grade IV PN was observed. Dose reductions for TV, T and alfa2-IFN were required in 33.3%, 33.7% and 19.5% of the patients, respectively. The discontinuation rate due to progressions was not significantly diferent among the three arms (35% vs 24% vs 20%, p=NS). The discontinuation rate due to toxicity was higher with thalidomide compared with TV (30.3% vs. 15.6%, p= 0.08) and with alfa2-IFN (30.3% vs. 18.3%, p=0.17). Patients with high-risk cytogenetics [t(4;14), t(14;16) and/or del 17p] had a trend towards a shorter PFS (p=0.1) and a significantly shorter OS (p=0.03). The incorporation of bortezomib was not able to overcome the poor impact of high-risk cytogenetics. Conclusion: The addition of bortezomib to thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide alone or with single agent alfa2-IFN with no increased toxicity. However, the addition of bortezomib did not overcome the poor impact of high-risk cytogenetics. Disclosures: Rosiñol: Janssen, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Celgene, Janssen: Consultancy, Speakers Bureau. Granell:Janssen: Honoraria; Celgene: Honoraria. de Arriba:Jansen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria; Onix: Honoraria; Novartis: Honoraria. Bladé:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria.

Purpose To characterize efficacy and safety of bortezomib-based versus nonbortezomib-based induction regimens through an integrated analysis of data from phase III studies in transplantation-eligible patients with previously untreated myeloma. Patients and Methods Patient-level data from the IFM 2005-01 (bortezomib-dexamethasone v vincristine-doxorubicin-dexamethasone [VAD] induction), HOVON-65/GMMG-HD4 (bortezomib-doxorubicin-dexamethasone v VAD), and PETHEMA GEM05MENOS65 (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) studies were pooled in an integrated analysis of efficacy and safety. Study-level data from the GIMEMA MM-BO2005 study (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) supplemented the integrated patient-level analysis. Key efficacy end points were post-transplantation complete plus near-complete response (CR+nCR) rate and progression-free survival (PFS). Results Patient-level data for 1,572 patients (bortezomib-based induction, n = 787; nonbortezomib-based induction, n = 785) were included. Post-transplantation CR+nCR rate was significantly higher following bortezomib-based versus nonbortezomib-based induction (38% v 24%; odds ratio, 2.05; P < .001); the benefit remained similar (pooled odds ratio, 1.96) when GIMEMA MM-BO2005 data were included. Median PFS was 35.9 months versus 28.6 months with bortezomib-based versus nonbortezomib-based induction, respectively (hazard ratio, 0.75; P < .001); 3-year overall survival (OS) rates were 79.7% and 74.7%, respectively (hazard ratio for OS, 0.81; P = .0402). Median duration of induction treatment was 11 weeks in both treatment groups. Rates of peripheral neuropathy during induction were 34% versus 17% (grade ≥ 3, 6% v 1%). Overall, 3% and 4% of patients died during bortezomib-based and nonbortezomib-based induction, respectively. Conclusion Bortezomib-based induction results in significant improvements in response and PFS/OS compared with nonbortezomib-based induction and is generally well tolerated, with a higher rate of peripheral neuropathy but no apparent increase in risk of death during induction.

Abstract 743 Background There has been considerable recent focus upon the molecular classification of myeloma. However, the prognostic impact of molecular changes has mostly been assessed from small and/or incomplete studies from single institutions or groups. There has been no large scale analysis of molecular features linked to ISS stage. Methods In order to clarify the overall impact of molecular changes we undertook a collective analysis of 9,897 patients through the International Myeloma Working Group (IMWG). Within this population 2,295 patients had presence of cytogenetic abnormalities (Any CA); 1,713 hypodiploidy; 1,673 hyperdiploidy; 2,309 cytogenetic deletion 13; 3,226 deletion 13 by FISH; 1,573 FISH t(4;14); 1,486 FISH del p17; 1, 683 FISH t(11:14); and 366 FISH t(4;16). Enrolled patients had complete clinical and treatment details available including baseline standard prognostic factors, ISS stage, as well as both progression free survival (PFS) and overall survival (OS) information. Data came from 14 sites: 3 from the US and the remainder from Europe, Asia, and Latin America as for the ISS staging system analyses. Univariate and multivariate analyses were performed. Results Each of the known adverse molecular features had a negative impact upon both PFS and OS (p=002 - In univariate correlations the most predictive correlations with OS were presence of Any CA, t(4;14), 17p-, hypodiploidy, cytogenetic 13q- with R2 values of 6.9%, 4.5%, 4.1% and 3.8% respectively. In multivariate analyses, ISS stage provided the best predictions: R2 values = 13.3%. The added contributions from molecular features were: t(4;14) 3.8%; cytogenetic 13q- 2.9%; Any CA 2.3%; and 17p- 1.0%. The maximum total R2 for OS was 22%. Conclusions This large multicenter analysis confirms the correlations between abnormal molecular findings and outcomes. Combinations with ISS Stage provide the best predictive capability. Presence of Any CA, t(4;14), 17p-, hypodiploidy and cytogenetic 13q- contribute to poorer outcomes by ISS stage. The presence of hyperdiploidy and/or t(11;14) contribute to better outcomes. There is thus validation of prior molecular studies related to prognosis utilizing this large IMWG database. Disclosures: No relevant conflicts of interest to declare.

In the novel agent era, the role of double autologous transplantation (ASCT) as up-front therapy for MM still remains undefined. Recently, several European cooperative groups prospectively compared bortezomib-based vs non-bortezomib-based induction regimens before ASCT for newly diagnosed myeloma (MM). By study design, patients enrolled into these trials were prospectively assigned to receive either a single or double ASCT. A multivariate regression analysis revealed that the leading factors independently associated with shorter PFS and OS were ISS 3, presence of high-risk cytogenetic abnormalities (hr-cyto), including t(4;14) and/or del(17p) by FISH, failure to achieve CR after induction therapy and assignment to receive a single ASCT. In comparison with patients for whom a single ASCT was planned by study design, those who were assigned to receive a double ASCT had significantly longer PFS (median: 38 vs 50 months, p Disclosures: Cavo: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Salwender:Janssen and Celgene: Honoraria. Rosiñol:Janssen and Celgene.: Honoraria. Moreau:Janssen and Millennium: Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria. Petrucci:Janssen and Celgene: Honoraria. Bladé:Janssen and Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx and Glaxo-Smith-Kline (GSK): Membership on an entity’s Board of Directors or advisory committees; Janssen: Grant, Grant Other. Attal:Celgene and Janssen: Membership on an entity’s Board of Directors or advisory committees. Weisel:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. San Miguel:Jansen, Celgene, Onyx, Novartis, Millenium: Membership on an entity’s Board of Directors or advisory committees. Lahuerta:Janssen and Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Facon:Janssen and Celgene: Speakers Bureau; Millennium, Onyx, Novartis, BMS, Amgen: Membership on an entity’s Board of Directors or advisory committees. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Goldschmidt:Celgene and Janssen: Membership on an entity’s Board of Directors or advisory committees.

Abstract 477 In 2005, Spanish Myeloma Group (GEM/Pethema) activated a two-stage, randomized trial including 260 elderly untreated myeloma patients. In the first stage, patients received induction therapy based mainly on a once per week dosing of bortezomib in combination with prednisone plus either melphalan (VMP) or thalidomide (VTP). The results of this first stage were already published (Mateos et al. Lancet Oncology 2010) and among all the 260 patients included in the trial, VMP and VTP as induction regimens yielded similar overall responses rate (80% and 81%, respectively). Patients completing the six induction cycles, in absence of disease progression or toxicity, moved to the second stage, in which each of the arms were equally randomly assigned to maintenance therapy with bortezomib plus prednisone (VP) or bortezomib plus thalidomide (VT). Maintenance consisted of one conventional cycle of bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11) every 3 months, plus either oral prednisone 50 mg every other day or oral thalidomide 50 mg daily, for up to 3 years. We report the results of this second stage of the trial comparing VT with VP for up to three years as maintenance following induction with VMP or VTP. 178 out of 260 patients were randomized to receive VT or VP. Concerning baseline characteristics, both groups were well balanced, including the response status at the moment of randomization to maintenance (23% of patients were in CR in VT arm and 20% in VP arm). Median follow-up after randomization to maintenance therapy was 34 months (8–54). Overall, maintenance therapy resulted in an improvement of the depth of response and the IF-CR rate was increased from 24% after induction up to 42%. Although no significant differences were observed between VT and VP, the IF-CR rate was slightly higher for VT versus VP (46% versus 39%). For all patients receiving maintenance therapy, the median progression free survival (PFS) from initiation of treatment was 35 months (95% CI 29–39) and the median overall survival (OS) 60 months (95%C CI 51–69). From the randomization to maintenance therapy, the median PFS was 30 months (95% CI 21–39) for patients receiving VT and 24 months (95% CI 15–33) for those receiving VP (p=0·1). The slight benefit of VT versus VP as maintenance was independent of the type of induction therapy (VMP or VTP) (p=0·9). No differences in overall survival from this timepoint for VT and VP arms were observed (HR 1·4, 95% CI 0·8–2·4). Concerning safety profile, grade 3 or higher hematological toxicity was recorded only as neutropenia in one patient (1%) in each arm and grade 1–2 occurred in less than 5% of patients (3% and 2% of patients in VT arm developped neutropenia and thrombocytopenia, respectively; and 1% of anemia in VP arm). Concerning non-hematological toxicity, although more of the side effects were of grade 1–2 in both arms, their incidence was superior for VT as compared with VP arm (p=0·0001). Of note, seven patients (7%) in VT arm developped cardiac events, consisting on bradycardia (2 pts), tachycardia (2 pts), heart attack (2 pts) and cardiac failure (1 pt), while only one patient in VP arm. Gastrointestinal toxicity, as constipation or paralitic ileus, was reported in 11 patients (11%) in VT and 3 patients (3%) in VP arm. Grade 3–4 peripheral neuropathy was observed in 9 patients (9%) in VT and 3 (3%) in VP arm. In summary, VT or VP as maintenance therapy resulted in a substantial increase in complete response rate, from 24% after induction to 42%, which can not be attributed to thalidomide or prednisone single agents but to their combination with bortezomib. In terms of CR, PFS and OS, although no significant differences between VT and VP were observed, a trend to better outcome for VT patients was observed, with a PFS that is one of the longest so far reported for elderly MM patients (39 months from diagnosis). However, VT arm was also associated with a higher incidence of non-hematological toxicity. These regimens, including bortezomib-based induction schemes that use weekly dosing of bortezomib, followed by bortezomib-maintenance schemes represent a platform for further optimisation of the treatment for elderly patients with multiple myeloma through use of lenalidomide instead of thalidomide by reducing adverse events and potentially improving the efficacy. Disclosures: Mateos: Celgene: Honoraria; Janssen-Cilag: Honoraria. Off Label Use: BORTEZOMIB, THALIDOMIDE AND PREDNISONE ARE NOT APPROVED FOR THE MAINTENANCE THERAPY.

Abstract 3951 Aim: The aims of this study were on one hand, to evaluate the significance of achieving molecular response (MR) by fluorescent-PCR (F-PCR) of Ig genes in a prospective way, particularly in patients with singular cytogenetics' features. On the other hand, to compared MR with immunophenotypic response (IR) and complete remission by immunofixation (CR). Patients: 130 new MM patients who had achieved CR or VGPR were analyzed by PCR, multiparametric flow cytometry (MFC) and immunofixation at diagnosis, and after induction therapy or transplantation: 48 patients received conventional chemotherapy as induction therapy followed with ASCT and were included in the GEM2000 trial and the other 82 patients were enrolled in the GEM2005 clinical trials in which the induction and maintenance therapy were based on Bortezomib and/or Thalidomide. Methods: The molecular analysis of Immunoglobulin (Ig) gene rearrangements at diagnosis was carried out by fluorescent PCR in DNA from bone marrow samples according to the Biomed-2 protocols. Briefly three different multiplex PCRs: DHJ; Ig Kappa light chain (IGK) rearrangements K-VJ and Kappa deleting element (KDE). DHJ and light chain rearrangements detected at the diagnosis were used in the follow-up. The sensitivity of PCR was between 1/103 and 1/104 as Martínez P. et al previously published in BJH, 2008. Regarding MFC the following monoclonal antibody combinations (FITC/PE/PerCP-Cy5.5/APC) were used at the diagnosis to identify different aberrant plasma cells phenotypes which were used as patient-specific probes for Minimal Residual Disease. Results: 64 patients had negative F-PCR and 66 patients had positive F-PCR after induction therapy. The OS was 77.32% and 59.18%, respectively and the medians OS were 116 and 67 months for each group (P= 0.03). Regarding the PFS, 28 of the 64 F-PCR negative patients relapsed while there were 44 relapses in the group of positive F-PCR. The 5y PFS was 56.44% and 27.43% respectively; the medians PFS were 60 and 36 months respectively (P= 0.0005). The multivariate analysis showed that achieving molecular response by F-PCR had a independent prognostic value in PFS (P=0.003, HR 2.3). Interestingly amongst patients who achieved CR, F-PCR identified a population of patient with a better PFS, figure A (P= 0.04, HR 2.179).The applicability of the F-PCR was almost equivalent to that observed by MFC (91.5 vs. 92%). Nevertheless we found discordant results between these two response criteria. Approximately the 20% of patients who had achieved a MR no obtained IR. The opposite pattern also was observed (IR/noMR) in 10% of the patients. In order to see if the PCR showed differences in terms of survival in patients with high or low risk cytogenetics features at the diagnosis, we made two independent analysis: in one hand we analyzed 14 patients with high-risk cytogenetics [t(4;14), t(14;16) and/or del(17p)] and on the other hand 72 patients with standard-risk cytogenetics. In the former analysis, 4 of the 8 who had negative F-PCR relapsed after the induction therapy while the totality of the other six with positive F-PCR did. The medians PFS were 32 and 17 months respectively (P= 0.0002). In connection with the 72 patients with standard-risk cytogenetics, 13 of the 34 who had negative F-PCR relapsed while 24 of the 38 with positive F-PCR did. The medians PFS times were 75 and 38 months respectively, figure B (P= 0.01). Conclusion: F-PCR of IgH rearrangements is a simple, cheap and feasible method for evaluating response in MM patients after induction therapy or transplantation. Additionally achieving MR provides a similar prognostic value to IR in patients differentially treated, and particularly in patients with singular cytogenetics' features as well as in patients with CR by immunofixation. Disclosures: Paiva: Jansen-Cillag: Honoraria; Celgene: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Blade:Centocor Ortho Biotech Research & Development: Research Funding. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Celgene: Honoraria; Janssen: Honoraria.

Excerpt To the editor: We read with interest the article by Fauci and colleagues (1) on Wegener's granulomatosis. Despite references to neoplasias as probable consequences of the use of cyclophosph...

Excerpt To the editor: Barton and Conrad reported in the February 1979 issue (1) an association of elevation of the aspartate transaminase (AST) levels with improved prognosis of acute myelogenous ...

Excerpt To the editor: In the NIH conference on the human interleukin-2 receptor (1), it is reported that interleukin-2 receptors in adult T-cell leukemia are overexpressed by the leukemic cells. I...