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Over the last years, incorporation of novel agents into autologous stem cell transplantation (ASCT) has improved markedly the outcomes of younger patients with newly diagnosed multiple myeloma (MM). Superior results with experimental treatments vs previous standards of care have been frequently reported after preliminary analyses and need to be confirmed with longer follow up. The randomized phase 3 GIMEMA-MMY-3006 study was designed to compare bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double ASCT. Data from the initial analysis, with a median follow up of 36 months, demonstrated that patients randomized to the VTD arm enjoyed superior complete/near complete response (CR/nCR) rates after both induction and consolidation therapy, and had a significantly longer PFS compared to those prospectively assigned to the TD arm. We performed an updated analysis of the study after a median follow up of 59 months and results are herein reported. A persistent TTP and PFS benefit with incorporation of VTD into ASCT was confirmed. On an intention-to-treat analysis of 236 patients randomized to the VTD arm, median TTP was 62 months and median PFS was 57 months. The median values for 238 patients randomly assigned to the TD arm were 45 months for TTP (HR=0.64, p=0.001) and 42 months for PFS (HR=0.66, p=0.001) (Fig. 1). With the longer follow up of this analysis, an initial divergence between OS curves could be appreciated after 4 years, although the difference was not yet statistically significant at 6 years (75% for VTD vs 69% for TD). Superiority of VTD over TD for TTP and PFS was retained across prespecified subgroups of patients with high risk and low risk disease. In particular, PFS benefit with VTD was seen for patients age >60 years (HR=0.62, p=0.013) and younger than 60 years (HR=0.70, p=0.026), with ISS stage 1 (HR=0.59, p=0.009) and ISS stage 2-3 (HR=0.69, p=0.018), and for those with t(4;14) and/or del(17p) (HR=0.43, p3.5 mg/L (HR=1.7, 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. Tacchetti:Janssen and Celgene: Honoraria. Zamagni:Celgene: Honoraria; Janssen-Cilag: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Brioli:Celgene: Honoraria.

Background. Achievement of CR is generally associated with improved clinical outcomes for patients (pts) with MM and represents a primary endpoint of current clinical trials. The GIMEMA Italian Myeloma Network phase 3 study demonstrated that VTD regimen was superior over thalidomide-dexamethasone (TD) as induction therapy prior to and as consolidation therapy after the double ASCT for newly diagnosed MM (rate of >nCR: 31% vs 11% (pnCR affected by VTD resulted in extended progression-free survival (PFS), prediction of CR by pharmacogenomic tools is likely to be an important goal to prospectively select those pts who are more likely to benefit from a given therapy. Methods. We assessed the ability of GEP to predict attainment of CR in 122 pts enrolled in the VTD arm of the study. CD138+ plasma cells were obtained at diagnosis from each pts and were profiled for their gene expression (Affymetrix U133 Plus2.0 platform). Results. 34/122 pts (28%) who were included in the present analysis achieved a ≥nCR after VTD induction therapy and were characterized by the differential expression of 2157 probesets (p≤0.01). According to the unsupervised hierarchical clustering, the population of 122 profilated pts resulted stratified into 2 subgroups, the first one including 79% and the second one 21% of ≥nCR pts. To obtain a classifier for response to VTD induction therapy, the differentially expressed genes was analyzed to identify a small group of predictor genes. The best predictive capability was obtained with a 41-gene classifier that provided 88% sensitivity, 97% specificity, 91% PPV and 95% NPV. A GeneGo® network analysis showed that the most relevant network nodes included tumour suppressor genes, genes involved in inflammatory response and genes involved in B cell development. To asses the relevance to know since diagnosis the sensitivity for a particular therapy, we evaluated the prognostic impact of the response prediction in our clinical context. Pts predicted to be responder to VTD induction therapy according to the 41-gene classifier were more likely to attain a ≥nCR after the consolidation therapy. The 3 years estimate of PFS of pts ≥nCR after the consolidation therapy was significantly higher as compared to pts who failed this objective (p=0.03). Conclusions. GEP analysis of a subgroup of pts who received VTD induction therapy provided a 41-gene classifier that was able to predict attainment of >nCR and, conversely, failure to achieve at least nCR in 91% and 95% of cases, respectively. These favorable results might represent a first step towards the possible application of a tailored therapy based on the single patient's genetic background. Supported by: Fondazione Del Monte di Bologna e Ravenna, Ateneo RFO grants (M.C.) BolognAIL. Citation Format: Carolina Terragna, Daniel Remondini, Marina Martello, Annalisa Pezzi, Francesca Patriarca, Anna Levi, Lucia Pantani, Daniela Donnarumma, Lorenzo Montanaro, Claudia Crippa, Sarah Bringhen, Alessandro Rambaldi, Massimo Offidani, Paolo Corradini, Franco Narni, Giuseppe Fioritoni, Alfonso Zaccaria, Luca Baldini, Tommaso Caravita, Giorgio La Nasa, Sergio Cortellazzo, Giovanni Martinelli, Michele Cavo. A 41-gene signature predicts complete response (CR) to Bortezomib-Thalidomide-Dexamethasone (VTD) as induction therapy prior to autologous stem-cell transplantation (ASCT) in multiple myeloma (MM). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2207. doi:10.1158/1538-7445.AM2013-2207

Abstract 4210 In a previous analysis performed with a median follow-up of 36 months (mos), superior CR/nCR rates and extended PFS were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autotransplantation (ASCT) for newly diagnosed myeloma (MM). Here we report an updated analysis of that study, including a detailed analysis of outcomes after relapse or progression (R/P), an important issue for patients (pts) who received up-front a triplet novel agent-based therapy incorporated into ASCT. After a median follow-up of 52 mos, continued TTP and PFS benefits with VTD vs TD were demonstrated, while no difference in OS was seen between the two arms. Median PFS for pts randomized to the VTD arm was 56 mos vs 42 mos for those assigned to TD (HR=0.64, p=0.001). Similarly to PFS, median TTP for pts in the VTD group was longer than in the TD group (57 vs 45 mos, HR=0.63, p=0.0006), reflecting a 37% reduction in the risk of R/P with VTD. The probabilities of R/P in the VTD and TD arms were 41% vs 55% (p=0.002). In comparison with the VTD-treated group, a higher percentage of pts in the TD arm required the immediate start of salvage therapy after symptomatic R/P was documented (67% vs 82.5%). By the opposite, the fraction of pts with asymptomatic R/P that did not require any antimyeloma therapy until the cut-off date for the analysis was higher in the VTD arm compared with the TD-treated group (33% vs 17.5%, p=0.016). In these pts, the median interval from the date of R/P to the cut-off date for the analysis was 7 mos for the TD-treated group vs 17 mos for the VTD-treated group. Median time to subsequent antimyelomatherapy (defined as the interval between start of induction therapy and administration of the first dose of second-line therapy) was significantly longer for pts who experienced R/P in the VTD arm in comparison with pts who progressed in the TD arm (35 vs 29 mos, p=0.018). The associated interval between last administration of front-line therapy (e.g. consolidation for pts who received the entire treatment program or every other treatment before consolidation for those who discontinued earlier) and first administration of second-line therapy (salvage therapy-free interval) was 22.5 mos for the VTD-treated group vs 15 mos for the TD-treated group (p=0.009). Both bortezomib and lenalidomide were the most frequently used agents at the time of R/P (82% of all cases), while only 18% of pts were treated with conventional cytotoxic drugs. As expected, the majority of pts in the TD arm received a second-line therapy that included bortezomib (70%), while lenalidomide-dexamethasone was received by 10% of pts. By the opposite, in the VTD arm both bortezomib- and lenalidomide-based salvage therapies were equally distributed (41% vs 39%). The probability to achieve at least a partial response after second-line therapy including bortezomib was 60% for pts with prior exposure to VTD vs 63% for those randomized to TD. No difference in post-R/P OS was demonstrated between VTD-treated and TD-treated subgroups of pts who received bortezomib-based salvage therapy after R/P (2-yr estimates: 48% vs 53%, p=0.59). In the overall population, post-R/P OS was significantly shorter for pts who received salvage therapy with conventional cytotoxic drugs (2-yr estimate: 41%) in comparison with pts treated with novel agents, including bortezomib or lenalidomide (2-yr estimates: 52% and 53%, respectively) (p=0.0001). In conclusion, front-line therapy with VTD incorporated into ASCT was superior in comparison with TD plus ASCT in terms of extended TTP, PFS, time to subsequent antimyeloma therapy and salvage therapy-free interval. VTD-treated pts had a higher probability than TD-treated pts to experience long-lasting asymptomatic R/P not requiring second-line therapy. VTD-treated and TD-treated pts who subsequently received bortezomib-based salvage therapies had similar rates of response and post-R/P OS. This finding suggests that short-term exposure to VTD, as planned in our study, did not favor the selection of bortezomib-resistant clones, thus allowing to rechallenge bortezomib as (part of) second-line therapy after symptomatic R/P. Disclosures: Cavo: Janssen, Celgene, Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Di Raimondo:Celgene, Janssen: Honoraria, Speakers Bureau. Offidani:Janssen, Celgene: Honoraria. Caravita:Celgene, Janssen, Novartis, Genzyme: Honoraria. Boccadoro:Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 594 Survival of patients with multiple myeloma (MM) has been extended with the introduction of autologous stem cell transplantation (ASCT). More recently, availability of highly effective novel agents has further improved patient outcomes. However, it is still the matter of debate whether a proportion of patients treated with ASCT can enjoy a long term survival, while sustaining prolonged high quality response. To address this issue and to identify those variables which were related to long-term survival, we performed a post-hoc analysis of two large prospective clinical trials of ASCT in newly diagnosed MM patients, the first one comparing single versus double ASCT and the second one incorporating thalidomide-dexamethasone (TD) into double ASCT. A total of 321 patients were randomly assigned in the first study to receive either a single or double ASCT, as previously described (Cavo M et al, JCO 2007). Three hundred and fifty seven patients were enrolled in the subsequent multicenter phase 2 study incorporating TD from the outset until the second ASCT; details of the protocol were previously reported (Cavo et al, J. Clin. Oncol 2009). Results were updated as of 30 March 2012 and compared with those previously reported. All the analyses were performed on an intention-to-treat basis. After a median follow-up of 61 months for the entire treatment population of the first study, PFS remained significantly longer with tandem versus single ASCT (median 37 vs 25 months, P= 0.012), while OS was similar in the two groups (median 71 vs 67 months). 47% and 33% of the patients in the double and single ASCT group achieved a CR+nCR (P= 0.008). Overall, in 24% and 11% of the patients, CR+nCR was sustained for more than 5 and 10 years, respectively. In a multivariate Cox regression analysis, best response (CR+nCR) ever achieved was the most important variable significantly extending PFS (P= 0.003) and OS (P=0.050); random assignment to double ASCT was an additional variable predicting for prolonged PFS(P= 0.026). After a median follow-up of 84 months from starting TD in the second study, median values of PFS and OS were 47.2 and 109.6 months, respectively. The final rate of CR+nCR was 34%, which was maintained for a median of 53 months. Overall, in 42.1% and 9.1% of the patients CR+nCR was sustained for more than 5 and 8 years, respectively. On multivariate analysis, failure to ever achieve at least CR+nCR, low Hb, high β2-m and t(4;14)±del(17p) were found to be independent variables predicting for poorer outcomes. In particular, a shorter OS was seen for patients ever lacking high-quality responses (HR: 0.35, 0.23–0.54, p Overall, 23% and 20% of patients in the first and second study were alive over 10 or 8 years, respectively (long-term survivors). Median PFS of long-term survivors in the 2 studies were 74 and 87.7 months, respectively, versus 25 and 37 months for the rest of the population (P= 0.0000). Median duration of CR+nCR were 70 and 78 months in the long-term survivors group for the first and second study, respectively, in comparison with 21 and 49 months in the remaining patients (P In conclusion, although the comparison between TD incorporated into ASCT and ASCT without thalidomide was not directly addressed by this analysis, TD + ASCT was associated with extended PFS and OS. Approximately 20% of the patients undergoing up-front ASCT can achieve long term survival (8–10 years from start of treatment), with 33% of them remaining relapse free. Attainment of sustained high-quality responses was the leading independent variable predicting for long-term OS. Prolonged survival after relapse was a contributing factor to long-term OS. Disclosures: Off Label Use: One of the 2 protocols discussed includes the use of thalidomide as induction prior to ASCT.

Abstract 1871 Introduction: In a randomized phase 3 study, the use of VTD as induction therapy prior to and consolidation therapy following double ASCT increased the rate of complete or near complete response (CR/nCR) and extended PFS in comparison with TD given as induction and post-ASCT consolidation therapy in 474 newly diagnosed MM patients (Cavo et al, Lancet 2010). However, the specific impact of VTD consolidation on improved clinical outcomes was not defined. Methods: To address this issue, we performed a per-protocol analysis of 321 patients who received the entire treatment program, including the two pre-planned cycles of consolidation therapy with either VTD (160 of 236 patients, 68%) or TD (161 of 238 patients, 68%). By study design, two 35-d cycles of VTD (V 1.3 mg/m2 on days 1, 8, 15, and 22; T 100 mg/d on days 1–35; D 40 mg on the days of and after each V administration) or TD (at the same doses as in VTD) were given as consolidation therapy to patients randomly assigned to each of the two respective induction regimens. Patient and disease characteristics at baseline were comparable in the two groups of patients. Results: The rates of CR and CR/nCR were significantly higher after consolidation therapy with VTD compared with TD (CR: 61% vs 47%; p=0.012; CR/nCR: 73% vs 61%; p=0.020). The impact of VTD consolidation on post-ASCT enhanced rates of CR and CR/nCR was confirmed by the McNemar test (CR: p=0.0009; CR/nCR: p=0.004) which conversely failed to demonstrate a significant increase in the frequencies of CR (p=0.052) and CR/nCR (p=0.110) with TD consolidation therapy. The absolute probability of upgrading from less than CR before consolidation to CR after consolidation was 31% with VTD and 17% with TD (Pearson chi-square test: p=0.03). Ninety six percent of patients who upgraded from less than CR to CR after VTD consolidation were in nCR (44%) or VGPR (52%) before starting consolidation therapy. A landmark analysis (with the landmark set as the start of consolidation therapy) was performed to compare time to progression (TTP), PFS, and overall survival (OS) between treatment groups. With a median follow-up of 30 months, the estimated 3-year probability of relapse or progression was 38% with VTD and 52% with TD (p=0.039 by Kaplan-Meier analysis) (HR: 0.68, 95% CI: 0.47–0.98, p=0.041). PFS was significantly longer for patients receiving VTD consolidation than for those treated with TD (3-year estimates: 62% vs 46%; p=0.025) (HR: 0.66, 95% CI: 0.46–0.95, p=0.027), a gain particularly evident for patients who failed to achieve CR after ASCT (3-year PFS estimates: 66% vs 43%; HR: 0.54, 95% CI: 0.32–0.91, p=0.022). Superior PFS with VTD vs TD consolidation was retained across poor prognosis subgroups, including patients with t(4;14) and/or del(17q) (HR: 0.44, p=0.004), del(13q) (HR: 0.44, p=0.002), β2-microglobulin >3.5 mg/L (HR: 0.57, p=0.025), lactate dehydrogenase >190 U/L (HR: 0.57, p=0.005), or ISS stage 2 and 3 (HR: 0.57, p=0.021). In a multivariate regression analysis, the most important and independent variables positively correlated with PFS were VTD consolidation therapy (p=0.002), double ASCT (p=0.001), low β2-microglobulin (p Conclusions: In comparison with TD, post-ASCT consolidation therapy with the triplet VTD regimen significantly increased the rates of CR and CR/nCR, and extended landmarked TTP and PFS. Superior PFS with VTD consolidation was maintained across poor prognosis subgroups, including those with advanced ISS stage and/or high-risk cytogenetic profiles. In a multivariate regression analysis VTD consolidation was confirmed to be an independent variable favorably affecting PFS. The superior activity seen with VTD versus TD as induction therapy before ASCT was retained despite the same triplet regimen being used as post-ASCT consolidation. Disclosures: Cavo: Millennium: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Genzyme: Honoraria. Off Label Use: Bortezomib and Thalidomide as post autotransplantation consolidation therapy in myeloma. Patriarca:Schering-Plough: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Petrucci:Celgene: Honoraria; Janssen: Honoraria. Di Raimondo:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Palumbo:Merck: Honoraria; 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; Amgen: Honoraria. Offidani:Celgene: Honoraria; Janssen: Honoraria. Baccarani:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 1821 Introduction: PN is an important complication of MM and its incidence has been further increased after the introduction of the novel agents thalidomide and bortezomib. In a phase 3 trial comparing TD with VTD as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation for previously untreated MM patients, the VTD arm was significantly superior over TD in terms of improved rates of complete or near-complete response (CR/nCR) (the primary study endpoint) and progression free survival (PFS). Toxicity of VTD and TD regimens, including PN, was a secondary study endpoint. Methods: We performed a subanalysis of the study to assess the frequency, reversibility, risk factors and molecular markers associated with treatment-emergent PN. PN was graded by use of National Cancer Institute's Common Toxicity Criteria (NCI CTCAE) version 3.0. Since grade 1 PN could be misinterpreted and does not interfere with the daily activities, only patients who developed PN of at least grade 2 were evaluated. A total of 474 patients (of whom, 236 randomized to the VTD arm and 238 to TD) were stratified according to the development or not of grade ≥2 neurological adverse events (NAEs). Gene expression profiles (GEP) of pre-treatment CD138+ bone marrow plasma cells (BMPCs) were analyzed in a subset of 127 VTD-treated patients for whom biological samples taken at diagnosis were adequate for genomic analysis. GEP experiments were performed using the Affymetrix HG-U133 Plus 2.0 platform and class comparison of groups of array was done with one-way ANOVA Partek Genomic Suite (version 6.4). Results: Occurrence of PN throughout the entire treatment program was significantly higher in the VTD arm compared with TD. In particular, the rate of grade ≥2 PN was 35% vs 10% (p Conclusions: Although VTD incorporated into double ASCT was associated with a higher incidence of grade ≥2 PN compared with TD, the probability of complete resolution or improvement to at least grade 1 was comparable in both VTD- and TD-treated groups. Importantly, NAEs did not adversely affect the rate of CR/nCR, and TTP and PFS. No relationship between development of PN and both patient demographics and disease characteristics was observed. Conversely, GEP analysis of BMPCs from patients with VTD-induced PN showed the significant deregulated expression of genes involved in the nervous system function. Disclosures: Off Label Use: Bortezomib and Thalidomide as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation in newly diagnosed multiple myeloma. Tosi:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Mayers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: 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.

The availability of novel drugs such as immunomodulatory drugs, IMiDs, and proteasome inhibitors, PI, for the front line treatment of Multiple Myeloma (MM) has dramatically changed patients’ outcomes, significantly prolonging progression free survival (PFS) and translating into an extended overall survival (OS). Despite these impressive results, concerns have been raised regarding the possibility that IMiDs (lenalidomide and thalidomide) might increase the risk of developing SPMs, especially when associated with alkylating agents such as melphalan (MEL). It has long been known that the use of MEL can result in an increased incidence of SPMs, and this risk seems to be increased by the association with IMiDs. By the opposite, the use of PI in newly diagnosed MM (NDMM) patients (pts) was not associated with an increased risk of SPMs in a phase III study aimed at comparing BOR, MEL and prednisone (MP) vs MP.[1] Despite these results, the full impact of an upfront treatment containing both a PI and an IMiD in association with high dose MEL still has to be investigated. To address this issue, we have evaluated the incidence of SPMs in pts enrolled in the GIMEMA 26866138-MMY-3006 multicentre phase III study aimed at comparing BOR, thalidomide and dexamethasone (VTD) versus TD as induction before, and consolidation after, a double course of high dose MEL. The trial, conducted in Italy from 2006 to 2008, enrolled 480 transplant eligible NDMM, of which 474 received assigned treatment. Data on the incidence of SPMs are available for 299 pts (63%, 148 VTD and 151 TD). With a median follow up of 73 months, 25/299 pts (8%) developed a SPM: 7 (2%) SPMs were hematologic and 18 (6%) were non hematologic. The median time from trial entry to development of the SPM was 36 months (range 8.4-69.0). The number of pts developing a SPM was lower in VTD arm (5%) compared to TD arm (11%, p=0.068). Among pts developing a SPM, the proportion of solid malignancies was similar between treatment arms (75% and 71% in VTD and TD, respectively). Similarly, the percentages of hematologic SPMs was 25% for VTD pts and 29% for TD. On the overall population, the incidence rate (IR) of developing a SPM was 1% at 1 year and 9.9% at 6 years (yrs). This incidence was significantly lower for patients randomised to VTD compared with patients receiving TD (6% vs 13% at 6 yrs, p=0.037). When looking at the IR of solid tumours we noticed that only 5% of VTD-treated patients developed a solid SPM, as compared to 9.6% in TD; similarly, less hematologic SPMs were observed in the BOR arm (1% vs 4% at 6 yrs for VTD and TD, respectively). When the analysis was performed according to SPMs type, no statistical significance could be demonstrated. Our data compare favourably with data previously reported on the incidence of developing SPMs in NDMM treated with BOR frontline in association with MEL. With a follow up of 6 years, we were able to confirm that treatment with PI is associated with a low risk of developing SPM. Interestingly our data suggest that treatment with PI might decrease the risk of developing a SPM compared to IMiDs based treatment. Randomised trials with PI and IMiDs treatment should prospectively evaluate this issue. References 1. San Miguel, J.F., et al., Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol, 2013. 31(4): p. 448-55. Disclosures Musto: Janssen: Honoraria; Celgene: Honoraria. Cavo:Onyx: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Millenium Pharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder whose risk of progression to symptomatic MM (MM) is highly variable. Therefore, the identification of predictors of progression into MM is a relevant end point. Several markers (serum M protein, percentage of bone marrow plasma cells, free light chain, FLC, ratio, immunophenotyping of aberrant plasma cells and focal lesions, FLs at MRI) have already been established to identify sub-groups of SMM patients (pts) with a highest risk of progression into MM. Among imaging methods, FDG-PET/CT is a reliable technique for assessing early skeletal involvement and for predicting outcomes at the onset of MM. However, no data are available regarding the impact of PET/CT FLs in SMM on time to progression (TTP) into symptomatic disease. To address this issue, we prospectively studied pts with a suspected diagnosis of SMM with FDG-PET/CT. A cohort of 73 pts, with a median age of 61 years old (range 27-83) and a confirmed diagnosis of SMM, followed for a median of 2.2 years, is herein reported. By study design, all the pts were studied with PET/CT at baseline. Bone marrow involvement was described as negative, diffuse or focal. The number of FLs, as well as size and associated standardized uptake values (SUV) were recorded. For each FL, the presence of eventual underlying osteolytic lesion was investigated by the CT part of the scan; pts with osteolytic lesions were excluded from the present study, as they were considered as having symptomatic MM. Follow-up took place every 3-4 months and included clinical history, serum and urine markers and PET/CT plus axial MRI for occurrence of symptoms or an increase in M component. Progression to MM was defined by the presence of CRAB features. Skeletal progression was defined by the appearance of one or more sites of osteolytic bone destruction, pathological fractures and/or soft masses at PET/CT or MRI. The start of systemic therapy was defined as the date of event for the analysis of TTP. Baseline patient characteristics were as follows: 83% had IgG isotype, 8% IgA and 9% BJ, with a median M component of 2.5 g/dL; 70% had ISS stage I, 23% stage II and 7% stage III. Median plasma cell involvement on bone marrow (BMPC) was 30% (range 5-100%), with 16% of the pts having more than 60% BMPC. The median serum involved/uninvolved FLC ratio was 14.39 (range 1.28-2255), with 11% of the pts presenting with a ratio ≥ 100. PET/CT was negative in 64/73 pts (88%) and positive in 9/73 (12%) of them; 5 pts had 1 FLs, 1 pt 2 FLs, 2 pts more than 3 FLs and 1 pt a diffuse bone marrow involvement. Median SUV max value was 4.45 (range 2.5-5.2). No significant differences between patients with positive or negative PET/CT were found regarding the other baseline characteristics. At the time of the present analysis, 63% of the pts remained in the asymptomatic phase while 37% of them progressed to MM, in a median time of 4 years, including 21% with skeleton involvement, with/without the appearance of other CRAB symptoms, and 16% with exclusive serological signs of progression. Sixty six per cent of the pts with positive PET/CT progressed to MM in comparison to 33% of the pts with negative PET/CT (P = 0.034). The relative risk of progression of the pts with a positive PET/CT was 2.3 (95% CI 09.-5.9, P= 0.06). Moreover, the relative risk of skeletal progression was 4.0 (95% CI 1.3-12, P= 0.013), with a median TTP of 2.2 years for pts with positive PET/CT versus 7 years for those with negative PET/CT (figure 1). The probability of progression within 2 and 3 years for pts with positive PET/CT was 48% and 65%, respectively, in comparison to 32% and 42% for negative pts. In conclusion, approximately 10% of the pts with SMM have a positive PET/CT, mainly with few FLs, without underlying osteolytic lesion, with a low FDG uptake. PET/CT positivity significantly increased the risk of progression of SMM into active MM. PET/CT could become a new risk factor to define high risk SMM. A larger cohort of pts will be presented at the meeting. Further studies are warranted to find and optimal cut off point of FLs to capture the higher risk of progression at 2 year and to merge with other prognostic factors. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract 826 Incorporation of novel agents into ASCT allowed the achievement of unprecedented high rates of CR in young MM patients, a gain which translated into extended PFS and OS. As a consequence, interest in the evaluation of the depth of CR has progressively grown. More sensitive tools, such as multiparametric flow cytometry or molecular biology, led to the demonstration of a correlation between the depth of CR and prognosis, but failed to identify the persistence of residual disease outside of the bone marrow level. 18 F-FDG PET/CT is a careful technique to detect with high sensitivity and specificity the presence of active bone lesions and/or bone marrow involvement in newly diagnosed and previously treated MM. We prospectively analysed the prognostic significance of FDG-PET/CT at diagnosis, after induction therapy and ASCT in an homogeneous population of 192 patients with newly diagnosed MM, followed for a median of 43 months. By study design, all patients were studied with FDG-PET/CT at baseline, after induction treatment, after 3 months from ASCT (single or double), once a year during the maintenance/follow-up phase and at time of relapse. Bone marrow involvement was described as negative, diffuse or focal. The number of focal lesions (FLs), as well as size and associated standardized uptake values (SUV) were recorded. Extra-medullary disease (EMD), if present, was described by location, size, number and SUV. Twenty four percent of the patients had a negative PET/CT scan at diagnosis. Among PET/CT-positive patients, 44% showed ≥3 FLs, 46% had SUV values >4.2 and in 6% EMD could be detected. These 3 variables adversely affected 4-year estimates of PFS and OS. In particular, both EMD and severe FDG uptake were significantly associated with shorter PFS and OS. Thirty seven percent of the patients were PET/CT-negative after induction. A strong correlation between conventional response and SUV max reduction was evident, the mean SUV value of patients achieving CR being significantly lower in comparison with that of patients reaching very good partial response (VGPR) or partial response (mean: 1.4 vs 3, respectively) (Cuzick's trend test, P= 0.016). Persistence of severe FDG uptake (SUV max still >4.2) after induction predicted for shorter PFS at 4 years (P= 0.004). PET/CT negativity (PET-CR) was observed in 65% of patients after 3 months from ASCT(s). A close relationship between PET/CT negativity and response to ASCT was evident, since 95% of patients with a negative PET/CT had achieved at least a VGPR (P= 0.003). Moreover, a correlation between conventional response and SUV max reduction was evident after ASCT as well (mean: 0.8 vs 1.8, respectively) (Cuzick's trend test, P= 0.001). PET-CR after ASCT conferred superior PFS and OS in comparison with persistence of FDG uptake. In particular, the 4-year estimates of PFS and OS for PET-CR patients were 66% and 89%, respectively, as compared with 45% and 65% for positive patients (P=0.02 both for PFS and OS). Notably, 23% of patients achieving CR according to conventional criteria still had positive PET/CT scans and their 4-year estimate of PFS was 30%, as compared with 61% for negative patients (P=0.02). After ASCT, patients were followed with evaluation of M protein every 3 months and of PET/CT once a year. In 44% of those who had a conventionally-defined relapse or progression, the mean time to relapse/progression was 27.6 months for PET-negative patients as compared with 18 months for positive patients (P=0.05). In PET-positive patients, the SUV max was inversely correlated to the time to relapse (correlation coefficient −0.7, P= 0.003). In multivariate analysis, both severe PET/CT involvement at diagnosis (SUV >4.2 and/or EMD) and persistence of FDG uptake after ASCT were independent predictors of worst PFS (SUV >4.2= HR: 2.0, 95%CI: 1.13–3.72; EMD= HR: 15.0, 4.0–55.8; FDG uptake after ASCT= HR: 2.12, 1.19–3.77) and OS (EMD= HR: 6.99, 2.28–21.46; FDG uptake after ASCT= HR: 3.57, 1.03–12.39). In conclusion, PET-defined CR was linked to conventionally-defined CR and was an independent prognostic factor in MM patients receiving up-front novel agent-based induction therapy and ASCT. PET/CT contributed to a more careful definition of CR, in particular after ASCT, and could be usefully incorporated into the algorithm to evaluate the depth of response in young MM patients. Disclosures: No relevant conflicts of interest to declare.

Introduction sFLC assay is an important advance in the diagnosis and monitoring of MM, however data on prognostic significance are still limited. Methods We performed a retrospective analysis aimed to investigate the role of sFLC assay as predictor of outcomes in newly diagnosed MM patients (pts) treated up-front with bortezomib based regimens. sFLC assay (Freelite; The Binding Site, Birmingham, UK) was performed by BN II nephelometer (Date Behring, Deerfield, IL, USA). sFLC-k, sFLC-l and sFLC k/l ratio were serially measured at baseline, during treatment and follow-up. sFLC k/l ratios were classified as normal (0.26-1.65) or abnormal (1.65) according to the IMWG criteria. An involved sFLC level >=100 mg/L, defined by the IMWG criteria as the level to identify a sFLC evaluable disease, was categorized as high. Results We analyzed 110 pts who received first-line bortezomib-based treatments: 67% incorporated into autotransplantation and 33% combined with conventional chemoterapy. The median age was 63 years, 47 pts (43%) were female and 63 (57%) were male. Fifty-eight pts (53%) had IgG heavy chains, 25 (23%) IgA, 1 (1%) IgM and 1 (1%) IgD; 23 pts (21%) had light chain only disease, and 2 pts (2%) had nonsecretory MM. Overall, the involved light chain was kappa in 69 pts (64%), lambda in 36 (33%) and both in 2 (2%), whereas 3 pts (3%) had no detectable light chains. An abnormal sFLC k/l ratio was detected in 91 pts (83%) at baseline, whereas 76 pts (69%) had an involved sFLC >=100 mg/L. The median involved k and l concentrations were 720 and 479 mg/L, respectively. Baseline sFLC >=100 mg/L correlated with higher frequency of Bence Jones isotype (p=0.041), higher beta-2-microglobulin (b2M) (p=0.011), lower hemoglobin concentration (p=0.003) and higher frequency of del(13q) (p=0.016). No correlation was found between high baseline sFLC and other parameters including ISS stage, LDH, bone marrow infiltration, and presence of t(4;14) or del(17p). IMWG response was: 43% stringent complete response (sCR), 11% complete response (CR), 18% very good partial response (VGPR) and 15% partial response (PR). Overall, 83 pts (75%) achieved a normalization of sFLC k/l ratio during treatment. With a median follow-up of 26 months (mos), 36 pts progressed and 17 died. The median time to progression (TTP), progression free survival (PFS) and overall survival (OS) were 46, 46 and 75 mos, respectively. In comparison with a baseline sFLC =100 mg/L was associated with a reduced rate of sCR/CR (71% vs 48%, p=0.028), a lower probability to normalize sFLC k/l ratio (94% vs 67%, p=0.002) and a shorter median TTP (not reached vs 36 mos, p=0.047) and PFS (not reached vs 35 mos, p=0.034), whereas the OS was similar in the two groups (65 vs 75 mos, p=0.16). By the opposite, pts who achieved a normalization of sFLC k/l ratio during treatment had an extended TTP (53 vs 20 mos, p=100 mg/L at relapse was associated with earlier start of salvage therapy, compared with sFLC =100 mg/L (p=0.047) as variables independently associated with a reduced probability to normalize sFLC k/l ratio. By Cox regression analysis, the normalization of sFLC k/l ratio was an independent factor predicting for extended TTP and PFS (p=0.022 and p=0.001) together with ISS 1-2 (p=0.042 and p=0.007). Conclusions High sFLC at baseline was associated with more aggressive disease characterized by a lower probability to achieve sCR/CR and shorter TTP and PFS. Moreover, high sFLC at relapse predicted for short-lasting asymptomatic phase. By opposite, the achievement of normal sFLC k/l ratio during treatment resulted a considerable prognostic indicator of longer TTP and PFS. Disclosures: Tacchetti: Janssen: Honoraria; Celgene: Honoraria. Zamagni:Janssen-Cilag: Honoraria; Celgene: Honoraria. Brioli:Celgene: Honoraria. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; Ariad: Consultancy. 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.

INTRODUCTION. Although remarkable advances have been reported in Multiple Myeloma (MM) therapy, mainly due to the introduction of novel agents, the disease remains incurable in most of the patients. The iperactivation of self-renewal mechanisms, like Hedgehog (Hh) pathway, which controls the refuel of the tumor clone, might be critical to disease recurrence. Whilst several studies suggestthatHh pathway is activated in the putative CD138- Myeloma Propagating Cells (MPCs), it is likely that also terminally differentiated CD138+ plasma cells might contribute to drug resistance, by reverting to an immature phenotype. AIM. In order to dissect the role played by Hh pathway in different MM cells compartments, and to evaluate the impact of Hh pathway expression on patientsÕ clinical outcomes, a high-throughput molecular characterization was employed to explore the transcriptomic and genomic profiles in both CD138+ plasma cells and CD138-19+ B cells progenitors obtained from newly diagnosed MM patients. PATIENTS AND METHODS. The study included a cohort of 126 patients, homogenously treated with bortezomib-based regimens and ASCT, who were randomly included in a training set and a test set. For each patient, the CD138+ plasma cell fraction was isolated by immunomagnetic beads method; CD19+ B cells were isolated in 18 patients. Gene expression profiling (GEP) (HG U133 Plus 2.0 chip) and genomic analysis (SNP 6.0 chip) were performed on Affymetrix platform. dChip analysis software was used to perform GEP clustering. Expression data were analyzed by Ingenuity Pathway Analysis software and were validated by Western Blot assays. Copy number analysis was carried out using Nexus Copy Number software. RESULTS. The expression of Hh pathway genes resulted deregulated in both CD138+ and CD19+ cells, as compared to their normal counterparts. By unsupervised hierarchical clustering, an Hh signature of 10 genes - SHH, IHH, DHH, SMO, PTCH1, PTCH2, SUFU, GLI1, GLI2 and GLI3 - was identified, and was able to significantly cluster patients in two subgroups: cluster 1 included 39 patients while 37 were included in cluster 2. Clustering robustness was validated in an independent cohort of 50 patients (test set), of whom 31 were assigned to cluster 1 and 19 to cluster 2. An overall significant activation of Hh pathway was shown in cluster 2, as compared to cluster 1. Of note, the Hh pathway was down regulated in CD19+ B cells obtained from patients included in cluster 2, while it was overexpressed in cluster 1 patients. Western blots on both cell fractions confirmed this opposite Hh genes behavior. Peculiar genomic and transcriptomic profiles characterized patients included in clusters 1 and 2: indeed, a higher genomic instability (e.g. higher frequencies of both t(4;14) and del(17p)) was demonstrated in CD138+ plasma cells from cluster 2 patients and, at least 5 known tumor suppressor genes, such as RB1, BRCA2, PDX1, FOXO1 and TP53 were included in deleted regions. Conversely, cluster 1 patients were mainly characterized by hyperdiploid karyotypes. The more aggressive phenotype of cluster 2 patients was confirmed by an overall deregulation of cell adhesion processes (CD44, LIMS1, COL4A2, CTGF, COL1A1, FN1), increased proliferation (MYCBP, IL22, SDPR, SOX2, SOX6) and impaired DNA repair mechanisms (SP1, SMARCD3, FOXA3). Hh pathway activation significantly influenced patientsÕ outcome, since those included in cluster 2 had a shorter PFS and OS compared to cluster 1. In fact, the 5-year PFS estimates were 31% vs 56% (p=0.0062), whereas the OS probabilities were 66% and 83%, respectively (p=0.0071) (Fig.1,2). Of note, both hazard ratios for PFS and OS were doubled in patients included in cluster 2, as compared to patients included in cluster 1. Finally, multivariate analyses confirmed that being included in cluster 2 was an independent prognostic factor for both PFS and OS, along with del(17p) and ISS 3 (Tab. 1). CONCLUSION. Sorts of Òying -yang Ó effect of Hh pathway between mature CD138+ plasma cells and immature CD138-CD19+ MPCs could be hypothesized, where two alternate Hh-driven subtypes of MM at diagnosis correlated well with patientsÕ outcomes. Stratification of patients according to their molecular background might help the fine-tuning of future clinical studies. Supported by Regione-Universita 2010-12 (L. Bolondi), FP7 NGS-PTL project. Disclosures Zamagni: Celgene Corporation: Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Martinelli:AMGEN: Consultancy; BMS: Consultancy, Speakers Bureau; Ariad: Consultancy; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy; ROCHE: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria.