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37th European Photovoltaic Solar Energy Conference and Exhibition; 2038-2041, SocialRES aims at fostering energy democracy through social innovations defined as cooperatives, aggregators of renewable energy and crowdfunding platforms. The photovoltaic technology is one of the most promising technology in terms of social acceptance since it can be adapted to a variety of surfaces in buildings [1] and can offer a competitive source for the electricity supply almost everywhere nowadays [2]. PV is therefore often included among the technologies to be financed through energy cooperatives and crowdfunding campaigns. Moreover, as decentralized source of renewable electricity, it is utilized in Peer to Peer (P2P) virtual platforms implemented by aggregators as a concrete alternative to the traditional utilities based on power plants supplied by fossil fuels. Small - scale decentralised PV systems can be considered as the utilities of the future, when managed by aggregators as Virtual Power Plants (VPPs). They will therefore represent a fundamental piece in the path towards energy democracy. In order to make this sustainable future possible, having in mind the urgency generated by the climate change, a disrupted shift is needed in terms of implementation of social innovations for the energy sector. SocialRES aims to devise effective ways of increasing social innovation leading to greater social acceptability of renewable energy systems. This is done by a better understanding of support structures for successful social innovations in the renewable energy sector such as renewable energy cooperatives, aggregators and crowdfunding platforms. These businesses facilitate consumers to take an active role in the energy sector. Through research excellence and cocreation of knowledge, SocialRES will develop socially innovative and inclusive strategies for the energy system of the future. SocialRES will supplement the existing fragmented data on social innovations with new understandings from businesses, end-users and stakeholders to provide a comprehensive evidence base for policy design. Innovative techniques are employed such as a Peer to Peer (P2P) crowd-investing for renewable energy sources projects, P2P lending and P2P virtual photovoltaic electricity platforms for aggregators. Within the SocialRES project, an innovative P2P photovoltaic virtual platform will be developed as a pilot software application in off-line mode and will facilitate the understanding about existing barriers within current electricity markets and policies. Experience will be accumulated related to the main issues with the common access for energy trades between different actors on the market: prosumers, consumers, balancing responsible party and distributed photovoltaic generators. SocialRES is a research and innovation project funded by the European Commission.

Background Diffusion‐weighted whole‐body MRI (DW‐MRI) is increasingly used in the management of multiple myeloma (MM) patients, but data regarding the prognostic role of DW‐MRI imaging response after treatment are lacking. The Myeloma Response Assessment and Diagnosis System (MY‐RADS) imaging recommendations recently proposed the criteria for response assessment category (RAC) with a 5‐point scale in order to standardize response assessment after therapy, but this score still needs to be validated. Methods We investigated the prognostic role of RAC criteria in 64 newly diagnosed MM patients after autologous stem cell transplantation (ASCT), and we combined the results of MY‐RADS with those of minimal residual disease (MRD) assessment by multiparametric flow cytometry (MFC). Results Superior post‐ASCT PFS and OS were observed in patients with complete imaging response (RAC1), with respect to patients with imaging residual disease (RAC≥2): median PFS not reached (NR) versus 26.5 months, p = 0.0047, HR 0.28 (95% CI: 0.12–0.68); 3‐year post‐ASCT OS 92% versus 69% for RAC1 versus RAC ≥2, respectively, p = 0.047, HR 0.24 (95% CI: 0.06–0.99). Combining MRD and imaging improved prediction of outcome, with double‐negative and double‐positive features defining groups with excellent and dismal PFS, respectively (PFS NR vs. 10.6 months); p = 0.001, HR 0.07 (95%CI: 0.01–0.36). Conclusion The present study supports the applicability of MY‐RADS recommendations after ASCT; RAC criteria were able to independently stratify patients and to better predict their prognosis and the combined use of DW‐MRI with MFC allowed a more precise evaluation of MRD., The present study supports both the applicability and the clinical usefulness of the proposed Myeloma Response Assessment and Diagnosis System (MY‐RADS) recommendations applied to DW‐MRI imaging obtained after first‐line treatment of MM including ASCT. MY‐RADS RAC criteria were able to independently stratify patients and to better predict their outcome and their prognosis. DW‐MRI proved to be a powerful tool for the assessment of residual bone disease by functional imaging: it complemented bone marrow flow cytometry and may, therefore, represent a step forward in the clinical management of the increasing number of MM patients achieving CR with the novel treatment approaches.

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19-75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.

Background sustained MRD negativity is emerging as a surrogate biomarker of patients (pts)’ outcome in clinical trials. We implemented this tool in our clinical practice and we analyzed outcome according to sustained MRD negativity in MM pts treated with autologous stem cell transplantation (ASCT) at our Institution. Methods We retrospectively analyzed the outcome of 77 newly diagnosed MM pts (median age 61 years) diagnosed between January 2015 to December 2019 in ≥ VGPR after ASCT. Bone marrow samples were collected for MRD by 8-color FCM (Sn 10-5) at day +100 after ASCT, before maintenance. Sustained 1 year MRD negativity was also evaluated and the prognostic impact of MRD status on PFS and OS was analyzed. Results out of 77 pts, 28 (36%) were ISS stage 3 and 18 (23%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 51, VRD 5, Dara-VRD 5, KRD 14, KCD 2. Single ASCT with MEL200 conditioning was performed in 49 pts (64%), whereas 28 pts (36%) received double ASCT. Subsequent maintenance was performed with lenalidomide (70), daratumumab-lenalidomide (5), carfilzomib-lenalidomide (2). Response rates were VGPR 26%, CR 61% and sCR 13%. MRD before maintenance was positive in 20 pts (26%) and negative in 57 (74%). Sustained MRD negativity lasting ≥ 1 year was documented in 49 pts (64%), whereas early loss of MRD negative status was observed in 8 (10%) of cases. After a median follow up of 40.2 months, PFS was significantly longer in pts with sustained MRD negativity (≥1 year) compared to MRD positive patients before maintenance: median NR vs 41.4 months, p 0.0002, HR 0.17 (0.044-0.65). The worst PFS (24.7 months) was observed in pts with early loss of MRD negativity ( Conclusion we confirm the predictive value of MRD assessment after ASCT and therefore the importance of achieving sustained MRD negativity regardless of different treatment strategies. Moreover, the detection of early loss of MRD negativity can help the physician to identify pts with particularly poor prognosis

© The Author(s) 2021., This study reports on 382 COVID-19 patients having undergone allogeneic (n = 236) or autologous (n = 146) hematopoietic cell transplantation (HCT) reported to the European Society for Blood and Marrow Transplantation (EBMT) or to the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH). The median age was 54.1 years (1.0–80.3) for allogeneic, and 60.6 years (7.7–81.6) for autologous HCT patients. The median time from HCT to COVID-19 was 15.8 months (0.2–292.7) in allogeneic and 24.6 months (−0.9 to 350.3) in autologous recipients. 83.5% developed lower respiratory tract disease and 22.5% were admitted to an ICU. Overall survival at 6 weeks from diagnosis was 77.9% and 72.1% in allogeneic and autologous recipients, respectively. Children had a survival of 93.4%. In multivariate analysis, older age (p = 0.02), need for ICU (p < 0.0001) and moderate/high immunodeficiency index (p = 0.04) increased the risk while better performance status (p = 0.001) decreased the risk for mortality. Other factors such as underlying diagnosis, time from HCT, GVHD, or ongoing immunosuppression did not significantly impact overall survival. We conclude that HCT patients are at high risk of developing LRTD, require admission to ICU, and have increased mortality in COVID-19., JA acknowledges the support of the UK NIHR Imperial College Biomedical Research Centre.

COVID-19 is a severe infectious complication in patients with underlying medical conditions such as having undergone hematopoietic stem cell transplantation (HCT). This prospective survey reports outcome on 272 COVID-19 patients from 19 countries having undergone allogeneic (n = 175) or autologous (n = 97) HCT reported to the EBMT registry or to the GETH. All patients had the diagnosis of SARS-CoV-2 documented by PCR. Patients were included in this analysis if COVID-19 diagnosis was before April 10, 2020. The overall survival was estimate by using the Kaplan Meier methods, considering the death due to any cause as an event and the time from COVID-19 infection to the latest follow-up as survival time; difference between groups were tested by the log-rank test. Univariate and multivariate risk factor analysis for overall survival were performed with the Cox regression model. The median age was 54.4 years (1.0 - 80.3) for allogeneic and 60.9 years (7.7 - 73.4) for autologous HCT patients. 20 patients were children (< 18 years of age; median age 11.3 (1.0 - 16.9)). The median time from HCT to diagnosis of COVID-19 was 13.7 months (0.2 - 254.3) in allogeneic and 25.0 months (-0.9 - 350.3) in autologous recipients. Lower respiratory tract disease (LRTD) developed in 84.8% and 21.5% were admitted to an intensive care unit (ICU). At the time of analysis, 68/238 (28.6%) patients had died (47/155 allogeneic patients; 21/83 autologous patients). No follow-up had been received on 34 patients. The median time from infection to death was 19 days (0-102). Five patients were reported to have other primary causes of death than COVID-19. Of the patients reported to be alive, the median follow-up was 44 days. 144 (84.7%) patients (93 allogeneic; 51 autologous) had virologic resolution of the COVID-19 infection having at least one negative PCR. 26 patients were alive and known to be still COVID-19 positive (15 allogeneic; 11 autologous). For 34 patients the resolution status was unknown. Factors influencing the likelihood of resolution in multivariate analysis were underlying diagnosis (p=.01) and longer time from transplant to diagnosis of COVID-19 (p=.035). Overall survival at 6 weeks from COVID-19 diagnosis was 76.8% and 83.8% in allogeneic and autologous HCT recipients (p =ns), respectively (figure 1). Children (n=20) tended to do better with a 6-week survival of 95.0% although the difference was not significantly different (p =.12). In multivariate analysis of the total population older age (HR 1.26; 95% CI 1.05 - 1.51; p = .01) increased the risk and better performance status decreased the risk for fatal outcome (HR 0.79; 95% CI 0.69 - 0.90; p = .0003). The same factors had significant impact on overall survival in allogeneic HCT recipients (age HR 1.28; 95% CI 1.05 - 1.55; p=.01; performance status HR 0.79; 95% CI 0.68 - 0.92); p=.002) while only age impacted survival among autologous HCT patients (data not shown). Other transplant factors such as underlying diagnosis, time from HCT to diagnosis of COVID-19, graft-vs-host disease, or ongoing immunosuppression did not have a significant impact on overall survival. We conclude that HCT patients are at an increased risk compared to the general population to develop LRTD, require admission to ICU, and have increased mortality in COVID-19. Figure 1 Disclosures Duarte: Incyte Corporation: Other: Has received speaker and advisor fees. Kwon:Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Mielke:Novartis: Honoraria, Other: received via my institution, Speakers Bureau; Celgene/BMS: Honoraria, Other: received via my institution , Speakers Bureau; Bellicum: Honoraria, Other: received via my institution, Speakers Bureau; Kite/Gilead: Honoraria, Other: received via my institution , Speakers Bureau; Miltenyi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: received via my institution , Speakers Bureau; KIADIS Pharma: Honoraria, Other: received via my institution , Speakers Bureau; DNA Prime: Honoraria, Other: received via my institution , Speakers Bureau. López Jiménez:MSD: Speakers Bureau; Roche: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Abbvie: Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau.

Autologous stem cell transplantation (ASCT) is feasible and effective in selected older patients with Multiple Myeloma, but specific criteria for evaluating ASCT eligibility in elderly patients are lacking. We evaluated 131 patients aged 65-75 considered for ASCT at our center: The Charlson Comorbidity Index (CCI), Hematopoietic cell transplantation comorbidity index (HCT-CI) and IMWG frailty score were obtained at diagnosis, but the intensity of treatment was left to physician's choice. The scores and age's impact on outcome was analyzed: 85 patients were judged transplant eligible, whereas 46 patients received a less intensive treatment (median follow up 27 months). No patients classified as frail had been considered eligible to ASCT with a worse outcome compared to fit and unfit patients (median PFS (progression free survival): 7.9 vs 32.9 and 29.6 months; P < .001). PFS was superior in the ASCT group (35.6 vs 19.9 months, P .013). In the ASCT group, PFS was better in patients aged 65-69 years than in patients ≥70 (51.5 vs 27.7 months, P.004). Indeed, in unfit patients aged ≥70 the PFS of the ASCT group was comparable to NO ASCT group (18 vs 27 months, P = .33) whereas in unfit patients aged 65-69 PFS was superior in the ASCT group: 43.3 vs 18.4 months, P .01. ISS III and impaired functional status independently affected PFS in a multivariate analysis (P .011 and P .006). While CCI and HCT-CI did not predict different outcome in ASCT patients, the IMWG frailty score would be of help in identifying unfit patients aged 70-75, whose outcome with ASCT selected by clinical judgment was no better than with less intensive treatments.

BACKGROUND: Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma (MM). However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed-duration therapies for relapsed MM. METHODS: In this open-label, phase III study, we randomized MM patients at first relapse to receive either 9 cycles of bortezomib-cyclophosphamide-dexamethasone (VCD) or lenalidomide-cyclophosphamide-dexamethasone (RCD). The primary endpoint was the achievement of a very good partial response (VGPR) or better at six weeks after 9 treatment cycles. FINDINGS: From March 2011 to February 2015, 155 patients were randomized. The primary endpoint was met by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (p=0·70). Median progression-free survival (PFS) was 16·3 (95% CI: 12·1-22·4) with VCD and 18·6 months (95% CI: 14·7-25.5) with RCD, and the 2-year overall survival (OS) was 75% (95% CI: 66%-86%) and 74% (95% CI: 64%-85%), respectively. By subgroup analysis, no differences in PFS were observed in bortezomib and lenalidomide- naive patients, nor in patients who received a bortezomib-based regimen in first line. Adverse events were consistent with the well-established safety profiles of bortezomib and lenalidomide. INTERPRETATION: Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse. Nevertheless, the two drugs have a different safety profile. Clinical Trial Number: This study is registered as EUDRACT 2010- 021557-40. Funding Statement: Associazione Italiana per la Ricerca sul Cancro - AIRC grant IG-10419; Associazione Italiana contro le Leucemie-Linfomi e Mieloma (AIL); Fondazione Adiuvare, Lugano. Declaration of Interests: VM has received honoraria and travel grants from Janssen, Celgene, Bristol-Myers Squibb, Amgen. AC has not competing interests. MG has received honoraria and travel grants from Janssen, Celgene, Bristol-Myers Squibb. IA has not competing interests. SP has not competing interests. CCarniti SP has not competing interests. FP has received honoraria and travel grants from Janssen and Celgene. FG has not competing interests. RZ has not competing interests. SS has not competing interests. MM has not competing interests. AN has not competing interests. CCrippa has not competing interests. AMC has received honoraria and travel grants from Janssen and Celgene. LB has not competing interests. PC has honoraria from advisory board and speaking fees from Celgene, Janssen, Novartis, Roche, Takeda, Sanofi, Abbvie, Amgen, Gilead, and Klowa Kirin. Ethics Approval Statement: The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Ethics committees at each study site reviewed and approved the protocol.

This paper describes a research investigation on a project led by two libraries, Hamilton Public Library and McMaster University Library, in Hamilton, Canada, concerning the use of proximity-based technologies to share digital stories about a city’s culture. Proximity-based technology systems, such as iBeacons, allow users to receive information automatically when they are close to a physical spot. The project involved the setup of iBeacons that disseminated digital stories pertaining to Gore Park – a prominent historical park in the heart of downtown Hamilton. To test the viability of using iBeacon technologies to raise interest in a city and promote appreciation for a city’s cultural heritage, a pilot study was conducted. The study included one-on-one interviews and a short survey with 50 participants from the general public immediately after these participants used an iBeacon app to experience digital stories about Gore Park. Findings suggest iBeacons are viable tools to share city cultural heritage stories that yield improved perceptions of a city and greater appreciation for a city’s culture and history. Participants were appreciative of the digital stories and the iBeacon app. All participants mentioned that they learned something new about the city and that the app was very informative. Findings indicate that individual differences are important and can affect not only the acceptance and use of an iBeacon digital storytelling app, but also the extent to which the app can promote interest in a city and appreciation for a city’s cultural heritage.

Introduction: The role of minimal residual disease (MRD) in Multiple Myeloma (MM) as a surrogate biomarker of patients' outcome, as well as the prognostic information of functional imaging response after treatment have been established in recent years. Furthermore, the predictive relevance of sustained MRD negativity assessed by marrow and imaging techniques and its association with an excellent outcome is emerging in clinical trials. Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used in the management of MM patients, but data regarding the predictive role of sustained DW-MRI response after treatment are lacking. The Myeloma Response Assessment and Diagnosis System (MY-RADS) recommendations have established criteria for Response Assessment Category (RAC) (Messiou C et al, Radiology 2019) with a 5 point scale defining the probability of complete imaging response (i.e. RAC 1) or progressive disease after treatment (i.e. RAC 5). We implemented the RAC criteria in our clinical practice and DW-MRI at 1-year in MM patients treated with autologous stem cell transplantation (ASCT) followed by maintenance therapy. Patients and methods: We retrospectively analyzed the outcome of 57 newly diagnosed MM patients (median age 61 years) diagnosed at our institution from January 2015 to December 2019 receiving maintenance therapy after ASCT. Patients underwent DW-MRI evaluation according to MY-RADS criteria at day +100 after ASCT, before maintenance, and after 1 year with the aim of monitoring imaging residual disease. Bone marrow samples were collected for MRD assessment by 8-color FCM (sensitivity 10-5) at day +100 after ASCT, before maintenance, and after 1 year. We focused on sustained 1-year DW-MRI negativity evaluated according to RAC response, and its potential predictive role at that timepoint on progression free survival (PFS) and overall survival (OS). In patients with available 1-year MRD evaluations, concordance between 1-year MRD and DW-MRI results was calculated and the level of agreement was expressed by Cohen's kappa statistics. Results: Out of 57 patients, 23 (40%) were ISS stage 3 and 14 (25%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 42, VRD 5, Dara-VRD 6, KRD 3, KCD 1. Single ASCT with MEL200 conditioning was performed in 33 patients (58%), whereas 24 patients (42%) received double ASCT. Subsequent maintenance was performed with lenalidomide (49 patients, 86%) or daratumumab-lenalidomide (8 patients, 14%). Response rates after ASCT were PR 9%, VGPR 23%, CR 51% and sCR 17%. According to MY-RADS, a complete imaging response (RAC1) at day +100 after ASCT was observed in 34 patients (60%). Sustained 1 year complete imaging response during maintenance therapy was observed in 43 patients (75%). Some residual disease was identified at that timepoint in 14 patients (25%) [RAC 2: 6 (11%), RAC > 2: 8 (14%)]. After a median follow up of 36 months, PFS and OS were significantly longer in patients with sustained 1-year imaging negativity, compared to patients with imaging residual disease (RAC 1 vs RAC ≥2): median PFS 56 vs 24,1 months, p Conclusion: Our real-life data analysis confirms the predictive value of imaging residual disease assessment with DW-MRI after ASCT and highlights the importance of achieving sustained imaging MRD negativity during maintenance therapy regardless of different treatment strategies. Moreover, given the high rates of CR seen in patients with MM with novel effective treatment combinations, the detection of residual disease with the combined evaluation of marrow and functional imaging techniques during maintenance therapy can help the physician to identify patients with increased risk of early relapse and particularly poor prognosis. Our preliminary data regarding the high concordance observed between DW-MRI and MRD results during maintenance therapy suggest that DW-MRI could represent a reliable non-invasive technique to monitor residual disease. Disclosures Belotti: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Ribolla: Janssen: Membership on an entity's Board of Directors or advisory committees. Cancelli: Amgen: Membership on an entity's Board of Directors or advisory committees. Roccaro: Amgen, Celgene, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZeneca,: Research Funding; Associazione Italiana per la Ricerca sul Cancro (AIRC): Research Funding; European Hematology Association: Research Funding; Fondazione Regionale per la Ricerca Biomedica (FRRB), Transcan-2 ERA-NET: Research Funding. Rossi: Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

SocialRES aims to devise effective ways of increasing social innovation leading to greater social acceptability of renewable energy systems. This is done by a better understanding of support structures for successful social innovations in the renewable energy sector such as Renewable Energy Cooperatives, Aggregators and Crowdfunding Platforms. These businesses facilitate consumers to take an active role in the electricity system. Through research excellence and co-creation of knowledge, SocialRES will develop socially innovative and inclusive strategies for the energy system of the future. SocialRES will supplement the existing fragmented data on social innovations with new understandings from businesses, end-users and stakeholders to provide a comprehensive evidence base for policy design. Innovative techniques will be employed such as a Peer to Peer (P2P) crowd-investing for renewable energy sources projects, P2P lending and P2P virtual photovoltaic electricity platform for aggregators. The innovative P2P photovoltaic virtual platform will be developed as a pilot software application in off-line mode and will facilitate the understanding about existing barriers within current electricity markets and policies. Experience will therefore be accumulated related to the main issues with the common access for energy trades between different actors on the market: prosumers, consumers, balancing responsible party and distributed photovoltaic generators.

Maintenance demonstrated to improve survival in newly diagnosed multiple myeloma (NDMM) patients and the achievement of complete response (CR) is a strong predictor of survival. Nevertheless, the role of maintenance according to response after induction/consolidation has not been investigated so far. To evaluate the impact of maintenance according to response, we pooled together and retrospectively analyzed data from 955 NDMM patients enrolled in two trials (GIMEMA-MM-03-05 and RV-MM-PI-209). Primary endpoints were progression-free survival (PFS)1, PFS2 and overall survival (OS) of CR patients randomized to maintenance and no maintenance. Secondary endpoints were PFS1, PFS2 and OS in very good partial response/partial response (VGPR/PR) patients. Overall, 213 patients obtained CR after induction/consolidation, 118 received maintenance and 95 no maintenance. In patients achieving CR, maintenance significantly improved PFS1 (HR 0.50, P

Complete response (CR) is associated with better outcome in patients with multiple myeloma (MM) treated with autologous transplant even though the progression-free survival (PFS) can be very variable among patients with good response. No simple and reliable prognostic scoring system, able to predict the duration of response, are so far available. Aim of this study was to identify any correlation between baseline clinical findings, response after transplant and the length of PFS, and thus develop a prognostic model. The new prognostic model was developed in a learning cohort of 549 patients with MM transplanted in five Italian hospitals. The prognostic value of this new score was confirmed in a validation cohort of 276 distinct patients with MM transplanted in two different Italian hospital. Univariate and multivariate analyses were performed using Cox models. The most important independent baseline predictor of transplant outcome, together with response after transplant, was International Staging System (ISS). We thus incorporated response to transplant and baseline ISS in a new scoring system, named response-adjusted international scoring system (RaISS), that was able to classify patients in three risk groups (low, intermediate, high) with different probabilities of progression after transplant (median PFS 35.9-15.4 months). The prognostic value of this new score was confirmed in the validation cohort. In conclusion, RaISS is a new simple and easily available scoring system that, accurately defining the risk of progression, can allow to identify patients who could deserve further treatment after transplant (consolidation, maintenance).

Evidence of long-term response to lenalidomide in heavily pretreated patients with multiple myeloma is lacking. This study sought to assess whether long-term responders exist, long-term responders' characteristics, and predictive factors of a long-term response. One hundred and four patients with multiple myeloma treated with lenalidomide and dexamethasone after ≥2 therapy lines (median, 3) were analyzed. Long-term response was defined as at least a partial response (≥PR) lasting ≥12 months. The overall response rate was 73%, and 80.3% of the responses were achieved within 5 months. The median response was 14.3 months. Patients evaluable for long-term response numbered 87, and a total of 47% were long-term responders. Compared to non-long-term responders, long-term responders had better overall survival, less light-chain multiple myeloma, and higher incidence of t(11;14). Previous allogeneic transplant (alloSCT) and the response quality predicted a long-term response. In conclusion, patients treated with lenalidomide can become long-term responders; alloSCT and response quality predict long-term response.

Purpose In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens. Patients and Methods A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment. Results Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, −3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, −1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded. Conclusion In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.

Introduction: Autologous stem cell transplantation (ASCT) has proven effective in Multiple Myeloma (MM) patients (pts) aged 65. With the increase of treatment options, several geriatric assessment tools have been proposed to help physicians in selecting treatment of appropriate intensity. However specific criteria for evaluating ASCT eligibility in elderly MM pts have been seldom investigated.Patients and Methods: From January 2013 to December 2017 131 consecutive newly diagnosed symptomatic MM pts aged 65-75 (M/F: 66/65) were considered for ASCT at our center according to physician's clinical judgement. The variables included in Charlson Comorbidity Index (CCI), Hematopoietic cell transplantation comorbidity index (HCT-CI), and International Myeloma Working Group (IMWG) frailty score were not considered for selection but were retrieved for this study and pts were classified accordingly. Of note, ADL and IADL were referred to pts status prior the occurrence of MM related symptoms. The impact of age and the predictive role of the above mentioned scores on progression-free survival (PFS) of pts selected or not for ASCT was analyzed. Pts characteristics are shown in Table 1. Results: Of 131 pts, 85 (65%) were judged transplant eligible (ASCT ITT arm) by the clinician and received bortezomib-based induction (VTD 94%, VD 5%, VCD 1%); 72 of them (85%) actually underwent ASCT (70% single, 30% double) with melphalan conditioning 200 mg/sqm in 68% of cases. The 46 pts considered ineligible to ASCT received a less intensive first line treatment (89% VMP, 4% Daratumumab-VMP, 2% MP, 5% steroids/palliation). Complete remission (CR) after the first ASCT was higher in the ASCT (ITT) vs the NO ASCT group (43,5% vs 26%, respectively; p 0.048), whereas ORR and ³VGPR rates were comparable (83% vs 74% and 76,4% vs 61%, respectively). Transplant related mortality (TRM) was 0%. 2 year death rate was 13% in the ASCT (ITT) arm and was due to PD in 91% of cases (the latter 9% concerns a cardiac arrest secondary to aspiration pneumonia in a pt in VGPR 3 months after first ASCT). After a median follow-up of 27 months, PFS was 35,6 in the ASCT (ITT) group vs 19,9 months in NO ASCT pts, respectively; p 0,013, HR 0,42 (95% CI: 0,25-0,71). HCT-CI was ≥2 in 87% of pts overall. PFS was better in pts with HCT-CI 0-1 compared to HCT≥2 (NR vs 27,3 months; p 0,025, HR 0,45, 95% CI 0,23-0,91) and also in pts with HCT-CI ³2 undergoing ASCT (ITT) than in NO ASCT pts: median 34 vs 19,9 months, p 0,008 (HR 0,5, 95%CI 0,30-0,84). CCI was 0-3 in 78% of pts. Their outcome according was similar to pts with CCI >3 but ASCT performed better than NO ASCT also in the few (median PFS 51,4 vs 16,9 months; p 0,04, HR 0,37, 95%CI 0,15-0,95). IMWG frailty score was more useful. No pts classified as FRAIL had been considered eligible to ASCT by clinical decision with a significantly worse outcome compared to FIT and UNFIT pts (median PFS: 7,9 months vs 32,9 and 29,6; FIT vs FRAIL: p < 0.0001, HR 0,02, 95%CI 0,004-0,008; UNFIT vs FRAIL: p < 0,001, HR 0,03 95%CI 0,007-0,12). Unlike HCT-CI and CCI, the distribution of patients according to IMWG score was more balanced both overall and between the ASCT (ITT) and NO ASCT groups, particularly for UNFIT pts. However on the whole no outcome differences were observed between FIT and UNFIT pts. PFS was better in FIT&UNFIT pts in the ASCT (ITT) group than in the NO ASCT group: median 35,6 months vs 25,8 months; p 0,04, HR 0,54, 95%CI 0,31-0,97. However, in the ASCT (ITT) group, the age group 65-69 years fared better than pts ³70 years (51,5 vs 27,7 months, p 0,0037; HR 0.34, 95% CI 0.17-0.7). Indeed, in IMWG UNFIT patients aged ³70, the PFS of the ASCT (ITT) group was comparable to NO ASCT group (18 vs 27 months, p 0,33) whereas in UNFIT pts aged 65-69, PFS was superior in pts treated more intensively by physician choice: 43,3 months in ASCT (ITT) arm vs 18,4 months in NO ASCT (p 0.01, HR 0.03; 95%CI 0.003-0.24). Conclusion: In an unselected series of elderly MM pts aged 65-75 and undergoing ASCT according to clinical judgement the outcome of ASCT pts was better than those of NO ASCT. CCI and HCT-CI score proved of little help for better identifying the best candidates to ASCT. Conversely the IMWG frailty score would be of help in identifying the category of UNFIT pts aged 70-75 whose outcome with ASCT selected by clinical judgement was no better than with less intensive treatments. Table 1: Disclosures Belotti: Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Cattaneo:GILEAD: Other: Advisory Board. Rossi:TEVA: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD; SANOFI: Other: ADVISORY BOARD; MUNDIPHARMA: Honoraria; ABBVIE: Other: ADVISORY BOARD; JANNSEN: Other; PFIZER: Other: ADVISORY BOARD; ROCHE: Other: Advisory Board; NOVARTIS: Honoraria; SANDOZ: Honoraria; GILEAD: Other: ADVISORY BOARD; BMS: Honoraria; JAZZ: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD.

Introduction: The phase 3 GIMEMA-MMY-3006 trial comparing bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (MM) provided the first demonstration of increased CR rate, the primary study endpoint, and prolonged PFS with VTD (Cavo M et al, Lancet 2010). However, updating trial results with longer follow-up than earlier reported is needed to assess the effects of treatment interventions on OS and to identify factors predicting for favorable long term outcomes. Aims: We performed a post-hoc analysis of that study to evaluate long term results and construct a prognostic index of survival. Methods: 474 patients were enrolled, 236 randomized to VTD and 238 to TD. Median follow-up for surviving patients was 124 months (IQR: 117-131). Analyses were performed on an intention-to-treat basis. Semi-parametric Cox regression analysis was used to construct the prognostic index. To assess the evolution of prognosis over time, conditional survival CS(t|s) estimate for PFS was calculated as the probability of surviving without progression a further 2 (t) years (yrs) after having already survived s yrs. Results: Estimates of PFS and OS at 10 yrs for the VTD arm were 34% (HR=0.62; 95% CI=0.50-0.77; p Conclusions: With a follow up of 10 yrs, the final analysis of the GYMEMA MMY-3006 trial comparing VTD versus TD showed a persistent PFS benefit translating into extended OS for the VTD arm. A prognostic model based on cytogenetic, ISS stage and achievement of CR, identified three risk groups with statistically different long-term survival probabilities. Both IR and HR groups significantly benefited from VTD. A PFS time of 78 months predicted for long term survival outcomes in the LR and IR groups. Disclosures Tacchetti: Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Zamagni:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Offidani:Celgene: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Montefusco:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Cavo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction. Bortezomib (Bort) and lenalidomide (Len) are standard treatments for relapsed MM, but, so far, a comparative trial between them has never been conducted. We designed a multicenter, open label, phase III study to compare bortezomib/cyclophosphamide/dexamethasone and lenalidomide/cyclophosphamide/dexamethasone in a fixed duration design protocol. The combination of Bort and Len with chemotherapy was devised to improve efficacy and to allow a fixed duration treatment in patients not heavily pretreated. Methods. The primary endpoint was the achievement of very good partial remission (VGPR) or better at six weeks after 9 cycles. The study enrolled patients at first relapse with measurable disease. Patients could have received Bort or Len in their first line, but they should have obtained at least a PR longer than one year, and previous Bort or Len maintenance was an exclusion criteria. Enrollment started on April 2011, and was ended on April 2015. Patients were assigned 1:1 to sc Bort 1.3 mg/ms on days 1, 8, 15, 22, oral dexamethasone (Dex) 20 mg on days 1-2, 8-9, 15-16, 22-23, iv cyclophosphamide (Cyclo) 500 mg/ms on day 1 and 8 in a 35 days cycle (VCD) or to Len 15 mg from day 1 to 21, oral Dex 20 mg on days 1-2, 8-9, 15-16, 22-23, iv Cyclo 500 mg/ms on day 1 and 8 in a 28 days cycle (RCD). Nine courses of therapy without maintenance were planned. Efficacy and safety were assessed at each cycle using the IMWG response criteria for efficacy assessment (Durie et al. Leukemia 2006), and CTCAE v4.0 for safety. Results. One hundred fifty-seven patients were enrolled, 155 were randomized, 77 were assigned to the VCD, and 80 to the RCD arm, respectively. Both arms were well balanced according to the baseline characteristics. Median age was 65 years (range 41-79), and 63 years (range 46-76) for VCD and RCD, respectively. ISS stage was grade I in 36 and 33, grade II in 20 and 28, and grade III in 16 and 15 patients in the VCD and RCD arms, respectively. Previous treatment included Bort in 35 and 42, Len in 7 and 7, Bort- and Len-free chemotherapy in 32 and 29, thalidomide in 35 and 31, and autologous stem cell transplantation in 58 and 63 patients in the VCD and RCD arms, respectively. The primary endpoint, represented by achievement of VGPR or better at 6 weeks after 9 courses, was met by 12 (16%) and 16 (20%) patients in the VCD and RCD arms, respectively (p=0.70). Median progression-free survival (PFS) was 16.3 (range 13.3 - 22.4) and 20.2 (range 14.7 - 26.8) months (p=0.70), and median overall survival (OS) was 31.1 and 36.2 months (p=0.83), in the VCD and RCD arms, respectively. In subgroup analysis, patients that were Bort and Len naïve at enrollment had a PFS of 20.0 (range 12.2 - 31.8) and 20.2 months (range 12.0 - 29.9) (p=0.44), and a median OS of 31.1, and 22.5 months (p=0.72), for the VCD and RCD arms, respectively. Patients that were Bort exposed, but Len naïve at enrollment, had a PFS of 15.6 (range 9.9 - 22.4) and 19.5 months (range 11.1 - 28.6) (p=0.35), and a median OS of 29.2, and 34.7 months (p=0.62), for the VCD and RCD arms, respectively. Adverse events were consistent with the well-established safety profile of Bort and Len, and grade III and IV toxicities were not significantly different between the 2 arms. Conclusions. This is the first head-to-head study comparing fixed duration therapy of Bort and Len in first relapse patients. We show that both drugs are equally effective, in terms of depth of response, PFS, and OS. Despite drug-specific toxicity profiles, incidence of grade III and IV toxicities were not different between the 2 arms. Disclosures Corradini: Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Amgen: Honoraria; Gilead: Honoraria.

ITF2357, an orally effective member of the family of histone deacetylase inhibitors, is a potent inducer of apoptosis and death of multiple myeloma (MM) cells. We performed a phase-II, multiple-dose clinical trial in 19 patients with relapsed or progressive MM to determine the maximum tolerated dose (MTD) of ITF2357 administered twice daily for four consecutive days every week for 4 weeks (i.e., first cycle). The first six patients received 150 mg ITF2357 twice daily. Since two of them experienced a dose-limiting toxicity (DLT) during the first cycle, the subsequent patients received 100 mg ITF2357 twice daily. This was the MTD, as only one DLT occurred. Up to 12 weeks (i.e., three cycles) of treatment were scheduled. Oral dexamethasone was allowed to a maximum weekly amount of 20 mg. Median duration of treatment was 6 weeks, ranging from two (two patients) to 12 weeks (five patients). Four patients suffered from serious adverse events. Three patients experienced grade 3-4 gastro-intestinal toxicity and three had transient electrocardiographic abnormalities. Thrombocytopenia occurred in all but one patient (grade 3-4 in ten patients). At last follow-up, five patients were in stable disease, five had disease progression, and nine had died all of progressive MM. In conclusion, when given at a dose of 100 mg twice daily alone or combined with dexamethasone, ITF2357 proved tolerable but showed a modest clinical benefit in advanced MM.

Background Tailoring treatment intensity is critical in Hodgkin's lymphoma (HL). Ongoing prognostic parameters may be an useful adjunct to pretreatment stratification. We used the kinetics of computed tomography (CT) scan response and residual gallium (Ga)-67 uptake to better stratify risk. Materials and methods Patients received 4–8 adriamycin, bleomycin, vinblastine and dacarbazine courses according to stage. Disease was reassessed evaluating late computed tomography scan response improvement (CTRI) and Ga-67 uptake. Patients received no further treatment, radiotherapy (RT) or additional chemotherapy + RT according to the presence of none (low risk), one (intermediate risk) and both parameters (high risk). Patients with bulky mediastinum received RT anyhow. Results Among 102 assessable patients, 35 showed late CTRI and 9 residual Ga-67 uptake. In 30 patients with bulky mediastinum, the 3-year progression-free survival (PFS) was significantly better when neither parameter was present (100% versus 69%; P = 0.02). In 72 patients without bulky mediastinum, treatment was tailored according to risk assignment. Relapses occurred in 5 of 47 low-risk and 3 of 21 intermediate-risk patients, with no differences between the two groups, and in 3 of 4 high-risk patients. Conclusion This study shows that two on-treatment parameters, late CTRI and residual Ga-67 uptake, can predict PFS in HL and identify patients in which RT can be spared without apparently affecting the outcome.

e46 therapies. Activating mutations of KRAS, NRAS and BRAF have been reported in approximately 23%, 20% and 6% of MM cases. Detection of these actionable mutations currently requires bone marrow (BM) aspirates that are invasive and can yield suboptimal samples. Targeted, ultra-deep sequencing of cfDNA is a promising tool for accessing the tumour genome that has not been studied in MM.We set out to identify actionablemutations andmutational load through cfDNA analysis and compare the results to matched tumourderived DNA.Methods: MM patients (pts) with active disease were identified and consented to have their peripheral blood drawn for analysis. Where possible, matched tumour DNA derived from BM CD138+ selected cells was also obtained and sequenced. cfDNA was extracted from 3-15 mL of plasma using the QIAamp Circulating Nucleic Acid Kit and tagged with sequencing barcodes for subsequent pooling. All exons of KRAS, NRAS, BRAF, PIK3CA and EGFR genes were isolated using a custom hybrid capture panel (IDT xGen Lockdown) and sequenced on an Illumina HiSeq 2000. Reads were aligned to the human genome reference (hg19) using bwa and somatic mutations were detected using muTect. Results: We have collected 39 plasma samples from 35 pts, 10 newly diagnosed and 25 from relapsed pts who had a median of 3 prior lines of therapy (range 1-7). The median yield of cfDNA was 17.4ng/mL of plasma (range: 2.7298) with a trend towards higher yield from pts with ISS stage 3 disease. Somatic mutations in at least 1 of the 5 genes were present in 22 of 35 pts (63%) with mutant allele frequencies ranging from 0.1942%.Mutations in KRAS, NRAS and/or BRAF were identified in 21 pts with some having multiple actionable mutations (Figure 1). Twenty-five samples from 23 pts had matching BM-derived tumour DNA from which 26 coding mutations were detected and all but two were found in the cfDNA (92.3% sensitivity). In addition, 6 mutations (4 BRAF in one patient) were only detected in cfDNA, making for a specificity of 97.1%. Conclusion: Ultra-deep targeted sequencing of cfDNA derived from blood of MM pts is feasible and able to identify tumour-derived mutations with high sensitivity and specificity. cfDNA analysis identified key actionable mutations and thus represents a non-invasive source of tumour DNA that can potentially inform treatment options for pts with MM.

BACKGROUND Patients who have aggressive, refractory or recurrent non-Hodgkin lymphomas (NHLs) that are refractory to first-line anthracycline-containing regimens (ACRs) have a dismal outcome. Achieving complete remission (CR) is essential for a favorable outcome. To improve the CR rate in these patients, the authors designed a new protocol that contained hyperfractionated cyclophosphamide (CTX), high-dose arabinosylcytosine (HiDAC), and high-dose methotrexate (MTX) delivered sequentially in the same cycle and followed by the administration of granulocyte-colony stimulating factor (G-CSF) (HyperCHiDAM Verona 897). METHODS Between February 1998 and May 2002, 28 consecutive adult patients (median age, 44 years) with aggressive NHL (B-lineage in 21%, T-lineage in 7%, and Ki-67 percentage > 50 in 82%) were entered on the protocol after they had failed on ACRs (15 patients with refractory disease, 6 patients with stable disease, 5 patients with recurrent disease, and 2 patients in partial remission). Patients characteristics were as follows: Twenty-two patients had Stage III–IV NHL (78.6%), 19 patients had B symptoms (67.8%), 22 patients had extranodal disease (78.6%), 12 patients had bulky mass (42.8%), 18 patients elevated lactate dehydrogenase levels (66%), and 8 patients had high-intermediate/high International Prognostic Index scores (64.3%). Patients received hyperfractionated CTX (300 mg/m2) and HiDAC (2 g/m2) every 12 hours on Days 2–4 and received high-dose MTX (400 mg/m2 bolus plus 1600 mg/m2 as a 24-hour continuous infusion on Day 1 with folinic rescue), followed by G-CSF. Subsequently, 15 patients underwent autologous stem cell transplantation (SCT), and 4 patients underwent allogeneic SCT. RESULTS A CR was achieved by 18 of 28 patients (64.3%), a partial remission was achieved by 6 patients (21.4%), 4 patients were nonresponders or had progressive disease (14.3%), and there was 1 early toxic death (3.5%). Two of 18 patients developed recurrent disease (11.1%). The median follow-up for all patients was 35 months (range, from 2 months to ≥ 74 months). Among the patients who achieved a continuous CR, the median follow-up was 48 months (range, from ≥ 32 months to ≥ 73 months). At the time of the current report, 13 of 28 patients (46.42%) were event-free. CONCLUSIONS HyperCHiDAM Verona 897 was an effective regimen for patients with aggressive NHL who failed on ACRs, and it allowed patients to undergo subsequent SCT. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODS: We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P

Introduction: Immunoglobulin light chain amyloidosis (AL) may occur in association with a recognizable plasma cell (PC) clone diagnostic for multiple myeloma (MM) both with CRAB symptoms (AL-CRAB) and without them but with more than 10% marrow PCs (AL-PCMM). Prognosis of AL-CRAB and AL-PCMM was significantly poorer than AL in a large retrospective study by the Mayo Clinic (Kourelis et al, JCO 2013). Treatment with autologous stem cell transplantation (ASCT) improved the 5-y overall survival (OS) rates of all the three entities by approximately 40%. Therefore it is debated if patients with AL should receive more MM-oriented treatment including ASCT and if patients with AL-PCMM or AL-CRAB should receive the same treatment as MM patients. Aims: to contribute to this debate we analysed the outcome of patients with amyloidosis treated at our center according to their underlying disease: AL, AL-PMCC and AL-CRAB. Furthermore, we analysed the outcome according to the use of ASCT as part of first line treatment strategy. Methods: Of 53 patients newly diagnosed between Jan 1999 to June 2016 (median age 62 years), 19 (36%) were affected by AL, whereas 23 (43%) presented with AL-PCMM and 11 (21%) with AL-CRAB. Of 53 patients 18 (34%) underwent first line ASCT (21% of AL patients, 35% of AL-PCMM and 55% of AL-CRAB patients), upfront (6) or following induction chemotherapy (12). The 35 patients (66%) who didn't receive ASCT were treated with CyBorD regimen (21), melphalan-dexamethasone (8), VMP (4) or lenalidomide-dexamethasone (2). Risk groups were identified as follows: cTnI >0.1ng/ml and/or ECOG PS ³3: high risk; age ²65 years with normal cTnI levels, ECOG PS 50ml/min: low risk. Intermediate risk patients were defined if not meeting criteria for high or low risk. Mayo Stage classification (Dispenzieri et al, JCO 2004) was also applied to stratify risk categories. MM diagnosis was made according to IMWG criteria. Haematological and organ response (OR), OS and event free survival (EFS: time to 2nd line therapy or death) were analysed. Results: the proportion of high risk patients was 37%, 44% and 18% in AL, AL-PCMM and AL-CRAB, respectively, whereas the proportion of Mayo stage III patients was 47%, 30% and 9% for each subgroup. Median dFLC was similar (150, 150 and 146, respectively), such as baseline NT-proBNP (1318, 1301 and 1396). No difference was observed in terms of haematologic and organ response between patients with AL only or with concomitant MM: overall response rate (ORR) and complete remission (CR) were 63% and 37% in AL only patients and 88% and 32% if concomitant MM was present, whereas organ response was 47% and 56%, respectively. Similar results were seen among high risk or Mayo Stage III patients between the two subgroups. Haematologic response was similar between patients receiving ASCT in first line treatment and patients who did not: ORR and CR rates were 89% and 44% in the ASCT group and 71% and 29% in the no ASCT group, respectively. However, OR was significantly higher in the ASCT group (83% vs 37%, p 0.0014). Toxicity was manageable in both groups. After a median follow up of 32 months no significant difference was seen overall between AL only and AL with concomitant MM in terms of EFS (65% vs 85% at 2 years, respectively; HR 1,46, 95% CI 0,64-3,35) and OS (71% vs 87% at 2 years, respectively; HR 2,28, 95% CI 0,75-6,95). ASCT significantly improved both EFS and OS, comparing patients receiving or not transplantation (EFS 87% vs 64% at 2 years, p 0,013; HR 0,41, 95% CI 0,21-0,83; OS 100% vs 71% at 2 years, p 0,005; HR 0,23, 95% CI 0,08-0,64, see Figure 1). Of note, in patients achieving OR, similar OS was observed regardless of having received ASCT or not. Our data confirm the survival advantage with ASCT reported by Kourelis et al. The better outcome observed in AL with concomitant MM may be due to the more frequent use of a transplant strategy in first line treatment for AL-MM at our institution. Conclusion: We confirm that selected patients with AL AL-PCMM and AL-CRAB may have a survival advantage when receiving ASCT. These results may be related to the higher OR rates obtained with ASCT and to the improvement in OS in patients achieving OR. As no difference in terms of treatment response were observed between different underlying diseases, our study also supports the use of conventional MM treatment therapies incorporating high doses of melphalan followed by ASCT also for patients with AL Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background The role of single vs double autologous stem cell transplantation (ASCT) in patients with newly diagnosed (ND) multiple myeloma (MM) needs to be prospectively investigated in the novel agent era. Methods The phase III EMN02/HO95 study was designed to compare (first randomization, R1) (stratification according to ISS stage) standard-dose intensification therapy with bortezomib-melphalan-prednisone (VMP) vs high-dose intensification therapy with melphalan at 200 mg/m2 (HDM) followed by ASCT after 3-4 cycles of bortezomib-cyclophosphamide-dexamethasone as induction therapy. A second randomization to consolidation therapy vs no consolidation was performed after intensification therapy, to be followed by lenalidomide maintenance until progression or toxicity in both arms. A primary study endpoint was progression-free survival (PFS) from R1. In centers with a policy of double ASCT, patients were randomized in a 1:1:1 ratio to either VMP or single ASCT (ASCT-1) or two sequential courses (administered 2 to 3 months apart) of HDM and double ASCT (ASCT-2) in order to prospectively compare ASCT-1 with ASCT-2, which was an additional study objective. Results From February 2011 to April 2014, 1510 pts aged ≤65 years with symptomatic NDMM were registered and 1192 of these were eligible for R1. According to the design of the study, 614 eligible patients who received the diagnosis of MM in centers with a double intensification policy were randomly assigned to either VMP (n=199) or ASCT-1 (n=208) or ASCT-2 (n=207). Patients randomized to ASCT-1 or ASCT-2 were included in the current pre-specified analysis. Median age was 59 years for patients in the ASCT-1 group and 57 years for those in the ASCT-2 group. The frequency of ISS stage III was 18% and 19%, while revised ISS stage III was 9% and 11%, respectively. Cytogenetic abnormalities were detected by FISH analysis of CD138+ plasma cells. A high-risk (HR) cytogenetic profile, defined by t(4;14) and/or del(17p) and/or t(14;16) (HR cyto-3), was observed in 26% of evaluable patients who were randomized to ASCT-1 and in 21% of those randomly assigned to ASCT-2. If amp(1q) and/or del(1p) were added for the definition of high-risk disease, a HR cytogenetic profile that included at least 1 of the 5 above mentioned chromosomal abnormalities (HR cyto-5) was reported in 55% of evaluable patients in the ASCT-1 group and in 54% of those in the ASCT-2 group. Median follow-up from R1 was 27 (IQR: 20-35) months. On an intention-to-treat basis, the median PFS was 45 months in the ASCT-1 arm and was not yet reached for patients in the ASCT-2 arm; 3-year estimates of PFS were 60% and 73%, respectively (HR=0.66; 95% CI=0.45-0.96; P=0.030). PFS benefit with ASCT-2 was retained across predefined subgroups, including patients with β2-microglobulin >3.5 mg/L (HR=0.59; CI=0.34-0.99; P=0.005), bone marrow plasma cells >60% (HR=0.41; CI=0.22-0.77; P=0.006), LDH values above the upper limits (HR=0.52; CI=0.28-095; P=0.034), revised ISS stage II (HR=0.50; CI=0.31-0.80; p=0.004), HR cyto-3 (HR=0.49; CI=0.24-1.02; P=0.057) and HR cyto-5 (HR=0.57; CI=0.35-0.93; P=0.024). In a multivariate Cox regression analysis stratified by ISS stage, randomization to ASCT-2 (HR=0.62; CI=0.40-0.95; P=0.027) and HR cyto-5 (HR=2.63; CI=1.63-4.16; P Conclusions Upfront double ASCT after bortezomib-based induction therapy for newly diagnosed MM was superior over a single ASCT in terms of prolonged PFS. Clinical benefits of double ASCT were mostly seen in patients with disease-related factors predicting for poor prognosis. Disclosures Cavo: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Offidani:Janssen: Honoraria; Celgene: Honoraria, Research Funding. Boccadoro:Janssen: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbivie: Honoraria.

We performed a phase 1/2 trial to determine the maximum tolerated dose (MTD) of pomalidomide and to explore its efficacy when combined with cyclophosphamide-prednisone in relapsed/refractory myeloma patients. Pomalidomide was given at 1 to 2.5 mg/d, cyclophosphamide at 50 mg every other day, prednisone at 50 mg every other day, for 6 28-day cycles, followed by pomalidomide-prednisone maintenance therapy. Thromboprophylaxis was recommended. Sixty-nine patients were enrolled, 55 received the MTD (2.5 mg/d) and were evaluated. Best responses included complete response in 3 patients (5%), very good partial response in 10 (18%), partial response in 15 (27%), minimal response in 11 (20%), stable disease in 15 (27%), and progressive disease in 1 (3%), for an overall response rate of 51%. The median time-to-response was 1.83 months. After a median follow-up of 14.8 months, median progression-free survival was 10.4 months and 1-year overall survival was 69%. At the MTD, grade 3 to 4 toxicities included anemia (9%), thrombocytopenia (11%), neutropenia (42%), neurologic events (7%), dermatologic events (7%), and thromboembolism (2%). Grade 3 to 5 infections occurred in 5 patients (9%). Five patients (9%) discontinued treatment for toxicity. New grade 3 to 4 adverse events were low during maintenance. Pomalidomide-cyclophosphamide-prednisone is safe and effective in relapsed/refractory myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT01166113.

Abstract 805FN2 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 designed a phase 3 study to demonstrate that the triplet VTD regimen was superior over a doublet such as thalidomide-dexamethasone (TD) as induction therapy prior to double ASCT for newly diagnosed MM. On an intention-to-treat basis, the rate of complete or near complete response (CR/nCR) was 31% for the 236 pts on VTD induction therapy, while it was 11% (p Methods. For this purpose, in a molecular substudy to the main clinical study we assessed the ability of gene expression profile (GEP) to predict attainment of CR/nCR in 122 pts enrolled in the VTD arm of the study. Their characteristics at baseline, including cytogenetic abnormalities, were comparable with those of the whole population of 236 pts. Highly purified CD138+ plasma cells were obtained at diagnosis from each of these pts and were profiled for gene expression using the Affymetrix U133 Plus2.0 platform. In order to build a low-dimensional signature with optimal performance, genomic data were analyzed with an original algorithm that exploits quadratic discriminant analysis with a bottom-up approach that builds N-gene signatures starting from two-dimensional signatures. Gene models were applied to test datasets to predict achievement of either CR/nCR or less than nCR, and classification performances were validated by a leave-one-out crossvalidation procedure. Results. Thirty four pts out of the 122 (28%) who were included in the present analysis achieved a CR/nCR, while the remaining 88 patients failed this objective. The molecular approach described above allowed to identify several gene signatures among which we choose a 163-gene signature that provided a predictive capability of 79% sensitivity, 87% specificity, 71% positive predictive value (PPV) and 92% negative predictive value (NPV). These expression values were used in an unsupervised hierarchical clustering to stratify the population of 122 profilated pts into 3 well defined subgroups. Seventy nine pts were included in subgroup A, while the remaining 43 pts were included in either subgroup B (n=22) or subgroup C (n=21). Notably, 19 out the 34 CR/nCR pts (56%) clustered in subgroup B, whereas the remaining 15 pts were randomly distributed within subgroup A. Analysis of demographic and disease characteristics of the pts belonging to the 3 major subgroups, revealed that in subgroup B the frequencies of pts carrying del(13q) (78%) or del(17p) (22%) or with an IgA isotype (54%) were significantly higher in comparison with the corresponding values found in subgroup A (47%, 4%, and 10%, respectively) and subgroup C (38%, 10%, and 5%, respectively). In order to obtain a more feasible set of genes predictive of CR/nCR, several smaller signatures originating from the 163-gene signature were further analyzed by means of the same algorithm described above. The best predictive capability was obtained with a 41-gene signature that provided 88% sensitivity, 97% specificity, 91% PPV and 95% NPV. A GeneGo ® network analysis of genes included in the signatures showed that the most relevant network nodes included tumour suppressor genes (FBXW7 and MAD), genes involved in inflammatory response (TREM1 and TLR4) and genes involved in B cell development (IKZF1, IL10 and NFAM1). Genes included in the signatures do not gather in specific chromosomes, thus confirming the absence of bias on selection of signatures genes, potentially due to prevalence of MM typical chromosomal aberrations. Conclusions. GEP analysis of a subgroup of pts who received VTD induction therapy allowed to provide a 41-gene signature that was able to predict attainment of CR/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. Disclosures: Bringhen: Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Merck Sharp & Dhome: Membership on an entity's Board of Directors or advisory committees. Offidani:Janssen: Honoraria; Celgene: Honoraria.

A sequential approach including bortezomib induction, intermediate-dose melphalan, and autologous stem cell transplantation (ASCT), followed by lenalidomide consolidation-maintenance, has been evaluated. Efficacy and safety data have been analyzed on intention-to-treat and results updated. Newly diagnosed myeloma patients 65 to 75 years of age (n = 102) received 4 cycles of bortezomib-pegylated liposomal doxorubicin-dexamethasone, tandem melphalan (100 mg/m(2)) followed by ASCT (MEL100-ASCT), 4 cycles of lenalidomide-prednisone consolidation (LP), and lenalidomide maintenance (L) until disease progression. The complete response (CR) rate was 33% after MEL100-ASCT, 48% after LP and 53% after L maintenance. After a median follow-up of 66 months, median time-to-progression (TTP) was 55 months and median progression-free survival 48 months. Median overall survival (OS) was not reached, 5-year OS was 63%. In CR patients, median TTP was 70 months and 5-year OS was 83%. Median survival from relapse was 28 months. Death related to adverse events (AEs) occurred in 8/102 patients during induction or transplantation. Rate of death related to AEs was higher in patients ≥70 years compared with younger (5/26 vs 3/76, P = .024). Bortezomib-induction followed by ASCT and lenalidomide consolidation-maintenance is a valuable option for elderly myeloma patients, with the greatest benefit in those younger than 70 years of age.

Introduction and aim of the study: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) have a distinct risk of evolving towards symptomatic multiple myeloma (MM) but it is widely accepted that they should not be treated until clinical evolution. The clinical presentation of symptomatic MM includes severe complications like acute renal failure, spinal cord compression by vertebral collapse, pathologic bone fractures which cannot be completely avoided even by strict follow-up of MGUS/SMM patients. The recent availability of effective and less toxic therapies has fueled renewed interest in the identification of prognostic models able to predict the risk of impending progression of MGUS/SMM patients to symptomatic MM and criteria for MM defining events have been recently broadened to allow an earlier start of treatment even in asymptomatic patients (Rajkumar SV et al, Lancet Oncol 2014). However, from a clinical perspective it would be more important to prevent the development of severe MM related complications by treating those MGUS/SMM considered at high risk of developing them. To this end, we have analyzed known risk factors for MGUS/SMM progression and other disease biomarkers in order to identify those able to consistently predict an high risk of "severe MM" development. Methods: we retrospectively analyzed 67 patients with symptomatic MM with a known previous history of MGUS/SMM, referred to our division from 1985 to December 2014 (23 males, 44 females; median age at MGUS/MM diagnosis 60 years). Focusing on the first assessment of their asymptomatic disease, we compared patients who subsequently developed severe CRAB criteria (Bladé J et al, Hematol Oncol Clin North Am. 2007), defined as having at least one of the following: hypercalcemia > 11.5mg/dL, creatinine > 4mg/dL, Hb < 8 mg/dL, severe bone lesions characterized by pathological fractures or causing spinal nerve compression, and called "severe MM" with patients who lacked severe CRAB symptoms at MM diagnosis, in order to identify risk factors for "severe MM" during its asymptomatic phase. Variables analyzed for comparison were: involved/uninvolved free light chains (FLC) ratio, monoclonal component (MC) quantification, presence of evolving pattern of MC (defined as an increase in the level of MC of at least 10% in 6 months), presence of immunoparesis, LDH levels, 24h-urinary protein levels, Ig isotype and bone marrow plasma cells percentage. Frequency of follow up was also considered (every 6 months or more). Time to treatment start (TTTS) from MGUS/SMM diagnosis, progression free survival (PFS) from first line treatment and overall survival (OS) were also calculated. Results: median 24-hour urine protein levels were significantly higher in MGUS/SMM patients who subsequently developed "severe MM", compared with patients without severe CRAB symptoms at MM diagnosis (140 vs 90mg/24h, p 0.022, see Figure 1), with an increased risk of severe myeloma related complications for MGUS/SMM patients with more than 200mg/24h urine proteins (Odds Ratio 2.65, p 0.037). Risk was highest in 4 MGUS/SMM patients with 24h-urinary protein levels higher than 1500mg (Odds Ratio 8.43, p 0.030) who invariably developed "severe MM". No difference were found comparing other variables. Of note, there was no difference between the two subgroups in terms of median TTTS (5.3 vs 8.3 years for MGUS patients and 1.7 vs 1.6 years for SMM, respectively), PFS ( 24.4 vs 32.2 months, respectively) and OS (nr vs 4.36), although a higher early mortality was observed in patients with "severe MM" (2 y OS 69% vs 93%). Conclusions: increased 24h-urinary protein levels (> 200mg) in MGUS/SMM patients are associated with a higher risk of the occurrence of severe CRAB symptoms at MM progression. Further data with larger series of patients are needed to better define the best predictive threshold for "severe MM". However, patients with more than 1500mg/24h urinary protein loss represent a small subgroup of MGUS/SMM patients who should better start treatment while still asymptomatic. Figure 1. 24h-urinary protein (mg) levels in the asymptomatic phase Figure 1. 24h-urinary protein (mg) levels in the asymptomatic phase Disclosures No relevant conflicts of interest to declare.

Lenalidomide has raised concerns regarding its potential impact on the ability to collect stem cells for autologous stem cell transplantation, especially after prolonged exposure. The use of cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells may overcome this concern. In newly diagnosed multiple myeloma (MM) patients, we investigated the influence of lenalidomide on stem cell collection. In a prospective study, 346 patients received four cycles of lenalidomide-dexamethasone (Rd). Stem cells were mobilized with cyclophosphamide and G-CSF. Patients failing to collect a minimum of 4 × 10(6) CD34(+)/kg cells received a second mobilization course. After mobilization, a median yield of 8.7 × 10(6) CD34(+)/kg was obtained from patients receiving Rd induction. After first mobilization, inadequate yield was observed in 21% of patients, whereas only 9% of patients failed to collect the target yield after the second mobilization attempt. In conclusion, we confirm that a short induction with lenalidomide allowed sufficient stem cells collection to perform autologous transplantation in 91% of newly diagnosed patients.

Purpose We investigated the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included bortezomib, thalidomide, and dexamethasone (VTD) in patients with multiple myeloma (MM) responding to autologous stem-cell transplantation (auto-SCT). Patients and Methods Patients achieving at least very good partial response who had an available molecular marker based on the immunoglobulin heavy-chain rearrangement received four courses of treatment every month: four infusions per month of bortezomib at 1.6 mg/m2, thalidomide at 200 mg/d, and dexamethasone at 20 mg/d on days 1 to 4, 8 to 11, and 15 to 18. Patients were studied with tumor-clone–specific primers by qualitative nested PCR and RQ-PCR. Results Of 39 patients enrolled, 31 received the four VTD courses. Immunofixation complete responses increased from 15% after auto-SCT to 49% after VTD. Molecular remissions (MRs) were 3% after auto-SCT and 18% after VTD. Median time to maximum response was 3.5 months. So far, no patient in MR has relapsed (median follow-up, 42 months). VTD consolidation induced an additional depletion of 4.14 natural logarithms of tumor burden by RQ-PCR. Patients with a tumor load less than the median value after VTD had outcomes better than those who had tumor loads above the median value after VTD (at median follow-up: progression-free survival, 100% v 57%; P < .001). Conclusion To the best of our knowledge, this study is the first to document the occurrence of persistent MRs in a proportion of MM patients treated without allogeneic transplantation. Moreover, the major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs.

Abstract 1898 Background: Multiple myeloma (MM) cells growth is sustained by several stimuli derived from surrounding cells of bone marrow (BM) microenvironment. Besides the increase in growth factors production, a constitutive activation of several pathways determining protection from apoptosis and growth advantage have been reported too. Aberrant activation of Met/HGF (Hepatocyte Growth Factor) pathway has been described in several tumors causing cell proliferation, cell migration and neoplastic angiogenesis. A qualitative analysis demonstrated that Met transcription is present in MM plasma cells and increase plasmatic levels of HGF has been related to a bad prognosis subgroup of patients. However a comprehensive investigation of quantitative analysis on Met expression, plasmatic HGF values and correlation with clinical outcome on a large amount of MM patients treated with novel agents is still missing. Aim: : to investigate the role of Met mRNA expression and HGF levels in a large panel of myeloma patients treated with novel drugs. Patients and Methods: one hundred and five samples of purified plasma cells derived from newly diagnosed myeloma patients have been included in this study. Fifty two patients received 9 courses of Velcade-Melphalan-Prednisone (VMP) as part of the VMP-VMPT trial (Palumbo A, 2009 ASH Meeting, abs 128) while fifty three patients have been included in the PAD-MEL100-LP-L trial (Palumbo A, JCO 2010). Met and HGF mRNA quantitative expression have been investigated on both purified plasma cells (CD138+ bone marrow fraction) and on bone marrow CD138 negative fraction. mRNA expression has been evaluated using a quantitative Real-Time PCR (qRT-PCR) on Abi Prism 7900 (Applied Biosystems) with a relative quantification based on ΔΔCt approach. JUM2 cell line was used as calibrator and Gus as housekeeping gene. HGF serum level has been evaluated on 76 of those patients too. ELISA assay has been employed to determine HGF serum value. On 51 samples with higher levels of mRNA Met expression, a FISH analysis reaching for Met amplification has been performed. Purified plasma cells were treated with a dual-color FISH assay using a MET/CEP7 probe cocktail (Cytocell, Cambridge, UK). Results: Met mRNA expression was higher in CD138+ cells than in CD138- fractions (median 76,90 range 0,81-916,51 vs 11,03 range 0–243,88 respectively; p=0,0001). Similarly HGF mRNA expression was higher in CD138+ cells than in CD138- population (median 2,07 range 0–65,34 vs 0,49 range 0,11-3,22 respectively; p=0,03). Patients with high and low Met levels were divided using the median value of Met expression as cutoff. At a median follow up of 30 months, patients with low Met mRNA expression displayed a higher progression free survival (PFS) and overall survival (OS) compared with those with high Met levels (PFS 73% vs 42% respectively, p Conclusions: 1) high Met mRNA expression levels identify a group of patients with worse prognosis even when treated with novel drugs containing regiments; 2) Met amplification has been described for the first time in myeloma cells and can determine high Met mRNA levels characterizing a more aggressive disease. Disclosures: Cavallo: Celgene: Honoraria. Patriarca:Roche: Honoraria; Janseen-Cilag: Honoraria; Celgene: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janseen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janseen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Purpose To evaluate the effect of bortezomib as induction therapy before autologous transplantation, followed by lenalidomide as consolidation-maintenance in myeloma patients. Patients and Methods Newly diagnosed patients age 65 to 75 years were eligible. Induction (bortezomib, doxorubicin, and dexamethasone [PAD]) included four 21-day cycles of bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), pegylated liposomal doxorubicin (30 mg/m2 on day 4), and dexamethasone (40 mg/d; cycle 1: days 1 to 4, 8 to 11, and 15 to 18; cycles 2 to 4: days 1 to 4). Autologous transplantation was tandem melphalan 100 mg/m2 (MEL100) and stem-cell support. Consolidation included four 28-day cycles of lenalidomide (25 mg/d on days 1 to 21 every 28 days) plus prednisone (50 mg every other day), followed by maintenance with lenalidomide (LP-L; 10 mg/d on days 1 to 21) until relapse. Primary end points were safety (incidence of grade 3 to 4 adverse events [AEs]) and efficacy (response rate). Results A total of 102 patients were enrolled. In a per-protocol analysis, after PAD, 58% of patients had very good partial response (VGPR) or better, including 13% with complete response (CR); after MEL100, 82% of patients had at least VGPR and 38% had CR; and after LP-L, 86% of patients had at least VGPR and 66% had CR. After median follow-up time of 21 months, the 2-year progression-free survival rate was 69%, and the 2-year overall survival rate was 86%. During induction, treatment-related mortality was 3%; grade 3 to 4 AEs included thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%). During consolidation-maintenance, grade 3 to 4 AEs were neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). Conclusion Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance, is an effective regimen.

Abstract 960 Background and aims: We have recently shown that multiple myeloma (MM) patients undergoing autologous transplantation (ASCT) followed by a consolidation with Bortezomib/Thalidomide/Dexamethasone (VTD) achieve molecular remission in 17% and major tumor shrinking assessed by real time-quantitative (RQ) PCR in the majority of cases (Ladetto et al, ASH Meeting 2008). However little is known on the minimal residual disease (MRD) kinetics occurring after such an extensive cytoreduction. In this study we have investigated the disease kinetics in the post-consolidation phase with the aim of identifying the RQ-PCR patterns associated with persistent remission or increased risk of relapse. Patients and methods: Inclusion criteria and consolidation treatment for this study have been already reported and included: 1) a documented complete or very good partial remission following ASCT delivered as first line treatment; 2) no previous treatment with thalidomide and bortezomib; 3) presence of a molecular marker based on the immunoglobulin heavy chain rearrangement (IgH-R). Consolidation consisted of four courses of: a) Bortezomib 1.6 mg/m2 on days 1, 8, 15, 22; b) Thalidomide at the initial dose of 50 mg/day with increments up to 200 mg; c) Dexamethasone 20 mg/day on days 1 to 4, 8 to 11 and 15 to 18. MRD was assessed on bone marrow samples at diagnosis, study entry, after two VTD courses, at the end of treatment and then at six months intervals. Qualitative and RQ-PCR analysis were carried out using IgH-R derived patient specific primers as already described (Voena et al, Leukemia 1997; Ladetto et al, Biol Bone Marrow Transpl 2000). MRD kinetics of relapsing vs non relapsing patients has been measured using observed marginal medians of ln RQ-PCR values. For the predictive value of MRD kinetics patients were defined as having low tumor burden (TB) if they reached after VTD a MRD level Results: Feasibility, toxicity and clinical outcome of the trial have been already reported (Ladetto et al, ASH Meeting 2008). Thirty-nine patients were enrolled. Median follow-up from study entry is currently 32 months (50 from start of first line treatment). Following VTD, six patients achieved molecular remission (MR). Of these none has so far experienced a clinical relapse. MR was persistent in all patients, with an occasional PCR positive result in a patient who later reverted to PCR negativity. Among PCR positive patients 12 clinical relapses have been so far reported (50 months PFS: MR 100% vs no MR 62% - Figure 1A, p Conclusions: Our results indicate that: 1) MRs following VTD are stable over time with no evidence of clinical and molecular relapse; 2) The vast majority of relapses occur in patients failing to achieve a low and stable TB; 3) Molecular monitoring of MRD allows to identify a large subset of patients (51% of cases) with an extremely low-risk of short-term relapse. Disclosures: Ladetto: CELGENE: Honoraria; JANSSEN-CILAG: Research Funding. Cavallo:CELGENE: Honoraria. Caravita:CELGENE: CONSULTANCY. Musto:JANSSEN-CILAG: Honoraria; CELGENE: Honoraria. Boccadoro:CELGENE: CONSULTANCY, ADIVISORY COMMITTEES, Research Funding; JANSSEN-CILAG: CONSULTANCY, ADIVISORY COMMITTEES, Research Funding; PHARMION: CONSULTANCY, ADIVISORY COMMITTEES, Research Funding. Palumbo:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria.

Abstract 351 Introduction A phase III study of melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) incorporating thalidomide (T) and dexamethasone (D) with or without the addition of bortezomib (V) as first-line therapy for younger (≤65 years) patients (pts) with newly diagnosed multiple myeloma (MM) is currently being conducted by the Italian Myeloma Network GIMEMA. Patients and Methods By study design, pts were random assigned to receive three 21-d cycles of either bortezomib-thalidomide-dexamethasone (VTD) (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or thalidomide-dexamethasone (TD) (both drugs at the same dose and schedule than in VTD) as induction therapy in preparation for ASCTs. Two 35-d cycles of either VTD or TD were given as consolidation therapy following ASCTs (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle). Primary study end point was the rate of high-quality responses [immunofixation negative complete response (CR) and ≥very good partial response (VGPR)] to induction therapy. Secondary study end points included response to, and toxicity of, subsequent treatment phases (including first and second ASCTs, and consolidation therapy), progression-free survival (PFS) and overall survival (OS). Analyses were intent to treat. All the 474 pts were evaluated for response to, and toxicity of, induction therapy. Responses reported by study investigators were centrally reassessed to confirm CR and VGPR; pts reported as complete responders but in whom bone marrow aspirate was not evaluable or not performed were reassessed as in VGPR. The VGPR category included the subcategories of near CR and VGPR. Results The study was closed to pts accrual after a total of 480 pts were enrolled; of these, 6 failed inclusion criteria and the remaining 474 were randomized to the VTD (n=236) or TD (n=238) arm. The mean total dose of V received in induction therapy was 14.7 mg (or 94% of that planned). Grade 3 peripheral neuropathy (PN) and skin rash (SR) were reported more frequently with VTD induction therapy than with TD (PN: 9.7% vs 2.1%, respectively; P Conclusions Incorporation of VTD into double ASCT for newly diagnosed MM resulted in a significant improvement in clinical outcomes (CR, ≥VGPR, PFS) in comparison with TD and double autotransplantation. Superior benefit with VTD and double ASCT in comparison with the control group was maintained in pts at high risk of progression or death, including those with t(4;14) and/or del(17p). Disclosures: Cavo: Celgene: Honoraria; Ortho Biotech, Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Honoraria; Novartis: Honoraria.

Abstract 1821 Poster Board I-847 Background Over-expression of the tyrosine kinase receptor Met has been reported in several solid tumors and increases cell proliferation, cell migration (scattering) and neoplastic angiogenesis. The Hepatocyte Growth Factor (HGF) is the only known Met ligand and the HGF/Met pathway seems to play a pivotal role in Multiple Myeloma (MM) pathogenesis. HGF is secreted by bone marrow stromal cells and Met is expressed at the surface of malignant plasma cells and endothelial cells. The phosphorylation of Met induced by HGF is a strong signal for cell growth and migration. The activity of the HGF/Met pathway and the heterogeneity of HGF/Met expression on MM cells suggest that the over-expression of Met could be a prognostic marker in MM patients. Aims To investigate the role of HGF/Met pathway as prognostic marker predictive of response rate, progression-free survival (PFS) and overall survival (OS) in MM patients treated with novel agents. Methods 102 newly diagnosed MM patients received the PAD-Mel100-LP-L regimen (Palumbo A, Abs 159, ASH 2008): as induction, four 21-day PAD cycles (Bortezomib, Pegylated-lyposomal-doxorubicin, Dexamethasone); as transplantation, tandem Mel100 (Melphalan 100 mg/m2) followed by stem cell support; as consolidation four 28-day LP cycles (Lenalidomide plus Prednisone) followed by Lenalidomide alone as maintenance. Samples from 47 newly diagnosed patients enrolled in this study have been analyzed. On CD138+ and CD138- cells separated from bone marrow (BM) aspirate, HGF and Met mRNA levels have been evaluated using a quantitative Real-Time PCR (qRT-PCR) on Abi Prism 7900 (Applied Biosystems). The JUM2 cell line was used as a calibrator for relative quantification of mRNA using the σσCt approach and Gus has been used as housekeeping gene. The cut-off value of Met mRNA expression/percentage calibrator was selected according to Receiver Operating Characteristic (ROC) analysis. Results mRNA expression of Met was higher in CD138+ cells than in CD138- cells (median 103, range 2 – 586 vs median 31, range 0-243 respectively; p=0.002). Met mRNA expression was significantly higher in CD138+ cells of patients with suboptimal response (partial response PR, stable disease SD, progression disease PD), compared with patients achieving complete response (CR) or very good partial remission (VGPR) (median 140 range 27-586 vs median 36.5 range 1-163 respectively; p=0.0001) (FIG 1A). With a median follow-up of 18 months, the 2-year PFS was 54% in patients with high Met mRNA expression and 87% in patients with low Met mRNA expression (p=0.007, FIG 1B); 2-year OS was 72% in patients with high Met mRNA expression and 95% in patients with low Met mRNA expression (p=0.047, FIG 1C). Patients with high levels of Met mRNA displayed albumin and beta-2-microglobuline levels similar to that observed in patients with low levels of Met mRNA. The BM plasma cells infiltration was also comparable (median 61% vs 65%) within the two groups. A similar percentage of patients in both groups showed the following cytogenetic abnormalities: t(4;14), t(14;16), del17 and del13. Interestingly, the percentage of patients carrying t(11;14) was higher in the group of patients with low Met mRNA levels in comparison with patients with high Met mRNA levels (28% vs 6%). mRNA expression of HGF was similar in responders and non responders patients and did not predict PFS and OS. Conclusion 1) mRNA level of Met on CD 138+ cells is a biological marker predictive of response; 2) high level of Met mRNA at diagnosis delineates significantly inferior progression-free and overall survival in MM patients treated with both bortezomib and lenalidomide based regimens. Disclosures Patriarca: Celgene: Honoraria. Caravita:Celgene: Consultancy. Ladetto:Celgene: Research Funding; Janssen-Cilag: Research Funding. Boccadoro:Celgene: Consultancy, advisory Committees, Research Funding; Janssen-Cilag: Consultancy, advisory Committees, Research Funding; Pharmion: Consultancy, advisory Committees, Research Funding. Palumbo:Celgene: Honoraria; Janssen-Cilag: Honoraria.

Over the last few years, Thalidomide-Dexamethsone (TD) has been one of the most commonly used induction regimens for the treatment of newly diagnosed multiple myeloma (MM). In a phase III study conducted by the Italian Myeloma Network GIMEMA, TD was compared with Velcade-Thalidomide-Dexamethasone (VTD) as induction therapy in preparation for, and as consolidation after, melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) in pts aged ≤65 years with symptomatic MM. Up-front VTD comprised Velcade, 1.3 mg/m2 on d 1, 4, 8, and 11; Dexamethasone, 40 mg on each day of and after Velcade administration; Thalidomide, 200 mg/d through d 1 to 63. Pts randomized to TD received Thalidomide as in VTD and Dexamethasone, 40 mg/d on d 1–4 and 9–12 of every cycle. Primary study end point was the rate of complete response (CR)/near CR (nCR) following three 21-d cycles of induction therapy. The study was started in May 2006 and was closed to accrual in April 2008, after a total of 480 pts were enrolled. Of these, 399 pts (199 randomized to VTD and 200 to TD) could be evaluated for primary study end point and toxicity of induction regimens (secondary end point). All analyses were intent to treat. In comparison with TD, VTD effected significantly higher rates of response (≥partial response: 78.5% vs 92%, P

Bortezomib has been evaluated as induction regimen to improve cyto-reduction before autologous stem cell transplant. Combinations including bortezomib, doxorubicin and dexamethasone have shown encouraging results. Melphalan at 100 mg/m2 has been suggested as reduced-intensity conditioning regimen for elderly patients. In this prospective multicenter phase II study, bortezomib, pegylated-liposomal-doxorubicin and dexamethasone (PAD) followed by tandem melphalan 100 mg/m2 has been investigated in newly diagnosed patients aged 65–75 years. The induction regimen included four 21-day PAD cycles (bortezomib 1.3 mg/m2 days 1, 4, 8, 11, pegylated-liposomal-doxorubicin 30 mg/m2 day 4 and dexamethasone 40 mg days 1–4, 8–11, and 15–18 for cycle 1 and days 1–4 for cycles 2–4). Cyclophosphamide (3 g/m2) plus G-CSF were used to harvest stem cells. Patients were then conditioned with tandem melphalan 100 mg/m2 followed by stem cell infusion. A single interim analysis has been planned. Sixty-five patients have been enrolled in the study and 37 completed the induction cycles. Median age was 69 years; median β2-microglobulin 3 mg/L; median albumin 4.1 g/L; chromosome 13q deletion was detected by FISH in 35% of patients. After the 4 courses of PAD 97.1% of patients achieved at least a partial response (PR), 50% at least a very good partial response (VGPR), 11.8% an immunofixation negative complete remission (CR). After tandem melphalan 100 mg/m2, all patients achieved at least a PR, 80% at least a VGPR and 30% an immunofixation negative CR. After 4 cycles of PAD, grade 3–4 hematologic events were thrombocytopenia (13.5%) and neutropenia (8.1%); more frequent grade 3–4 non-hematologic toxicities were peripheral neuropathy (21.6%) and infections (10.8%). One early toxic death was reported (central nervous system bleeding) and two patients had to discontinue therapy due to pneumonia and HBV reactivation. Eighty-two percent of patients achieved successful stem cell harvest (>4 CD34+ cells/Kg). PAD is an effective induction approach, it may improve autologous transplant results in selected elderly patients. Updated results of the interim analysis will be presented at the meeting.

Background: The risk of venous thromboembolism (VTE) is high in newly diagnosed myeloma (MM) patients who receive thalidomide-containing regimens. Anticoagulant prophylaxis is recommended but it’s not clear which is more appropriate. In this prospective, multicenter phase III trial we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) or low-fixed dose warfarin (WAR) as anticoagulant prophylaxis. Methods: In a GIMEMA study, newly diagnosed MM patients were randomized to VTD (Velcade 1.3 mg/m² d 1,4,8,11; Thalidomide 200 mg/d; high-dose Dexamethasone 320 mg/21 d) or TD (Thalidomide 200 mg/d; high-dose Dexamethasone 320 mg/21 d) or VMPT (Velcade 1.3 mg/m² d 1,8,15,22; Melphalan 9 mg/m² d 1–4; Prednisone 60 mg/m² d 1–4; Talidomide 50 mg/d) or VMP (Velcade 1.3 mg/m² d 1,8,15,22; Melphalan 9 mg/m² d 1–4; Prednisone 60 mg/m² d 1–4). In a sub-study, patients treated with VTD or TD or VMPT were randomly assigned to receive LMWH (Enoxaparin 40 mg/d) or ASA (Aspirin 100 mg/d) or WAR (Warfarin 1.25 mg/d) for the duration of the induction therapy. Patients treated with VMP did not receive any prophylaxis and were used as controls. End-points were incidence of VTE, acute cardiovascular events, sudden death, bleeding and any other serious adverse events. A total of 950 patients will be included in this study. An interim analysis was performed after the first 200 patients were enrolled. Results: Eighty-two patients received VTD, 84 TD, 34 VMPT and 35 VMP. Two-hundred patients (117 males, median age 58 years) were analyzed: 65 patients were randomized to LMWH, 66 to ASA and 69 to WAR. Patient characteristics were similar in all groups. All patients completed at least the first 3 cycles of therapy. The incidence of VTE was 2/65 (3%) in the LMWH group, 6/66 (9%) in the ASA group and 2/69 (3%) in the WAR group, but differences did not reach statistical significance. VTEs were 2/35 (6%) in the VMP group who did not received any prophylaxis. The cumulative incidence of VTE was 4/116 (3%) in patients treated with Velcade plus Thalidomide, and 6/84 (7%) in those treated with TD (p=0.33). No acute cardiovascular events or sudden deaths were reported. The incidence of bleeding was 0/65 (0%) in the LMWH group, 2/66 (3%) in the ASA group and 2/69 (3%) in the WAR group. Conclusion: The overall incidence of VTE was less than 10% in all groups. ASA patients had higher frequency of VTE; LMWH patients had lower risk of bleeding; patients who received Velcade had lower frequency of VTE. An update of these data and an analysis of risk factors will be presented at the meeting.