ALBERT

Description: In the framework of the EU Copernicus programme, the European Centre for Medium-Range Weather Forecasts (ECMWF) on behalf of the Joint Research Centre (JRC) is forecasting daily fire weather indices using its medium-range ensemble prediction system. The use of weather forecasts in place of local observations can extend early warnings by up to 1–2 weeks, allowing for greater proactive coordination of resource-sharing and mobilization within and across countries. Using 1 year of pre-operational service in 2017 and the Fire Weather Index (FWI), here we assess the capability of the system globally and analyse in detail three major events in Chile, Portugal and California. The analysis shows that the skill provided by the ensemble forecast system extends to more than 10 d when compared to the use of mean climate, making a case for extending the forecast range to the sub-seasonal to seasonal timescale. However, accurate FWI prediction does not translate into accuracy in the forecast of fire activity globally. Indeed, when all fires detected in 2017 are considered, including agricultural- and human-induced burning, high FWI values only occur in 50 % of the cases and are limited to the Boreal regions. Nevertheless for very large events which were driven by weather conditions, FWI forecasts provide advance warning that could be instrumental in setting up management and containment strategies.

Description: A global fire danger rating system driven by atmospheric model forcing has been developed with the aim of providing early warning information to civil protection authorities. The daily predictions of fire danger conditions are based on the U.S. Forest Service National Fire-Danger Rating System (NFDRS), the Canadian Forest Service Fire Weather Index Rating System (FWI), and the Australian McArthur (Mark 5) rating systems. Weather forcings are provided in real time by the European Centre for Medium-Range Weather Forecasts forecasting system at 25-km resolution. The global system’s potential predictability is assessed using reanalysis fields as weather forcings. The Global Fire Emissions Database (GFED4) provides 11 yr of observed burned areas from satellite measurements and is used as a validation dataset. The fire indices implemented are good predictors to highlight dangerous conditions. High values are correlated with observed fire, and low values correspond to nonobserved events. A more quantitative skill evaluation was performed using the extremal dependency index, which is a skill score specifically designed for rare events. It revealed that the three indices were more skillful than the random forecast to detect large fires on a global scale. The performance peaks in the boreal forests, the Mediterranean region, the Amazon rain forests, and Southeast Asia. The skill scores were then aggregated at the country level to reveal which nations could potentially benefit from the system information to aid decision-making and fire control support. Overall it was found that fire danger modeling based on weather forecasts can provide reasonable predictability over large parts of the global landmass.

Description: Background:Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors.Cytogenetic abnormalities (CA) has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. Although there are some reports indicating that 1q gains may be considered as a poor-risk feature, the information is not uniform. Furthermore, there are important controversies about whether or not novel agents-based combinations are able to overcome the poor prognosis of CA. In the relapse setting, the combinations including proteasome inhibitors and immunomodulatory drugs have shown to improve, and some of them to overcome, the outcome of patients with high-risk CA. Here we report a preplanned analysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM2010 trial and receiving VMP and Rd, in a sequential or alternating approach, in order to evaluate the influence of CA by FISH on the response rate and outcome. Patients and methods: 242 pts were randomized to receive a sequential scheme consisting of 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the IV administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. FISH analysis for t(4;14), t(14;16), del(17p) and 1q gains was performed at diagnosis according to standard procedures using purified plasma cells. Results: In 174 out of the 233 patients evaluable for efficacy and safety, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 32 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=142 patients without high-risk CA). The rates of CA was similar in both treatment arms. Response Rates (RR) were no different in the high-risk vs standard-risk groups, both in the sequential (74% vs 79% RR and 42% vs 39% CR) and alternating arms (69% vs 86% RR and 39% vs 38% CR). After a median follow-up of 51 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 33 months, p=0.03) and this also translated into a significantly shorter OS (38.4m vs not reached, p=0.002). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (29.5 months vs 31.5 months, p=0.9) and OS (46m vs 63m, p=0.1). This beneficial effect observed in the sequential arm applied to both t(4;14) or del(17p). As far as 1q gains is concerned, 151 patients had 1q information and 76 of them had 1q gains (50.3%), defined as the presence of more than 3 copies in at least 10% of plasma cells. The rate of 1q gains was well balanced in both sequential and alternating arms. The ORR was similar in patients with or without 1q gains (83% vs 80%) as well as the CR rate (45% vs 31%), and no differences were observed between sequential and alternating arms. Patients with or without 1q gains had a similar PFS (36 months vs 29 months) and 4-years OS (63% vs 68%) in the whole series and no differences were observed between the sequential and alternating arms. This effect has been observed in patients with 1q gains as isolated CA and the outcome was slightly but not significantly worse when 1q gains were present plus either t(4;14) and/or del17p. Conclusions: The total therapy approach including VMP and Rd administered in a sequential approach is able to overcome the poor prognosis of the presence of high-risk CA in elderly patients with newly diagnosed MM. The presence of 1q gains has no impact in the PFS and OS of elderly patients treated with VMP and Rd. Disclosures Mateos: Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Martínez-López:Novartis: Honoraria, Speakers Bureau. Oriol:Celgene: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

Description: During the last years, the study of molecular alterations associated with multiple myeloma (MM) has been mostly focused on the analysis of the genome, transcriptome and DNA methylome. These analyses are showing that (epi)genetic heterogeneity and extensive perturbation of the transcriptional landscape are hallmarks of MM. Our previous analysis of the whole DNA methylome of MM revealed that this epigenetic mark globally shows a poor correlation with gene expression, and therefore did not allow us to better understand gene deregulation in MM. In contrast, the chromatin structure and histone modifications are emerging as essential epigenetic layers to understand the mechanisms underlying gene expression changes in cancer, but remain widely unexplored in MM. We have now performed a deep ChIP-seq profiling of CD138+ sorted cells from bone marrow samples obtained from four MM patients and three biological replicates of normal plasma cells (NPCs) using antibodies against H3K4me3, H3K4me1, H3K27ac, H3K36me3, H3K27me3 and H3K9me3. Different combinations of these marks allow us to segment the MM and NPC genome into functional chromatin states, including active, weak or poised promoters, active or weak enhancers, transcriptional elongation, polycomb-repressed regions and heterochromatic regions. The initial unsupervised exploration of the data showed that the chromatin landscape of MM is widely altered as compared to NPCs. A supervised analysis of chromatin states revealed that MM globally shows a more active chromatin structure than NPCs. From over 40,000 regions identified with differential chromatin structure between MM and NPCs, 88% were de novo activated in neoplastic plasma cells. Analyzing the chromatin of individual genes, we observed that there were roughly ten times more genes gaining activity upon neoplastic transformation than those acquiring repressed chromatin marks. Interestingly, the genes showing more activate chromatin were enriched with biosynthesis and metabolic processes, while genes with repressed chromatin were related to gene ontology terms related to B cell signaling. Among those genes gaining de novo activity in MM, we selected several candidates and we are currently performing functional in vitro assays to explore their implication in MM pathogenesis. Furthermore, as extensive chromatin activation is a hallmark of MM, we are currently analyzing additional 15 MM cases and NPCs by ChIP-seq for H3K27ac (marking active promoters and enhancers) and ATAC-seq (marking active regulatory regions) to validate our initial findings and explore chromatin heterogeneity in MM. Collectively, our initial exploration of histone modification profiles in MM has revealed that MM cells acquire a more active chromatin landscape, with thousands of regions gaining activation as compared to NPCs. Reversing this global activation by epigenetic drugs, such as BET inhibitors, may represent an attractive therapeutic option for MM. During the meeting, updated information will be presented, including data from all 19 MM patients studied as well as functional data from new candidate genes involved in MM pathogenesis. Disclosures Paiva: Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

Description: Key Points DLBCL patients carrying the HLA-B44 supertype have a worse progression-free and overall survival after R-CHOP-like treatment. The HLA-DRB1*01 allele increases the risk of DLBCL development.

Description: Introduction:SMM is an asymptomatic and heterogeneous plasma cell disorder. The Spanish Myeloma Group demonstrated that patients at high risk of progression benefit from early treatment with Rd. In addition, our preliminary results of the curative approach (GEM-CESAR) showed encouraging results (Mateos ASH 2017). Aim: The primary end-point was to evaluate the Minimal Residual Disease negative (MRD-ve) rate by next generation flow (NGF) after induction and ASCT and the sustained MRD-ve rate at 3 and 5 yrs after ASCT as secondary end-points. Our aim was to increase the MRD -ve rate from 34% (reported in NDMM patients after VTD and ASCT) to 50%. As all patients have completed induction and ASCT, we report the results of the primary end point, efficacy and safety after induction and ASCT. Methods: In this phase II single arm trial, 90 SMM patients at high-risk of progression (〉50% at 2 yrs), younger than 70 yrs and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo criteria) or ifonly one criterion was present, patients must have a proportionof aberrant PCs within the total PCsBM compartment by immunophenotypingof 95% plus immunoparesis (Spanish criteria). Asymptomatic MM patients with any of the three biomarkers recently included into the definition of active MM were allowed to be included. Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m2twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2followed by ASCT was given as intensification therapy and three months later, patients received two KRd consolidation cycles followed by maintenance with R at dose of 10 mg on days 1-21 plus dex at dose of 20 mg weekly for up to 2 yrs Results: Between June 2015 and June 2017, the 90 SMM patients at high risk of progression were recruited. Twenty-eight pts (32%) shared at least one of the new biomarkers predicting imminent risk of progression to MM. The primary end point of the trial was met, since 55% of the patients who completed induction and ASCT achieved MRD -ve by NGF (sensitivity 3 x 10-6). Upon analyzing the results after induction, 88 patients completed the 6 induction cycles and were evaluable for response (two patients early discontinued): the ORR was 98% including 41% of ≥CR (32% sCR and 9% CR) and 41% of VGPR rate. Two patients were mobilization failures and one patient rejected ASCT. Two additional patients experienced biological progression before ASCT and went off the study. Eighty-three patients, therefore, proceeded to HDT-ASCT and were evaluable at day +100: the ORR was 100% including ≥CR in 63% of the patients (51% sCR and 12% CR) and VGPR rate in 23%. The MRD-ve rate increased from 31% after induction to 55% with the ASCT. No differences in outcome have been observed according neither to the definition of high risk (Mayo or Spanish model) nor ultra high risk SMM. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were the most frequent non-hematological AE observed in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three patients reported hypertension (G2 in two and G3 in one). Thirteen patients required lenalidomide dose reduction whilst carfilzomib was not reduced in any patient. In four patients, dexamethasone was reduced. In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All patients engrafted. Consolidation and maintenance phases are ongoing. After a median follow-up of 17 months (5-36), 94% of patients remain alive and free of progression and 97% of them alive. Three patients experienced biological progression and discontinued the study: one of them was refractory to the rescue therapies and died and the other two are receiving rescue therapies. One additional patient died early during induction due to a massive ischemic stroke unrelated to the treatment. Conclusions: Although longer follow-up is required, this "curative strategy for high risk SMM" continues being encouraging with an acceptable toxicity profile. The study has met its primary endpoint. The depth of response improved over the treatment: 63% of patients who completed induction and ASCT achieved ≥CR with a MRD-ve rate of 55%. Disclosures Mateos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Clínica Universidad de Navarra: Employment. Ocio:AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Oriol:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Alegre:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: 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. Puig:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. García Mateo:Binding Site: Research Funding; Amgen: Honoraria; Celgene: Honoraria. Bladé:Janssen: Honoraria. Lahuerta: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; Amgen: 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. San-Miguel:Novartis: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Roche: Honoraria.