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Background. Proteasome inhibitor (PI)-based induction/consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2 plus autologous stem-cell transplantation (MEL200-ASCT). High response rates have been reported with carfilzomib (K) plus lenalidomide-dexamethasone (KRd) or cyclophosphamide-dexamethasone (KCd). Lenalidomide (R) alone is a standard of care for post-ASCT maintenance; K maintenance showed promising results in phase I/II studies, but no data on KR maintenance vs R are available. Aims. The aims of this analysis were to evaluate the progression-free survival (PFS) of KRd induction-ASCT-KRd consolidation (KRd_ASCT) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd_ASCT) and the PFS of KR vs R maintenance. Secondary aims were efficacy in different subgroups of pts and safety of the maintenance phase. Methods. NDMM pts ≤65 years were randomized [R1: 1:1:1, stratification International Staging System (ISS) and age] to: KRd_ASCT: 4 28-day cycles with KRd induction (K 20/36 mg/m2 IV days 1,2,8,9,15,16; R 25 mg days 1-21; dexamethasone [d] 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd_ASCT: 4 28-day induction cycles with KCd (K 20/36 mg/m2 IV days 1,2,8,9,15,16; cyclophosphamide 300 mg/m2 days 1,8,15; d 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized (R2) to maintenance with KR (K 36 mg/m2 days 1,2,15,16, subsequently amended to 70 mg/m2 days 1,15 for up to 2 years; plus R 10 mg days 1-21 every 28 days until progression) or R alone (10 mg days 1-21 every 28 days until progression). Centralized minimal residual disease (MRD) evaluation (8-color second-generation flow cytometry, sensitivity 10-5) was performed in pts achieving ≥very good partial response before maintenance and every 6 months (m) during maintenance. Data cut-off was June 30, 2020. Results. 474 NDMM pts were randomized (KRd_ASCT, n=158; KRd12, n=157; KCd_ASCT, n=159) and analyzed. Pt characteristics were well balanced. Intention-to-treat (ITT) data of pre-maintenance MRD (KRd_ASCT, 62%; KRd12 56%, KCd_ASCT 43%) and safety of the induction/consolidation phases in the 3 arms were already reported (F. Gay et al. ASH 2018; S. Oliva et al. ASH 2019). After a median follow-up from R1 of 45 m, median PFS was not reached with KRd_ASCT, 57 m with KRd12 and 53 m with KCd_ASCT (KRd_ASCT vs KCd_ASCT: HR 0.53, P During maintenance, a similar proportion of pts experienced ≥1 grade (G)3-4 hematologic adverse events (AEs)/serious AEs (SAEs) in the 2 arms (KR 22% vs R 23%); the most frequent were neutropenia (KR 18% vs R 21%) and thrombocytopenia (KR 3% vs R 3%). Rate of ≥1 G3-4 non-hematologic AEs/SAEs was higher with KR (27%) compared with R (15%), P=0.012; the most frequent were infections (KR 4% vs R 7%); all other events were reported in ≤5% of pts and included: gastrointestinal (KR 5% vs R 2%), cardiac (KR 4% vs R 1%), hypertension (KR 3% vs R 0%), and thrombotic microangiopathy (3% vs 0%). 4 pts developed a second primary malignancy in KR (breast 1 pt; thyroid 1 pt; myelodysplastic syndrome 1 pt; non-melanoma skin cancer 1pt) vs 1 pt in R (acute lymphoblastic leukemia). Dose reductions of R were reported in 23% of KR and 29% of R pts; dose reductions of K were reported in 20% of pts. The rate of discontinuation due to AEs was similar in the 2 arms (KR 10% vs R 9%). Conclusions. Treatment with KRd_ASCT significantly improved PFS compared with both KRd12 and KCd_ASCT. Maintenance with KR also improved PFS vs R. Figure Disclosures Gay: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto:Celgene: Honoraria; Amgen: Honoraria. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Belotti:Jannsen: 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. Zamagni:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. De Sabbata:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Liberati:VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; INCYTE: Honoraria; JANSSEN: Honoraria; CELGENE: Honoraria; AMGEN: Honoraria; BMS: Honoraria; BEIGENE: Honoraria; ARCHIGEN: Honoraria; BIOPHARMA: Honoraria; FIBROGEN: Honoraria. Offidani:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau. Boccadoro:AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).

Background Despite an improvement in treatment response, high-risk multiple myeloma (MM) patients (pts) experience early relapse and short disease-free survival. Together with more validated high-risk features, high levels of circulating plasma cells (high CPC) have been considered a marker of aggressive disease and poor outcome (F. Gay et al, ASH 2019; W.I. Gonsalves et al, Am J Hematol 2020). To date, there are no uniform data on the optimal cut-off predictive of clinical outcome. No prospective data on CPC are available in the setting of novel-drug clinical trials with comprehensive baseline evaluation and minimal residual disease (MRD) assessment. Aims 1) To identify the best cut-off for CPC to predict progression-free survival (PFS); 2) to assess the impact of high CPC levels on the clinical outcome of newly diagnosed (ND)MM pts in the context of concomitant risk features and MRD evaluation. Methods In the multicenter randomized FORTE clinical trial, 474 NDMM pts ≤65 years were randomized (R1) to receive either: carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous stem-cell transplant-KRd consolidation (KRd_ASCT); KRd for 12 cycles (KRd12); or carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation (KCd_ASCT). Thereafter, pts were randomized (R2) to maintenance treatment with lenalidomide alone (R) or plus carfilzomib (KR). MRD was assessed by 2nd-generation multiparameter flow cytometry (MFC, sensitivity 10-5) in pts who achieved ≥very good partial response before maintenance and then every 6 months. At diagnosis, single-platform FC was used to sort and count CPC. Receiver Operating Characteristic (ROC) analysis was used to define a cut-off based on PFS at 36 months as outcome. Correlations between high CPC and the most important baseline prognostic features (age, International Staging System (ISS), lactate dehydrogenase (LDH), chromosomal abnormalities (CA) by FISH [(del17p, t(4;14), t(14;16), t(11;14), amp1q, del1p, del13], Revised-ISS (R-ISS)) were explored. Hence, we performed a multivariate (MV) analysis to assess the impact of high CPC on the achievement of MRD negativity, on PFS and OS. Finally, we evaluated the impact of baseline CPC and MRD achievement. Results CPC analysis was performed in 401/474 pts at diagnosis; median follow-up was 44.2 months (39.6-47.9) and baseline features were similar to those reported in the overall FORTE population. Median CPC were 0.02% (IQR 0-0.14). The optimal CPC cut-off to predict PFS (ROC analysis) was 0.07% (5 cells/ul, 0.005 x109/l) and was consistent with a cut-off previously identified as a predictor of sustained MRD negativity (MRDsus12; L. Bertamini et al, EHA 2020). High-CPC pts (>0.07%) were 130/401 (32%), while 271/401 (68%) had low CPC (≤0.07%). The proportion of high-CPC pts was comparable among treatment arms. Baseline features significantly associated with high CPC in a MV analysis were: ISS II/III, high LDH, amp1q, t(4;14), t(14;16) and bone marrow plasma cells (>60%). Regarding PFS, in a MV analysis adjusted for R-ISS and R1 treatment, including all the baseline features, high CPC were associated with a lower PFS (HR 2.49, 95% CI 1.76-3.51, P The impact of baseline CPC levels on PFS was consistent in all high-risk subgroups (Fig. 1C), except in those patients who achieved pre-maintenance MRD negativity [(neg); interaction P=0.03]. Low-CPC and MRD-neg pts showed the best outcome with a 3-year PFS of 84%. Low-CPC MRD-positive (pos) and high-CPC MRD-neg pts had similar 3-year PFS (70% vs 68%). High-CPC MRD-pos pts had a dismal outcome (3-year PFS 32%; Fig. 1D). Conclusion High CPC with a cut-off of 0.07% (5 cells/ul, 0.005 x109/l) is a strong and independent high-risk factor, predicting a shorter PFS and OS even in the context of other high-risk features. The achievement of MRD neg independently improved the poor prognosis of high-CPC patients. Figure 1 Disclosures D'Agostino: GSK: Membership on an entity's Board of Directors or advisory committees. Galieni:Janssen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Molica:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tacchetti:Oncopeptides: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Gay:GSK: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Takeda: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding. Oliva:Adaptive Biotechnologies: 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; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).

Background. High rates of response and minimal residual disease (MRD) negativity have been reported with the use of novel treatment options in multiple myeloma (MM) patients (pts) eligible for autologous stem-cell transplantation (ASCT). Despite very promising results, there is still a proportion of pts who do not respond to therapy or relapse early. This represents an unmet medical need. Aim. To identify the main factors predictive of early relapse in the context of novel treatment approaches. Methods. Data from newly diagnosed MM (NDMM) pts ≤65 years enrolled in the FORTE trial were analyzed. The evaluated baseline standard clinical and biological features included: age, Hb, creatinine, tumor circulating plasma cells (PCpb) evaluated by flow cytometry, bone marrow plasma cells (PCbm) evaluated as continuous variables, free light chain (L vs K), M-component subtype (IgA vs others), Revised International Staging System (R-ISS II/III vs I), LDH (>ULN vs ≤ULN), ISS (III vs II vs I), presence vs absence of chromosomal abnormalities detected by FISH [(del17p, t(4;14), t(14;16), t(11;14), amp1q, del1p, del13], and presence vs absence of plasmacytomas. Pts were randomized to receive carfilzomib, lenalidomide, dexamethasone (KRd) induction - ASCT intensification - KRd consolidation (arm A); KRd12 (arm B); and carfilzomib, cyclophosphamide, dexamethasone (KCd) induction - ASCT intensification - KCd consolidation (arm C). Thereafter, patients were randomized to maintenance with lenalidomide alone or lenalidomide plus carfilzomib. Pre-maintenance MRD evaluation was performed by 8-color second generation flow cytometry (sensitivity 10-5) in patients who achieved at least a very good partial response (VGPR). Early relapse was defined as relapse ≤18 months from randomization. Univariate feature selection was performed between both categorical and continuous baseline variables and the achievement of pre-maintenance MRD negativity, according to Chi-square and Kruskal tests. The same baseline features, plus the achievement of MRD negativity, were included in a univariate analysis to select candidate predictors of early relapse. Selected features were then included in a multivariate logistic model. A multivariate analysis was performed to evaluate predictors of MRD negativity and early relapse. The model was adjusted for age and administered therapy. Results. 474 patients were enrolled in the trial. Baseline features were well balanced in the 3 arms. Predictors of MRD negativity (10-5): In univariate analysis, the baseline factors selected basing on the probability of achieving pre-maintenance MRD negativity were creatinine levels, ISS stage, R-ISS stage, del17p, PCbm (P=0.004) and PCpb. In multivariate analysis, including single variables not aggregated in R-ISS, increased creatinine levels (OR 0.48, 95% CI 0.25-0.94, P=0.03), increased PCbm (OR 0.95, 95% CI 0.91-0.99, P=0.01) and presence of del17p (OR 0.44, 95% CI 0.23-0.83, P=0.01) reduced the probability of achieving MRD negativity (Table). Predictors of early relapse: In univariate analysis, the main baseline factors selected basing on the risk of early relapse were LDH, ISS, R-ISS, PCbm, PCpb, del17p and achievement of MRD negativity. In multivariate analysis, R-ISS II/III vs I (OR 3.7, 95% CI 1.24-11, P Discussion. In the context of novel highly effective treatment approaches, creatinine levels, PCbm and, in particular, presence of del17p reduced the probability of achieving MRD negativity. Multivariate analysis combining baseline features and MRD negativity highlights how comprehensive baseline evaluation including baseline R-ISS (or in particular high LDH levels, which may have an independent role) and circulating PC can help to identify patients at high risk of early relapse. However, the achievement of MRD negativity is the factor that may reduce the risk of early relapse. Disclosures Gay: Takeda: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: 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. Offidani:Bristol-Myers Squibb: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vozella:Celgene: Honoraria; Amgen: Honoraria. 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. Galli:Takeda: Honoraria; Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Gozzetti:Celgene: Honoraria; Amgen: Honoraria; Jansenn: Honoraria; BMS: Honoraria. Giuliani:Janssen: Research Funding. Musto:Amgen: Honoraria; Celgene: Honoraria. Cavo:sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

Introduction Monosomy 7 (-7) and interstitial deletions of chromosome 7 (7q-) are among the most recurrent chromosomal aberrations found in myeloid neoplasms. Patients carrying these cytogenetical alterations present a poor overall survival (OS), mainly due to a low sensitivity to standard chemotherapy and a high incidence of relapse. In our study, we aimed to disentangle the biology of patients with -7/7q- and find new candidate therapeutic targets for a disease with such a dismal prognosis, by integrating wide genomic approaches. Methods We collected bone marrow samples from 487 adult patients at diagnosis, treated in 3 institutions: Institute L. & A. Seragnoli (Italy, n = 213), CEMM (Austria, n = 160), University of Michigan (US, n = 114, GSE23452). Three hundred ninety-five samples were analyzed by SNP arrays (Affymetrix™), 51 samples by mass spectrometry (Metabolon™) and 57 samples by GEP (Affymetrix™) approaches. Chi-squared, fisher's exact test and ANOVA were used to test differences in proportion and distributions. False discovery rate, Bonferroni correction, and Welch's correction were calculated whenever appropriate. Results Among the 474 patients with evaluable karyotype, 65 (13.7%) had -7/7q-; 47 (9.9%) had -7, while 18 (3.8%) had 7q-. In our sets, the median age at AML diagnosis was 64 years (21-86) and most of the subjects had a de novo AML (65.1%). WBC count at diagnosis was significantly lower in -7/7q- patients (10.4 vs 35.2 k/mm3 p Within patients tested for FLT3, NPM1 and TP53 mutation at diagnosis, 1/50 among -7/7q- patients vs 59/300 controls harbored FLT3 ITD mutation (350 patients tested, 2% vs 19.7%, p In terms of outcome, -7/7q- AML had a median of overall survival of 10.3 months (95% C.I 5.8-14.8), which accounted for 49.5 months (95% C.I. 40.5-58.4) in other AML cases. GEP data of a cohort of 57 patients (8 with -7/7q- and 49 controls) revealed that 24 genes were under-expressed in -7/7q- AML (with e-4 significance threshold, Figure 1A). Twenty-three out of 24 genes mapped on chromosome 7; one gene, COX17, mapped on chromosome 3 (Figure 1A). COX17 plays a role in the recruitment of copper to mitochondria. By metabolomic analyses, we considered quantitative data of 300 different metabolites in 32 patients (4 with -7/7q- vs 28 controls, 19 patients were excluded because samples at diagnosis were not available). In -7/7q- AML, fatty acids (sphingomyelin, 1-linoleoylglycerol), β-cytrilglutamate and the UDP were overrepresented if compared with other AML cases; on the other hand, galactiol and 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC were underrepresented in -7/7q- patients. Furthermore, -7/7q- AML cells seem to accumulate 3-hydroxy-3-methylglutarate and to have lower levels of 2-Hydroxyglutarate (Figure 1C). With SNP arrays, we considered copy number alterations in 395 patients (52 -7/7q- patients vs 343 controls, Figure 1B). 5q was the most recurrent concurrent deletion, with a minimal common deleted region (MCDR) in q31.3-q33.3. Additionally, 17p (MCDR p11.2 - p13.1), 12p (MCDR p12.3-p13.1), 16q (MCDRs q11.2-q12.1, q21-q22.1 and q24.2-q24.3), 16p (MCDR p11.2) and chromosome 4 (MCDRs q34.1 and q35.2) deletions also co-occurred in -7/7q-, listed per frequencies (Figure 1B). These regions are enriched for genes controlling cell signaling, DNA transcription, post-transcriptional modifications (such as SUMOylation), mRNA splicing and cellular senescence. Conclusions SNP, GEP and metabolomic approaches gave new insights on -7/7q- AML biology, identifying 24 new genes differentially expressed in -7/7q-, and 6 MCDR associated with -7/7q- AML. Deletion of chromosome 16q and 4 were never reported in literature associated to AML. Furthermore, for the first time, we described metabolites associated with -7/7q- AML. These data may represent a useful backbone to search for candidate targets in the setting of one of the most aggressive AML subtypes. Supported by:EHA Non-Clinical Junior Research Fellowship,HARMONY,Fondazione del Monte,FP7-NGS-PTL,AIRC. *MCF and MO equally contributed &CP and GS shared the last authorship Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kralovics:MyeloPro Diagnostics and Research GmbH: Equity Ownership. Soverini:Incyte Biosciences: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Martinelli:Ariad/Incyte: Consultancy; Celgene: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Roche: Consultancy; Jazz Pharmaceuticals: Consultancy. Cavo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; AbbVie: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Introduction Relapsed/refractory (R/R) AML patients continue to be a formidable clinical challenge, mainly in consideration of associated very poor outcome, with a median overall survival (OS) of less than 12 months. SCT represents the only curative option for these patients. Although, there is no standard-of-care approach which may serve as a bridge to SCT. Our study aims to investigate the effectiveness of MEC regimen as a rescue therapy for R/R AML patients by specifically addressing the CR rate, including minimal residual disease (MRD) negativity, the number of patients who subsequently underwent SCT and the presence of predictive factors of response. Methods Fifty-five consecutive adult AML patients were treated with MEC regimen in our Institution. In patients under 66 years old, we administered mitoxantrone 6 mg/sqm/die from day 1 to day 6, etoposide 100 mg/sqm/die from day 1 to day 6 and cytarabine 1000mg/sqm/die from day 1 to day 6, whereas in patients over 66 years old, the treatment schedule was reduced to 4 consecutive days. Data were retrospectively collected by using RedCap in accordance with Helsinki declaration and GCP. We used Kaplan-Meyer to estimate survival, and log rank to test differences in survival. Chi-squared, fisher's exact test and linear-by-linear correlation were used to test differences in proportions and distributions. Response was defined in accordance with 2017 ELN recommendations. CTCAE 4.03 was used to grade adverse events. MRD was assessed with WT1 or specific fusion transcripts. Results Fifty-five patients received MEC from 2008 to 2018. Age at diagnosis ranged from 17 to 72 years, with a median age of 51 years. Our set was enriched for high-risk patients. Interestingly, twenty percent of patients harbored FLT3-ITD at diagnosis (table 1). Two main groups were included: resistant AML, 28/55 patients (50,9%), and relapsed AML, 27/55 patients (49,1%). At induction, almost half of patients received "3+7" (n=25, 45,5%), while fludarabine-based regimens were administered to 14 patients (25,5%). In our set, after MEC median duration of hospitalization was 30 days (14-78); PMN >500/mm3 was reached after 26 days (range 18-67). Fever and febrile neutropenia was the most recurrent adverse events (AE). AEs were low in grade; out of 80 graded AEs, 38 (47,5%) were grade 2, 27 (33,8%) were grade 3, 9 (11,3%) were grade 4 and only 3 events resulted in death (3,8%). E. coli was the most recurrent cause of infection (10 cases). Overall, 25/55 patients (45,5%) achieved a complete remission (CR) after one course of MEC chemotherapy. Twelve patients (21.9%) achieved MRD negativity and 13 patients (23,6%) obtained an MRD+ CR or had no MRD test. Six patients (10,9%) had a partial response (PR) and 1 patient (1,8%)had hematological improvement (HI). Four patients (7.3%) died during post-MEC aplastic phase. Disease risk at diagnosis and R/R status did not influence the chance to obtain CR (figure 1 A). In 12 patients, a second MEC was administered. Four out of 12 patient improved their response with the 2nd MEC (2 patients obtained MRD - from MRD+ CR, 1 patient obtained PR and 1 patients obtained CR from hematological improvement). MEC was an effective bridge to SCT, 32/55 patients (58,2%, figure 1 B), received SCT; 15/32 patients (46,9%) received SCT directly after the 1st course of MEC, 9/32 patients (28,1%) after the 2nd course of MEC and 2 patients (6,3%) after an additional course of post-remission chemotherapy. Of note, only 6 patients (18,8%), who were not responsive to MEC, underwent SCT after an alternative rescue therapy. Median overall survival (OS) from MEC was 455 days (95% C.I. 307-602 days.); 1-year OS, 3-year OS and 5-years OS were 57,9%, 33,2% and 23,1%, respectively (std. error ± 0,067). Patients who responded to MEC (CR MRD+ or CR MRD- after 1 or 2 courses) had better OS than non-responders (median OS 1389 vs 160 days, p=.003). Stepwise multiple logistic regression analysis with COX-HR model established that pre-MEC R/R status, diagnosis class risk, response to one or two courses of MEC, and SCT were independent predictors of survival in the optimal model. Conclusions Taken together, our data indicate that MEC is an effective salvage regimen with affordable toxicity, and gives a high chance to obtain CR. MEC is particularly useful as a bridge to SCT, and has to be considered as a rescue therapy whenever a clinical trial is not available. *GM and AT equally contributed Disclosures Martinelli: Ariad/incyte: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Roche: Consultancy. Cavo:Takeda: 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; AbbVie: 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; 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.