Abstract: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P 〈 .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P 〈 .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

Abstract: Multiple Myeloma (MM) maintenance therapy is a low intensive, prolonged treatment, commonly administered to newly diagnosed patients (pts) at the end of fixed-time, front-line regimens. Lenalidomide (LEN) is considered the best available maintenance option for MM able to prolong pts survival. However, the actual benefits or disadvantages of a LEN-based continuous maintenance and its potential role as selective pressure able to induce genomic changes are still unclear. The identification of specific therapy-driven modifications has been so far prevented by the scarce number of homogeneously-treated cohorts of pts with paired samples (diagnosis, D and relapse, R). In this study we estimated the role of LEN maintenance therapy in eliciting genomic changes in a cohort of MM pts homogeneously up-front treated with PI-based regimens. Whole genome Copy Number Aberrations (CNAs) landscape was obtained by SNPs array in 54 pts whose BM-CD138+ were collected both at D and at first R. Pts had an high-risk (HR) disease, as defined both by the presence of HR cytogenetic aberration at baseline in 81% of pts and by the 29 m median TTP. RawCopy 1.10 was used for the segmentation of SNPs array signals; samples' purity was adjusted by using manually reviewed ASCAT solutions. A custom gene-level CN calling approach was set up, to match every gene's CN value at D and R, thus generating genomic evolutive patterns based on changes of these values. Finally, high-risk genomic loci were computed using GISTIC 2.0_v7 to derive focal regions with oncogene and/or tumor suppressor genes relevant for MM biology. After induction therapy, 31/54 pts were treated with HD chemotherapy followed by either single or double ASCT; LEN maintenance therapy was then offered both to 20/31 auto-transplanted and to 6/23 not auto-transplanted pts. Three main evolutive trajectories (linear L, drift D, and branching B) were defined according to the CN changes' direction, reflecting a putative positive, negative, or both positive and negative selective pressure, respectively. A fourth, stable (S) trajectory was also observed, characterized by the absence of CN changes between D and R. Overall, 29, 15 and 10 pts relapsed with B/D, L and S pattern, respectively; at R, all LEN-treated pts quantitively and qualitatively changed their sub-clonal architecture: a B/D evolutive pattern characterized 70% of pts. By contrast, genome remained mostly stable in 61% of not-treated pts. We then focused on CN changes of specific chromosomal regions and/or genomic loci, whose prognostic role has been already established in MM (i.e. CN losses of TP53 on chr17p, RB1 on chr13q, CYLD on chr16q, CDKN2C and FAM46C on chr1p; CN gain of CKS1B on chr1q). When present at D these CNAs tended to persist throughout the disease course regardless of whether pts received or not maintenance. The emersion of any of these CNAs at R was widely observed both in pts receiving or not maintenance, whereas a negative selective pressure over them was more likely to occur in pts receiving maintenance, as compared to the others (50% vs 11% of B/D trajectories in LEN-treated vs not-treated pts, respectively). Strikingly, in LEN-treated pts, the extension of both TTP and OS was favored by the extinction and/or negative selection of the HR CNAs (B/D patterns), and shortened by their stability or positive selection (L/S patterns) (median TTP 46 vs 32 m HR=3,6 CI 1,2-10,6, p=0.01; median OS 111 vs 63 m HR 5,7 CI 1,1-32,4, p=0.04 in B/D vs L/S pts, respectively). On the contrary, the absence of maintenance selective pressure seemed to affect neither the evolution trajectory, nor the clinical course of not-treated pts (fig 1). The extinction of sub-clones carrying HR lesions in pts receiving maintenance therapy is likely to be associated to the negative selection exerted by the therapy itself. This might explain the extended survival of pts receiving maintenance and relapsing with B/D evolution patterns, as compared to that of pts whose genomic landscape either tended to remain stable or let the prevalent emersion of HR genomic features. On the contrary, the sub-clonal architecture of pts not receiving maintenance seemed to randomly evolve, due to the absence of a specific therapy-related selective pressure. Overall, information on the genomic changes occurring throughout the disease course might be relevant for the recognition of pts most benefitting from a continuous therapy. Thanks to AIRC_IG2014-15839, RF-2016-02362532 Disclosures Zamagni: Takeda: Honoraria, Speakers Bureau; Sanofi: Honoraria, Other: Advisory Board, Speakers Bureau; Janssen: Honoraria, Other: Advisory board, Speakers Bureau; Amgen: Honoraria, Other: Advisory board, Speakers Bureau; BMS: Honoraria, Other: Advisory Board, Speakers Bureau; Celgene Corporation: Honoraria, Other: Advisory board, Speakers Bureau. Tacchetti:BMS: Honoraria; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria; Oncopeptides: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Mancuso:Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Petrucci:Janssen-Cilag: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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. Liberati:Incyte: Consultancy; Servier: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol & Mayer: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Rossi:Roche: 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria. Cavo:amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; 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; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background The role of consolidation treatment for newly diagnosed, transplant eligible MM (NDMM) patients has never been prospectively addressed in a randomised trial. Methods The EMN02/HOVON95 trial was designed to compare intensification therapy using 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) plus single or double autologous stem cell transplantation (ASCT), after induction with VCD (R1) (M. Cavo et al. Lancet Haemat 2020, 7, e456-68). A second randomisation was performed after intensification for consolidation treatment with 2 cycles of bortezomib-lenalidomide-dexamethasone (VRD) vs no consolidation (R2), in both arms followed by lenalidomide (10 mg) maintenance until progression or unacceptable toxicity. Patients assigned to consolidation treatment received two 28-day cycles of VRD, each comprising bortezomib (1·3 mg/m2 either i.v. or s.c., on days 1, 4, 8, and 11) combined with lenalidomide (25 mg orally, on days 1 through 21), and dexamethasone (20 mg orally, on days 1, 2, 4, 5, 8, 9, 11, and 12). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. Secondary endpoints included response and survival. Here we report the final analysis for R2 which was performed in July 2020. Results From February 2011 to April 2014, 1503 pts aged ≤ 65 years with symptomatic MM were enrolled in 172 EMN centres, of whom 1500 were eligible. Of these, 1212 were randomised (stratification by ISS stage) to VMP (495 pts) or HDM (1 or 2 ASCT) (702 pts). For R2 894 patients were eligible, of whom 878 had also been included in R1. These 878 patients were randomised to consolidation (451 pts) or no consolidation (427 pts). Median follow-up from R2 was 71.3 months (IQR 63-80). Response status at time of R2 was equal in both arms, ie ≥ CR (20%), ≥ VGPR (67%), ≥ PR (92%). At the time of this final analysis, 512 events for PFS after R2 had been reported. 5-year PFS from R2 was 50% (95% confidence interval (CI) 45-55) with consolidation and 42% (95% CI 37-46) without, while median PFS from R2 was 59 vs 43 months, respectively. PFS from R2 with adjustment for R1 was prolonged in pts randomised to VRD consolidation (hazard ratio (HR)=0.80; 95% CI=0.67-0.95; P=0.013), which is consistent with the results of the first and second interim analyses (P. Sonneveld et al. ASH 2016, abstract #242; EHA 2018, abstract #1525). With Cox regression analysis revised ISS3 stage (HR 2.05, 95%CI 1.43-2.92) and ampl1q (HR 1.68, 95%CI 1.38-2.06) were adverse prognostic factors at diagnosis. The PFS benefit was observed across most predefined subgroups, including revised ISS stage I-III, standard-risk cytogenetics and both treatment arms of the first randomisation (VMP or HDM treatment). The median duration of maintenance treatment was 33 months (0-97+ months), with 32% of patients still on treatment at 5 years after start of lenalidomide. The secondary endpoint response & gt;=CR after consolidation vs no consolidation before start of maintenance was 34% vs 18%, respectively (p & lt;0.001) Overall response & gt;=CR on protocol was 59% with consolidation and 45% without, respectively (p & lt;0.001). At 4 years from R2 overall survival (OS) was 81-82% in both arms, while at 6 years OS was 75% (95% CI 71-79) in the consolidation arm versus 69% (95% CI 64-73) without consolidation, indicating that longer follow-up is required. Toxicity from VRD was acceptable and manageable with 5% CTCAE grade 4, mainly neutropenia (2%) and thrombocytopenia (2%). The cumulative incidence of second primary malignancies at 6 years from R2 excluding superficial skin cancer was 5-6% in both arms. Conclusions Consolidation treatment with VRD followed by continuous lenalidomide maintenance improves PFS and quality of response in NDMM as compared to maintenance alone. The rate of toxicity and second primary malignancies is acceptable. This study is registered with EudraCT number 2009-017903-28 and ClinicalTrials.gov NCT01208766, and has completed recruitment. This independent trial was supported by the Dutch Cancer Society (grant 2010-4798), and unrestricted grants from Celgene and Janssen Figure Disclosures Sonneveld: Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Ludwig:Takeda: Research Funding; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau; Seattle Genetics: Other: Advisory Boards. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Hajek:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria. Gay:GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: 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; Bristol-Myers Squibb: Honoraria, 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; 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. Mellqvist:Janssen. Celgene, Amgen: Honoraria. Schjesvold:Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Offidani:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Boccadoro: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; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees.

Abstract: BACKGROUND MM patients (pts) are characterized by a prevalence of aneuploidies and Copy Number Alterations (CNAs) broadly scattered over the whole genome. Along with translocations and/or single nucleotide variants, they account for the MM-distinctive genomic heterogeneity, which characterizes the onset of symptomatic MM and identifies each pts. AIM. To deeply explore the genomic landscape of newly diagnosed, homogeneously treated MM pts, to assess the prognostic relevance of whole genome aneuploidies, CNAs, and structural aberrations. PATIENTS AND METHODS 344 highly purified BM CD138+ samples were profiled by SNPs array. R scripts were employed to analyse genomic data. Pts, enrolled in the EMN02 phase III trial, were randomized to receive VMP (121 pts) or high-dose MEL and autologous stem cell transplantation (223 pts), after bortezomib-based induction. At a median follow-up of 46 months (m), the estimated PFS and OS rates were 55% and 83%, respectively. RESULTS To evaluate the contribution of each genomic variables to the overall pts variability, a Principal Component Analysis of the whole genome’s numerical and structural aberrations was performed, highlighting that a “common ground” of at least 4 chromosomal aberrations (hyperdiploidy, H, 13qCN loss, IgH-t and 1qCN gains) was sufficient to describe and resume the MM overall genomic heterogeneity. Therefore, since 13qCN loss and 1qCN gains co-segregate, 3 pts sub-types might be identified, partially overlapping, even though well-defined by the presence of either H, or IgH-t or 13qCN loss and 1qCN gain. Outcomes of the latter MM sub-type was explored. Pts carrying 13qCN loss and 1qCN gain were characterized by the presence of several small deletions in MM-critical genes (YAP1, TRAF3, CYLD), and by the markedly de-regulated expression of CCND2 and CCND1 (as evaluated by the analysis of CoMMpass-derived RNAseq expression dataset). Their 46-m PFS and OS estimates were shorter as compared to that of patients carrying either just one or any of these CNAs (PFS: 39%, 44% and 73%, respectively; p=0.0001. OS: 68%, 83% AND 91%; p=0.0001). PFS and OS hazard ratios (HR) of pts carrying 13qCN loss and 1qCN gain (PFS: 1.76; OS: 2.24) were comparable to that of pts carrying either del(17p) (PFS: 2.1; OS: 2.1) or t(4;14) (PFS: 1.80; OS: 1.7), resulting as an independent factor predicting both PFS and OS in a Cox multivariate analysis. Survival data were confirmed on additional SNPs array data derived from 151 unrelated MM pts not included in the EMN02 trial, as well as on 700 pts, whose CNAs data were extrapolated from the MMRF CoMMpass Study dataset. CONCLUSIONS We propose a simple way to stratify MM pts, according to the detection of 2 CNAs, which is able to select pts with high (25%) and with low (40%) risk of progression and/or death, allowing to predict the clinical outcome in most MM pts. Supported by AIRC, Fond. del Monte Bo-Ra, Fond. Berlucchi, BO-AIL, Harmony Citation Format: Carolina Terragna, Marina Martello, Andrea Poletti, Vincenza Solli, Enrica Borsi, Rosalinda Termini, Lucia Pantani, Elena Zamagni, Giulia Marzocchi, Paola Tacchetti, Nicoletta Testoni, Serena Rocchi, Luca Cifarelli, Luca Dozza, Giovanni Martinelli, Michele Cavo. Chromosomal instability and bad prognosis both connote a multiple myeloma (MM) sub-type carrying 13qCN loss and 1qCN gain [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 470.

Abstract: Background: Urinary tract infection (UTI) represents one of the most common infectious diseases and a major cause of antibiotic prescription in children. To prevent recurrent infections and long-term complications, low-dose continuous antibiotic prophylaxis (CAP) has been used. However, the efficacy of CAP is controversial. The aim of this document was to develop updated guidelines on the efficacy and safety of CAP to prevent pediatric UTIs. Methods: A panel of experts on pediatric infectious diseases, pediatric nephrology, pediatric urology, and primary care was asked clinical questions concerning the role of CAP in preventing UTIs in children. Overall, 15 clinical questions were addressed, and the search strategy included accessing electronic databases and a manual search of gray literature published in the last 25 years. After data extraction and narrative synthesis of results, recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Results: The use of CAP is not recommended in children with a previous UTI, with recurrent UTIs, with vesicoureteral reflux (VUR) of any grade, with isolated hydronephrosis, and with neurogenic bladder. CAP is suggested in children with significant obstructive uropathies until surgical correction. Close surveillance based on early diagnosis of UTI episodes and prompt antibiotic therapy is proposed for conditions in which CAP is not recommended. Conclusions: Our systematic review shows that CAP plays a limited role in preventing recurrences of UTI in children and has no effect on its complications. On the other hand, the emergence of new antimicrobial resistances is a proven risk.

Abstract: 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 〈 0.001) and 60% (HR=0.68, 95% CI=0.51-0.90; p=0.007), respectively, compared with TD (corresponding values, 17% and 46%), representing a 38-32% reduction in the risk of progression and death with VTD. Outcome benefits with VTD were seen for patients with high-risk cytogenetic abnormalities (HCRA), including t(4;14) and/or del(17p) by FISH, (PFS: 17% vs 3% at 10 yrs, HR=0.45, 95% CI=0.30-0.69; p 〈 0.001; OS: 42% vs 22% at 10 yrs, HR=0.54, 95% CI=0.34-0.88; p=0.011) and lacking HRCA (PFS: 40% vs 20%, HR=0.60, 95% CI=0.46-0.79; p 〈 0.001; OS: 67% vs 52%, HR=0.66, 95% CI=0.46-0.95; p=0.025). On multivariate Cox regression analysis, randomization to VTD predicted for both prolonged PFS (HR=0.60, 95% CI=0.48-0.76; p 〈 0.001) and OS (HR=0.68, 95% CI=0.50-0.91; p=0.010). Specific multivariate regression analysis not including therapy revealed that the leading factors adversely affecting PFS were the presence of HRCA (HR=1.86, 95% CI=1.45-2.38; p 〈 0.001), ISS stage II+III (HR=1.38, 95% CI=1.10-1.74; p=0.006), and failure to achieve CR as time-dependent variable (HR=2.01, 95% CI=1.59-2.53; p 〈 0.001). The three variables were used to build a scoring system that stratified patients into three risk groups with divergent clinical outcomes: low-risk (LR) (22%, none of the 3 adverse variables), intermediate-risk (IR) (39%, 1 adverse variable), and high-risk (HR) (39%, 2 or 3 adverse variables). Estimated 10-yr PFS rates were 44% for patients in LR, 28% for IR, and 9% for HR (p 〈 0.001). Estimated 10-yr OS rates were 76%, 58%, and 32%, respectively (p 〈 0.001). Consensually, the prognostic score identified three groups with statistically different PFS and OS within the TD and VTD arm (p 〈 0.001). On VTD, the 10-yr PFS and OS rates were 51% and 79% for LR, 41% and 62% for IR, 13% and 43% for HR, respectively. Randomization to receive VTD was associated with longer PFS for the IR (41% vs 15% at 10 yrs, HR=0.50, 95% CI=0.34-0.73; p 〈 0.001) and HR (13% vs 7% at 10 yrs, HR=0.66, 95% CI=0.47-0.92; p=0.015) subgroups compared with TD. Moreover, HR patients assigned to VTD had significantly longer OS in comparison with the same group of patients on TD (43% vs 23% at 10 yrs, HR=0.65, 95% CI=0.43-0.97; p=0.033). Assessment of conditional survival revealed that the probability of surviving without progression a further 2 yrs improved progressively after 36 months, being 65% and reaching the 91% at 96 months (p value for trend=0.009). The conditional PFS became superimposable after 78 months for the LR and IR (87% and 86%, respectively), while resulted significantly lower in the HR (62.5%) (p=0.008). 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.

Abstract: BACKGROUND: Multiple Myeloma (MM) maintenance therapy is a low intensive, prolonged treatment, commonly administered to newly diagnosed patients (pts) at the end of front-line regimens. Lenalidomide (LEN) is considered the best available maintenance option for MM, the actual benefits or disadvantages of a LEN-based maintenance and its potential role as “selective pressure” on MM sublcones are still unclear. AIM: In this study we estimated the role of LEN maintenance therapy in eliciting genomic changes in a cohort of MM pts homogeneously up-front treated. PATIENTS-METHODS: Whole genome Copy Number Alterations (CNA) was obtained by SNPs array in 54 pts samples collected both at diagnosis(D) and at first relapse(R). Pts had an high-risk (HR) disease, defined by a median TTP of 29m. A custom gene-level CN calling algorithm was set up, to compute the evolution of every gene CN value and the genomic evolutive trajectories associated to changes of these values. High-risk genomic loci were defined using GISTIC to derive target genomic relevant for MM biology. After PIs induction therapy, 31/54 pts were treated with HD chemotherapy followed by either single or double ASCT; LEN maintenance therapy was then offered both to 20/31 auto-transplanted and to 6/23 not auto-transplanted pts. RESULTS: Three main evolutive trajectories (linear L, drift D, and branching B) were defined according to the CN changes' direction, reflecting a putative positive, negative, or both positive and negative selective pressure, respectively. A fourth, stable (S) trajectory was also observed, characterized by the absence of CN changes. Overall, 29, 15 and 10 pts relapsed with B/D, L and S pattern, respectively; at R, all LEN-treated pts changed their sub-clonal architecture: a B/D evolutive pattern characterized 70% of pts. By contrast, genome remained mostly stable in 61% of not-treated pts. We then focused on CN changes of specific chromosomal regions and/or genomic loci identified as high-risk, whose prognostic role has been already established in MM (i.e. TP53, CDKN2C, CKS1B). When present at D, these CNA tended to persist throughout the disease course, regardless of whether pts received or not maintenance. The emersion of any of these CNAs at R was widely observed both in pts receiving or not maintenance, whereas a negative selective pressure over them was more likely to occur in pts receiving maintenance, as compared to the others (50% vs 11% of B/D trajectories in LEN-treated vs not-treated pts, respectively). Strikingly, in LEN-treated pts, the extension of both TTP and OS was favored by the extinction and/or negative selection (B/D patterns) of the HR CNAs, and shortened by their stability or positive selection (L/S patterns) (median TTP 46 vs 32m HR=3.6, p=0.01; median OS 111 vs 63m HR 5.7, p=0.04 in B/D vs L/S pts, respectively). On the contrary, the absence of maintenance selective pressure seemed to affect neither the evolution trajectory, nor the clinical course of not-treated pts. CONCLUSION: The extinction of sub-clones carrying HR lesions in pts receiving maintenance therapy is likely to be associated to the negative selection exerted by the therapy. This might explain the extended survival of these pts. On the contrary, the subclones of pts not receiving maintenance might randomly evolve, due to the absence of a specific selective pressure. Citation Format: Andrea Poletti, Vincenza Solli, Marina Martello, Enrica Borsi, Lucia Pantani, Agboyi Lakpo, Silvia Armuzzi, Luca Nunzio Cifarelli, Elena Zamagni, Paola Tacchetti, Serena Rocchi, Katia Mancuso, Ilaria Rizzello, Giulia Marzocchi, Nicoletta Testoni, Luca Dozza, Maria Teresa Petrucci, Anna Marina Liberati, Giuseppe Rossi, Mario Boccadoro, Michele Cavo, Carolina Terragna. Negative selective pressure exerted by maintenance therapy promotes the extinction of sub-clones carrying high-risk lesions in multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2700.

Abstract: Postoperative atrial fibrillation (POAF) occurs in 30% to 50% of patients undergoing cardiac surgery and is associated with increased morbidity and mortality. Prospective identification of structural/molecular changes in atrial myocardium that correlate with myocardial injury and precede and predict risk of POAF may identify new molecular pathways and targets for prevention of this common morbid complication. Methods: Right atrial appendage samples were prospectively collected during cardiac surgery from 239 patients enrolled in the OPERA trial (Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation), fixed in 10% buffered formalin, and embedded in paraffin for histology. We assessed general tissue morphology, cardiomyocyte diameters, myocytolysis (perinuclear myofibril loss), accumulation of perinuclear glycogen, interstitial fibrosis, and myocardial gap junction distribution. We also assayed NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT, CRP (C-reactive protein), and circulating oxidative stress biomarkers (F2-isoprostanes, F3-isoprostanes, isofurans) in plasma collected before, during, and 48 hours after surgery. POAF was defined as occurrence of postcardiac surgery atrial fibrillation or flutter of at least 30 seconds duration confirmed by rhythm strip or 12-lead ECG. The follow-up period for all arrhythmias was from surgery until hospital discharge or postoperative day 10. Results: Thirty-five percent of patients experienced POAF. Compared with the non-POAF group, they were slightly older and more likely to have chronic obstructive pulmonary disease or heart failure. They also had a higher European System for Cardiac Operative Risk Evaluation and more often underwent valve surgery. No differences in left atrial size were observed between patients with POAF and patients without POAF. The extent of atrial interstitial fibrosis, cardiomyocyte myocytolysis, cardiomyocyte diameter, glycogen score or Cx43 distribution at the time of surgery was not significantly associated with incidence of POAF. None of these histopathologic abnormalities were correlated with levels of NT-proBNP, hs-cTnT, CRP, or oxidative stress biomarkers. Conclusions: In sinus rhythm patients undergoing cardiac surgery, histopathologic changes in the right atrial appendage do not predict POAF. They also do not correlate with biomarkers of cardiac function, inflammation, and oxidative stress. Graphic Abstract: A graphic abstract is available for this article.

Abstract: The International Myeloma Working Group (IMWG) guidelines recommend using electrophoresis and immunofixation to define response and progressive disease (PD) in immunoglobulin (Ig) secretory multiple myeloma (Ig‐MM), whereas the role of serum‐free light chain (sFLC) is controversial. We retrospectively analyzed the value of adding sFLC assays in the definition of response and PD according to IMWG criteria in 339 Ig‐MM patients treated with a first‐line novel agent‐based therapy (median follow‐up 54 months). sFLC PD was defined according to conventional criteria plus increased sFLC levels, or sFLC escape (sFLCe); progression/sFLCe‐free survival (ePFS) was the time from the start of treatment to the date of first PD or sFLCe, or death; overall survival after PD/sFLCe (OS after Pe) was the time from first PD or sFLCe to the date of death. 148 (44%) patients achieved a complete response and 198 (60%) a normal sFLC ratio (sFLCR). sFLCR normalization was an independent prognostic factor for extended PFS (HR = 0.46, p  = 0.001) and OS (HR = 0.47, p  = 0.006) by multivariable analysis. 175 (52%) patients experienced PD according to the IMWG criteria, whereas 180 (53%) experienced PD or sFLCe. Overall, a sFLCe was observed in 31 (9%) patients. Median PFS and ePFS were both equal to 36 (95% CI = 32–42, and 32–40, respectively) months. sFLC PD adversely affected the OS after Pe compared to PD with increasing monoclonal Ig only (HR = 0.52, p  = 0.012). Our results support the inclusion of the sFLC assay for defining response and PD in Ig‐MM.