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Immunoglobulin light chain (AL) amyloidosis is caused by a small, minimally proliferating B-cell/plasma-cell clone secreting a patient-unique, aggregation-prone, toxic light chain (LC). The pathogenicity of LCs is encrypted in their sequence, yet molecular determinants of amyloidogenesis are poorly understood. Higher rates of N-glycosylation among clonal κ LCs from patients with AL amyloidosis compared to other monoclonal gammopathies indicate that this post-translational modification is associated with a higher risk of developing AL amyloidosis. Here, we exploited LC sequence information from previously published amyloidogenic and control clonal LCs and from a series of 220 patients with AL amyloidosis or multiple myeloma followed at our Institutions to define sequence and spatial features of N-glycosylation, combining bioinformatics, biochemical, proteomics, structural and genetic analyses. We found peculiar sequence and spatial pattern of N-glycosylation in amyloidogenic κ LCs, with most of the N-glycosylation sites laying in the framework region 3, particularly within the E strand, and consisting mainly of the NFT sequon, setting them apart with respect to non-amyloidogenic clonal LCs. Our data further support a potential role of N-glycosylation in determining the pathogenic behavior of a subset of amyloidogenic LCs and may help refine current N-glycosylation-based prognostic assessments for patients with monoclonal gammopathies.

Despite the recent approval of novel immunotherapies, as immunomodulatory drug, proteasome inhibitors and anti-CD38 monoclonal antibodies, Multiple Myeloma (MM) remains incurable and the acquisition of triple-refractoriness leads to really dismal outcomes, in even earlier lines of therapy. More recently, innovative therapeutic strategies targeting B cell maturation antigen (BCMA), highly expressed on the plasma cell surface, are drawing different future landscapes in terms of effectiveness and outcomes. Belantamab Mafodotin, a first-in-class anti-BCMA antibody drug conjugates, demonstrated good efficacy and safety profile in triple-refractory patients in the phase 2 DREAMM-2 trial and it was approved for the treatment of MM triple-exposed patients with >4 prior lines of therapy. Here, starting from Belantamab Mafodotin clinical trials also exploring combination studies and different schedules in order to improve its efficacy and toxicity, we focused on real life experiences all over the world, which have confirmed clinical trial data and encourage further Belantamab Mafodotin investigations

Multiple myeloma (MM) is a plasma cell disorder that develops in the bone marrow (BM) and is characterized by uncontrolled proliferation and the ability to disseminate to different sites of the skeleton. Sialofucosylated structures, particularly Sialyl Lewis a/x (SLea/x), facilitate the homing of MM cells into the BM, leading to resistance to bortezomib in vivo. Platelets have been shown to play an important role in tumor metastasis. Platelets can bind to the surface of cancer cells, forming a “cloak” that protects them from the shear stress of the bloodstream and natural killer (NK) cell-mediated cytotoxicity. In this study, we showed that the presence of SLea/x induced a strong binding of MM cells to P-selectin, leading to specific and direct interactions with platelets, which could be inhibited by a P-selectin-blocking antibody. Importantly, platelets surrounded SLea/x-enriched MM cells, protecting them from NK cell-mediated cytotoxicity. The interactions between the platelets and MM cells were also detected in BM samples obtained from MM patients. Platelet binding to SLea/x-enriched MM cells was increased in patients with symptomatic disease and at relapse. These data suggest an important role of SLea/x and platelets in MM disease progression and resistance to therapy.

Lenalidomide and dexamethasone (Rd)-based triplets, in particular carfilzomib-Rd (KRd) and daratumumab-Rd (DaraRd), represent a standard of care in lenalidomide-sensitive multiple myeloma (MM) patients in first relapse. Meta-analysis of randomized clinical trials (RCT), suggested better outcome with DaraRd. Trying to address this issue in clinical practice, we collected data of 430 consecutive MM patients addressed to Rd-based triplets in first relapse between January 2017 and March 2021. Overall, the most common used regimen was DaraRd, chosen in almost half of the cases (54.4%), followed by KRd (34.6%). Different triplets were used much less commonly. In an attempt to limit the imbalance of a retrospective analysis, we conducted a propensity score matching (PSM) comparison between DaraRd and KRd. After PSM, efficacy of DaraRd versus KRd was similar in terms of overall-response rate (ORR) (OR: 0.9, P=0.685) as well as of very good partial response (VGPR) or better (OR: 0.9, P=0.582). The median progression-free survival (PFS) was significantly longer for DaraRd (29.8 vs. 22.5 months; P=0.028). DaraRd was tolerated better, registering a lower rate of grade 3-4 non-hematological toxicity (OR: 0.4, P

Prognostic role of chromosomal translocations (CT) in myelodysplasia (MDS) was retrospectively analyzed in 77 patients from GROM-L registry. Forty (51.9%) balanced, 28 (36.4%) unbalanced and 9 (11.7%) concomitant balanced and unbalanced CT were identified. Five-year overall survival (OS) of the entire cohort was 34.5% (CI 95% 22.5-46.5). Five-year OS of patients with unbalanced CT was significantly shorter than that of patients carrying balanced CT [22.3% (CI 95% 4.0-40.6) vs 44.0% (CI 95% 26.7-61.3) (

High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is the standard treatment for young patient ≤65 years with multiple myeloma (MM). The role of auto-SCT in elderly patients older than 70 years remains controversial in the era of novel agents and especially since the recent introduction of monoclonal antibodies (AbMo). In this study, we evaluated 12 patients with MM over 70 years old undergoing auto-SCT (elderly graft cohort) in seven centers of GIMEMA Working Group Lazio. We compared the baseline characteristics, treatment and outcome with 97 MM elderly patients who did not receive auto-SCT (nontransplant patients) from the same registry who were ≥ 70 years old, but did not undergo auto-SCT. The median progression free survival (PFS) for graft versus no-graft cohort was 56.4 versus 26.1 months, respectively. There was a trend for better PFS among graft compared to nontransplant patient (p = .1). On the other hand, the median overall survival for transplant versus nontransplant cohort was 107.6 versus 49.5 months (p = .02). Despite the small number of patients aged ≥70 years and ≤74 years, it seems that auto-SCT is well tolerated, safe and effective. Therefore, we propose that it should be considered an important treatment option in the era of new drugs in elderly fit patients with MM.

PURPOSE High levels of circulating tumor plasma cells (CTC-high) in patients with multiple myeloma are a marker of aggressive disease. We aimed to confirm the prognostic impact and identify a possible cutoff value of CTC-high for the prediction of progression-free survival (PFS) and overall survival (OS), in the context of concomitant risk features and minimal residual disease (MRD) achievement. METHODS CTC were analyzed at diagnosis with two-tube single-platform flow cytometry (sensitivity 4 × 10–5) in patients enrolled in the multicenter randomized FORTE clinical trial (ClinicalTrials.gov identifier: NCT02203643 ). MRD was assessed by second-generation multiparameter flow cytometry (sensitivity 10–5). We tested different cutoff values in series of multivariate (MV) Cox proportional hazards regression analyses on PFS outcome and selected the value that maximized the Harrell's C-statistic. We analyzed the impact of CTC on PFS and OS in a MV analysis including baseline features and MRD negativity. RESULTS CTC analysis was performed in 401 patients; the median follow-up was 50 months (interquartile range, 45-54 months). There was a modest correlation between the percentage of CTC and bone marrow plasma cells ( r = 0.38). We identified an optimal CTC cutoff of 0.07% (approximately 5 cells/µL, C-index 0.64). In MV analysis, CTC-high versus CTC-low patients had significantly shorter PFS (hazard ratio, 2.61; 95% CI, 1.49 to 2.97, P < .001; 4-year PFS 38% v 69%) and OS (hazard ratio, 2.61; 95% CI, 1.49 to 4.56; P < .001; 4-year OS 68% v 92%). The CTC levels, but not the bone marrow plasma cell levels, affected the outcome. The only factor that reduced the negative impact of CTC-high was the achievement of MRD negativity (interaction P = .039). CONCLUSION In multiple myeloma, increasing levels of CTC above an optimal cutoff represent an easy-to-assess, robust, and independent high-risk factor. The achievement of MRD negativity is the most important factor that modulates their negative prognostic impact.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with the majority of cases being of B lineage [1]. B-cell precursor ALL (BCP-ALL) is a heterogeneous disease in which risk ass...

CD38 is a transmembrane glycoprotein expressed on the surface of different cell lines with several functions (receptor, adhesion molecule, ectoenzyme). Based on its high expression in multiple myeloma cells, CD38 is one of the main molecules used in the target therapy age. Daratumumab is the first fully human monoclonal antibody tested in clinical trials, showing efficacy in relapsed/refractory multiple myeloma patients, especially in combination with immunomodulants and/or proteasome inhibitors. The synergic effect concerns multiple myeloma cells as well as the microenvironment (NK cells, macrophage, regulatory B/T cells and CD8+ effector cells). Therefore, the anti-multiple myeloma activity of Daratumumab greatly depends on the immune system: this is the reason why several ongoing clinical trial are testing its efficacy in the naïve patients, with a more effective immune system.

Venous thromboembolism is a common complication of patients with hematologic malignancies, due both to release of procoagulant factors by tumor cells and to external factors, such us drugs. In multiple myeloma patients, the risk is increased by use of immunomodulants, especially when associated to multidrug therapy, during the induction phase. Prevention of venous thromboembolism in myeloma patients is highly recommended but specific guidelines are still lacking. The most common approach is to stratify the thrombotic risk according to individual, myeloma-related and therapy-related risk factors and to use aspirin for all patients, except those with two or more thrombotic risk factors who should be treated with traditional oral or parenteral anticoagulant. A more controversial approach indicates for prophylaxis either anticoagulant or aspirin, regardless of risk stratification. Recent trials investigate prophylaxis in myeloma patients with direct oral anticoagulants, based on studies showing efficacy and safety of this new class of drugs in the treatment and prophylaxis of thrombosis in patients with any malignancy. The results of these trials are encouraging but they need to be confirmed by larger studies. An international consensus about best prophylaxis to prevent venous thromboembolism in patients with multiple myeloma on treatment is still missing. Therefore, thrombosis in multiple myeloma remains an ongoing issue.

Background. The overall survival (OS) of multiple myeloma (MM) patients (pts) has improved over the years due to the introduction of several novel drugs, such as proteosome inhibitors (PI), immunomodulatory drugs (IMiDs) and, more recently, anti-CD38 monoclonal antibodies (moAb). Nevertheless, the majority of pts continues to relapse, and MM remains an incurable disease. To date, no standard of care has been established for relapsed/refractory (RR) MM pts who have been exposed to the main anti-myeloma drugs. Currently, these pts have a limited number of available treatment options and represent an unmet medical need. Moreover, the outcome of pts failing standard of care regimens, which is now defined as triple-refractory (including PI, IMiDs and moAb), is poor, with a median progression free survival (PFS) of 3-4 months and OS of 8-9 months. Novel therapeutic strategies with different mechanisms of action are warranted to overcome the natural occurrence of relapse or therapy resistance in RR MM pts. Immunotherapy, especially T-cell based approaches, represents the emerging therapeutic strategy for this subset of pts. Chimeric antigen receptor (CAR)-modified T cells are a promising new therapy approach for triple refractory RRMM. Different constructs and specific CAR-T targets are being studied, but BCMA-directed CAR-T cells have so far provided the most convincing evidence of activity, with one product (idecabtage vicleucel) recently approved by FDA. Aims. The primary endpoint of this observational and retrospective study was to define the clinical characteristics and outcome of a cohort of RR MM pts potentially eligible to CAR-T cell treatment according to the KarMMa trial criteria 1. Secondary endpoints were aimed at defining specific factors influencing CAR-T cell therapy eligibility and at identifying a real-life estimate of RRMM pts truly eligible for CAR-T cells. Methods and Results. This is a cohort analysis that used electronic REDCap, a data capture tool hosted at the Sapienza University, on RRMM pts managed between January 2018 and July 2021 at 4 Italian Centers of the Multiple Myeloma GIMEMA Lazio Group. At the time of data collection, 47 RRMM pts had underwent at least 3 prior therapy regimens; they had received a previous PI, IMiDs and a moAb and were considered refractory to the last regimen. The clinical characteristics are listed in Table 1. Median age was 68 years (43-86), 27 (61%) pts were >65 years; 27 (57%) were male. Of 47 pts, 33 (68%) were ECOG 0-1 and 14 (30%) were ECOG ³2; 21 pts (44%) were ISS III. The majority of pts, 28 (59%), had undergone an autologous stem cell transplantation; 31 pts (65%) had received 3 prior lines of therapy and 16 (34%) >3 prior lines of therapy. Thirty-seven (78%) were triple-refractory and 8 (17%) were penta-refractory. Based on the KarMMa trial criteria, 22/47 pts (47%) would be defined as eligible and 25 (53%) not eligible for CAR-T cell therapy. Specifically, 14 (30%) pts were not eligible because of an ECOG ³2, 24 (62%) had an organ dysfunction such as impaired renal function (eGFR After a median follow-up of 34.7 months (mo) (0-53.8), the median OS for the entire cohort was 21.7 mo (95% CI: 14.2-36.9) (Fig. 1). The median OS was 30.7 mo (95%, CI: 14.21-NA) in eligible pts vs 16.2 mo (95%, CI: 6.28-NA) in non-eligible pts (p=0.002) (Fig.2). The median PFS of the entire cohort was 7.7 mo (95%, CI: 5.39-13.85) (Fig. 3) and the median PFS was 7.8 mo (95%, CI: 5.16-19.1) in eligible pts vs 6.5 mo (95%, CI: 3.36-NA) (p=0.513) in non-eligible pts (Fig.4). Conclusions. Despite the limits of a retrospective study and a limited cohort, our real-life analysis shows that heavily treated pts with RRMM are less likely to be eligible for CAR-T cell therapy. Considering the emergent role of quadruplet combined approaches for first-line therapy and given the therapeutic relevance of CAR-T cells for the management of RRMM pts previously exposed to PI, IMiDs and moAb, our data could help to better define pts who could benefit from CAR-T cells under the current indications, while waiting for an extension of this approach to earlier disease stages. 1. N Engl J Med 2021;384:705-16 Figure 1 Figure 1. Disclosures Fazio: Janseen: Honoraria. Caravita di Toritto: celgene: Other: travel expenses, Research Funding; Janseen: Other: travel expenses, Research Funding; amgen: Other: advisory board; takeda: Research Funding; GSK-SANOFI: Other: advisory board. Martelli: Gilead: Other: advisory board; Novartis: Other: advisory board. Petrucci: Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board.

Background There is now great interest in using digital health tools to monitor patients' health status in real-world practice. Such tools often include electronic-patient-reported outcome (ePRO) systems in which symptoms questions are included into online interfaces for patient self-reporting, with real-time alerts triggered to the treating physician if severe symptoms or problems are reported. However, there is little information about the clinical utility and user perceptions of these systems, and this is particularly true in the area of hematology. Objectives This study investigates physicians' perceptions of usability and clinical utility of using remote ePROs in routine practice of patients with hematologic malignancies and explored implications in the delivery of patient care. Patients and Methods Remote ePROs are being gathered since December 2020 by the ALLIANCE Digital Health Platform, whose details of the development process have been previously described (Efficace F. et al., JMIR Res Protoc. 2021 Jun 1;10:e25271). Adult patients diagnosed with any hematologic malignancy are eligible to enter the platform, after having provided written informed consent. Aspects related to health-related quality of life (HRQoL), symptoms and medication adherence are assessed via validated PRO measures. The platform allows for real-time graphical presentation to physicians of individual patient symptoms and HRQoL outcomes. Based on a pre-defined algorithm, which includes the presence of clinically important problems and symptoms, the platform triggers automated alerts to the treating haematologists and medical staff. The definition of clinically important problems and symptoms is based on previously defined evidence-based thresholds (Giesinger J. et al., J Clin Epidemiol. 2020 Feb;118:1-8). We asked treating haematologists a feedback about their experience in using the platform, by an ad hoc web-survey consisting of 27 items covering several domains, including: usability and benefits, current use, evaluation of patient health-status, symptoms and adverse events, as well as physician-patient communication. We summarized characteristics of enrolled patients and treating haematologists by proportions, mean, median and range. We also used logistic regression analysis to check the possible association of characteristics of haematologists with survey results. Results Of the 201 patients invited to participate between December 2020 and June 2021 (cut-off date for current analysis), 180 (90%) accepted to enter the ALLIANCE platform, currently activated in 19 centers. The median age of patients was 57 years (range 21-91) and 58% were males. The majority were diagnosed with chronic myeloid leukemia (n=32, 18%) and multiple myeloma (n=31, 17%) and were in stable disease (n=89, 49%). Twenty-three hematologists (44% males) with a median age of 42 years (range 31-63) and an average 17 years (range 5-34) of experience in clinical practice, completed the survey. The majority of physicians (78%) accessed the platform at least once per month (of whom 39% at least once per week), regardless the alerts sent by the system about patients' clinically relevant problems. The frequency of access on a regular basis was also independent of physician sex (p=0.393) and years of experience in clinical practice (p=0.404). Overall, 57% of hematologists discussed often or very often ePROs with their patients, while 83% and 61% deemed this information helpful to better identify symptomatic adverse events (AEs) of grade 1-2 or of grade 3-4, respectively (see figure). Also, 87% and 91% of hematologists found ePROs useful to improve physician-patient communication and the accuracy of documentation of symptomatic AEs (regardless of severity), respectively. Physicians' responses to selected items of the survey are reported in the figure. Conclusions: Current findings support the clinical utility, from the perspective of the treating physician, of integrating ePROs into routine cancer care of patients with hematologic malignancies. Figure 1 Figure 1. Disclosures Efficace: Takeda: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Grants (to Institution); Amgen: Consultancy, Other: Grants (to Institution). Breccia: Bristol Myers Squibb/Celgene: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Fazio: Janseen: Honoraria. Petrucci: Karyopharm: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Rigacci: Merck: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: 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, Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tafuri: Roche: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Patriarca: Incyte: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Argenix: Honoraria. Luppi: Abbvie: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; MSD: Honoraria; Gilead Science: Honoraria, Other: Travel grant; Daiichi-Sankyo: Honoraria; Jazz Pharma: Honoraria. Vignetti: Novartis: Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria.

Treatment of multiple myeloma (MM) patients has radically changed over the last years following the introduction of next generation proteasome inhibitors (PI) and immunomodulatory derivative (IMiDs). In the last years, one further therapeutic option for MM patients is represented by monoclonal antibodies (MoAbs), that seem to change the paradigm of MM treatment, particularly for heavily pretreated or double refractory to a PI and IMiDs patients. Antibodies have an immune-based mechanism, induce durable responses with limited toxicity and combine well with existing therapies. The therapeutic effects are prevalently obtained by means of antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC) and concurrently by the induction of signals on cell effectors. Immunotherapeutic strategies offer a new and exciting approach to target key molecular pathways that continue to be implicated in the survival of malignant plasma cells. These targets include cell surface proteins (CD38, CD138 [SDC1], B cell maturation antigen [BCMA, TNFRSF17]), cytokines that play a role in plasma cell survival and proliferation (interleukin 6 [IL6] and B cell activating factor), signal regulators of bone metabolism (RANKL [TNFSF11], DKK1) and regulators of the immune system (PD-1[PDCD1], PD-L1[CD274]). This article focuses on new MoAbs and related innovative immunotherapeutic modalities currently under investigation in the treatment landscape of MM.

Familial clustering of myeloid malignancies with autosomal dominant (AD) inheritance was firstly recognized in 1999 by the identification of germline mutations associated with familial platelet dis...

Background: Lenalidomide (R) plus dexamethasone (d) triplet combinations have been indicated by ESMO guidelines as standard of care in first relapse for lenalidomide sensitive multiple myeloma (MM) patients (pts) (Dimopoulos et al, 2021). Meta-analysis of randomized clinical trials (RCT) shows better outcome with the combination of Daratumumab + Rd (DaraRd) over other Rd-based combinations (carfilzomib+Rd (KRd), elotuzumab+Rd (EloRd), Ixazomib+Rd (IxaRd). There are few real-life studies focusing on the pattern of utilization and outcome of different Rd triplets in first relapse MM. Aims: To explore performances of market-approved Rd-based triplets in unselected MM pts in first relapse. Patients and methods: After ethics committee approval, we review data of 366 MM pts in first relapse consecutively addressed to Rd-based triplets according to market-approved schedule after 2017. Rd-based therapies was distributed as follows: DaraRd 51.6% (189 pts), KRd 36.1% (132 pts), EloRd 8.7% (32 pts), IxaRd 3.6% (13 pts). Given the limited number of pts treated with IRd and EloRd, the analysis is focused only on DaraRd and KRd group after further excluding 51 pts (13%) addressed to salvage autologous stem cell transplant (ASCT) after daraRd (n=9)/KRd(n=42) fixed induction. Few pts in both groups were previously exposed to R/K/Dara (respectively 12 pts (3%), 8 (2%), 0). Treatment choice was influenced by market approval, with KRD regimen used more commonly in the IQR 2017- 2019, while DaraRd more commonly in the IQR 2018-2020. To limit the bias of a retrospective observation, we calculated a propensity score and we used it (after trimming of 5% of observations) to re-weight the data, according to the Inverse Probability of Treatment method (IPTW analysis). For the estimation of the propensity score, we used: age at Rd-triplet starting, ISS stage, presence of high-risk FISH, previous exposure to Bortezomib, previous ASCT, good response at first-line therapy (≥VGPR), time between diagnosis and relapse, myeloma defining events at diagnosis, type of relapse (symptomatic/biochemical), center. Details of these characteristics are reported in table1. Of note, pts addressed to DaraRd were slightly older (68,7 vs 63,4 years in KRd, p Conclusions: Our real-life study shows that DaraRd represents the most commonly received regimen at first relapse followed by KRd triplet. After propensity score matching, DaraRd and KRd combinations proved to be both effective with similar outcomes when used early in the treatment history, after one line of therapy. This study, in addition, points out the possible gap of outcome between RCT and clinical practice. Figure 1 Figure 1. Disclosures Mangiacavalli: BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; GSK: Honoraria. Galli: BMS, Celgene, Janssen, Sanofi, Takeda: 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; Takeda: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Fazio: Janseen: Honoraria. Petrucci: Celgene: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board.

Introduction In patients affected by monoclonal gammopathies, tumoral B cells or plasma cells secrete a monoclonal antibody (termed M protein), which can be used to track the presence of the tumor itself. Moreover, the M protein can directly cause potentially life-threatening organ damage, which is dictated by the specific, patient's unique clonal light and/or heavy chain, as in patients affected by immunoglobulin light chain (AL) amyloidosis. Yet, the current paradigm in the diagnosis and management of these conditions treats the M protein as a simple tumor biomarker to be identified/quantified. Patients' specific M protein sequences remain mostly undefined and molecular mechanisms underlying M-protein related clinical manifestations are largely obscure. Methods By combining the unbiased amplification of expressed immunoglobulin genes with long-read, single molecule real-time DNA sequencing and bioinformatics analyses, we have established a method to identify the full-length sequence of the variable region of expressed immunoglobulin genes and to rank the obtained sequences based on their relative abundance, thus enabling the identification of the full-length variable sequence of M protein genes from a high number of patients analysed in parallel. Results The assay, which we termed Single Molecule Real-Time Sequencing of the M protein (SMaRT M-Seq), has undergone an extensive technical validation. Sequencing of contrived bone marrow samples generated through serial dilutions of plasma cell lines into control bone marrow, as well as sequencing of bona fide bone marrow samples from AL patients and comparison with gold-standard techniques of immunoglobulin gene sequencing showed: 100% sequence-accuracy at the individual base-pair level; High repeatability (CV Noteworthy, SMaRT M Seq was applied to a cohort of 86 consecutive patients with AL amyloidosis (17 κ and 69 λ; median BMPC infiltration 9%, IQR 6-13%; median dFLC 176 mg/L, IQR 75-370 mg/L), including cases with small clonal burden and M protein which was undetectable with conventional M protein studies. A full-length sequence of the variable region of the clonal light chain was obtained in all patients (median molecular clonal size of 88.3%, IQR: 70.7 - 93%). The most common κ germline genes were IGKV1-33 and IGKV4-01 (24% each of the 17 κ AL patients), and the most common λ germline genes were IGLV6-57 (26% of the 69 λ AL patients), IGLV2-14 (17%), IGLV3-01 (17%) and IGLV1-44 (10%). The most frequent λ and κ germline genes together (IGLV6-57, IGLV2-14, IGLV3-01, IGLV1-44, IGKV1-33 and IGKV4-01) accounted for 66% of all the clones. Germline gene usage correlated with selected clinical features. Sequence information was then exploited to improve mass spectrometry-based amyloid typing on fat pad aspirates and to enable the sensitive detection of clonotypic sequences using short-read DNA sequencing of the involved light chain isotype (up to 10 -7 dilution). Conclusions We have established SMaRT M-Seq as a novel valuable assay to reliably identify the full-length variable sequence of M proteins. SMaRT M-Seq has undergone extensive technical validation, showing high accuracy, repeatability and sensitivity. The latter is determined by the number of reads analyzed per sample. This is in turn dictated by the sequencing output of the employed sequencing platform, and by the number of pooled samples analyzed in a given sequencing round, thus proving to be scalable. Even when analyzing multiple samples on a sequencing platform with low sequencing output, the achieved sensitivity of SMaRT M-Seq significantly exceeds the requirements for the identification of clonal B cells/plasma cells in patients with AL amyloidosis. Sequencing disease-associated M proteins from large cohorts of patients has the potential to uncover molecular mechanisms of M protein-related clinical manifestations which have remained largely unexplored so far, and could enable approaches of personalized medicine for the sensitive detection of patients' specific M proteins at diagnosis and after anti-clonal therapy. Disclosures Milani: Celgene: Other: Travel support; Janssen-Cilag: Honoraria. Fazio: Janseen: Honoraria. Petrucci: GSK: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board. Palladini: Pfizer: Honoraria; Siemens: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees. Nuvolone: Janssen-Cilag: Honoraria; Oncopeptides, Inc.: Research Funding.

INTRODUCTION. The proteasome inhibitor (PI) Ixazomib, approved for the treatment of relapsed/refractory multiple myeloma (MM), represents an appealing option for the management of elderly patients, due to its oral administration and the lack of peripheral neuropathy. We previously presented preliminary results of the phase II EMN10-Unito study investigating Ixazomib in combination with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd) as induction therapy followed by single-agent Ixazomib maintenance in transplant-ineligible newly diagnosed (ND) MM patients. Here we present updated results of the study with a longer follow-up. METHODS. Transplant-ineligible NDMM patients ≥65 years were enrolled. Treatment consisted of 9 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 or Id plus either Cyclophosphamide 300 mg/m2 orally on days 1,8,15 or Thalidomide 100 mg/day or Bendamustine 75 mg/m2 iv on days 1,8; followed by Ixazomib maintenance (4 mg on days 1,8,15) for up to 2 years. The primary endpoint was the selection of the most effective induction regimen considering a 2-year progression-free survival (PFS) ≥65% as satisfactory; secondary endpoints were very good partial response (VGPR), PFS2, overall survival (OS) and adverse events (AEs) during induction and maintenance. RESULTS. 171 patients (Id 41, ICd 59, ITd 60 and IBd 11) with a median age of 74 years were enrolled and started treatment. Two of the four investigational arms were prematurely closed due to low-enrollment (IBd arm, 11 patients enrolled) and high risk of inefficacy (Id, 41 patients enrolled). Median follow-up was 27 months. After the induction phase, ICd and ITd resulted in higher ≥ PR (75%-84% vs. 57%; p Overall, 102 patients (60%) completed the induction phase and proceeded to ixazomib maintenance (median follow-up from start of maintenance: 18 months). The best response during maintenance was PR in 26%, VGPR in 29%, and complete response (CR) in 26% of patients; 18% of patients improved the response obtained during induction by at least one IMWG category. The median PFS from start of maintenance was 15 months. The median duration of maintenance was 12 months. All grades AEs occurred in 39% of patients during maintenance, while grade 3-4 AEs occurred in 10% of patients. Grade 1-2 peripheral neuropathy (PN) was reported in 15% of patients, without grade 3-4 events. Overall, 15% required at least one dose reduction of ixazomib and 12% discontinued ixazomib maintenance due to AEs. CONCLUSIONS. Safety and efficacy data suggest that Id combined with cyclophosphamide was the most promising induction strategy compared to the other investigated combinations. Continuous treatment with single-agent Ixazomib confirmed its efficacy and tolerability in elderly NDMM patients. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Corradini:KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria. Liberati:CELGENE: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; 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; JANSSEN: Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. 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. Bringhen:Takeda: Consultancy; 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; Bristol-Myers Squibb: Honoraria; Karyopharm: 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. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).

Daratumumab demonstrated activity in the treatment of AL amyloidosis in two recently concluded phase II clinical trials in relapsed and refractory patients. Its role in upfront therapy is under evaluation in a phase III study. In this report we evaluated the safety and efficacy of 28-day cycles of daratumumab (single agent or combined with bortezomib or lenalidomide) in 72 previously treated patients with multiple myeloma and AL amyloidosis. Fifty (69%) were refractory to the last line of therapy. After eight infusions of daratumumab, 59 patients (82%) achieved a hematologic response, with 12 (16%) complete responses (CRs) and 30 (42%) very good partial responses (VGPRs). After 16 infusions, the quality of response improved with 22 patients (30%) achieving CR and 21 (29%) attaining VGPR. Cardiac response was observed in 11 of 37 evaluable patients (29%) and renal response in 23 of 38 patients (60%). Daratumumab is highly effective in heavily pretreated patients with relapsed/refractory AL amyloidosis and high bone marrow plasma cell burden. Renal responses, which are usually rare in this setting, were frequently observed.

In Italy, the Human Papillomavirus (HPV) vaccination was implemented for twelve years old girls in 2007, but its coverage was lower than the recommended level. Sicily is one of the Italian administrative regions with lower vaccination coverage, with a value of 59% for those born in 1996 increasing to 62% coverage for those born in 1999. The aim of the study was to investigate factors associated with the refusal of HPV vaccination among young adult women of Palermo, Italy. The study was approved by the Ethics Committee of the Policlinico “Paolo Giaccone” Hospital (Palermo 1) and the questionnaire was validated in a convenience sample representing 10% of the young women. A cross-sectional study was conducted through the administration of a telephone questionnaire, consisting of 23 items on HPV infection and vaccination knowledge based on the Health Belief Model framework. The eligible population were young women (18–21 years old) who had at least a vaccination among all included in the Sicilian vaccination schedule, without starting or completing HPV vaccination. Overall, 141 young women were enrolled (response rate 22%). Among them, 84.4% were unvaccinated and 15.6% had at least one dose of the HPV vaccine. In multivariate analysis, the factors associated with the refusal of the HPV vaccination were a bachelor’s as the education level (OR = 10.2, p = 0.041), lower participation at school seminar on HPV (OR = 0.2, p = 0.047) and lower perception of HPV vaccine benefits (OR = 0.4, p = 0.048). Public health educational program focusing and tailored on benefits perception of HPV vaccine and HPV disease severity, carried out at school or during medical visits, can be useful to improve HPV vaccination uptake.

Objective In patients with familial combined hyperlipidemia (FCHL), without metabolic syndrome (MS), occurrence of non-alcoholic fatty liver disease (NAFLD) is related to a specific pro-inflammatory profile, influenced by genetic traits, involved in oxidative stress and adipokine secretion. Among FCHL or MS patients, hyperactivity of the ligand–receptor for advanced glycation-end-products (RAGE) pathway, as reflected by inadequate protective response by the endogenous secretory (es)RAGE, in concert with genetic predisposition, may identify those with NAFLD even before and regardless of MS. Methods We cross-sectionally compared 60 patients with vs. 50 without NAFLD. Each group included patients with FCHL alone, MS alone, and FCHL plus MS. Results NAFLD patients had significantly lower plasma esRAGE, IL-10 and adiponectin, and higher CD40 ligand, endogenous thrombin potential and oxidized LDL. The effects of MS plus FCHL were additive. The genotypic cluster including LOX-1 IVS4-14A plus ADIPO 45GG and 256 GT/GG plus IL-10 10-1082G, together with higher esRAGE levels highly discriminate FCHL and MS patients not developing NAFLD. Conclusions Among FCHL or MS patients, noncarriers of the protective genotypic cluster, with lower esRAGE and higher degree of atherothrombotic abnormalities coincide with the diagnosis of NAFLD. This suggests an interplay between genotype, adipokine secretion, oxidative stress and platelet/coagulative activation, accelerating NAFLD occurrence as a proxy for cardiovascular disease.