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Introduction: The objective of this study was to understand the potential use of single agents and drug combinations in multiple myeloma (MM) across treatment lines in the years 2021 and 2023. Methods: The method used was Delphi Panel Method survey, administered to European Myeloma Network (EMN) Italy Working Group centres. Future treatments were identified assessing all available web-based information sources, including therapies (single drugs or combinations) with strong evidence of efficacy, likely to be on the Italian market in 2021 and 2023. Participants were asked to report on the likelihood of prescription for MM therapies, across treatment lines. Results: Across the 15 centres taking part in the survey, about 890 patients per year are forecasted to receive a new diagnosis of MM. In 2021, the Panel forecasted 66% of 1L-TE (transplant eligible) patients will be treated with bortezomib-thalidomide-dexamethasone (VTD) and 32% of patients with daratumumab-bortezomib-thalidomide-dexamethasone (DVTd), with a substantial decrease of VTD (15%) and a marked increase of DVTd (81%) forecasted for 2023. The 2L and 3L R(lenalidomide)-based combination treatments are expected to drop and will likely be substituted by a steep increase in P(pomalidomide)-based regimes (from 7% to 23%). On the contrary, in 3L treatment, all combination therapies (with the exception of IsaPd – isatuximab-pomalidomide-dexamethasone) are expected to lose market share in favour of the most recent new therapies. Conclusions: Expert Panel agrees that many different new drugs and combinations will be used in MM, with different mechanisms of action, both at diagnosis and in subsequent phases of the disease, with a corresponding decline of the drugs currently used.

Lymphoproliferative disorders are a heterogeneous group of malignant clonal proliferations of lymphocytes whose diagnosis remains challenging, despite diagnostic criteria are now well established, due to their heterogeneity in clinical presentation and immunophenotypic profile. Lymphoid T-cell disorders are more rarely seen than B-cell entities and more difficult to diagnose for the absence of a specific immunophenotypic signature. Flow cytometry is a useful tool in diagnosing T-cell lymphoproliferative disorders since it is not only able to better characterize T-cell neoplasms but also to resolve some very complicated cases, in particular those in which a small size population of neoplastic cells is available for the analysis. Here, we report three patients with mature T-cell neoplasms with atypical clinical and biological features in which analysis of peripheral blood and bone marrow specimens by means of multicolor flow cytometry was very useful to identify and characterize three rare T-cell lymphoproliferative disorders, such as angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified and T-cell prolymphocytic leukemia. The aim of this case series report is not only to describe three rare cases of lymphoproliferative neoplasms but also to raise awareness that a fast, highly sensitive, and reproducible procedure, such as flow cytometry immunophenotyping, can have a determinant diagnostic role in these patients.

Background The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation.Methods In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (I S S), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1.3 mg/m 2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m(2) administered orally on days 1-4) and prednisone (60 mg/m(2) administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m(2)), stratified by site and ISS disease stage. In centres with a double HS CT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1.3 mg/m(2)either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment.Findings Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60.3 months (IQR 52. 2-67. 6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56.7 months [95% CI 49.3-64.5] vs 41.9 months [37.5-46.9]; hazard ratio [HR] 0.73, 0.62-0.85; p=0.0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42.1 months (IQR 32.3-49.2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58.9 months [54.0-not estimable] vs 45.5 months [39.5-58.4]; HR 0.77, 0.63-0.95; p=0.014). The most common grade >= 3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]).Interpretation This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Background: Bortezomib-based induction followed by high-dose melphalan (200 mg/m2) and autologous stem-cell transplantation (MEL200-ASCT) and maintenance treatment with lenalidomide alone is the current standard of care for young and fit patients with newly diagnosed multiple myeloma. We aimed to evaluate the efficacy and safety of different carfilzomib-based induction and consolidation approaches with or without transplantation and of maintenance treatment with carfilzomib plus lenalidomide versus lenalidomide alone in newly diagnosed multiple myeloma. Methods: UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done in 42 Italian academic and community practice centres. We enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 65 years or younger with a Karnofsky Performance Status of 60% or higher. Patients were stratified according to International Staging System stage (I vs II/III) and age (

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).

We evaluated differences in density and 18F-FDG PET/MRI features of lytic bone lesions (LBLs) identified by whole-body low-dose CT (WB-LDCT) in patients affected by newly diagnosed multiple myeloma (MM). In 18 MM patients, 135 unequivocal LBLs identified by WB-LDCT were characterized for inner density (negative or positive Hounsfield unit (HU)), where negative density (HU

Chimerism analysis is a well-established method for monitoring the state of hematopoietic stem cell transplantation (HSCT) over time by analyzing peripheral blood or bone marrow samples of the recipient in several malignant and non-malignant hematologic diseases. From a clinical point of view, a continuous monitoring is fundamental for an effective early therapeutic intervention. This paper provides a comparative overview of the main molecular biology techniques which can be used to study chimerism after bone marrow transplantation, focusing on their advantages and disadvantages. According to the examined literature, short tandem repeats (STR) analysis through simple PCR coupled with capillary electrophoresis (STR-PCR) is the most powerful method which guarantees a high power of differentiation between different individuals. However, other methods such as real-time quantitative PCR (qPCR), digital PCR (dPCR), and next-generation sequencing (NGS) technology were developed to overcome the technical limits of STR-PCR. In particular, these other techniques guarantee a higher sensitivity, which allows for the detection of chimerism at an earlier stage, hence expanding the window for therapeutic intervention. After a comparative evaluation of the various techniques, it seems clear that STR-PCR still remains the gold standard option for chimerism study, even if it is likely that both dPCR and NGS could supplement or even replace the common methods of STR analysis.

Secondary antibody deficiencies (SAD) may require immunoglobulin replacement therapy (IgRT). While the intravenous route (IVIG) is broadly considered effective in SAD, the use of subcutaneous immunoglobulins (SCIG) is mainly adopted from the experience in primary antibody deficiencies (PAD), where SCIG have been shown to perform as effective as IVIG. However, evidence-based data on SCIG administration in SAD patients are still insufficient. Herein we retrospectively evaluated the efficacy and safety profile of SCIG treatment in 131 SAD patients as compared to a group of 102 PAD patients. We found SCIG being equally effective in reducing annual infectious rate both in SAD and PAD patients. However, SAD patients required lower SCIG dosage and lower IgG through level to achieve similar biological effect in terms of infection burden, at the steady state. SAD patients also showed better correlation between SCIG dose and serum IgG achieved value. Furthermore, within SAD, SCIG were found to work irrespective of the underlying disease. Especially in Non-Hodgkin Lymphoma patients, whose indication to IgRT is still not included in all guidelines and for whom evidence-based data are still lacking, SCIG were as effective as in Chronic Lymphocytic Leukemia or Multiple Myeloma patients, and SCIG discontinuation, without evidence of B cell recovery, led to IgG decline and relapsed infections. Finally, treatment tolerance in SAD patients was comparable to the PAD cohort. Globally, our data suggest that SCIG, as already appreciated in PAD, represent a valuable option in SAD patients, independent on the disease leading to antibody deficiency.

Background Increasing use of antibodies targeting CD38 in first line (1L) for multiple myeloma (MM) has created a need for treatments for patients who are refractory to anti-CD38. This analysis describes the use of carfilzomib (K) with lenalidomide and dexamethasone (KRd) or with dexamethasone alone (Kd) in anti-CD38 refractory patients. Methods Patients with MM who received ≥ 1 K dose and an anti-CD38 in any prior line were retrieved from a prospective real-world study (NCT03091127) of 701 patients. Patients were deemed refractory if any of these criteria were met for any prior anti-CD38 treatment: the best response was stable or progressive disease; progression was the reason for discontinuation; date of relapse was after the start date and within 60 days after the last anti-CD38 dose. Results Of patients who had previously received anti-CD38 (daratumumab [D] or isatuximab), 33 KRd and 71 Kd patients were anti-CD38 refractory at K initiation. Most received D (97% of KRd and 96% of Kd patients), mainly in the immediate prior line. Patients were heavily pre-treated, with 3 and 4 median prior lines in KRd and Kd groups, respectively. Among KRd patients who were refractory to anti-CD38 in any prior line, 18% received anti-CD38 as maintenance therapy. Anti-CD38 was given as continuous therapy in 85% of KRd and all Kd patients, of whom 33% and 52% received it as monotherapy, respectively. The most common anti-CD38 combinations received in any prior line were triplets: D and a proteasome inhibitor (PI), bortezomib or ixazomib (33%) for KRd patients; DRd (41%) for Kd patients. At K initiation, 64% and 45% of KRd and Kd patients who were anti-CD38-refractory were also refractory to PI or IMiD (including 15% and 18% to lenalidomide), respectively, and 3% and 6% of patients were refractory to a PI and IMiD. All results are from anti-CD38 refractory patients who received KRd and Kd, respectively. In those who had a disease response assessment, overall response rates (ORRs) were 67% (18/27) and 52% (32/62), and 44% and 27% had a very good partial response or better (VGPR+). At 2L or 3L (2L/3L), ORR was 75% (9/12) and 67% (6/9), with 67% and 44% of patients achieving a VGPR+. At 4L+, ORR was 60% (9/15) and 49% (26/53), while 27% and 25% had a VGPR+. The median time to K discontinuation, most commonly due to disease progression, was 7 months overall (2L/3L: 12 months; 4L+: 4 months) in KRd and 5 months overall (2L/3L: 5 months; 4L+: 5 months) in Kd patients. Treatment-related adverse events occurred in 33% and 24% of patients, of which 6% and 10% led to K discontinuation. Conclusions These results expand on initial reports (Ghandi et al. Leukemia 2019) indicating K-based regimens are suitable treatment options for anti-CD38 refractory patients, providing evidence for the use of KRd and Kd from 2L with a consistent safety profile to previous studies. Patients completing 1L anti-CD38 therapy will continue to provide further real-world results.

(1) Background: Multiple myeloma is a rare cancer that primarily affects the bone marrow. Osteoclasts are responsible for increased bone resorption and, therefore, bone destruction. Bisphosphonates are a class of drugs that can slow down bone resorption by reducing the number and action of osteoclasts. Intravenous injections of bisphosphonates (generally Zoledronic Acid) are administered to patients affected by Multiple Myeloma, but BRONJ is described as a serious side effect. This 5-year retrospective study aims to evaluate the efficacy of appropriate dental treatment protocols prior to initiating bisphosphonate therapy to prevent the development of BRONJ. (2) Methods: A total of 99 patients with symptomatic multiple myeloma were involved in this study (41&ndash, 90 years, mean age 65 years, standard deviation 5 years). The data relating to the visits were tracked using a specific server and consulting the clinical reports. The AAOMS (American Association of Oral and Maxillofacial Surgeons) position was applied for both diagnosis and treatment. A total of 79 patients were examined before the administration of bisphosphonates (group A) and 20 after (group B). (3) Results: The entire sample required dental treatment: 23.2% underwent restorative therapy, 8% endodontic treatments, 44.4% tooth extractions. Periodontal disease was present in 41.4% of the patients. No osteonecrosis was observed in the first group, whereas BRONJ was found in five patients of the second one (25%) and two patients (10%) showed osteosclerotic areas under investigation [OR 0.026 (CI 0.0027 to 0.2454)]. (4) Conclusions: In the literature, there are no precise data about the prevalence of BRONJ. Despite the limitation of the present study, we point out that dental treatment before the treatment with intravenous bisphosphonates can help in reducing the incidence of BRONJ and good dental status is necessary for BRONJ prevention.

Background: Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. Methods: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18–70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m2, intravenous infusion, day 0; methotrexate 3·5 g/m2, the first 0·5 g/m2 in 15 min followed by 3 g/m2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m2, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m2, day 1; etoposide 100 mg/m2 per day in 500–1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine–thiotepa and autologous HSCT (carmustine 400 mg/m2 in 500 mL glucose 5% solution in a 1–2 h infusion, day −6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days −5 and −4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019. Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55–61). 49 patients (65%; 95% CI 54–76) had an objective response after MATRix–RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51–71) had an objective response, with a median duration of objective response of 26 months (IQR 16–37). At a median follow-up of 29 months (IQR 20–40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39–53). Grade 3–4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07–9·93). Interpretation: MATRix–RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile. Funding: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.

No abstract available

BACKGROUND Azacitidine (AZA) is the standard treatment for myelodysplastic syndromes (MDS); however, many patients prematurely stop therapy and have a dismal outcome. METHODS The authors analyzed outcomes after AZA treatment for 402 MDS patients consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche, and they evaluated the North American MDS Consortium scoring system in a clinical practice setting. RESULTS At treatment discontinuation, 20.3% of the patients were still responding to AZA, 35.4% of the cases had primary resistance, and 44.3% developed adaptive resistance. Overall survival (OS) was better for patients who discontinued treatment while in response because of planned allogeneic hematopoietic stem cell transplantation (HSCT; median OS, not reached) in comparison with patients with primary resistance (median OS, 4 months) or adaptive resistance (median OS, 5 months) or patients responsive but noncompliant/intolerant to AZA (median OS, 4 months; P = .004). After AZA discontinuation, 309 patients (77%) received best supportive care (BSC), 60 (15%) received active treatments, and 33 (8%) received HSCT. HSCT was associated with a significant survival advantage, regardless of the response to AZA. The North American MDS Consortium scoring system was evaluable in 278 of the 402 cases: patients at high risk had worse OS than patients at low risk (3 and 7 months, respectively; P < .001). The score was predictive of survival both in patients receiving BSC (median OS, 2 months for high-risk patients vs 5 months for low-risk patients) and in patients being actively treated (median OS, 8 months for high-risk patients vs 16 months for low-risk patients; P < .001), including transplant patients. CONCLUSIONS Real-life data confirm that this prognostic scoring system for MDS patients failing a hypomethylating agent seems to be a useful tool for optimal prognostic stratification and for choosing a second-line treatment after AZA discontinuation.

While the modern therapeutic armamentarium to treat multiple myeloma (MM) patients allows a longer control of the disease, this second-most-frequent hematologic cancer is still uncurable in the vast majority of cases. Since MM plasma cells are subjected to various types of chronic cellular stress and the integrity of specific stress-coping pathways is essential to ensure MM cell survival, not surprisingly the most efficacious anti-MM therapy are those that make use of proteasome inhibitors and/or immunomodulatory drugs, which target the biochemical mechanisms of stress management. Based on this notion, the recently realized discoveries on MM pathobiology through high-throughput techniques (genomic, transcriptomic, and other "omics"), in order for them to be clinically useful, should be elaborated to identify novel vulnerabilities in this disease. This groundwork of information will likely allow the design of novel therapies against targetable molecules/pathways, in an unprecedented opportunity to change the management of MM according to the principle of "precision medicine." In this review, we will discuss some examples of therapeutically actionable molecules and pathways related to the regulation of cellular fitness and stress resistance in MM.

Background: Novel agents have recently questioned the role of both autotransplantation and consolidation therapy after intensification in newly diagnosed multiple myeloma. We prospectively compared intensification with transplantation versus bortezomib-melphalan-prednisone (VMP), and bortezomib-lenalidomide-dexamethasone (VRD) consolidation versus no consolidation. Methods: In this randomized, open-label, phase 3 study we recruited previously untreated myeloma patients aged up to 65 years at 172 sites of the European Myeloma Network. Patients were first randomized (1:1) to VMP (4 cycles) or transplantation, and afterwards to VRD consolidation (2 cycles) or no consolidation, followed by lenalidomide-maintenance. Progression-free survival from first and second randomization were primary endpoints. Comparison of single versus double transplantation was a secondary endpoint. Findings: Between February, 2011 and April, 2014, 1503 patients were enrolled. Overall, 1197 patients were eligible for the first randomization: 702 received transplantation and 495 VMP; 877 patients underwent the second randomization: 449 received VRD consolidation and 428 no consolidation. Progression-free survival from first randomization was significantly better with transplantation than with VMP (median, 56·7 versus 41·9 months; hazard ratio [HR] 0·73, 95% CI 0·62-0·85, p=0·0001). VRD consolidation prolonged median progression-free survival from second randomization compared with no consolidation (58·9 versus 45.5 months; HR 0·77, 95% CI 0·63-0·95, p=0·014). Overall survival estimates at 5 years were 75% with transplantation and 71·6% with VMP (HR 0·90, 95% CI 0·71-1.13, p=0·35). Double transplantation significantly prolonged progression-free survival (HR 0·74, 95% CI 0·56-0·98, p=0·036) and overall survival (HR 0·62, 95% CI 0·41-0·93, p=0·022) compared to a single transplantation. The rate of at least one grade ≥3 adverse event was 88% with transplantation versus 52% with VMP. Transplant-related mortality was 1%. Interpretation: In newly diagnosed myeloma patients, intensification therapy with transplantation significantly prolonged progression-free survival compared with VMP, although overall survival was similar. After intensification, VRD consolidation significantly improved progression-free survival compared with no consolidation. Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT01208766. Funding Statement: The Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) sponsored and designed this study. Janssen and Celgene provided bortezomib and lenalidomide free of charge, respectively, and provided funding, but had no role in the analysis or interpretation of the data. Declaration of Interests: Michele Cavo: receives honoraria from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Takeda, AbbVie, Sanofi, Adaptive Biotechnologies, and is a member of Janssen’s and Celgene’s Speaker’s Bureau. Francesca Gay: receives honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, AbbVie. Meral Beksac: receives honoraria from Celgene, Janssen, Sanofi, Takeda, Amgen, and is a member of Celgene’s, Janssen’s, Takeda’s, Amgen’s Speaker Bureau Lucia Pantani: receives honoraria from Celgene, Janssen, Takeda, Amgen Maria Teresa Petrucci: receives honoraria from Celgene, Janssen-Cilag, Bristol-Myers Squibb, Amgen, Takeda, Sanofi. Meletios A Dimopoulos: receives honoraria from Amgen, Takeda, Celgene, Bristol-Myers Squibb, Janssen. Luca Dozza: NO COI. Bronno van der Holt: NO COI Stefania Oliva: receives honoraria from Amgen, Celgene, Janssen, Adaptive Biotechnologies, Takeda. Vincent H.J. van der Velden: NO COI. Elena Zamagni: receives honoraria from Janssen, Bristol-Myers Squibb, Amgen, Takeda. Giuseppe A. Palumbo: receives honoraria from Amgen, Celgene, Jannsen, Novartis Francesca Patriarca: receives honoraria from Celgene, Janssen. Vittorio Montefusco: receives honoraria, travel support and research funding from Celgene, Janssen. Monica Galli: receives honoraria from Bristol-Meyers-Squibb, Celgene, Janssen, Leadiant, Takeda. Vladimir Maisnar : receives honoraria from Janssen, Amgen, Celgene, Takeda, and is a member of the Board of Directors or advisory committees for Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda. Barbara Gamberi: receives honoraria from Amgen, Celgene, Sanofi, Janssen Stig Lenhoff: NO COI Angelo Belotti : receives honoraria from Jannsen, Celgene, Amgen. Ludek Pour: NO COI. Paula Ypma: NO COI. Mariella Grasso: NO COI. Sandra Croockewit: NO COI. Stelvio Ballanti: receives honoraria from Celgene, Janssen. Massimo Offidani: receives honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda. Donata Vincelli: NO COI. Renato Zambello: receives honoraria from Jannsen, Celgene. Anna Marina Liberati: receives research funding from Novartis, Janssen, Abbvie, Roche, Amgen, Celgene; receives honoraria from Abbvie, Amgen, Takeda, Servier; is a consultant for Incyte Niels Frost Andersen: NO COI. Sonja Zweegman: receives honoraria from Celgene, Sanofi, Takeda, Janssen, and research funding from Celgene, Takeda, Janssen. Rossella Troia: NO COI. Anna Pascarella: NO COI. Giulia Benevolo: receives honoraria from Novartis, Celgene, Amgen. Mark-David Levin: receives honoraria and travel support from Takeda, Janssen, Celgene, AmgenGerard Bos: NO COI. Heinz Ludwig: receives honoraria from Janssen, Celgene, Amgen, Sanofi, Bristol-Meyers Squibb, Seattle Genetics, is a member of Janssen’s, Celgene’s, Amgen’s, Sanofi’s, Bristol-Meyers Squibb’s, Seattle Genetics’s speakers bureau, and receives research funding from Amgen, Takeda Sara Aquino: receives honoraria from Amgen, Celgene, Janssen. Anna Maria Morelli: NO COI. Ka Lung Wu: NO COI. Rinske Boersma: NO COI. Roman Hajek: receives honoraria, and research funding from Amgen, Takeda, Celgene, Janssen, Abbvie, Novartis, PharmaMar, Bristol-Myers Squibb. Marc Durian: NO COI. Peter A von dem Borne: NO COI. Tommaso Caravita di Toritto: receives honoraria from Celgene, Janssen, Amgen. Christoph Driessen: NO COI. Giorgina Specchia: NO COI. Anders Waage: receives honoraria from Janssen, Takeda. Peter Gimsing: NO COI. Ulf-Henrik Mellqvist: receives honoraria from Amgen, Sanofi, Oncopeptides, Janssen, Takeda, Celgene. Marinus van Marwijk Kooy: NO COI. Monique Minnema: receives honoraria from Celgene, Amgen, Novartis, Servier, Jansen Cilag, Gilead, and receives research funding from Celgene. Caroline Mandigers: NO COI. Anna Mario Cafro: NO COI. Angelo Palmas: receives honoraria from Amgen, Janssen, Celgene, Takeda. Susanna Carvalho: NO COI. Andrew Spencer: is a Consultant for Celgene, Janssen, Secura Bio, Specialised Therapeutics Australia, AbbVie, Servier, Haemalogix, Sanofi; is a member of Celgene’s, Jannsen’s, Takeda’s Speaker’s Bureau; receives research funding from Celgene, Janssen, Amgen, Takeda, Servier, Haemalogi; receives honoraria from Celgene, Janssen, Amgen, Takeda, Secura Bio, Specialised Therapeutics Australia, AbbVie, Servier, Haemalogix, Sanofi Mario Boccadoro: receives honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, BristolMyers Squibb, AbbVie; receives research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, Mundipharma. Pieter Sonneveld: receives honoraria from Amgen, BMS, Celgene, Janssen, Karyopharm, Takeda, and receives research funding from Amgen, Celgene, Janssen, Karyopharm, SkylineDx, Takeda. Ethics Approval Statement: All patients provided written informed consent. The study was approved by the independent ethics committee or institutional review board at all participating sites and was done in accordance with International Conference on Harmonisation guidelines on Good Clinical Practice and the principles of the Declaration of Helsinki.

International audience; [No abstract available]

We report final results of a phase II trial addressing efficacy and feasibility of lenalidomide maintenance in patients with chemosensitive relapse of diffuse large B-cell lymphoma (DLBCL) not eligible for or failed after autologous stem cell transplantation (ASCT). Patients with relapsed DLBCL who achieved at least a partial response to salvage chemoimmunotherapy were enrolled and treated with lenalidomide 25 mg/day for 21 of 28 days for 2 years or until progression or unacceptable toxicity. Primary endpoint was 1-year PFS. Forty-six of 48 enrolled patients were assessable. Most patients had IPI ≥2, advanced stage and extranodal disease before the salvage treatment that led to trial registration; 28 (61%) patients were older than 70 years. Lenalidomide was well tolerated. With the exception of neutropenia, grade-4 toxicities occurred in

Neurolymphomatosis, the infiltration of the peripheral nervous system from lymphoid cells, represents an uncommon manifestation of lymphomas. We describe the challenging diagnostic work-up in a patient with neurolymphomatosis. A 58-year-old woman with previous breast diffuse large B-cell lymphoma treated with chemo- and radiation-therapy, presented with dysesthesias, neuropathic pain at left abdomen and thigh, and weakness at left lower limb 9 years after disease remission. Neurophysiology revealed left T10-L4 radiculo-plexopathy with no abnormalities at cerebrospinal fluid (CSF), nerve ultrasound, and 18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). MR-neurography disclosed left rectus abdominis muscle atrophy, neurogenic edema, and denervation. Radiation-induced damage, paraneoplastic, infectious radiculo-plexopathies, and atypical chronic inflammatory demyelinating polyradiculoneuropathy were ruled out. Neurolymphomatosis was suspected, and the patient treated with rituximab with improvement. Despite treatment, the radiculo-plexopathy eventually extended to the right side and sacral roots. Later in the disease course, sural nerve biopsy confirmed the diagnosis. Maintenance therapy was continued, until cutaneous localizations occurred, requiring salvage therapy and autologous stem cell transplant. Although rare, neurolymphomatosis should be considered in all patients with lymphomas and unexplained peripheral nervous system involvement. Hematological, CSF, and neuroimaging findings may be unremarkable, and a high index of suspicion required in order to achieve the diagnosis.

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

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.

The activity of the combination of rituximab, bendamustine, and low dose cytarabine (R-BAC) was evaluated in a phase 2 multicentre trial from the Fondazione Italiana Linfomi (FIL RBAC500) in previously untreated patients with mantle cell lymphoma (MCL) who were not eligible to stem cell transplant. Maintenance treatment was not planned after induction therapy, and no patient in the study received rituximab maintenance. Fifty-seven patients (median age 71 years, range 61-79) were recruited and treated with 4 to 6 cycles between 2012 and 2014. Despite some concern in terms of hematological toxicity, the R-BAC regimen was associated with high complete remission (CR) rate (91%), 2-years overall survival (OS) of 86% (74-93), and 2-years progression free survival (PFS) of 81% (68-89). Here, we present long-term survival outcomes. After 7 years of median follow-up (86 months, range 57-107), the median OS and PFS for all patients were not reached (Figure 1A and 1B). The 7-years PFS and OS rates were 56% (95%CI 41-67) and 63% (95%CI 46-72), respectively. Patients who achieved CR (n=53) had a 7 years PFS of 59% (95% CI 44-71), with the curve that appears to plateau after 6 years. Adverse predictive factors affecting PFS were blastoid morphology (p 30% (p Eight patients (14%) developed a secondary neoplasia: 1 parotid heteroplasia, 1 parotid nodular hyperplasia, 1 prostate cancer, 1 bladder cancer, 1 larynx, 1 thyroid cancer, 1 lung cancer and 1 secondary acute myeloid leukemia. Among the 25 relapsed patients, 8 did not receive any other treatment. Six had Ibrutinib monotherapy as second line, of whom 4 responded (3 are still in CR), 4 had CHOP or CHOP-like regimens with only partial responses. As per protocol, 31 patients with molecular marker at diagnosis and available samples were followed-up for minimal residual disease (MRD) with ASO-droplet digital polymerase chain reaction (D-PCR). Patients with MRD persistence at the end of induction, either in peripheral blood or bone marrow, had significantly worse 7 years-PFS (p In conclusion, in elderly patients with newly diagnosed MCL, R-BAC showed sustained efficacy over time, which compared favorably with any other reported immuno-chemotherapy regimen (with or without maintenance) in similar populations. With a median OS exceeding 60% after 7-years this regimen has significantly impacted on the life-expectancy of elderly patients with MCL. Figure 1 Figure 1. Disclosures Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nassi: Takeda: Consultancy; Incyte: Consultancy; Kyowa Kirin: Consultancy; Roche: Consultancy. Ferrero: Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Roche, Italfarmaco: Consultancy, Honoraria; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Merli: Janssen: 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, Other: Travel, Accomodations, Expenses; MSD: 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; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; EUSA Pharma: Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses.

Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular STAT3 mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients.

Background Gain and/or amplification of chromosome 1q are frequently associated with multiple myeloma (MM). The number of 1q copies correlates with a poor prognosis. Our aim was to evaluate the impact on clinical outcome and the transcriptome changes induced by Gain1q (3 copies of 1q) and 1q amplification (Amp1q, ≥4 copies of 1q) in patients (pts) enrolled in the randomized FORTE trial (NCT02203643). Methods Fluorescence in situ hybridization (FISH) on CD138+ purified bone marrow plasma cells was centralized and performed at baseline. The cut-off level of Gain1q was 10% of nuclei with ≥3 copies of 1q, while Amp1q was defined as ≥20% of nuclei with ≥4 copies of 1q. Transcriptome data from pts enrolled in the MMRF CoMMpass study (NCT01454297) were used to find differentially expressed genes (DEGs) in Gain/Amp1q pts. An independent cohort enrolled in the FORTE trial was subjected to RNAseq and used as validation. Results A total of 474 pts were enrolled in the FORTE trial. 1q copy number was missing in 74 pts; thus, 400 pts were evaluable. The median follow-up was 51 months; 219 (55%) pts belonged to the Normal 1q, 129 (32%) to the Gain1q, and 52 (13%) to the Amp1q group. In a multivariate analysis, progression-free survival (PFS) was shorter in the presence of Gain1q (HR 1.65 vs Normal 1q, p=0.005) and Amp1q (HR 3.13 vs Normal 1q, p Conclusion Amp1q universally predicts poor PFS and OS, despite the use of new drug combinations. A gene network centered on Myc may contribute to the high-risk behavior of these pts. The study of DEGs associated with Gain and Amp1q can identify new ‘druggable’ targets to be further tested in this high-risk patient population.

Aim To evaluate the modifications of the apparent diffusion coefficient (ADC) in myelomatous lesions before and after induction treatment and the correlation with patient response to therapy according to International Myeloma Working Group (IMWG) criteria. Materials and methods A homogeneous group of 18 patients with a diagnosis of symptomatic multiple myeloma who underwent whole-body MRI with diffusion-weighted imaging (DWI-MRI) before and after bortezomib-based induction chemotherapy were evaluated prospectively. Quantitative analysis of ADC maps of myelomatous lesions was performed with the following pattern types: focal pattern, diffuse pattern (moderate and severe), and “salt and pepper” pattern. Lesions were evaluated by quantitative image analysis including measurement of the mean ADC in three measurements. Imaging results were compared to laboratory results as the clinical reference standard. Results A statistically significant increase in ADC values were found in the lesions of patients that responded to treatment. Interestingly, focal lesions showed a strongly significant increase in ADC values in responders, whereas no significant variation in ADC value in non-focal lesions (diffuse pattern and “salt and peppers” pattern) between responders and non-responders group was demonstrated. Conclusions DWI-MRI could provide additional quantitative information useful in monitoring early therapy response according to ADC changes of focal lesions.

No adequate immunotherapy has so far been shown to be effective in anti-myelin-associated glycoprotein (MAG) antibody neuropathy.1 Rituximab was assessed in two randomised controlled trials, both including only patients with monoclonal gammopathy of undetermined significance (MGUS), with Waldenstrom’s macroglobulinaemia (WM) being an exclusion criterion.2 The aim of our multicentre retrospective study was to assess whether the response to rituximab in patients with anti-MAG antibody neuropathy would differ according to the associated haematological condition. We reviewed the clinical and laboratory features of 33 patients (21 men, mean age at time of therapy: 64.6±10.3, range: 41–87, mean neuropathy duration at time of therapy: 4.67 years±4.82, range: 0.5–17) with anti-MAG antibody neuropathy who underwent therapy with rituximab single agent in five Italian neurological centres. Twenty-five (73.5%) patients had Immunoglobulin M (IgM) MGUS and 8/33 had WM, according to bone marrow biopsy. The mean age was significantly different in the two groups (62.5±10.3 years in MGUS vs 70.5±7.9 years in WM, p=0.04). The mean neuropathy duration was 4.56±4.8 years in MGUS versus 5.6±5.1 years in WM (p=0.62, Mann-Whitney U test). Anti-MAG antibodies were assayed by ELISA (Buhlmann Laboratories AG) (28 patients) or Western blot (5 patients). The median antibodies titre was 51 200 (range: 7500–800 000) in MGUS and 56 000 (range: 11 126–600 000) in patients with WM. Patients with low (

Background: 18F-FDG-PET/CT is currently the standard technique to define imaging-minimal residual disease (MRD) in multiple myeloma (MM) patients. A joint analysis of 2 prospective randomized trials in newly diagnosed transplant-eligible MM (NDTEMM) patients applied for the first time the Deauville Scores (DS) to focal lesions (FS) and bone marrow uptake (BMS) showing the liver background (DS < 4) as the best cut-off to define PET/CT negativity after therapy and complete metabolic response (CMR) (Zamagni et al, ASH 2018). Validation of this new standardized criteria in an independent prospective series of NDTEMM patients is highly required. Imaging-PET/CT MRD also showed to be complementary to Multiparameter Flow Cytometry (MFC) in predicting patient's outcomes (Moreau P, JCO 2017). In this analysis, we aimed at confirming the applicability and validity of DS criteria to define PET/CT CMR and showing their impact on patient's outcomes in the multicenter phase II randomized FORTE trial for NDTEMM patients. We also looked at the complementarity with BM techniques, especially MFC. Methods: NDTEMM patients ≤ 65 years were randomized to receive carfilzomib, lenalidomide, dexamethasone (KRD) induction - autologous stem cell transplantation (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 plus carfilzomib. PET/CT scans were performed locally at baseline (B) and prior to the start of maintenance (PM). DS were applied both in the BM and FLs, as previously described (Zamagni E, EHA 2020). CMR was defined as DS < 4 both in the FLs and BM. MRD evaluation was performed by 8-color second-generation flow cytometry (sensitivity 10-5) in patients who achieved at least VGPR before maintenance (Gay F, ASCO 2019). The impact of each parameter on outcomes was evaluated by landmark analyses at PM. A multivariable Cox regression analysis was adopted to identify independent predictors for PFS and OS. Results: 182 out of the 474 global patients enrolled in the trial had a pre- and post-treatment PET/CT evaluation available and were included in this analysis. Patients' baseline characteristics were: median age 57 years, ISS and R-ISS stage III 18% and 10%, respectively, high-risk cytogenetics (t(4;14) ± del(17p) ± t(14;16), detected by FISH) 26%, reflecting baseline clinical features of the entire FORTE population. At B, 93% of patients had FLs, with a median maximum standardized uptake value (SUVmax) of 5.7 [IQR: 4.1-8.1], 7% presented extra-medullary lesions and nearly all patients had increased BM uptake, with a median SUVmax of 3.4 [IQR: 2.8-4.3]. FS and BMS ≥ 4 were present in 87% and 57% of patients, respectively. At PM, PET/CT negativity according to DS < 4, was present in 80% in the FLs and 85% in the BM, respectively. 63% showed CMR. 92% and 61% of patients achieved ≥ VGPR and CR as best response, respectively, while 73% of them achieved MFC MRD negativity. The achievement of a best CR significantly correlated with BMS < 4 at PM (P= 0.003). In univariate analysis, at Landmark time PM, FS Conclusion: In conclusion, the present analysis confirms the applicability and validity of DS criteria to define PET/CT CMR in an independent prospective series of NDTEMM patients. CMR significantly and independently correlated in uni- and multivariable analysis with patient's outcomes in terms of PFS and OS and was complementary to the MFC MRD negativity. Figure Disclosures Zamagni: Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, 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. Gay: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; 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; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; 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. D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Galli:Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria. 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. Rivolti:Celgene: Membership on an entity's Board of Directors or advisory committees. Tacchetti:Bristol-Myers Squibb: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Fanti:Bayer, Astellas, GE Healthcare, ANMI, Janssen: Membership on an entity's Board of Directors or advisory committees; Bayer, Astellas, GE Healthcare, Sanofi, AAA: Honoraria. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Oliva:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria.

Background: To understand carfilzomib (K) usage, effectiveness and safety in patients (pts) with relapsed or refractory multiple myeloma (RRMM) in real-life, we describe the results of an interim analysis by K-based regimens from a large prospective observational study (NCT03091127). Methods: Adult pts who received ≥1 prior line of therapy and ≥1 K dose in routine care were enrolled from 11 participating countries across the EU and Israel. Follow-up was until 30 days after last K dose or up to 18 months from initiation. Medical history and pt characteristics at the time of diagnosis and K initiation were collected. Cytogenetic risk status was as assessed by the physician and frailty was derived (Palumbo et al., Blood 2015;125:2068-74; Facon et al., Blood 2015;126:4239). Adverse events (AEs) of grade 3 or above (Gr3+) including serious adverse events (SAEs) were collected during the study. Results: As of 17 March 2020, a total of 701 pts were included in the analysis. Over half (55%) received the triplet K, lenalidomide and dexamethasone (KRd), and 39% were treated with K and dexamethasone alone (Kd). The remaining pts (n=46, 7%) received other K-based triplets, mainly: K, cyclophosphamide, dexamethasone (KCyd, 2%), K, pomalidomide, dexamethasone (KPomd, 2%), or K, daratumumab, dexamethasone (KdD, 1%). Due to the heterogenous nature of this subgroup, this data is not further described. At K initiation, pts who received KRd were younger than Kd pts: 65 vs 68 years (median age), respectively. Of the 32% of pts with known ISS status at K initiation, 23% and 38% had an ISS stage 3 in KRd and Kd pts, respectively. Among pts with derived frailty score at K initiation (65%), 31% of the KRd subset, and 51% of Kd were calculated as frail. Cytogenetic risk was reported in 34% and 18% of KRd and Kd pts, in which 43% and 64% were high risk, respectively. A large proportion of pts presented with pre-existing cardiovascular conditions in both cohorts (49% and 61% for KRd and Kd, respectively) which mostly consisted of hypertension (35% and 41% for KRd and Kd, respectively). KRd pts had received a median of 1 prior line of therapy while Kd pts were more heavily treated with a median of 3 prior lines. Previous autologous stem cell transplant was described for 64% of KRd pts 44% of Kd pts. Nearly all pts regardless of treatment (96% of KRd and 97% of Kd) had a prior exposure to bortezomib although more Kd pts (54%) were refractory to bortezomib according to IMWG criteria than KRd pts (31%). The proportions of lenalidomide-exposed/refractory pts were higher in Kd pts (68%/55%) than KRd pts (34%/19%). More pts treated with Kd had been previously treated with a monoclonal antibody (28%) than KRd pts (9%). Of pts with a response assessment reported, a high overall response rate (ORR) was seen in KRd pts with nearly one-third achieving a complete response (CR) or better and 66% achieving a very good partial response (VGPR) or better (Table). A good ORR (68%) was also seen in Kd pts considering the prognosis of this pt population, however, an ORR of 80% was achieved for pts with 1 prior line of therapy. Deeper responses were seen in earlier lines of therapy for both cohorts. The mean K dose intensity received relative to EU label for KRd (20/27 mg/m2 for K) and Kd pts (20/56 mg/m2 for K) was 90% and 83%, respectively. The Kaplan-Meier median estimate of treatment duration was 14.6 months (95% confidence interval [CI]: 12.9, 16.4) for KRd and 7.5 months (95% CI: 6.5, 8.8) for Kd pts. Gr3+ AEs were reported in 47% of KRd pts and 45% of Kd pts and 25% and 21% of KRd and Kd pts experienced an event considered to be treatment related. The most commonly reported events were blood disorders (21% KRd, 14% Kd), infections (14% KRd, 17% Kd), and vascular disorders (7% KRd, 5% Kd). SAEs occurred in 30% and 36% of KRd and Kd pts, respectively, and 3% and 8% were fatal. Conclusions: In this real-life setting, KRd use was in accordance with the label, inducing high responses that could be maintained for long durations. Compared with KRd pts, Kd was used in later lines to treat older and more heavily pre-treated pts with refractory disease. The benefit-risk profile of KRd and Kd in the real-world was consistent with clinical trial results from ASPIRE and ENDEAVOR, respectively. Both KRd and Kd achieved deeper responses in earlier lines of therapy, emphasizing the importance of optimizing MM therapies. Disclosures Terpos: Janssen: Honoraria, Other: travel expenses , Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Genesis: Honoraria, Other: travel expenses , Research Funding; Medison: Honoraria. 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. Badelita:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, expenses; Takeda: Consultancy, Honoraria, Other: Travel, accommodations, expenses; Novartis: Consultancy, Honoraria; Fundeni Clinical Institute: Current Employment; Amgen: Consultancy, Honoraria, Other: Travel, accommodations, expenses. Katodritou:Takeda: Honoraria, Other: Expenses, Research Funding; Karyopharm: Research Funding; Genesis Pharma: Honoraria, Other: Expenses, Research Funding; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theagenion Cancer Hospital: Current Employment; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding. Caers: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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kühr:Pfizer: Other; Celgene: Honoraria; Merck: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Lilly: Honoraria, Other: travel, accommodation, expenses; Amgen: Honoraria; Bayer: Honoraria, Other: Travel, accommodations, expenses; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Klinikum Wels-Grieskirchen: Current Employment. Suzan:Amgen: Current Employment, Current equity holder in publicly-traded company. Mohammad:Amgen: Current Employment, Current equity holder in publicly-traded company. Wetten:Amgen: Current Employment, Current equity holder in publicly-traded company. Leleu:Oncopeptide: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; GSK: Honoraria; Novartis: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Merck: Honoraria; Carsgen: Honoraria; Incyte: Honoraria.

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).

Background: With approvals of lenalidomide (Len) based therapy for the treatment of transplant ineligible patients (pts) with newly diagnosed multiple myeloma, and for pts receiving maintenance following transplant, there is an increasing use of Len as induction and maintenance therapy. As a result, treatment options for pts who become Len-refractory (LR) has become an emerging critical challenge. We report updated results from a large real-life cohort of pts by LR status, who received approved K regimens (K, lenalidomide and dexamethasone [KRd] at the dose of 27 mg/m2 twice-weekly or Kd at the dose of 56 mg/m2 twice-weekly). Methods: In 11 participating countries across the EU and Israel, adults with relapsed/refractory multiple myeloma (RRMM), who received ≥1 dose of a K regimen in routine clinical practice were included in the prospective cohort study (NCT03091127). Cytogenetic risk status was as assessed by the physician and frailty at K initiation was calculated according to Palumbo et al.,Blood 2015;125:2068-74 and Facon et al., Blood 2015;126:4239. Pts were classified as LR if they met at least one of the following 3 criteria to any prior regimen containing Len, as defined by the International Myeloma Workshop Group (Rajkumar et al., Blood 2011;117:4691-95): best response was stable or progressive disease; progression was the reason for stopping any regimen; or/and date of relapse/progression was after the start date and within 60 days after the last dose of Len. Results: At the data cut-off of 17 March 2020, the study included 382 KRd pts and 273 Kd pts. At K initiation, nearly one-fifth (19%, n=74) of KRd pts and over half (55%, n=151) of Kd pts were LR. In the KRd cohort, LR pts were older than non-LR (NLR) pts (median: 66 vs 64 years). At KRd initiation, characteristics of LR pts were comparable with NLR pts in terms of cytogenetic risk (over 40% at high-risk of 34% reported overall) but were more frail (43% vs 28% of 67% reported) and with higher ISS stage (ISS 3: 28% vs 22% of 30% reported). LR pts had a median of 3 prior lines of therapy vs 1 for NLR pts and were more likely to have received a monoclonal antibody (mAb) (20% and 6%, respectively). Most LR pts (60%) became refractory in their last prior therapy of whom 55% became refractory from their 2nd line (2L) therapy. In the Kd cohort, LR pts were older than NLR pts at K initiation (median: 69 vs 67 years). At Kd initiation, more LR pts had a high cytogenetic risk than NLR pts (71% vs 33% of 18% reported) but were more fit (22% vs 7%, of 71% reported) and had a lower ISS stage (ISS 1: 41% vs 31% of 35% reported). LR pts had received a median of 3 prior lines vs 2 for non-LR pts and were more likely to have received a mAb (41% and 12%, respectively). In LR pts, 43% became refractory in their last prior therapy of whom 52% became refractory from their 2L therapy. Among 93% of pts with an assessment overall, high overall response rates (ORR) were achieved in NLR pts for both KRd and Kd (Table). LR pts achieved lower ORRs in both cohorts although there are differences in pt population and treatment history. Despite this, almost half of LR pts in the KRd cohort and 30% in the Kd cohort achieved a very good partial response or better. The clinical benefit rate for LR pts was 72% and 62% in the KRd and Kd cohorts, respectively. The mean K relative dose intensity was comparable for LR and NLR pts (90% vs 88%) in the KRd cohort and slightly lower for LR (74%) vs NLR (80%) in the Kd cohort. The Kaplan-Meier estimate of median treatment duration was shorter for the LR vs NLR subgroups (KRd: 11.1 [95% CI: 5.7-13.9] vs 16.2 [95% CI: 13.5 - 16.9] months; Kd: 6.3 [95% CI: 4.7-7.7] vs 9.7 [95% CI: 7.4-11.6] months). The occurrence of adverse events of ≥grade 3 (Gr3+ AEs) was comparable between KRd subgroups (49% vs 47%, LR and NLR). Kd NLR pts experienced less Gr3+ AEs than LR pts (39% vs 50%). LR pts in both cohorts experienced more SAEs and fatal events than NLR pts (SAEs: KRd: 38% vs 28%; Kd: 39% vs 33%; fatal events: KRd: 7% vs 3%; Kd: 9% vs 7%), although there are differences in pt population and treatment history. Conclusion: In this real-world cohort, LR pts had received more prior lines of therapy and were exposed to more agents than NLR pts. Fair responses were achieved for this difficult to treat population in this unadjusted analysis, which are consistent with published subgroup analyses of the clinical trials. This real-world data further supports the use of carfilzomib for RRMM and emphasizes the strength of Kd as a strong back-bone treatment for LR pts. Disclosures Leleu: Karyopharm: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Oncopeptide: Honoraria; Novartis: Honoraria. 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. Badelita:Amgen: Consultancy, Honoraria, Other: Travel, accommodations, expenses; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, expenses; Takeda: Consultancy, Honoraria, Other: Travel, accommodations, expenses; Novartis: Consultancy, Honoraria; Fundeni Clinical Institute: Current Employment. Katodritou:Karyopharm: Research Funding; Abbvie: Research Funding; Genesis Pharma: Honoraria, Other: Expenses, Research Funding; Takeda: Honoraria, Other: Expenses, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theagenion Cancer Hospital: Current Employment. Caers: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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kühr:Celgene: Honoraria; Merck: Honoraria; Pfizer: Other; Takeda: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Lilly: Honoraria, Other: travel, accommodation, expenses; Amgen: Honoraria; Bayer: Honoraria, Other: Travel, accommodations, expenses; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Klinikum Wels-Grieskirchen: Current Employment. Suzan:Amgen: Current Employment, Current equity holder in publicly-traded company. Mohammad:Amgen: Current Employment, Current equity holder in publicly-traded company. Wetten:Amgen: Current Employment, Current equity holder in publicly-traded company. Terpos:Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Medison: Honoraria; Janssen: Honoraria, Other: travel expenses , Research Funding; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding.

Introduction: The multicentre, randomized, open-label, phase 3 EMN02/HO95 study for patients with newly diagnosed multiple myeloma (NDMM) included two randomization stages (1:1) to (R1) intensification therapy with either upfront ASCT or bortezomib-melphalan-prednisone (VMP), and thereafter to (R2) consolidation therapy or no consolidation, followed by lenalidomide maintenance in both arms. Results of the final analysis from R1 (M. Cavo et al. Lancet Haematol. 2020, 7, e456-68) showed that at a median follow-up of 60.5 months progression-free survival (PFS), the primary study endpoint, was significantly improved with ASCT compared with VMP (median, 57 versus 42 months; HR 0.73, 95% CI 0.62-0.85, adjusted p=0.0001). However, no difference between these groups was found in terms of overall survival (OS), a secondary endpoint (HR 0·90, 0·71-1·13, adjusted p=0·35). Methods: We performed an updated analysis of the study with longer-term follow-up. Efficacy endpoints included OS, PFS on next-line therapy (PFS2), and time to next treatment (TTnT). Analyses were restricted to patients randomized to either ASCT (n=702) or VMP (n=495). Clinical outcomes of patients randomized to upfront ASCT or receiving ASCT at the time of progression after primary randomization to VMP (delayed ASCT) were also explored. Results: At an extended median follow-up of 75 months (IQR 67-84), patients randomized to ASCT had a significantly longer OS than those randomized to VMP (Figure). Median OS was not reached in both arms, and the 75-month survival estimate was 69% (95% CI 65-73) in the ASCT group versus 63% (95% CI 59-68) in the VMP group (HR 0.81, 95% CI 0.66-0-98, adjusted p=0.034). Patients who benefited the most from randomization to ASCT were those with unfavourable prognostic characteristics at baseline, including ISS disease stage 2-3 (HR 0.78, 95% CI 0.61-0.99, p=0.047), R-ISS stage 2-3 (HR 0.79, 95% CI 0.62-0.99, p=0.042), and the presence of at least one of the following cytogenetic abnormalities on FISH analysis: t(4;14) and/or t(14;16) in ≥10% CD138-positive plasma cells, and/or del(17p) in ≥20% enriched plasma cells. Overall, the 75-month OS estimate for patients with a high-risk cytogenetic profile was 54% with ASCT versus 39% with VMP (HR 0.61, 95% CI 0.42-0.89, p=0.010). The magnitude of OS benefit with ASCT, as measured by the HR value, was the highest for patients with del(17p) positivity (HR 0.49, 95% CI 0.28-0.86, p=0.013). PFS2 from R1 was significantly longer for patients in the ASCT arm than for those in the VMP arm. The 75-month PFS2 estimate was 57% in the ASCT group and it was 49% in the VMP group (HR 0.76, 95% CI 0.64-0.90, adjusted p=0.002) (Figure). Patients randomized to ASCT had a significantly longer TTnT in comparison with those who were randomly assigned to VMP. Median TTnT values for these groups were 66 versus 47 months, respectively (HR 0.71, 95% CI 0.60-0.82, adjusted p Conclusions: Upfront ASCT significantly prolonged OS, PFS2 and TTnT in comparison with VMP in NDMM patients. Figure Disclosures Cavo: Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Gay:AbbVie: 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; 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; 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; 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dimopoulos:Amgen: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, 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. Petrucci:GSK: 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; BMS: 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; Amgen: 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. Zweegman:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. 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; Takeda: Honoraria, 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; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Palumbo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Maisnar:Janssen, Takeda, Amgen, BMS/Celgene, The Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Belotti:Celgene: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Offidani:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, 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. Liberati:Verastem: Research Funding; Janssen: Honoraria, Research Funding; Takeda: Research Funding; Morphosys: Research Funding; Novartis: Research Funding; GSK: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding; Onconova: Research Funding; Pfizer: Research Funding; Karyopharm: Research Funding. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Ludwig:Seattle Genetics: Other: Advisory Boards; Takeda: Research Funding; Sanofi: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Celgene: Speakers Bureau. Hajek:Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Mellqvist:Janssen. Celgene, Amgen: Honoraria. Boccadoro:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

Large granular lymphocyte leukemia (LGLL) is a rare and chronic lymphoproliferative disorder characterized by the clonal expansion of LGLs. LGLL patients can be asymptomatic or develop cytopenia, mostly neutropenia. Somatic STAT3 and STAT5b mutations have been recently reported in approximately 40% of patients. The aim of this study is to analyze clinical and biological features of a large cohort of LGLL patients to identify prognostic markers affecting patients’ outcome. In 205 LGLL patients, neutropenia (ANC

Large Granular Lymphocyte Leukemia (LGLL) is a rare chronic lymphoproliferative disorder characterized by the clonal expansion of Large Granular Lymphocytes (LGLs). Among LGLL, the 2016 WHO classification recognizes two different entities, i.e. T-LGLL and the provisional entity Chronic Lymphoproliferative disorder of NK cells (CLPD-NK). In both subtypes neutropenia represents the hallmark of the disease and is frequently regarded as the leading reason to start treatment. Leukemic LGLs are characterized by the up-regulation of several pro-survival signaling pathways, the most relevant being the JAK-STAT axis, whose constitutive activation is partly explained by somatic mutations in STAT3 and STAT5b. In addiction, in the last few years, a relationship between STAT3 mutations/activation and the development of neutropenia was found. Given that backbone treatment relying on immunosuppressive agents is generally unsatisfactory, novel agents targeting the JAK/STAT pathway can represent a turning point in LGLL treatment.

BACKGROUND: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. METHODS: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (

Bortezomib-melphalan-prednisone (VMP) and continuous lenalidomide-dexamethasone (Rd) represent the standard treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (MM). To date, no randomized trial has compared VMP to Rd, and there is no evidence of the optimal treatment for newly diagnosed MM, particularly in patients with high-risk cytogenetics [del(17p), t(4;14) or t(14;16)]. We pooled together data from patients with newly diagnosed MM treated with VMP or Rd induction followed by lenalidomide maintenance 10 mg (Rd-R) enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate the efficacy of these treatments in different subgroups of patients, focusing on those with standard- and high-risk cytogenetics. Overall, 474 patients were analyzed (VMP: 257 patients; Rd-R: 217 patients). No differences in progression-free survival (hazard ratio=0.96) and overall survival (hazard ratio=1.08) were observed between standard-risk patients treated with VMP or Rd-R, whereas among the high-risk patients, the probabilities of progression (hazard ratio=0.54) and death (hazard ratio=0.73) were lower in the patients treated with VMP than in those treated with Rd-R. In particular, standard-risk patients >75 years benefited less from VMP than from Rd-R (hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-randomized analysis, VMP and Rd-R were equally effective in younger (≤75 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196).

INTRODUCTION. Bortezomib- and/or lenalidomide-based combinations are standard initial approaches in transplant (ASCT) ineligible NDMM. Different studies confirmed the advantages of continuous treatment. Despite the benefits of bortezomib maintenance, the parenteral administration and the risk of peripheral neuropathy (PN) limit its long-term use. The oral proteasome inhibitor (PI) Ixazomib plus Lenalidomide-dexamethasone was effective and well tolerated at diagnosis or relapse. The need for a convenient and well tolerated PI-based frontline therapy for an extended duration with minimal cumulative toxicity remains an unmet need for the elderly. In this prospective, multicenter, phase II randomized study, we assessed Ixazomib in combination with dexamethasone, Cyclophosphamide, Thalidomide or Bendamustine, followed by Ixazomib maintenance in ASCT-ineligible NDMM. METHODS. NDMM patients (pts) ≥65 years old or younger ASCT-ineligible could be enrolled. Treatment consisted of nine 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 (Id) or combined with Cyclophosphamide 300 mg/m2 orally on days 1,8,15 (ICd) or plus Thalidomide 100 mg/day (ITd) or plus Bendamustine 75 mg/m2 iv on days 1,8 (IBd); followed by maintenance with Ixazomib 4 mg on days 1,8,15 until progression. Because the study included the novel drug Ixazomib, dual stopping rules combining efficacy (at least very good partial response [VGPR] rate), and safety (predefined toxicity possibly related to Ixazomib) were planned and analyzed in a cohort of 5 patients in each arm during the first 4 cycles. Here we report the results of the cohort analysis during the first 4 cycles and the efficacy and safety analysis during induction treatment. RESULTS. In February 2017, the protocol was amended due to a low enrolment and the IBd arm, the only one including an iv drug, was closed. After closing this arm, all the other all oral arms continued the enrolment. Overall, 175 pts were enrolled (Id 42, ICd 61, ITd 61, and IBd 11 pts) and 171 pts started treatment. Median age was 74 years, 20% of pts had high risk cytogenetics, 44% were fit, 30% intermediate and 26% frail, according to the IMWG frailty score. Median follow-up was 13.2 months (IQR 8.9-20.7). During the first 4 cycles, at least VGPR rate was 24% with Id, 33% with ICd, 31% with ITd and 18% with IBd. In March 2018, after the analysis of the 4th cohort, the Id arm was closed due to high risk of inefficacy. Overall response rate (ORR) during induction was 73%, VGPR was 39%. ≥VGPR rates were 24% in Id, 48% in ICd, 43% in ITd and 27% in IBd. Median time to first response was 2.4 and to the best response 4 months. Responses were comparable according to cytogenetics: in high risk pts, ORR was 77%, ≥VGPR 46% and ≥nCR 17% as compared to 71%, 36% and 18% in standard risk pts (p=0.53, p=0.33 and p=1, respectively). Response rates were also comparable according to frailty status: in frail pts, ORR was 73%, ≥VGPR 36% and ≥nCR 11% as compared to 75%, 40% and 17% in intermediate and 70%, 40% and 22% in fit pts (p=0.78, p=0.90 and p=0.32, respectively). Median number of induction cycles was 9 (IQR 5-9); 93 (53%) pts completed induction treatment and 14 (8%) pts are still on induction treatment. During the first 4 cycles, hematologic toxicity was limited, and non-hematologic toxicity manageable. The most frequent G3-4 adverse event (AE) was rash in ITd arm (11%); discontinuation rate due to toxicity was 6%. During induction, the rate of at least 1 hematologic G≥3 AE was 11% and at least 1 non-hematologic G≥3 AE was 44%. The most frequent G≥3 AEs were neutropenia (8%), gastrointestinal (9%), infections (11%), neurologic (11%) and dermatologic (6%). G3-4 thrombocytopenia (3%) and PN (5%) were limited. Ixazomib dose reduction due to AEs was required in 15% of pts. The rate of non-hematologic AEs was slightly higher in ITd arm (37% in Id, 37% in ICd, 53% in ITd, 55% in IBd). Early death rate ( CONCLUSIONS. ITd and ICd are convenient all-oral induction regimens for ASCT-ineligible NDMM, confirming an improved efficacy of a triplet vs a doublet combination, also in intermediate and frail patients. Id showed lower efficacy, thus suggesting a possible effect of the dose of Ixazomib or the absence of a third drug. Treatment was feasible, with limited toxicity and low discontinuation rate due to AEs, although ITd induced a slightly higher toxicity, but mainly attributable to Thalidomide. Disclosures Larocca: Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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. Corradini:Servier: Honoraria; Amgen: Honoraria; Gilead: Honoraria, Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; KiowaKirin: Honoraria; Jazz Pharmaceutics: Honoraria; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Celgene: Honoraria, Other: Travel Costs. Mina:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Liberati:Bristol-Myers Squibb: Honoraria; Roche: Other: Clinical trial support; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Honoraria, Other: Clinical trial support; Novartis: Other: Clinical trial support. Petrucci:Takeda: 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, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: 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. Patriarca:Celgene: 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. 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. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Cellini:Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Janssen: Honoraria. Galli:Takeda: Honoraria; Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Aquino:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. De Sabbata:Janssen: 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. Ballanti:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Offidani: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; 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Bringhen:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

8002 Background: Cytogenetic abnormalities (CA) are one of the most powerful prognostic factors in multiple myeloma (MM). In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd_ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12, HR 0.64) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd_ASCT, HR 0.53). KR maintenance significantly improved PFS vs R (HR 0.63). Methods: MM patients (pts) were randomized to KRd_ASCT vs KCd_ASCT vs KRd12 and, thereafter, to KR vs R maintenance. Subgroup analyses according to FISH evaluated the impact of each single high-risk (HiR) CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)] and that of combined CA, defining HiR by the presence of ≥1 HiR CA and double-hit (DH) by the presence of ≥2 HiR CA. Pts negative for all the HiR CA were considered at standard risk (SR). The primary objective was the impact of treatment on PFS according to pt risk. Results: 396 out of 474 enrolled pts were included in the analysis with complete FISH data: 243 HiR, 105 DH and 153 SR. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd_ASCT vs KRd12 (HR 0.47, p = 0.05) and KCd_ASCT (HR 0.38, p = 0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd_ASCT improved PFS vs KRd12 (HR 0.6, p = 0.04) and KCd_ASCT (HR 0.57, p = 0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd_ASCT vs KRd12 (HR 0.53, p = 0.07) and KCd_ASCT (HR 0.49; p = 0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Analyses by single CA were limited by the small number of pts in each subgroup, but a trend towards a PFS benefit from KRd_ASCT vs KRd12 was seen in pts with del17p (HR 0.61, p = 0.3), t(4;14) (HR 0.59, p = 0.2) and 1q gain (HR 0.45, p = 0.02). In pts with del1p, KRd_ASCT (HR 0.24, p = 0.06) and KRd12 (HR 0.33, p = 0.09) showed superiority over KCd_ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd_ASCT vs KCd_ASCT, HR 1.16, p = 0.73; KRd12 vs KCd_ASCT, HR 1.34, p = 0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p = 0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p = 0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p = 0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p = 0.37), t(4;14) (HR 0.59, p = 0.3), 1q gain (HR 0.54, p = 0.07) and del1p (HR 0.23, p = 0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p = 0.7). Conclusions: KRd_ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd_ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus supporting their use in HiR pts, who represent an unmet medical need. Clinical trial information: NCT02203643.

Objective:To evaluate long-term lenalidomide neurotoxicity and correlation with cumulative dose and hematologic response.Methods:Nineteen myeloma patients (7 men, mean age 63.2 years) underwent clinical and neurophysiologic assessment at baseline and at 2 (8 patients, group A) or 5 years (11 patients, group B) after starting lenalidomide therapy for relapsed/refractory multiple myeloma. Neuropathy was scored with Total Neuropathy Score clinical version (TNSc). Lenalidomide cumulative dose was correlated with severity of neuropathy and hematologic response.Results:At enrollment, 7/19 patients (3 in group A, 4 in group B) had neurophysiologic signs of neuropathy secondary to previous chemotherapy, in 2 of them subclinical. Neurophysiologic evidence of sensory axonal neuropathy occurred in 4/8 patients at 2 years follow-up (group A) and in 3/11 patients at 5 years follow-up (group B). Dorsal sural nerve sensory action potential amplitude was the earliest neurophysiologic abnormality. No relevant (≥4) clinical changes were found in TNSc score. Hematologic overall response was 62% in group A and 100% in group B. No correlation was found between lenalidomide cumulative dose and neuropathy or between neuropathy and hematologic response.Conclusions:In our study, up to 50% of myeloma patients on long-term lenalidomide therapy developed sensory axonal neuropathy. Reduced dorsal sural nerve sensory action potential amplitude was the first neurophysiologic alteration. Neuropathy was usually subclinical or mild, however. Neurotoxicity was independent of lenalidomide cumulative dose and hematologic response.

The optimal first-line treatment for advanced low-grade non-Hodgkin lymphomas (LG-NHL) is still highly debated. Recently, the StiL and the BRIGHT trials showed that the combination of rituximab and bendamustine (R-B) is non-inferior to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with a better toxicity profile. Utilizing a retrospective analysis, we compared the efficacy and safety of both regimens in clinical practice. From November 1995 to January 2014, 263 LG-NHL patients treated with either R-B or R-CHOP were retrospectively assessed in seven European cancer centers. Ninety patients were treated with R-B and 173 with R-CHOP. Overall response rate was 94 and 92 % for the R-B and the R-CHOP group, respectively. The percentage of complete response was similar for both groups (63 vs. 66 % with R-B and R-CHOP, respectively; p = 0.8). R-B was better tolerated and less toxic than R-CHOP. The median follow-up was 6.8 and 5.9 years for the R-CHOP and the R-B group, respectively. Overall, no difference in progression-free survival (PFS) (108 vs. 110 months; p = 0.1) was observed in the R-B group compared to the R-CHOP cohort. Nevertheless, R-B significantly prolonged PFS in FL patients (152 and 132 months in the R-B and R-CHOP group, respectively; p = 0.05). However, this result was not verified in multivariate analysis probably due to the limits of the present study. We confirm that the R-B regimen administered in patients with LG-NHL is an effective and less toxic therapeutic option than R-CHOP in clinical practice. © 2016, Springer-Verlag Berlin Heidelberg.

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not suitable for high dose chemotherapy with autologous stem cell transplantation (ASCT) has a dismal prognosis and no standard therapy. We designed an Italian multicenter retrospective study aimed at evaluating the safety and efficacy of rituximab plus bendamustine (R-B) as salvage treatment in patients not eligible for ASCT because of age and/or comorbidity or in patients with post-ASCT recurrence. Fifty-five patients with a median age of 76 years were included. The overall response rate was 50%, including 28% complete remission and 22% partial remission. The median overall survival (OS) was 10.8 months. The median progression free survival (PFS) was 8.8 months. Eleven patients are still alive and in complete remission at last follow-up (12-71 months). Toxicity was moderate, mainly grades 1 and 2. R-B showed promising efficacy results with an acceptable toxicity profile and should be further investigated, possibly in combination with novel drugs.

8533 Background: The role of MRD by MFC and NGS is well known in MM, with few data on the concordance of the two techniques. We analyzed and compared MRD data from the FORTE trial both by MFC and NGS. Methods: Newly diagnosed MM patients (pts) ≤65 years were randomized to: carfilzomib, lenalidomide, dexamethasone (KRd) induction-autologous stem cell transplant (ASCT) - KRd consolidation (KRd_ASCT); 12 KRd cycles (KRd12); carfilzomib, cyclophosphamide, dexamethasone (KCd) induction-ASCT-KCd consolidation (KCd_ASCT). Pts were then randomized to maintenance: lenalidomide alone or plus carfilzomib. MRD was assessed by 8-color second generation flow cytometry (sensitivity 10−5) in pts with ≥very good partial response (VGPR) before maintenance. In a subgroup of these pts, next generation flow (NGF; sensitivity 10−5-10−6) was performed. In ≥CR pts, MRD pre-maintenance was also assessed by NGS (Adaptive Biotechnologies; sensitivity 10−5-10−6). Thus, both MFC and NGS evaluations were available only in ≥CR pts. 1-year sustained MRD negativity by MFC and NGS was also analyzed in pts with at least one sample available at least 1 year apart. Results: MFC and NGS data were available in 184/233 (79%) CR pts (66 KRd_ASCT, 67 KRd12 and 51 KCd_ASCT). Median age of this ≥CR population was 57 years (IQR 52-62), 13% had International Staging System (ISS) III and 27% high risk cytogenetics by FISH [either del(17p) or t(4;14) or t(14;16)]. Table reports MRD negativity rate by MFC and NGS at a cut-off of 10−5 and 10−6 among ≥CR negative pts in the 3 arms. NGS negativity at a cut-off 10−6 was found in 36/133 (27%) ≥CR pts (for 51/184 CR pts 10−6 sensitivity was not reached). In evaluable pts, 1-year sustained 10−5 MRD negativity by MFC and NGS was superimposable (83%). We evaluated concordance of MRD results by the two techniques and observed agreement was 86% for MFC and NGS at 10−5 evaluable samples (n: 335; r: 0.61) and 78% for MFC and NGS at 10−6 evaluable samples (n: 56; r: 0.77). Conclusions: In pts who achieved ≥CR, similar rate of pre-maintenance 10−5 negativity by MFC and NGS has been reached in each arm, with 83% pts maintaining 1-year MFC or NGS 10−5 sustained MRD negativity. Concordance between MFC and NGS was good, particularly when the same sensitivity was reached. Longer follow up is needed to draw definitive conclusions. Clinical trial information: NCT02203643 . [Table: see text]

Immunotherapy represents a promising new avenue for the treatment of multiple myeloma (MM) patients, particularly with the availability of Monoclonal Antibodies (mAbs) as anti-CD38 Daratumumab and Isatuximab and anti-SLAM-F7 Elotuzumab. Although a clear NK activation has been demonstrated for Elotuzumab, the effect of anti-CD38 mAbs on NK system is controversial. As a matter of fact, an initial reduction of NK cells number characterizes Daratumumab therapy, limiting the potential role of this subset on myeloma immunotherapy. In this paper we discuss the role of NK cells along with anti-CD38 therapy and their implication in plasma cell dyscrasias, showing that mechanisms triggered by anti-CD38 mAbs ultimately lead to the activation of the immune system against myeloma cell growth.