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Background Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. Methods In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0–2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Findings Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60–72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61–72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0–8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2–5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64–0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4–22·8) in the melflufen group and 16·3 months (10·1–23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1–25·6) at a median follow-up of 19·8 months (IQR 12·0–25·0) in the melflufen group and 25·0 months (95% CI 18·1–31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8–23·7; HR 1·10 [95% CI 0·85–1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). Interpretation Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma., Oncopeptides AB

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

This national Israeli multicenter retrospective study aimed to characterize the clinical course of COVID-19 infection among patients with hematological malignancies, with special emphasis on treatment efficacy and outcome. Clinical and laboratory data from haemato-oncological patients diagnosed with COVID-19 from 16 medical centers were centrally reported. Multivariate regression analyses were used to determine variables associated with severe disease, hospitalization, and mortality. In total, 313 patients were included: 103 (35.7%) developed severe/critical respiratory infection, 178 (61.4%) were hospitalized, and 60 (20.0%) died. Age > 70 years was associated with severe/critical disease (p = 0.036) and mortality (p = 0.023), hypertension with severe/critical disease (p = 0.046) and hospitalization (p = 0.001), active haemato-oncological treatment with hospitalization (p = 0.009), and remdesivir treatment was associated with decreased mortality (p = 0.021). Convalescent plasma, enoxaparin, and corticosteroids resulted in no clinical benefit. In conclusion, COVID-19 infection seems particularly severe in patients with hematological malignancies, and of all examined therapies, remdesivir appears to be the most effective.

Background Lenalidomide and ixazomib maintenance improve long-term outcomes in newly diagnosed multiple myeloma (NDMM) patients. However, there is less evidence to support bortezomib (BTZ) maintenance therapy, and real-life data on maintenance are scarce. We investigated the efficacy and safety of BTZ maintenance therapy in NDMM. Patients and Methods A retrospective multisite study was performed in 6 medical centers in Israel. All consecutive patients with NDMM diagnosed between January 1, 2010, and July 3, 2019, who received a BTZ-based induction, with or without an autologous transplantation, followed by BTZ maintenance therapy, were identified. Maintenance therapy was defined as BTZ (1.3 mg/m2) once every 2 weeks, administered subcutaneously alone or with dexamethasone, or weekly BTZ monotherapy. Results A total of 105 patients were identified, 58 of whom had received a transplant (transplant eligible) and 47 who had not (not transplant eligible). During BTZ maintenance therapy, 96% had one or more adverse event, 11.5% had grade 3 or higher adverse events, and 11.5% discontinued treatment due to toxicity. Median progression-free survival (PFS) and overall survival were 45 and 91.5 months, respectively; 4-year survival was 88%. Adverse cytogenetics was associated with worse PFS (24 vs. 46 months, P = .001). In subgroup analysis, adverse cytogenetics were associated with worse PFS (P Conclusion Analysis of multisite real-life data showed that BTZ maintenance therapy is safe, well tolerated, and effective. Median PFS was similar to that reported with alternative maintenance strategies. Our findings further support its use among patients with adverse cytogenetics, it may also be relevant for patients with lenalidomide-intolerant disease.

To assess the usefulness of proton MR-spectroscopy (1H-MRS) and diffusion-weighted MRI (DW-MRI) sequences in the follow-up of CLL-patients with chemotherapy treatment.

Cytogenetic abnormalities are a recognized factor in the pathogenesis of multiple myeloma (MM). While chromosomal translocations involving the IGH gene have been investigated and reported, the implications of deletions or amplifications in the IGH gene have been less frequently examined. We conducted a retrospective analysis of 260 patients with MM from Northern Israel. Fluorescent in situ hybridization (FISH) analysis of separated CD-138 positive cells was done on bone marrow samples collected between 2016 and 2018. We used IGH break apart probes to identify IGH abnormalities and performed statistical analysis of clinical and prognostic features, comparing the different cytogenetic groups. Deletions in the variable region of the IGH (IGHv) were found in 17.3 % (n = 45) of patients and correlated with significantly worse progression free survival (PFS) after two years of follow up (p = 0.008), as well as with a worse response to 1st line treatment (p = 0.037). The median PFS was 7.1 and 17.7 months in patients with and without IGHv deletion, respectively. PFS differences remained significant (p = 0.017) in subgroup analysis of patients with high-risk cytogenetics (n = 108, 19 with IGHv deletion). Overall survival was not significantly different in the two groups. Constant region (IGHc) amplifications, were less frequently found (6.15 %, n = 16), yet significantly correlated with worse PFS after two years of follow up (p = 0.023). This difference remained valid in the high-risk subgroup (p = 0.001). In Conclusion, we identified that deletion of the IGH variable region and amplification in the IGH constant region, are both associated with poor prognosis and inferior outcome in MM.

Increased chemokine C-X-C receptor 4 (CXCR4) expression is related to unfavorable outcome in chronic lymphocytic leukemia (CLL). Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that has been shown previously to interact with CXCR4 in neuronal cells. Here, we studied the in vitro effect of BDNF on CXCR4 expression and chemotaxis toward stromal derived factor-1 (SDF-1) in freshly isolated CLL cells. We also explored the correlations between serum BDNF levels in CLL patients and disease characteristics and clinical course. Incubation of CLL cells with recombinant BDNF (50 ng/mL) resulted in a downregulation of CXCR4 surface expression and atenuated chemotaxis toward SDF-1. Higher serum BDNF levels were associated with a mutated immunoglobulin heavy chain variable (IGHV) gene, an early clinical stage, and a stable clinical course. Our findings suggest that increased circulating blood BDNF may be associated with a favorable effect in CLL. However, the exact mechanism of this favorable effect should be investigated further.

Del17p is a genomic imbalance occurring in ∼7%-10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib-based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M-Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M-Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches.

Background A significant percentage of red blood cell transfusions are inappropriately overused. This study investigated physicians from the western Galilee in terms of their knowledge of transfusion medicine as a potential reason for red blood cell overuse, and assessed the influence of personal background characteristics on their knowledge. Methods Data were collected via anonymous questionnaires. The questionnaires included a personal background section and a professional section. Study participants were grouped according to field of specialty, seniority, and location of medical school graduation, in order to correlate participant characteristics with knowledge. Results Scores were calculated on a 0–100 scale. The overall knowledge of the study population was low (mean score 47.8 ± 18.6). Knowledge regarding basic physiology of red blood cell transfusion was also low. Internal medicine physicians and senior physicians had significantly greater overall knowledge scores and were more familiar with a restrictive blood management policy than were surgeons and residents, respectively. Comparing knowledge scores, no difference was found regarding indications for transfusion. Conclusion General and fundamental knowledge in transfusion medicine is lacking among physicians in the non-operating room setting, which may play a role in red blood cell transfusion overuse. Field of specialty and professional status influenced knowledge of transfusion medicine. Educational programs and increased physicians’ awareness might help decrease unnecessary transfusions. Trial registration Not applicable. Electronic supplementary material The online version of this article (10.1186/s13584-017-0173-0) contains supplementary material, which is available to authorized users.

Rosai–Dorfman disease (RDD), otherwise known as sinus histiocytosis with massive lymphadenopathy (SHML), is a rare macrophage-related histiocytic disorder of unknown etiology, dominated by histiocy...

Introduction: The survival of double refractory multiple myeloma (MM) patients was poor in the pre- monoclonal antibody era, with a median overall survival (OS) of 9 months only. Daratumumab used as a single agent has shown significant efficacy resulting in an overall response rate (ORR) of 30%, and OS of 20 months in patients, failing immunomodulatory drugs (IMIDs) and proteosome inhibitors (PIs). Daratumumab combined with pomalidomide and dexamethasone has yielded ORR of 60% and median OS of 17.5 months in such patients. Daratumumab has been recently introduced to the early relapsed MM setting, providing significant improvement in progression-free survival when administered in combination with IMIDs or PIs. The current retrospective study has evaluated the characteristics and outcome of MM patients who had progressed while being receiving daratumumab, aiming to define prognostic factors and optimal therapeutic approaches for this patient population. Methods: MM patients treated with daratumumab alone or in combinations in 11 Israeli centers between 01.2014 and 07.2018, all experiencing disease relapse/progression were included. Data including demographics, disease-related parameters at diagnosis [MM type, extramedullary disease (EMD), ISS (International Scoring System), LDH level high-risk cytogenetics], prior treatment regimens, response duration to the last pre-daratumumab therapy, treatment and outcomes post-daratumumab failure were analyzed. Results: One hundred consecutive patients progressing on daratumumab were included in the study. Patient characteristics are presented in table 1. Daratumumab was used in 2nd-3rd line therapy in 17 patients (17%), 4th in 22 patients (22%) and 5th-9th line therapy in 61 patients (61%). Sixty four patients (64%) were refractory to at least 3 novel agents before starting a daratumumab combination; 36 (36%) of them were quadrate refractory to bortezomib, carfilzomib, lenalidomide and pomalidomide. Forty five patients (45%) received daratumumab as a single agent and 55 (55%) as a combination therapy (table 1). Median duration of response to the last pre-daratumumab therapy was 5 months, with duration of ³6 months predicting response to daratumumab (P=0.019). Fifty seven percent of patients achieved stable disease or better with daratumumab combinations, with an ORR of 38% [partial response (PR) or better] and 15% achieved very good PR (VGPR) or complete response. Median time to progression on daratumumab was 3.1 months. It was shorter in patients treated with daratumumab as a single agent than in those receiving a combination therapy (2.5 vs 4.7 months, p=0.012). Progression (n=13) or de novo (n=19) EMD was recorded in 32 patients (32%). At time of relapse/progression, daratumumab was stopped in 45 patients (45%), and continued in combination with other agents in 33 patients (33%). Data regarding actions taken post-daratumumab failure were unavailable for 22 individuals. In 58 patients, for whom data regarding response to a post-daratumumab regimen were available, the ORR was 34%. Median follow-up after daratumumab failure was 8 months (0 -33.5 months), with a median OS of 5.3 months; 25% of the patients survived 14.1 months. Notably, daratumumab given in combination with chemotherapy was associated with a worse prognosis (HR=2.7, P=0.007). No OS difference was found between those who stopped daratumumab at time of failure and those who continued it. Age, gender, high-risk cytogenetics and lines of previous therapies did not affect OS in this patient group. Longer duration of response to both pre-daratumumab and daratumumab therapy was found to be associated with a prolonged OS after daratumumab failure (HR=0.929, P=0.006 and HR=0.872, P=0.024, respectively). Conclusions: The prognosis of double refractory MM patients, failing daratumumab therapy, is poor, with a median OS of 5.3 months. Post-failure continuation of daratumumab in a different anti-myeloma combination has not improved OS. Durable responses to both pre-daratumumab and daratumumab therapy are both associated with a superior OS in patients progressing on daratumumab, most probably reflecting a more favorable disease biology. Given that most patients in this study have been heavily pretreated, further evaluation of treatment strategies in patients who fail daratumumab combinations at earlier disease stages is warranted. Disclosures Cohen: Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Tadmor:ABBVIE: Consultancy; JNJ: Consultancy; NOVARTIS: Consultancy; PFIEZER: Consultancy; ROCHE: Research Funding.

Macrofocal Multiple Myeloma (MFMM) has been described as a distinct entity of Multiple Myeloma (MM) characterized by young age, lytic lesions and limited bone marrow infiltration by clonal plasma cells (BMPCs), in the absence of other features of symptomatic MM (i.e. anemia, renal insufficiency and hypercalcemia). Few case studies have indicated a possible favorable prognosis of MFMM patients compared to patients with typical symptomatic MM. Our aim was to investigate the incidence, characteristics and outcome of patients with MFMM, under the light of modern therapeutic approach of MM. MFMM definition required: clonal BMPCs 3 lytic lesions). In 20/140 (14%) patients bone plasmacytomas preceded MM diagnosis. In 95/140 (68%) patients bone, soft tissue or mixed plasmacytomas in multiple locations, were present at diagnosis or during MFMM course and this was significantly more frequent compared with standard MM. Median BMPCs infiltration was 14% (range 0-19%); immunoparesis was less common in MFMM (55% vs. 90% in standard MM). Elevated lactate dehydrogenase (LDH) and β2 microglobulin (β2Μ) ≥ 3.5mg/L were found in 9% and 20% of patients, respectively. Cytogenetics by fluorescence in situ hybridization (FISH) were available in 60% of patients and high-risk features were found in 11%; overall, adverse prognostic parameters (i.e. high LDH, advanced age, high β2Μ, high risk cytogenetics) were less common in patients with MFMM compared with others (p Disclosures Kastritis: 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; 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; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cohen:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Terpos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; BMS: Consultancy; Novartis: Consultancy. Dimopoulos:Amgen: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

During the last two decades the importance of molecular biology in transfusion medicine has been growing. Reference centers for immunohematology commonly use molecular methods to clarify problems, discrepancies or unusual results in patient serology. Nowadays there are immunohematology reference laboratories that recommend using molecular genotyping for patient blood management. Our blood bank laboratory is not a reference center, but we routinely use molecular genotyping to solve serologic problems. Due to the proximity to the Syrian border, since the beginning of the Syrian civil war, our medical center has received hundreds of injured patients, some of them with unique features concerning the blood type testing. From our previous experience of such a case in Dec 2015, we realized that due to extreme war conditions and lack of medical amenities, severely injured patients are likely to receive unmatched blood transfusions in Syria, sometimes ABO-incompatible blood transfusions. The patients arriving to our medical center are usually in critical condition and without medical records. Serologic tests show double population (DP) blood type. Molecular genotype of blood samples is not helpful, because it can detect the blood type of the unmatched/incompatible donor. In these cases, we use molecular genotyping from a tissue specimen, usually skin. Until we receive the results, which take about 5 hours in our molecular lab, we give only type O blood and AB plasma. Since Dec 2015, 11 injured patients with DP on serologic typing were admitted to our medical center. Tissue genotyping was performed on 8 of these. We determined that seven of the eleven patients previously received ABO-incompatible blood in Syria. With one exception, all patients were transfused in Israel (detailed data not shown), three with incompatible blood upon admission, based on initial serotype (patients 1,3,4 in the table). Tissue genotyping allowed us to transfuse compatible ABO-matched blood components afterward. All patients survived and were released in good condition. Tissue molecular genotyping helps improve patient blood management in the population of injured causalities from Syria. Table. Table. Disclosures No relevant conflicts of interest to declare.

Introduction: Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. Methods: All consecutive patients with RR-MM who received carfilzomib-containing salvage therapy outside of a clinical trial between March 2013 and April 2015 were included in this study. For the response and survival analyses, patients were included only if they received at least one full cycle of carfilzomib and response evaluation was available. Carfilzomib was used either as a single agent or in combinations with other drugs, according to the treating physician's choice. Per manufacturer's recommendations, carfilzomib was given by intravenous infusion over 10-30 minutes on days 1, 2,8,9,15,16 of 28-days cycle. The recommended dose of carfilzomib was 20 mg/m2 on days 1 and 2 in cycle 1, which was increased on subsequent administrations to 27 mg/m2 (the 20/27 mg/m2 schedule), provided that the previous dose was well tolerated. Doses, however, were modified according to the treating physician's discretion. Results: One-hundred and thirty-five patients were included. The median age at carfilzomib initiation was 67.9 years (range, 41-88). Male and female patients were equally balanced. Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 was evident in 14.8% of patients. All patients were previously exposed to bortezomib and 93% to lenalidomide as well. The median time from last treatment to carfilzomib was 5.5 months (range, 0.3-43). Patients had received a median of 3 lines of therapy prior to carfilzomib (range, 1-7). The median number of administrated cycles of carfilzomib was 4 (range, 0.3-22). The majority of patients (79.3%) received carfilzomib according to the 20/27 mg/m2 dose schedule. The remaining patients received carfilzomib either at a dose that did not exceed 20 mg/m2 (11.8%) or at maximal dose higher than 27 mg/m2 (8.9%, mostly as a 20/27/56 mg/m2 dose schedule). Carfilzomib was administrated as a single agent in 5.1% of patients or combined with a second agent in 43% of them. Additionally, 46.7% of patients received carfilzomib as part of a three-drug combination and 5.2% of patients as part of four-drug combination or more. In comparison to patients who received two-drug combination (or carfilzomib alone), patients who received three-drug (or more) combination were younger, with less prior treatment lines and higher baseline haemoglobin, albumin and eGFR (Table I). There was also pre-selection by lower frequency of ImIds resistance in the three-drug combination sub-group, but bortezomib resistance was similar between sub-groups. One hundred and twenty three patients (91.1% of patients) were evaluable for response and survival analysis. The overall response rate was 48.8%, with one patient (0.8%) achieving complete response (CR), 30 patients (24.4%) attaining very good partial response (VGPR) and 29 patients (23.6%) with partial response (PR). Additionally, 15 patients (12.2%) achieved minimal response (MR), reaching a clinical benefit response (CBR) rate of 61%. A multivariate analysis revealed three parameters negatively impact the likelihood of achieving response: bortezomib resistance (odds ratio 0.33, 95% CI 0.12-0.94, p=0.03); lenalidomide resistance (odds ratio 0.31, 95% CI 0.11-0.91, p=0.03), and albumin Conclusion: In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields an effective results with a manageable toxicity. Drug resistance is an important factor in determining response quality to carfilzomib. Disclosures Raanani: Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board; BMS: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding.

Light-chain amyloidosis (AL) is associated with low survival rates, particularly in patients with cardiac involvement. We evaluated the outcome of 73 consecutive, non-selected ‘real-world’ AL patients, treated with first-line bortezomib-based induction, focusing on the benefit of concurrent administration of alkylating agents. Most patients had renal (77%), cardiac (66%), or multiorgan (74%) involvement. Sixty-eight per cent (n = 50) received alkylating agent (mostly cyclophosphamide). Severe adverse events were seen in 45%, most evident in patients with cardiac involvement, with no increased toxicity in patients receiving an alkylator agent. Hematological response (HemR) was obtained in 77% of patients, including 33% very good partial responses and 19% complete responses. Age

Introduction: BDNF is a neuronal growth factor that previously showed to exert survival effect in B cells. The role of BDNF in CLL is unknown. Objectives: To study the circulating levels of BDNF in CLL patients and their association with disease prognosis. We also looked for CXCR-4 as a possible mechanisms underlying BDNF effect in CLL. Design and methods: The total BDNF levels and the levels of the BDNF precursor; proBDNF were quantified in the serum of 36 CLL patients and 5 healthy controls by commercial ELISA kits (DY248 and DY3175 DuoSet, respectively, from R&D Systems, Minneapolis, MN, USA). The patients' BDNF levels were correlated to the disease characteristics and clinical course. mRNA and protein expression of the high affinity receptor for BDNF; TrkB were evaluated by real time PCR and flow cytometry respectively. The effect of BDNF on CXCR4 surface expression and migration of CLL cells towards SDF-1 were studied in-vitro. Results: The total serum levels of BDNF in CLL patients was not statistically different compared to healthy controls (mean±SD; 19.9±15.1ng/ml vs. 10.5±9.5ng/ml respectively, p=0.19). Serum proBDNF levels in both CLL patients and healthy controls were under the detection limit of the kit. Within the CLL group we found higher total BDNF levels in patients with mutated immunoglobulin variable heavy-chain (IGHV) status than in patients with unmutated IGHV (25.2±14.6ng/ml vs. 14.1±13.0 in mutated and unmutated status, respectively, p=0.028). We also found higher serum levels of total BDNF in CLL patients in Binet stage A compared to those with a more advance clinical stage (mean±SD ; 24.5±14.6ng/ml vs. 17.0±16.9 and 10.2±9.6 in A,B and C, respectively, p=0.013). Accordantly, higher BDNF levels were detected in patients who had a clinically stable disease compared to patients who had disease progression and required treatment (23.1±14.7ng/ml vs. 13.4±14.5, respectively, p=0.013). The mRNA levels of the BDNF receptor; TrkB, were twofold lower in CLL cells compared to normal B cells. However, the overall TrkB mRNA transcripts were very low in CLL cells and normal B cells compared to the normalized housekeeping genes of Beta-2-microglobulin and CD19. Likewise, surface expression of TrkB in CLL was undetectable using several commercial monoclonal Abs by flow cytometry. In vitro culture of CLL cells in serum free media for 24h resulted in an increased CXCR4 surface expression and greater apoptosis. Culture of CLL cells in the presence of recombinant BDNF (50ng/ml) resulted in downregulation CXCR-4 surface levels and protection from spontaneous apoptosis, irrespectively of the IGHV mutational status. The effect of BDNF on CXCR4 downregulation was also confirmed at 1h culture as it shows to induce similar effect to SDF-1 (50ng/ml) and additive effect when combined with SDF-1. Finally, possible competition between BDNF and SDF-1 was indicated as pretreatment of CLL cells with BDNF inhibit their migration toward SDF-1. Discussion: Our findings show association between high BDNF levels and favorable disease prognosis in CLL. Undetected TrkB expression in CLL cells is compatible with previous reports showing sequestration of TrkB in normal and malignant B cells and suggests TrkB independent effect of BDNF in CLL. The effect of BDNF on the survival and migration of CLL cells via CXCR-4 needs to be further investigated. Disclosures No relevant conflicts of interest to declare.

Introduction Improvement in overall survival (OS) is seen primarily within standard risk Multiple Myeloma (MM), however, high risk MM OS was still around 2-3 years until recently. Del17p is a genomic imbalance which includes deletion of the TP53 locus. It occurs in ~7-10% of MM at diagnosis and is associated with extramedullary disease and is a strong poor prognostic factor. Recently approved novel agents and combinations have demonstrated improved outcomes also in patients with negative cytogenetic features; however, their long term impact remains to be seen. Access to newer agents depends on time of diagnosis as well as availability of clinical trials, access programs and insurance coverage. The goal of this study is to analyze real world data including treatment patterns and outcomes among MM patients carrying 17p deletion, in a retrospective multi-site study. Methods An observational, retrospective, multi-center study. Consecutive patients diagnosed with multiple myeloma in the 8 participating centers in Israel, diagnosed between 1.1.2008 - 3.1.2016 that were proven to carry 17p deletion by means of FISH studies (any % of plasma cells), were identified by searching hospital records including cytogenetic lab records. Data concerning patient demographics, disease characteristics, treatment regimens and clinical endpoints were collected. Results A total of 57 patients carrying 17p deletion of FISH were identified. Patient's characteristics are described in table. Notably, most patients had bone disease; extramedullary disease (EMD) rate was relatively high, as was the presence of additional high risk FISH abnormalities. Most patients received a bortezomib-based induction, over half underwent ASCT. Fifteen (26%) of the patients participated in clinical trials or access programs (or both) (table). Overall response rate (ORR) after induction was 84%, response rate declined in subsequent treatment lines (figure 1). The median follow-up was 21 (range, 4-94) months. Median overall survival (OS) was 43 months; Median Progression free survival (PFS) was 20 months (figure 2A,B). In univariate analysis, presence of extra-medullary disease at diagnosis was associated with worse PFS (7.4 vs. 21.4 months, p=0.05, figure 2C); presence of additional high risk FISH findings also trended towards shorter PFS (13.5 vs 21.4 months, p=0.0569), while age, gender, ISS, %plasma cells, % cells with del17p, time of del17p detection, M-Spike and iFLC levels were not significantly associated with PFS. Among patients with a PFS greater than 6 months, ASCT was associated with a significant improvement in PFS (25.7 vs 9.0 months, p=0.0022 log-rank test) (figure 2D), 4 patients underwent allotransplant, with a median OS of 69 months. Conclusions Our data confirm the poor prognosis of myeloma patients with del17p, in a multi-site observational setting, and an even worse prognosis in the presence of extramedullary disease and additional high-risk FISH features. While ORR after induction is similar to that generally expected in a newly diagnosed myeloma patients, responses are shorter and thus PFS is inferior compared to recently reported upfront bortezomib-based regimens ranging from 30-40+ months. Responses decline further in subsequent lines yet remain non-negligible even in advanced therapeutic lines. Our data support the role of ASCT in these high risk patients, and the potential role of allotransplant in selected patients. High rate of participation in clinical trials and access programs throughout the course of therapy reflects the valued role of newer agents in the management of myeloma patients. Disclosures Avivi: Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche.

combination of these techniques could permit to detect early biological (non-symptomatic) relapses (EBR) in this setting. Aims: To analyze the usefulness of HLC and FLC to detect EBR in MM after ASCT. Patient and Methods: A retrospective study was performed following these criteria: all patients diagnosed of secretory MM, in our center, and treated (including ASCT), between May 2011August 2014; the protocol for follow-up included FLC, HLC, serum and urine electrophoresis (SPE, UPE) with immunofixation (IFX), pre-ASCT, after 12 weeks and every 3 months later (minimum follow-up: 6 months). EBR was defined as 25% on M-protein increase (any amount for patients on CR/SR) and/or 20mg/dl FLC increase, and/or 25% involved HLC increase with abnormal ratios. For urine, an increase >500mg/24 hrs of involved free-chain protein. Results: Fifty-five patients were registered. Median followup 21 months. MF ratio: 29/26, mean age 59.5 y (33-71). Immunoglobulin subtype: IgG-Kappa: 41.8% (23), IgG-Lambda: 23.6% (13), IgA-Kappa: 16.4% (9), IgA-Lambda: 7.3% (4), BenceJones-Kappa: 3.6% (2), Bence-Jones-Lambda: 7.3% (4). DurieSalmon Stage: IA: 13.5% (7), II-A: 32.7% (17), III-A: 44.2% (23), III-B: 9.6% (5), missing-data 3 case. All patients received Bortezomib based therapy and MEL200 as ASCT conditioning. Status pre-ASCT: minimal response: 12%, Partial Response (PR): 50.0%, very-good-PR (VGPR): 28.0%, complete response (CR): 6% and string response (SR): 4.0%. After ASCT, evaluation reveals that 13.0% achieved SR, 13.0% CR, 30.4% VGPR and 39.1% PR. During follow-up, 27/50 (54.0%) patients who achieved at least PR after ASCT, had a clinical relapse/progress, median PFS 24 months (19.8-28.1). EBR were detected in 19/27 relapsed patients at median time 7 (2-19) months before symptomatic relapse. The EBR were detected by FLCr (31.6%), HLCr (21.0%), FLC+SPE (10.5%), FLC+IFX (5.2%), FLC+HLC+SPE (15.8%), FLC+HLC+SPE+UPE (15.8%). Conclusion: Both FLC and HLC are useful tools to detect EBR in more than 50% of patients in our cohort ahead other techniques. PO-043 Absolute lymphocyte count as a prognostic marker in newly diagnosed multiple myeloma patients treated in the era of novel agents C. Suriu, L. Akria, D. Azoulay, E. Shaul, A. Braester Hematology Institute, Galilee Medical Center, Nahariya, Israel; Faculty of Medicine in Galilee, Bar-Ilan University, Israel Introduction: The survival of multiple myeloma (MM) patients has improved significantly in the last decade, attributed especially to the use of novel therapeutic agents. Several studies suggest a prognostic significance in the absolute lymphocyte count (ALC) as a surrogate marker of the immune status (Hilmi E. et.al, BJH 2008). Also, increased peripheral blood absolute monocyte count (AMC) and decreased lymphocyte monocyte ratio (LMR) have been reported to be poor prognostic factors in both malignant lymphoproliferative disorders and solid tumors (Berardi S. et.al, Journal of Oncology 2013). Objective: To evaluate the prognostic impact of the ALC, AMC and LMR in our cohort of patients, treated in the era of novel agents. Methods: We retrospectively reviewed the medical records of 62 patients treated at Galilee Medical Center, Israel. AMC and ALC were obtained at diagnosis from routine complete blood count.Overall survival (OS) was measured from the time of diagnosis to the date of death or last follow-up. Univariate and Multivariate Survival analysis was performed using Cox Regression Model and Kaplan-Meier method with Log Rank (Mantel-Cox) test. Results: 62 newly diagnosed MM patients were evaluated. The median age was 69 years (range: 46-88 years); 35 (56.5%) patients were male. 51 patients (82%) were treated with novel agents at diagnosis. The median follow-up for the entire cohort after the diagnosis was 28.2 months (range 0.5-98.8 months). At the time of writing, 41 (66.1%) patients were living. The optimal cut-off for the ALC and AMC, and the LMR was set at 1600/mL, 450/mL and 4 respectively (median value). Univariate analysis of overall survival (OS) showed that age 1600/mL (p1⁄40.066) . The AMC and LMR had no significance on survival in our patients. On multivariate analysis only age (p

1023 Background: Brain Derived Neurotrophic Factor (BDNF) is important for neuronal survival and repair. We hypothesized that a disregulated neuronal and peripheral BDNF may enhance vulnerability t...

Introduction: Brain-derived neurotrophic factor (BDNF) was previously shown to support the proliferation of human multiple myeloma (MM) cell lines and promote their resistance to bortezomib (Pearse et al, 2005). As platelets appear to be the main transportation system of BDNF in the human circulation (Fujimura et al, 2002), we hypothesized that early alterations in platelet derived BDNF levels may be associated with clinical response to bortezomib in patients with MM. Methods: The total BDNF levels as well as the levels of its precursor peptide (proBDNF) were measured by ELISA (DY248 and DY3175 Dou set ELISA kits, respectively, R&D Systems, Minneapolis, MN) in serum, platelet-poor plasma (PPP), and platelet lysate that were isolated from MM patients at diagnosis and along their treatment course with bortezomib-based protocol. Relative expression of precursor and mature forms of BDNF in the platelet lysates were analyzed by Western blot gel electrophoresis. BDNF levels at diagnosis were compared between patients who achieved complete response (CR) to patients with less then partial response (LTPR) to bortezomib treatment. The differential effect of bortezomib treatment between the two groups is presented by the calculated delta between BDNF levels at diagnosis and after 2 treatment cycles. Results: Twelve MM patients were analyzed. Five patients achieved CR to bortezomib and 7 patients showed LTPR to bortezomib. The overall BDNF levels were 6-22 ng/ml (mean±SD 13.08±5.9), 0-10.65 ng/ml (mean±SD 2.49±2.67) and 2.27-23.04 ng/mg total protein (mean±SD 8.77±5.68) for serum, ppp and platelet lysates respectively. proBDNF was not detected in patients samples either by ELISA or by Western blot gel electrophoresis, suggesting that total BDNF is comprised mainly of the mature form of BDNF. Significantly higher BDNF levels were found in the serum and platelet lysates, obtained at diagnosis from patients who later achieved CR compared to patients with LTPR (serum: 19.94±1.84 ng/ml vs. 8.46±6.78ng/ml , p Discussion and conclusions: Our preliminary data of higher platelet BDNF levels at diagnosis together with therapy related reduction of BDNF levels in patients achieving CR may indicate that myeloma activity in responding patients is highly dependent on BDNF. Validating these preliminary observations in a large number of patients may help to establish a new clinical tool which facilitates the ability to identify bortezomib resistance at earlier step of therapy. Disclosures No relevant conflicts of interest to declare.

The coexistence of chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL) has already been reported in the literature, but as an exceedingly rare event, because the presentation (clinical and laboratory) is generally CLL-like and HCL is discovered ‘by the way’. To prove that the concomitance between these two diseases is not as rare as previously believed, we have to think ‘semantically’: the question is not how many CLL cases are concomitant with HCL, but how many HCL cases are concomitant with CLL. CLL originates from antigen-stimulated mature B lymphocytes and is the most common type of leukemia in older adults, accounting for 25% of all leukemia cases. HCL is also a chronic lymphoproliferative disorder originating from mature B lymphocytes. HCL accounts for 2-3% of all leukemia cases. The male to female ratio is approximately 4:1. The etiology is not known. CLL and HCL have distinct clinical, morphological and immunophenotyping features. The occurrence of second neoplasm, especially non-Hodgkin’s lymphomas, is well known in HCL patients. In the past 10 years we have diagnosed in our hemato-oncologic clinic 22 cases of HCL, 4 of them (18% of all cases of HCL diagnosed during this period) concomitant with CLL. We did not perform immunoglobulin gene rearrangement analysis, so we cannot know whether the origin is from different B cell clones or not; we can only affirm that the same light chain type was present on the membranes of both CLL and HCL cells. All cases of lymphoproliferative disorders (LPD) are systematically screened in our lab for the presence of an additional monoclonal B-cell population. Conclusion: the concept that concomitant CLL and HCL is a rare event is challenged. It is a mere ‘trompe l’oeil’, due to the rarity of HCL.