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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

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.

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

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.