ALBERT

Description: Defibrotide has been shown to be effective in the treatment and prophylaxis of the VOD,a relatively common complication after allogeneic hematopoietic stem cell transplantation(SCT).We report our experience in 41 consecutive patients(pts) for a total of 43 SCT.The analysis,closed at day +35 after BMT,is limited to 39 SCT,since 4 pts not affected by VOD died on day +3,+11,+13 and +24,respectively.The pts(mean age 42 yrs,range 16–65) were affected by acute leukemia(14), chronic myeloid leukemia(5),lymphoma(15),multiple myeloma(2),myelodisplasia(1) and solid tumor(2).Other relevant clinical characteristics were:resistant or metastatic disease 9,previous autologous BMT 6,previous allogeneic SCT 2,previous B virus hepatitis 5,liver metastases 1 and lymphoma of the liver 1.All were transplanted from their HLA-identical sibling;the conditioning regimen was defined as reduced in 15(thiotepa,fludarabine and cyclophosphamide),while it was conventional in the other 24 SCT with use of busulphan(oral 13 and iv 11) and cyclophosphamide(VP16 added in few cases;never TBI). Thirteen received bone marrow and 26 peripheral blood as source of stem cells.No T-cell depletion was done and the GVHD prophylaxis regimen was CsA+MTX for 36 pts, CsA alone for 2 pts and FK506+MTX for 1 patient.For VOD prophylaxis no Heparin was administered,while Defibrotide was given at the dosage of 10 mg/Kg in continuous iv infusion starting on day +1 until day +21 after the SCT.Defibrotide was very well tolerated,and no hemorrhagic complications were observed.Blood coagulation significant alterations were:prolonged PT(4/39),prolonged aPTT(3/39),fibrinogen elevated(23/39,never over 800 mg/dl),low level(less than 50%) of ATIII,and/or protein C,and/or protein S(2/39).By using the VOD Baltimore criteria,only 1 case of VOD was observed at day +29 in a patient who died at day +36 with VOD,aspergillosis and CMV pneumonia.The bilirubin was more than 2 times the normal value in 20/39;US scan of the liver and Doppler,performed in 15 pts with a possibile sign of VOD,was positive only in the patient who died for VOD.We documented 29 infectious complications(14 FUO,9 gram positive bacteremias,2 pneumonia and 4 invasive aspergillosis).We observed acute GVHD in 10 pts(9 grade I–II and 1 grade III).Five pts died between +36 and +100 but none for VOD(3 for progression of their disease and 2 for aspergillosis).Since in this at risk transplanted population only 1 VOD has been observed,Defibrotide low-dose continous infusion, not associated with Heparin,seems able to play a relevant role in the VOD prophylaxis.On considering the favourable results obtained by us and Others,the absence of toxicity and the low cost of Defibrotide,we intend to continue this experience with defibrotide as VOD prophylaxis,even if we foretell a large randomized study to find better indications.

Description: Introduction: Multiple myeloma (MM) is still an incurable disease and patients may relapse despite achievement of complete remission (CR). Minimal residual disease (MRD) assessment by multiparameter flow cytometry (MFC) on bone marrow (BM) is a sensitive diagnostic tool to measure response and is highly predictive of outcome in MM as previously reported. The aim of this study is to evaluate the role of MRD monitoring by MFC in MM patients receiving novel agents with or without autologous stem cell transplantation (ASCT) and to investigate the efficacy of treatments by using MRD-negativity as a deeper response criteria. Methods: The RV-MM-COOP-0556 (EMN02/HO95 MM) study is a phase III, randomized, trial including newly diagnosed MM patients ≤ 65 years. All subjects received 4 cycles of Bortezomib-Cyclophosphamide-Dexamethasone (VCD) induction, followed by Cyclophosphamide chemotherapy and subsequent stem cell mobilization and collection. Afterward, patients were randomized to receive 4 cycles of Bortezomib-Melphalan-Prednisone (VMP) vs one or two cycles of High-Dose-Melphalan (HDM) followed by ASCT. After intensification patients were secondly randomized to receive two cycles of consolidation with Bortezomib-Lenalidomide-Dexamethasone (VRD) vs no consolidation, followed by Lenalidomide maintenance in both arms. Patients who achieved CR/sCR according to IMWG criteria (Rajkumar et al. Blood 2011) after intensification/consolidation treatment, were eligible for the MRD sub-study. MRD analysis by MFC was performed on BM samples after intensification/consolidation, after 6 courses of maintenance, and thereafter every 6 months until progression, to detect monoclonal plasma cells (PCs). Here, we used a double antibody combination (CD138Fitc/CD20PerCp-Cy5.5/CD117APC/CD45APC-H7/CD38PE-Cy7; cyKappaFitc/cyLambdaPE/CD19PerCp-Cy5.5/CD56APC/CD45APC-H7/CD38 PE-Cy7): one tube was employed to obtain PCs quantification, the other one to validate PCs clonality. MRD-negativity was defined when

Description: Background: The prognostic utility of minimal residual disease (MRD) analysis in multiple myeloma (MM) patients has been well described in the last few years. The role of prolonged maintenance therapy even in persistent MRD negative patients is still unclear. The aim of this study is to evaluate the role of MRD by allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) as predictor of progression-free survival (PFS) in newly diagnosed MM (NDMM) patients receiving Lenalidomide maintenance after frontline treatment. Patients and Methods: NDMM patients enrolled in the RV-MM-EMN-441 (NCT01091831) and the RV-MM-COOP-0556 (EMN02/HO95 MM) phase III trials achieving ≥ very good partial response (VGPR) after consolidation/intensification were included in the pooled MRD molecular analysis. After induction therapy, patients in the RV-MM-EMN-441 study were randomized to Cyclophosphamide-Lenalidomide-Dexamethasone (CRD) or Autologous Stem Cell Transplantation (ASCT); patients in the RV-MM-COOP-0556 were randomized to Bortezomib-Melphalan-Prednisone (VMP) vs ASCT (Gay F et al Lancet Oncol 2016, Cavo M et al J Clin Oncol 34, 2016 abstr 8000). All patients received Lenalidomide maintenance until progression or intolerance. MRD analysis was performed on bone marrow (BM) aspirates after intensification/consolidation, after 6 courses of maintenance and then every 6 months until clinical relapse. Patient-specific IgH rearrangements were amplified and directly sequenced from genomic DNA at diagnosis. IgH-based MRD detection by ASO-RQ-PCR was performed using an AbiPrism7900HT.MRD analysis was interpreted following the Euro-MRD guidelines(van der Velden VH et al. Leukemia 2007). Molecular-CR (m-CR) was defined as two consecutive negative MRD results by ASO-RQ-PCR with minimal sensitivity of 10−5. PFS was analyzed using the Kaplan-Meier method, curves were compared with the log-rank test. Multivariate Cox model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: a total of 105 patients entered the molecular MRD pooled study: a specific IgH molecular marker was identified in 73 patients (70%), 32 (30%) did not obtain a successful sequencing. Median age was 57 years (37-65); 30 (41%) patients had International Staging System (ISS) stage I, 33 (45%) stage II and 10 (14%) stage III. FISH risk profile was standard in 43 (59%) patients, high in 24 (33%) and not available in 6 (8%). Thirty-eight (52%) patients did not receive ASCT consolidation and 35 (48%) underwent ASCT. After consolidation/intensification 33/73 (45%) patients achieved m-CR: 19/35 (54%) ASCT patients and 14/38 (37%) no ASCT patients. The impact of m-CR on outcome after consolidation was explored: after a median follow-up of 44 months, median PFS was 48.8 months versus not reached in no m-CR vs m-CR patients, respectively (p=0.01). Lenalidomide maintenance further improved depth of MRD response: 11/40 (27%) MRD positive patients after consolidation obtained a m-CR during maintenance and a median of 2 natural logarithms of tumor burden reduction was recorded. In multivariable Cox analysis the risk of progression/death was higher for ISS stage II/III versus I (HR, 2.91, CI: 1.01-8.41, p=0.048), high-risk FISH versus standard-risk (HR, 2.23 CI: 0.81-6.10, p=0.12), age 〉 60 years versus ≤60 years (HR: 3.55, CI: 1.26-10.04, p=0.017) and patients who did not achieve m-CR during treatment versus patients who did (HR, 7.65 CI: 2.77-21.11, p

Description: Background: RI occurs in ≈ 20%-30% of newly diagnosed MM pts and is associated with poor prognosis (Knudsen et al. Eur J Haematol. 2000; Kyle et al. Mayo Clin Proc. 2003). Data from 2 pivotal trials (MM-002, MM-003) suggested comparable efficacy and tolerability of POM + LoDEX in pts with or without moderate RI (Siegel ASH 2012; Weisel ASCO 2013). However, these trials excluded pts with severe RI. MM-013 (NCT02045017) is a European multicenter, open-label phase 2 study designed to assess the efficacy, safety, and pharmacokinetics of POM + LoDEX in RRMM pts with moderate or severe RI, including those on dialysis. Methods: The trial is enrolling RRMM pts (N = 80) across 3 cohorts: cohort A (moderate RI, estimated glomerular filtration rate [eGFR] ≥ 30 to 〈 45 mL/min/1.73 m2, n = 33), cohort B (severe RI without dialysis, eGFR 〈 30 mL/min/1.73 m2, n = 33), and cohort C (severe RI requiring dialysis, n = 14). Pts must have MM-related RI and have received ≥ 1 prior Tx (including lenalidomide). POM 4 mg is administered on days 1-21 of a 28-day cycle and LoDEX 40 mg/day (20 mg for pts aged 〉 75 yrs) on days 1, 8, 15, and 22 until progressive disease (PD) or unacceptable toxicity. At the time of submission of this abstract, 17 pts terminated Tx; this abstract focuses on tolerability in these pts. Results: This trial is still recruiting; at the time of data cutoff for this abstract, 39 pts were enrolled. Data are included for 17 pts who discontinued Tx. Of all 39 pts, 12 were assigned to cohort A, 18 to cohort B, and 9 to cohort C. The median age of the total population was 72 yrs (range, 52-86 yrs), with 67.7% being male. The median number of prior lines of therapy was 4.0 (3.5 in cohort A, 5.0 in cohort B, and 3.0 in cohort C). This distribution was similar in the 17 pts who discontinued Tx so far (4, 7, and 6 in cohorts A, B, and C, respectively), with a median age of 72 yrs and 58.8% being male. Reasons for discontinuation of Tx were PD (7 pts), adverse events (AEs; 3 pts), death (5 pts: 2 pts due to PD, 2 pts due to infections, 1 pt due to hyperkalemia), and other reasons (2 pts: 1 pt aged 86 yrs with general health problems, 1 pt with increasing RI). Median Tx duration in these pts was 6.9 weeks in cohort A, 12.6 weeks in cohort B, and 12.9 weeks in cohort C. The dosage of POM was reduced to 3 mg in 3 pts (1 patient in each cohort), in all cases due to an AE (thrombocytopenia in 2 pts, pneumonia in 1 pt). However, no further Tx reductions occurred. The most frequent toxicity of any grade in the pts who discontinued was hematologic (82.4% [14 pts]), notably neutropenia in 58.8% (50% in cohort A, 42.9% in cohort B, 83.3% in cohort C), anemia in 52.9% (50% in cohort A, 28.6% in cohort B, 83.3% in cohort C), and thrombocytopenia in 52.9% (75% in cohort A, 14.3% in cohort B, 83.3% in cohort C). Grade 3/4 neutropenia occurred in 47.1%; grade 3/4 thrombocytopenia occurred in 35.3%. Notably, febrile neutropenia was reported in only 1 pt in cohort A. Granulocyte colony-stimulating factor was used in 52.9% of pts. Non-hematologic AEs were less frequent. Infections occurred in 7 pts (41.2%), all of which were pulmonary infections, with the exception of 1 case of nasopharyngitis. Asthenia (23.5%) and fatigue (23.5%) occurred predominantly in cohort C. No thromboembolic events or secondary primary malignancies have been reported to date. Conclusions: These data suggest that the combination of POM and LoDEX can be safely administered in pts with RI. A starting dose of POM 4 mg can be used throughout all stages of RI, and the side effects seen in this population have been previously reported with POM use (ie, mainly hematologic events and infections). Rates of neutropenia and thrombocytopenia are similar to reports in a non-RI population. Dose modifications should be considered in pts who develop neutropenia and thrombocytopenia; in pts showing signs of infections, dose interruptions may be considered. Disclosures Off Label Use: Pomalidomide in MM patients with renal insufficiency.. Dimopoulos:Janssen: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Onyx: Honoraria; Novartis: Honoraria; Amgen: Honoraria. van de Donk:Janssen Pharmaceuticals: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Gamberi:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kueenburg:Celgene Corporation: Consultancy, Honoraria. Rosettani:Celgene Corporation: Employment. Collins:Celgene Corporation: Employment. Lersch:Celgene Corporation: Employment. Bacon:Celgene Corporation: Employment, Equity Ownership. Weisel:Noxxon: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support; Novartis: Other: Travel Support; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support. Sonneveld:Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Description: Background: Approximately 20–40% of pts with NDMM present with RI, which is associated with a negative impact on survival (Rajkumar, 2005). In the pivotal phase 3 FIRST trial (median follow-up 37 months [mos]), continuous Rd improved progression-free survival (PFS) vs. melphalan-prednisone-thalidomide (MPT) in elderly NDMM pts by 28% (25.5 vs. 20.7 mos; HR = 0.72; P 〈 0.01) (Facon, Blood 2013). Although 121 pts receiving continuous Rd are still on Tx, the interim overall survival (OS) analysis showed a 22% reduction in the risk of death in favor of continuous Rd vs. MPT (HR = 0.78; P = 0.02). The present analysis was conducted to determine the impact of RI on PFS, OS, and time to 2nd antimyeloma Tx (AMT) as clinical study outcomes. Methods: Pts were randomized to 3 Tx arms: continuous Rd until progression (n = 535); Rd for 18 cycles (72 weeks) (Rd18; n = 541); or MPT for 12 cycles (72 weeks) (n = 547). Enrolled NDMM pts were categorized according to their renal function: 24% had normal renal function (creatinine clearance [CrCl] ≥ 80 mL/min), 44% presented with mild RI (≥ 50 and 〈 80 mL/min), 23% had moderate RI (≥ 30 and 〈 50 mL/min), and 9% had severe RI (〈 30 mL/min). Pts requiring dialysis were excluded. Lenalidomide starting dose was 25 mg QD for pts with normal renal function or mild RI, 10 mg QD for moderate RI, and 15 mg QOD for severe RI. Melphalan dose was reduced by 50% in pts with moderate or severe RI. The primary endpoint was PFS (continuous Rd vs. MPT); secondary endpoints were OS, overall response rate, time to response, duration of response, time to Tx failure, time to 2nd AMT, health-related quality of life, safety, and improvement in renal function from baseline. Improvement in RI was defined as shifts from baseline to most extreme post-baseline value of the calculated CrCl as a measure of renal function during the active Tx (N = 1484). Results: A PFS benefit favored continuous Rd vs. MPT irrespective of the degree of renal function (Table 1): there was a benefit in pts with normal renal function (HR = 0.72 (0.51–1.02); P = 0.06), and better in pts with mild RI (HR = 0.79 (0.62–1.00); P = 0.05) and moderate RI (HR = 0.62 (0.45–0.85); P 〈 0.01). A PFS benefit was also seen with continuous Rd vs. Rd18 (a secondary comparison) in pts with mild RI and moderate RI (P 〈 0.01 for both). An interim OS benefit with continuous Rd vs. MPT was observed in most renal subgroups. Similar results were observed between Rd18 and MPT in terms of PFS or interim OS in any of the renal subgroups. Continuous Rd, compared with Rd18 or MPT, extended time to 2nd AMT in most renal groups except severe RI (CrCl 〈 30mL/min) (Table 2). Improvement in RI was observed more frequently in pts treated with continuous Rd than those with Rd18 or MPT: improvement of mild RI, 48%, 43%, and 48%, respectively; of moderate RI, 67% 61%, and 62%; and of severe RI, 64%, 59%, and 56%. Overall, 〈 5% of pts in any Tx group experienced a worsening in renal function status during Tx (continuous Rd 2.2%; Rd18 2.8%; MPT 2.7%). The most common grade 3–4 adverse events (AEs) for these Txs were anemia, neutropenia, thrombocytopenia, deep-vein thrombosis/pulmonary embolism (DVT/PE), and peripheral sensory neuropathy (Table 3). Tx discontinuation due to AEs increased in pts with moderate and severe RI, regardless of the type of Tx (Table 3). Conclusions: PFS, OS (at interim analysis), and time to 2nd AMT outcomes generally improved continuous Rd vs. Rd18 or MPT in transplant-ineligible NDMM pts with normal renal function, and in those with mild or moderate RI. The small number of pts in the severe RI group precluded a meaningful conclusion. Continuous Rd was generally well tolerated and renal function improved in the majority of pts during Tx with continuous Rd vs. Rd18 or MPT. Disclosures Dimopoulos: Celgene Corporation: Consultancy, Honoraria. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Roussel:Celgene: Consultancy, Lecture fees Other, Research Funding. van der Jagt:Celgene Corporation: Research Funding. Jaccard:Celgene Corporation: Honoraria, Research Funding. Tosikyan:Celgene: Consultancy. Karlin: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; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:Celgene Corporation: Consultancy, Research Funding. Schots:Celgene: Research Funding. Chen:Celgene Corporation: Employment. Marek:Celgene Corporation: Employment, Equity Ownership. Ervin-Haynes:Celgene Corporation: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: INTRODUCTION: Cytogenetic abnormalities (CA) are one of the major factor for risk stratification in Multiple Myeloma (MM). Approximately 50% of MM patients (pts) harbour a translocation involving the Immunoglobulin Heavy chain locus (IgH). Each translocation is associated with deregulation of a D group cyclin, either directly in t(11;14)(q13;q32) and t(6;14)(p21;q32) or indirectly in t(4;14)(p16;q32) and in MAF translocations: t(14;16)(q32;q23) and t(14;20)(q32;q12). Some translocations are recurrent but rare events, occurring in less than 5% of the pts: t(6;14) is considered a standard prognostic feature, whereas t(14;16) and t(14;20) are associated with bad prognosis. As a result of their low incidence, few data support their use of these abnormalities in the risk stratification. Currently, deletion(17)(p13) and gain(1)(q21) are linked with adverse clinical outcome and, recently, also deletion(1p) has been considered adverse prognostic factor. AIM: To assess the type and frequency of these rare IgH translocations and their association with other adverse genetic lesions and with clinical characteristics, in a large series of newly diagnosed MM pts. METHODS: A total of 682 pts newly diagnosed MM pts, enrolled in several prospective clinical trials of bortezomib-based induction therapy and subsequent autologous stem cell transplantation, including most recent EMN02 clinical trial, were analyzed. Probes for FISH analysis were used to detect t(4;14), t(6;14), t(11,14), t(14;16), t(14;20); deletion of 1p32, 13q14, 17p13; gain of 1q21; trisomy of chromosomes 5/9/15. RESULTS: On evaluable cases, the frequency of each IgH translocation, as detected by FISH was as follows: t(11;14) in 114/596 (19.1%), t(4;14) in 78/605 (12.9%), t(14;16) in 27/603(4.5%), t(14;20) in 9/591(1.5%) and t(6;14) in 7/587(1.2%). Every rare translocation was associated with deletions flanking the breakpoints, either as unique pattern or with classical translocation. The t(6;14) was closely associated with del(6)(p21)(6/7), del(13q)(4/7) and del(16)(q23)(3/7); additional gain 1q and deletion 17p was observed in a single case. All together, the high-risk (HR) translocations, t(14;16) and t(14;20), were detected in 36 pts: 63.9% were females and 36.1% males. The t(14;16) was frequently occurred with del(13q) (84.6%), gain(1q) (74.1%; 20/27) and del(16)(q23) (74.1%; 20/27), while t(14;20) was associated with del(13q) (88.9%; 8/9), gain(1q) (5/9; 55.6%) and del(20)(q12) (5/9; 55.6%). In selected cases, the presence of these additional abnormalities was shown also by SNPs arrays. Beyond del(13q), gain(1q) was the most frequent additional abnormality (69.4%; 25/36), occurring in 56.4% (44/78) of t(4;14) cases and in 20.2% (23/114) of t(11;14) cases (p

Description: BACKGROUND: Real-world data can provide important information on the safety profile for recommended treatment options, but these data are collected infrequently. The ongoing post-authorization safety study (PASS) MM-034 (NCT03106324) is a prospective non-interventional study in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible. This study allows for the collection of robust safety data for currently recommended regimens for the management of these pts. Global guidelines recommend lenalidomide (LEN) regimens, such as LEN plus dexamethasone (DEX; Rd) and LEN plus bortezomib (BORT) plus DEX (Vd), and BORT regimens, including BORT plus melphalan plus prednisone (VMP). METHODS: Transplant-ineligible adult pts with NDMM initiating therapy in centers throughout Europe are being enrolled in the ongoing MM-034 trial. Pts receiving any first-line regimen are eligible, but the decision for which treatment regimen will be used must be made prior to study inclusion. The primary endpoint is the incidence of cardiovascular events. Secondary endpoints include the incidence of renal impairment, infections, and second primary malignancies. In this analysis, the safety profiles of Rd, Vd, and VMP were compared. RESULTS: As of April 12, 2019, 145 Rd, 53 Vd, and 83 VMP pts were enrolled in the study (evaluable cohort). At the time of data cutoff, treatment was ongoing in 64.8% of Rd pts, 41.5% of Vd pts, and 61.4% of VMP pts. Median age was 79 years in Rd pts and 75 years in both Vd and VMP pts. The proportion of pts with ISS stage III disease was higher in the Vd group (24.8% Rd vs 32.1% Vd vs 24.1% VMP), and more pts in the VMP group were male (49.7% Rd vs 58.5% Vd vs 65.1% VMP). Adverse events (AEs) of all grades confirmed the expected side effects. Any-grade neutropenia occurred in 7.6%, 11.3%, and 13.3% of Rd, Vd, and VMP pts, respectively, and thrombocytopenia occurred in 6.2%, 5.7%, and 12.0%, respectively. However, any-grade febrile neutropenia was seen only in the VMP group, at 2.4%, but not in the other 2 groups. Any-grade polyneuropathy was reported in 1.4% of Rd pts, but in 18.9% of Vd pts and 19.3% of VMP pts. Any-grade infections of all kinds occurred in 28.3% of Rd pts, 41.5% of Vd pts, and 20.5% of VMP pts, with pneumonia in 3.4%, 11.3%, and 2.4% of Rd, Vd, and VMP pts, respectively. Any-grade thrombosis was reported in 4.8% of Rd pts and 3.8% of Vd pts and in no VMP pts. Grade 3/4 AEs occurred in 42.8% of Rd pts, 52.8% of Vd pts, and 43.4% of VMP pts. Grade 3/4 neutropenia was reported in 4.8%, 9.4%, and 8.4% of Rd, Vd, and VMP pts, respectively, and thrombocytopenia in 2.8%, 0%, and 8.4%, respectively. Grade 3/4 infections were lower in Rd pts (6.9% vs 24.5% Vd and 12.0% VMP); pneumonia, the most important of these, was reported in 0.7%, 5.7%, and 2.4% of Rd, Vd, and VMP pts, respectively. Grade 3/4 peripheral neuropathy was not seen in the Rd group; however, it was reported in 3.8% of Vd pts and 2.4% of VMP pts. Grade 3/4 venous thrombosis was reported in only 0.7% of Rd pts, with no events reported in the Vd and VMP groups. CONCLUSIONS: The results from this analysis, along with those from a previous analysis of cardiovascular events in the LEN-treated and non-LEN treated cohorts of pts from the European PASS MM-034 study (De Stefano, EHA 2019), provide real-world evidence for the safety profile of Rd as first-line therapy and support the role of Rd in the treatment of pts with NDMM who are transplant ineligible. Disclosures Cavo: celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, 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, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tromp:Janssen: Other: Grant. Dhanasiri:Celgene Corporation: Employment, Equity Ownership. Kueenburg:Celgene: Consultancy. Rosettani:Celgene International: Employment. Martin:Celgene: Employment. Pozzi:Celgene: Consultancy. Bacon:Celgene: Employment, Equity Ownership. Gamberi:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Front-line treatment (of any type) was at the discretion of the investigator.

Description: Background: As the use of lenalidomide (Len) combinations for the management of multiple myeloma (MM) broadens in frontline, Len-refractoriness is a growing issue among the relapsed MM patient (pt) population and raises the need for efficient Len-sparing treatment options. However, current data with Len-sparing combinations is limited. Here we report the results of a real-life cohort of MM pts with at least 1 prior treatment line, who received carfilzomib (CFZ) and dexamethasone (Kd), by Len-refractory (LR) status. Methods: The prospective cohort study (NCT03091127) recruited adults with relapsed or refractory MM who received ≥1 dose of a CFZ combination regimen in routine clinical practice. In the 10 participating countries across the EU and Israel, 56 mg/m2 twice-weekly was the only approved Kd regimen. Pts were classified as LR if they met at least one of the following 3 criteria to any prior regimen containing Len as defined in the report of the International Myeloma Workshop Consensus published by Rajkumar et al. (Blood 2011 [117] 4691-4695): 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. Pts were followed until 18 months after CFZ initiation or until 30 days after final administration, whichever was earlier. Results: Of the 93 pts who received Kd between 14 March 2017 and 22 October 2018 (cut-off date of planned interim analysis), over two-thirds (69%, n=64) were LR at Kd initiation. Median age at CFZ initiation was 70 years for the overall Kd population and LR pts. Pt characteristics, where available, were also similar in terms of ISS stage or ECOG status 0-2 at Kd initiation. However, where reported (18/93 pts), 8 of the 9 pts with a high cytogenetic risk were in the LR subgroup. LR pts had received a median of 3.5 prior lines of therapy compared with 2 for non-LR (NLR) pts. Only 3 LR pts were at first relapse compared with 10 for the NLR pts. In the NLR subgroup, 41% had been exposed to Len. Time since last prior treatment discontinuation was much shorter for LR vs NLR subgroup: 0.8 vs 3.3 months. Comorbidities were similar regardless of LR status, with over one-third of pts with hypertension and 20% of cardiac disorders (mainly cardiac arrhythmia) at MM diagnosis. The overall response rate (ORR) among evaluable pts was 65% for LR pts and 55% for NLR pts (Table). Minimal response was reported for 1 LR pt and 2 NLR pts, which resulted in a similar clinical benefit rate (CBR) for LR and NLR pts (67% vs 65%, respectively). Regardless of LR status, at least one-third of Kd pts achieved a very good partial response or better (VGPR+). The vast majority of pts (92% of LR vs 93% of NLR) planned a twice-weekly Kd schedule. The mean proportion of CFZ label dose received was slightly lower for LR (71%) vs NLR (79%) pts. The Kaplan-Meier estimate of median treatment duration (95% confidence interval) was shorter for the LR vs NLR subgroup: 7.1 months (5.1, 9.6) vs 9.5 months (5.5, 19.0), respectively. At the time of this interim analysis, 39% of LR pts and 52% of NLR pts were still on treatment. Out of pts who discontinued CFZ, a higher proportion of LR vs NLR pts discontinued mainly due to disease progression/refractoriness (51% vs 29%, respectively). The occurrence of AEs of grade 3 or above (Gr3+) was comparable between LR (38%) and NLR pts (41%) and consisted mostly of infections (15%) and blood disorders (10%). Four out of 5 Gr3+ cardiac events were reported in LR pts, including 2 cases of heart failure leading to CFZ discontinuation. Four of the 5 fatal events occurred in LR pts. Conclusion: Compared with the ENDEAVOR Kd pivotal trial population, this real-world Kd cohort was older (median 70 vs 64 years), received Kd in later lines (median number: 3 vs 2) and included a higher proportion of LR pts (69% vs 24%). Higher levels of discontinuation due to Gr3+ cardiac and fatal events were observed in the more heavily pre-treated LR pts. Response to treatment was similar irrespective of LR status, and ORR (65%) was similar to ENDEAVOR Len-exposed Kd pts with 2-3 prior lines. Kd benefit-risk profile was favorable in this real-world cohort and appears to be a suitable Len-sparing treatment option. Disclosures Leleu: Carsgen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria. Caers: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; 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. Gamberi:BMS: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heibl: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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Pfizer: Honoraria; Mundipharma: Honoraria; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Suzan:Amgen (Europe) GmbH: Employment, Equity Ownership. Mohammad:Amgen Ltd.: Employment, Equity Ownership. Wetten:Amgen Ltd.: Employment, Equity Ownership. Terpos:Takeda: Honoraria, Other: Travel Grant, Research Funding; Janssen: Honoraria, Other: Travel Grant, Research Funding; Celgene: Honoraria.

Description: Background: 18F-FDG-PET/CT is currently the standard technique to define minimal residual disease (MRD) status outside the bone marrow (BM) in multiple myeloma (MM) patients. A joined analysis of two 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) and showed the liver background (DS 〈 4) to be the best cut-off to define PET negativity after therapy (Zamagni et al, ASH 2018). Multiparameter Flow cytometry (MFC) at the sensitivity level of 10-5 is one of the standardized methods to assess MRD in the BM (Kumar SK, Lancet Oncol 2016). In this analysis, we aimed at comparing MRD data by PET/TC assessment and MFC in the multicenter phase II randomized FORTE trial for NDTEMM patients. 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 lenalidomide plus carfilzomib. 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). PET/CT scans were performed locally at baseline (B) and prior to the start of maintenance (PM) and the DS were applied both in the BM and FLs as previously described. Cramér's V coefficient was used to measure the concordance between PET/TC and MFC; Fisher or X2 tests were adopted, where appropriate, to evaluate the statistical significance, at the level of 0.05. Results: 182 out of the 474 global patients enrolled in the trial had a matched PET/CT and MFC evaluation available and were included in the present analysis. Baseline characteristics of the patients were as follows: 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, 92% of the patients had FLs, with a median maximum standardized uptake value (SUVmax) of 5.7 [IQR: 4.1-8.1], 11% presented extra-medullary lesions and nearly all the patients had increased BM uptake, with a median SUVmax of 3.3 [IQR: 2.8-4.3]. FS and BMS ≥4 were present in 87% and 59% of the patients, respectively. A higher FS at B was significantly correlated with ISS stage III (P= 0.04), while higher BMS with lower hemoglobin level (P= 0.002) and higher free light chain ratio (P= 0.004). At PM, PET/TC negativity according to DS 〈 4, was present in 78% in the FLs and 85% in the BM, respectively. No significant correlations between PET/CT negativity after therapy and baseline prognostic factors or PET/CT characteristics were found. 95% and 67.5% of the patients achieved ≥ VGPR and CR as best response, respectively, while 75% of them achieved MFC MRD negativity. The achievement of a best CR significantly correlated with BMS 〈 4 at PM (P= 0.013). We analyzed the concordance between MRD results by the two techniques and Cramér's V coefficient measured a strong association, with a value of 0.76 (p

Description: Introduction Elotuzumab (Elo), an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), received marketing approval in Italy for relapsed or refractory multiple myeloma (RRMM), in combination with lenalidomide (R) and dexamethasone (d) (EloRd) in April 2017. Here we report preliminary data of an Italian real-life experience on EloRd as salvage therapy for RRMM patients treated outside of controlled clinical trials. The primary objectives of this study were to assess the toxicity profile and the efficacy of EloRd administered as salvage therapy in a real-world setting. Methods Retrospective data collection received approval from local ethic committee. The cohort included 180 RRMM patients from 28 Italian centers who received at least one cycle of EloRd as salvage treatment between April 2017 and June 2018. Patients were treated with EloRD according to marketing approval as follows: Elo 10 mg/kg i.v. on days 1, 8, 15, and 22 during the first two cycles and then on days 1 and 15 of each following cycle, R 25 mg on days 1 to 21 of each cycle and d at a dose of 40 mg during the week without Elo, and 36 mg on the day of Elo administration. Responsive patients had to reach at least a partial remission (PR). Results Baseline characteristics are shown in Table 1. Median age of the 180 patients was 72 years (range 48-89 years); 53.9% were males (Table 1). The median number of previous therapy regimens was 1 (range 1-7); 69 patients (38.3%) received a previous autologous stem cell transplantation (ASCT). One hundred and ten patients (61.1%) showed a symptomatic relapse, 36 (20%) a biochemical relapse, and 34 cases (18.9%) were refractory to the last therapy, including bortezomib in 12.8% of patients. Forty-four patients (24.4%) had creatinine clearance ≤60 mL/min. Among the 138 cases evaluable for International Scoring System (ISS), 54 (39.1%) had stage I, 56 (40.6%) stage II, and 28 (20.3%) stage III. At last data collection (June 2018), 164 cases were evaluable for response. The median number of courses administered so far was 5 (range 1-18). The overall response rate (ORR) was 78%, with 9 complete remissions (CRs) (5.5%) and 49 very good partial remissions (VGPRs) (35.4%). A significant higher ORR was observed in patients who had received only 1 previous line of therapy than those who had received 〉1 line (64% vs 37.5%; p=0.004). Age (