ALBERT

Description: Retrospective studies could not proof a correlation of elevated platelet counts at diagnosis with thrombotic events. However, randomized and prospective clinical studies on platelet lowering therapies justify recommendations for the normalization of platelet counts as an appropriate endpoint for treatment in high-risk essential thrombocythemia (ET). Furthermore, there is increasing evidence that leukocytosis is an important risk factor for arterial thrombosis, especially in WHO classified ET. Leukocytosis is even more pronounced in prefibrotic primary myelofibrosis (PMF) compared to WHO classified ET. Patient cohorts that were diagnosed prior to the WHO classification likely consist of a mixture of ET and prefibrotic PMF. Some authors suppose interplay between white blood cells (WBC) and platelets in patients with myeloproliferative diseases. The current study considers the Austrian cohort of a European registry, which was established to document the efficacy of the platelet-lowering therapeutic anagrelide in myeloproliferative neoplasms. Out of 845 patients, only those with a confirmed diagnosis of ET according to the PVSG classification until 2001 or according to the WHO classification thereafter were included in the analysis. Median follow up of the 620 included patients is 3.1 years (range 1.21-5.73 years), corresponding to 2428 patient years. 418 patients (67%) were females and the median age at study entry was 62 years (range 51-72 years). Thirty four patients (5.5%) experienced at least one major arterial or venous event until data analysis corresponding to 1.40 events per 100 patient years. The influence of platelet and WBC counts on thrombotic risk was assessed by correlating the first major thrombotic event with the median of all blood counts recorded during the course of the disease until an event or until end of observation. The median platelet counts until the first event occurred and until end of observation (in patients without an event) were 595.8 G/l (range 495.0-743.0 G/l) and 500.0 G/l (range 410.5-619.5 G/l), respectively, and thus were substantially different (p= 0.008). The median WBC counts until the first event occurred and until end of observation (in patients without an event) were statistically not different but might indicate a trend with 9.60 G/l (range 8.70-10.95 G/l) and 8.42 G/l (range 7.05-10.70 G/l), respectively (p=0.084). By using the calculated (Youden index) cut offs of 574.5 G/L for platelets and 8.48 G/L for WBC counts, respectively, the Cox regression analysis revealed a clear influence of platelets (p= 0.008) as well as WBC counts (p= 0.011) above the cut offs until the time to a major event. Interestingly, in this analysis, the influence of higher platelet counts on major thrombotic events was more pronounced than that of higher WBC counts. The frequency of major events per 100 patient years was highest when both platelet and WBC counts ranged above the calculated cut offs and was substantially different from the frequency when both, platelet and WBC counts ranged below the cut offs (3.05 vs. 1.4, p

Description: Abstract 5064 Background: In 2001 Thromboreductin® was registered in Austria as the first EU country for the treatment of Essential Thrombocythemia (ET). Due to the low incidence of ET authorities demanded to establish a patient registry to evaluate safety and efficacy of anagrelide in the long-term treatment of ET. Following market authorization in several EU countries the patient registry is now being maintained in 10 Central European countries. Whereas most clinical trials have only a relatively short follow-up, a patient registry is able to provide long-term data. Patients and Methods: This multinational, multi-center post-marketing observational registry is conducted to assess long-term efficacy and safety of anagrelide in patients with ET under “real-life” conditions. The clinical information is entered into the registry by the treating physicians. Besides relevant clinical data such as risk factors, past thrombotic as well as bleeding events, disease symptoms classified as “major” and “minor” events and previous ET therapies including anticoagulation, laboratory values including renal and liver function parameters as well as blood counts are monitored regularly. Results: This evaluation of the Thromboreductin® Patient Registry database includes 1572 ET patients (median age: 59 years), 1059 (67%) were women and 513 (33%) were male patients; 62% of patients were pretreated with cytoreductive agents, 38% were treatment naïve. The median observation period was 1.9 years (range: 7 days – 10 years), with 168 patients (11%) being followed for at least 5 years. Treatment with anagrelide lowered the platelet count from a median of 742 × 109 /l (95%CI 717/757) to a median of 415 × 109 /l (95%CI, 397/435). Eighty-four percent of patients achieved platelet counts 〈 450 × 109 /l, no differences between pretreated (85%) and treatment-naïve /82%) patients were observed. During the 3464 patient years (PY) included in this evaluation a total of 338 ET-related events (including both thrombotic and bleeding events) were reported of which 102 (2,9% per PY) were considered as “major”. Of the 220 patients with a history of ET-related events, 178 patients (81%) have so far remained event-free under anagrelide therapy. Adverse effects were lower than those previously reported in clinical trials with headache, palpitations and diarrhea being the most frequent side effects (all 〈 3%) leading to treatment discontinuation in 43 patients (2,7%). No new toxicities have been observed. Conclusion: We consider anagrelide to be safe and effective in terms of lowering platelet counts and reducing disease-related events in unselected ET patients treated outside clinical trials under “real-life” conditions. Based on our favourable long-term data we suggest that anagrelide may be considered a first-line agent in the management of ET. Disclosures: Steurer: AOP Orphan Drugs: Honoraria. Petrides:AOP Orphan Drugs: Consultancy.

Description: There is compelling evidence that white blood cell (WBC) counts impact the risk of thrombosis in patients with myeloproliferative neoplasms (MPN) (Barbui Blood 2013). Moreover, recent publications disclosed significant differences regarding certain disease characteristics and the course of disease in WHO 2008 (Tefferi Blood 2007) classified essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (PMF) (Kvasnicka Am J Hematol 2008; Barbui JCO 2011; Buxhofer-Ausch Am J Hematol 2012). Hence, patients cohorts classified prior to WHO 2008 may likely consist of a mix of patients with ET and prefibrotic PMF. We aimed to reproduce the influence of WBC counts on the thrombotic risk in patients under real-life conditions. Therefore we assessed data of 825 Austrian patients from a patient registry for anagrelide in ET that was initiated 2001 in Austria due to an official authorities demand and is now being maintained in several Central European countries. Efficacy of treatment was assessed by investigating the course of platelet counts and event free survival relating to the first minor or major thrombotic event. WBC counts from the first available time points were correlated with the first thrombotic event. The cut off for the WBC subgroup analysis was set at 8,5 G/l. Statistical analysis was performed using the open-source R statistical software package, version 3.0.2. Non-parametric two-sided 95% confidence intervals for medians were calculated. Survival probabilities were assessed by applying the Kaplan-Meier method. For the comparison of time to event between the leukocyte- specific subgroups the log-rank test was used. Median Follow up of the study cohort is 3,07 years. Platelet count at start of anagrelide was median 777 G/l (95% CI 757-803). After 12, 24 and 36 months patients presented with median platelet counts of 473, 457 and 438 G/l, respectively. Median WBC count at start of therapy was 9 G/l (95% CI 8,7-9,3) and after 12, 24 and 36 months 8,5 G/l, 9,2 G/l and 8,7G/l, respectively. Incidence of thrombotic events per 100 patient- years was 5,14 for all events and 1,65 for major events only. 102 patients experienced at least one minor or major thrombotic event (major events n=36). Median time to the first minor or major thrombotic event was 1,27 years. Probability of event free survival at 1 year is 94,4% and at 3 years 87,6%. Patients with a baseline WBC count of higher than 8,5 G/l exhibit a significantly shorter probability of event free survival than patients below the cut off (p= 0,007 for all thrombotic events; p= 0,026 for major events only). This data proof the efficacy of anagrelide in lowering platelet counts and reducing significantly the risk of thrombotic events in patients with ET. The significantly shorter event free survival of patients with a WBC count above 8,5 G/l confirms earlier studies for the first time in a real-life setting. This result emphasizes the separation of true ET from prefibrotic PMF by using the WHO 2008 classification. Moreover, further investigations are needed to assess, whether a correlation of certain platelet and leukocyte counts modifies the risk of thrombotic events in MPN. Disclosures Schloegl: AOP Orphan Pharmaceuticals AG: Research Funding.

Description: BACKGROUND: Treatment options in patients with RRMM who are refractory to bortezomib (BORT) and lenalidomide (LEN) are limited. POM/LoDEX is approved in patients with RRMM after ≥2 prior treatment regimens (including both BORT and LEN), who relapsed on the last line of therapy. The aim of this ongoing, multi-center, non-interventional study is to prospectively collect real world data in RRMM patients treated with POM/LoDEX in an Austrian clinical routine setting. PATIENTS & METHODS: Adult patients with RRMM who had received ≥2 prior antimyeloma treatments (including LEN and BORT) who experienced disease progression on the previous line of therapy were enrolled and treated with POM/LoDEX until disease progression or unacceptable toxicity. Emphasis was put on the collection of safety data (adverse events [AEs]) and of efficacy data (objective response rate [ORR; ≥partial response, PR]; progression-free survival [PFS]). A source data verification level of 75% was reached in 74% of patients. Descriptive statistics were used to summarize the data. RESULTS: From 09/2014 to 06/2018, 63 patients were enrolled by 9 Austrian centers; 61 of them were eligible for analysis. At inclusion, the median age was 69 years (range 44-90); 15 patients (25%) were older than 75 years; 37 patients (61%) were male. Most patients (96%) had an ECOG performance status of ≤2. ISS stages were evenly distributed (I: 39%; II: 25%; III: 30%). The median number of prior lines of therapy was 4 (range 1-10). Prior treatments of almost all patients included an immunomodulatory drug (98%) and a proteasome inhibitor (97%). Half of the patients (49%) underwent a prior stem cell transplantation. The most frequent starting dose of POM was 4 mg per day (82%); 43% of the patients received the full LoDEX dose of 40 mg weekly. The median number of POM treatment cycles was 10 (range 1-63). At cycle 10, 81% of patients still received POM at a dose of 4 mg, while only 19% still received LoDEX at the full dose of 40 mg. The median PFS for 49 evaluable patients was 11.8 months. Response information was available for 46 patients. The ORR with POM/LoDEX was 50%. Seven patients (15%) achieved a complete response (CR), 5 patients (11%) a very good PR, and 11 patients (24%) a PR; 4 patients still have an ongoing response. A total of 23 patients (38%) received at least one additional antimyeloma agent at any time (57% started upfront; 43% delayed onset) during their treatment with POM/LoDEX. The ORR in this subgroup (n=16) was 63%. The median PFS and ORR stratified by application of a third or further antimyeloma agent are shown in Table 1. Safety information was available for 47 patients (77%), 250 AEs were documented; of those, 94 (38%) were drug-related. Most AEs were non-serious (78%); 18% required hospitalization, 2% (not drug related) were fatal. The most common AEs were infections (22%) and neutropenia (9%). The most common reasons for treatment discontinuation were tumor progression (n=36, 59%), and death (n=4, 7%); one patient (2%) discontinued treatment due to toxicity. At the time of data cutoff, 13 patients (21%) were still on treatment. CONCLUSION: This interim analysis of real-world data demonstrates that POM/LoDEX is an effective and safe treatment in patients with RRMM. Presented response data (PFS: 11.8 months; ORR: 50%) are somewhat better compared to data from earlier, randomized trials (MM-003, NCT01311687). Despite the limitations of a non-interventional study approach, these encouraging findings may also be a consequence of the increased practical experience clinicians have with POM/LoDEX today. In contrast to LoDEX, dose reductions of POM are rare, underlining its good tolerability. As indicated by an increase of the ORR from 43 to 63% (subgroup analysis), efficacy of POM/LoDEX may be enhanced by addition of a third antimyeloma agent. Disclosures Lechner: Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Greil:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hartmann:Novartis: Research Funding; Amgen: Research Funding; Roche: Research Funding; Celgene: Research Funding. Krauth:Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Gisslinger:AOP Orphan: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Shire: Honoraria; Takeda: Consultancy, Honoraria. Vogl:BMS: Consultancy, Honoraria; Eisei: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Janssen: Honoraria; Pfizer: Consultancy, Honoraria; Eli-Lilly: Consultancy, Honoraria; Celgene: Honoraria; Merck: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Servier: Honoraria; Astellas: Honoraria; Bayer: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Ohler:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Greinix:Celgene: Consultancy; Amgen: Consultancy, Speakers Bureau; Therakos: Speakers Bureau; Roche: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Gilead: Speakers Bureau. Sormann:Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Andel:Roche: Research Funding, Speakers Bureau; Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Rechberger:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Agis:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Prothena: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Description: Introduction: Recent data from the ARROW and CHAMPION-1 study show significant activity of once weekly carfilzomib administration. Furthermore, the recent MUK5 and CARF studies show significantly increased PFS with carfilzomib maintenance therapy. Here, we compare 9 cycles of weekly KRd with weekly KTd (after 2 cycles of biweekly therapy) followed by a second randomization to 12 cycles of carfilzomib maintenance or observation only in elderly NDMM. Methods: 75 of 146 planned pts (median age: 75 years, range 55-84) with NDMM have been enrolled so far in this randomized phase 2 study. Treatment regimen: Carfilzomib 20mg/m2 on day 1+2, 27mg/m2 on day 8, 9, 15 and 16; cycle 2: 27mg/m2 on day 1,2,8,9,15 and 16; Carfilzomib was switched to once weekly dosing (56mg/m2, d1, 8, 15) from cycle 3 on until cycle 9. Patients received dexamethasone weekly (20mg in pts ≥75 years) and either lenalidomide 25mg d 1-21, or thalidomide 100mg/day, day 1-28 (50mg in pts ≥75 years). Patients with ≥SD after 9 cycles were randomized to carfilzomib 56mg/m2 (or last tolerated dose) on day 1 and 15 q 4 weeks, or to control for one year. FISH testing was done according recommended standards. NGF MRD testing was done in pts reaching CR or VGPR. Survival estimates were calculated according to Kaplan-Meier. Differences in response rate were assessed using Fisher's exact test, while the Log-Rank test was used for evaluating differences in survival. This trial is registered on clinicaltrials.gov (NCT02891811). Results: Median follow up was 11.7 months. 58 of the 75 pts completed ≥2 cycles (per protocol population (PP)), 12 pts discontinued therapy within the first 2 cycles due to AE/unacceptable toxicity [4 (5.3%)], death [3 (4%)], investigator decision [2 (2.7%)], patient's decision [2 (2.7%)], or other reason [1 (1.3%)]. As the trial is still ongoing, response rates and survival data are given for both groups (KRd and KTd) combined. Overall response was noted in 56 of the 58 pts (96.6%) with response data available, CR in 21 (36.2%), VGPR in 22 (37.9%), PR in 13 (22.4%), and MR in 2 (3.4%) pts. Of the 17 pts with MRD testing available, 47.1% achieved MRD negativity. PFS was 22.3 months in both the PP and ITT pts. Overall survival at 24 months was 78% in the ITT and 79% in the PP group, respectively. Between very elderly pts 75 years of age or older and pts below 75 years, no difference in ORR (96.8% vs. 96.3%, p=1), ≥VGPR (67.7% vs. 81.5%, p=0.3678) and PFS was found (ITT group: 22.3 months vs. not reached, p=0.926; PP group: 22.3 months vs. not reached, p=0.895). Likewise, OS did not differ in both age groups (data not shown). Outcome was also similar between pts with and without high-risk cytogenetics: ORR 100% vs.97.1%, p=1; ≥VGPR 80% vs. 71.4%, p=1; PFS not reached vs. 22.3 months, p=0.342; OS at 24 months was 85% for high-risk and 67% for standard-risk pts. In a safety evaluation with 66 patients, the most frequent grade 3/4 hematologic adverse events were anemia (4.5%), leukopenia (1.5%), and thrombocytopenia (6.0%). The non-hematologic grade 3/4 AEs were infections (21.2%), cardiac failure, gastrointestinal disorders, and renal impairment (6.0% each), neurologic disorders, hypertension, and rash (3.0% each), and hepatic failure, SPM, VTE, and psychiatric disorders (1.5% each). Conclusion: Once weekly carfilzomib 56mg/m² in combination with either lenalidomide or thalidomide resulted in high response rate and deep responses including MRDneg status in 47.1% of tested elderly patients with NDMM. Results were similar in very elderly pts (³75 years) and in those aged

Description: Introduction Carfilzomib-based induction therapy is highly effective in newly diagnosed pts with multiple myeloma (NDMM), but information on quality of life (QoL) during first line and maintenance therapy is not available. Here, we analyze patient-reported QoL in transplant-non eligible (TNE) NDMM pts randomized to either KTd or KRd induction therapy followed by second randomization to carfilzomib maintenance, or control. Patients and Methods At time of analysis, 101 TNE pts with NDMM had been enrolled, but QoL data documented for ≥ 2 cycles were available in 78 pts so far (median age: 75 years, ISS stage I: 26.6%, II: 35.4%, III: 38.0%, ECOG status 0: 51.9%, 1: 48.1%). Patients were randomized to either 9 cycles KTd or KRd, and subsequently (46 pts with ≥PR) to either carfilzomib maintenance therapy (d1 and 15) or to control for 12 months. Carfilzomib was administered twice weekly (27mg/m2) during cycles 1 and 2, and thereafter weekly at a dose of 56mg/m2. Thalidomide was given daily at 100mg (50mg in pts ≥75 years), lenalidomide at 25mg, d1-21 per 4 week cycle, and dexamethasone at 40 mg (20mg in pts ³75 years) once weekly. QoL was assessed by the QoL questionnaire EORTC QLQ-C30. Assessments were done at baseline, and monthly thereafter for 21 months. A two-sided t-test was used for comparison with the general population. Wilcoxon signed-rank tests were applied to evaluate differences in QoL dimensions within the treatment groups. A clinically meaningful improvement has been defined as a change of ≥10 score points. Results Comparison with the general population : Mean scores for health-related global QoL (54.1±22.6) and physical functioning (61.2±25.0) were significantly lower in pts compared to those reported for the general population of similar age (67.2±20.6, p

Description: Background The depth of response to myeloma therapy shows significant variation between individual patients. Responsiveness depends on the activity of the treatment regimen, the genetic aberrations of the predominant myeloma clone(s), and on the composition of the bone marrow environment, particularly of the immune compartment, in patients treated with drugs having broad immune effects. Here, we evaluated possible relationships between multiple immune cells and response to therapy in a series of newly diagnosed patients randomized to either carfilzomib-lenalidomide-dexamethasone or to carfilzomib-thalidomide-dexamethasone. Patients and Methods Forty-one patients with newly diagnosed multiple myeloma enrolled in a randomized phase II trial (AGMT_MM 02) with baseline bone marrow phenotyping were enrolled. Median age: 74 years (range: 58-84 years), R-ISS I: 23.8%, R-ISS II: 33.3%, and R-ISS III: 42.9%, IgG: 57.1%, IgA: 21.4%, light chain only: 19.0%, IgM: 2.4%, ECOG Status 0: 42.9%, 1: 57.1%. Treatment: Carfilzomib : Cycle 1 day 1+2: 20mg/m2, days 8+9 and 15+16: 27 mg/m2 ; Cycle 2 day 1,2,8,9,15 + 16: 27 mg/m2 Cycle 3-9: 56mg/m2 on days 1, 8 and 15. Lenalidomide: 25mg p.o. on days 1-21/cycle or thalidomide: 100 mg p.o. on days 1-28; in patients ≥75 years of age 50mg p.o. on days 1-28, dexamethasone: 40 mg p.o. on days 1, 8, 15, 22 (± 1 day), in patients ≥ 75 years of age 20 mg p.o. this treatment was administered for nine cycles. Thereafter, patients were randomized to carfilzomib maintenance at last tolerated dose on days 1+15 or to control for 12 cycles. BM samples were stained with 3 different antibody combinations for the analysis of T, B and NK cells (T cells: CD45RA, CD127, CD8, TCRgd, CD25, CD197, CD4, CD3, B/NK cells: CD57, CCR7, CD314, CD85j, CD62L, CD3, CD16, CD56, CD335, HLADR, CD337) using sample preparation protocols standardized by EuroFlow. We used a semi-automated pipeline to unveil full cellular diversity based on unbiased clustering. The median and range of each cellular subgroup was calculated in patients with CR and compared with results obtained in non-CR patients. Statistical significance of these comparisons was calculated using the Wilcoxon test. Results Median follow up is 15.9 months. Thirteen of the 41 patients achieved a CR (31.7%) and 9 (75%) of the 12 who had MRD testing were shown to be MRD negative at a sensitivity of 10-6. Nine (22.0%) of the 41 patients did already progress. High numbers of total B cells (p=0.011), B-cells expressing CD62L (p=0.027), CD4+ CD127+ central memory T cells (p=0.009), and CD337+ (p=0.012), or adaptive CD57lo (p=0.002) cytotoxic NK cells were significantly associated with achievement of CR. By contrast, lower numbers of T-NK cells (CD3+CD56+) (p=0.006), CD127- double-negative T cells (CD4- CD8-) (p=0.013), CD85j+ tissue resident immunoregulatory NK cells (p=0.002) and CD56+CD57+ (p=0.002) and CD56+ HLADR+ (p=0.003) T cells correlated significantly with achievement of CR. Significant correlations were also noted when NK cell subsets were analyzed for a possible association with progressive disease. Higher numbers of CD85j+ tissue resident immunoregulatory NK cells (p=0.001) were associated with progressive disease. In contrast, higher numbers of canonical cytotoxic NK cells (p=0.015) and CD314+ circulating immunoregulatory NK cells (p=0.033) correlated with sustained response. Conclusion Our data show significant correlations between the composition of bone marrow immune cells with achievement of CR and sustained response in newly diagnosed patients uniformly treated with carfilzomib-based therapy. High cytotoxic NK cell and B-cell, and low CD56+ T cell numbers among others were associated with deep response to carfilzomib-based therapy. Furthermore, higher numbers of specific NK cell subsets (CD85j+, CD57lo), correlated with disease progression while for other NK cell subtypes (canonical cytotoxic NK cells and CD314+ circulating immunoregulatory) a correlation with sustained response was noted. This study paves the way towards clinically relevant immune monitoring, whereby a holistic and unbiased assessment of the immune tumor microenvironment is connected with patients' treatment, depth of response and outcome. Disclosures Greil: Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding. Podar:Amgen, BMS-Celgene, Janssen, Roche: Consultancy, Honoraria, Research Funding. Petzer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: 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; Roche: 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. Agis:Janssen: Honoraria, Research Funding; Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Schreder:BMS-Celgene, Amgen: Consultancy. Paiva:Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding; SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Amgen: Honoraria. Ludwig:Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau; Seattle Genetics: Other: Advisory Boards; Takeda: Research Funding; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau. OffLabel Disclosure: Use of Carfilzomib in myeloma first-line treatment