Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor ...trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2). Patients who received D monotherapy could cross over to D + T 150/2 postprogression. Efficacy and safety were analyzed 4 and 5 years after initiation in patients with ≥ 5 years of follow-up. Results As of October 13, 2016, 18 patients who received D + T 150/2 remained in the study (13 24% of 54 enrolled at this dose plus five 11% of 45 initially administered D who crossed over to D + T). With D + T 150/2, overall survival (OS; 4 years, 30%; 5 years, 28%) and progression-free survival (4 and 5 years, both 13%) appeared to stabilize with extended follow-up. Increased OS was observed in patients who received D + T with baseline normal lactate dehydrogenase (5 years, 45%) and normal lactate dehydrogenase with fewer than three organ sites with metastasis (5 years, 51%). With extended follow-up, one additional patient who received D + T 150/2 improved from a partial to a complete response. No new safety signals were observed. Conclusion This 5-year analysis represents the longest follow-up to date with BRAF + MEK inhibitor combination therapy in BRAF V600-mutant MM. Consistent with trends observed in landmark analyses with shorter follow-up, this therapy elicits durable plateaus of long-term OS and progression-free survival that last ≥ 5 years in some patients with MM.
Patient-reported outcomes may help inform treatment choice in advanced/metastatic renal cell carcinoma (RCC), particularly between approved targeted therapies with similar efficacy. This double-blind ...cross-over study evaluated patient preference for pazopanib or sunitinib and the influence of health-related quality of life (HRQoL) and safety factors on their stated preference.
Patients with metastatic RCC were randomly assigned to pazopanib 800 mg per day for 10 weeks, a 2-week washout, and then sunitinib 50 mg per day (4 weeks on, 2 weeks off, 4 weeks on) for 10 weeks, or the reverse sequence. The primary end point, patient preference for a specific treatment, was assessed by questionnaire at the end of the two treatment periods. Other end points and analyses included reasons for preference, physician preference, safety, and HRQoL.
Of 169 randomly assigned patients, 114 met the following prespecified modified intent-to-treat criteria for the primary analysis: exposure to both treatments, no disease progression before cross over, and completion of the preference questionnaire. Significantly more patients preferred pazopanib (70%) over sunitinib (22%); 8% expressed no preference (P < .001). All preplanned sensitivity analyses, including the intent-to-treat population, statistically favored pazopanib. Less fatigue and better overall quality of life were the main reasons for preferring pazopanib, with less diarrhea being the most cited reason for preferring sunitinib. Physicians also preferred pazopanib (61%) over sunitinib (22%); 17% expressed no preference. Adverse events were consistent with each drug's known profile. Pazopanib was superior to sunitinib in HRQoL measures evaluating fatigue, hand/foot soreness, and mouth/throat soreness.
This innovative cross-over trial demonstrated a significant patient preference for pazopanib over sunitinib, with HRQoL and safety as key influencing factors.
Abstract Background Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This ...phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed. Methods Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m2 (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2 mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups. Results Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67–1.44; P = .453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients ( n = 103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia. Conclusions The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.
BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK ...inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .
Advanced systemic mastocytosis (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms ...and organ damage (eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss). Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level.
We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator–related symptoms in patients with advSM.
In 116 patients with systemic mastocytosis (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study ClinicalTrials.gov identifier NCT00782067), QOL and symptom burden were assessed during treatment with midostaurin by using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale patient-reported questionnaires, respectively. MC mediator–related symptoms were evaluated by using a specific physician-reported questionnaire.
Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and Memorial Symptom Assessment Scale scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator–related symptoms.
QOL and MC mediator–related symptoms significantly improve with midostaurin treatment in patients with advSM (ClinicalTrials.gov identifier, NCT00782067).
Display omitted
ObjectiveLonger time to progression (TTP) is associated with prolonged post-progression survival (PPS) in anaplastic lymphoma kinase+non-small cell lung cancer (NSCLC). This study evaluated whether ...TTP is associated with PPS among previously treated patients with metastatic v-Raf murine sarcoma viral oncogene homolog B V600E NSCLC receiving dabrafenib as monotherapy or in combination with trametinib.DesignSecondary analysis of phase II clinical trial data.SettingPatients who experienced disease progression treated with dabrafenib monotherapy or in combination with trametinib as second line or later in an open-label, non-randomised, phase II study.Primary outcome measuresThe primary outcome was the TTP–PPS association. PPS was assessed with Kaplan-Meier analysis among patients with shorter versus longer TTP (< or ≥6 months). The TTP–PPS association was quantified in the Cox models adjusting for clinical covariates.ResultsOf the 84 included patients who progressed on dabrafenib monotherapy (n=57) or combination therapy (n=27), 60 (71%) died during post-progression follow-up. Patients with TTP ≥6 months experienced significantly longer PPS compared with those with TTP <6 months (median PPS: 9.5 vs 2.7 months, log-rank p<0.001). Each 3 months of longer TTP was associated with a 32% lower hazard of death following progression (HR 0.68, 95% CI 0.52 to 0.88) in the multivariable Cox model. Similar associations were seen in each treatment arm.ConclusionA longer TTP duration after treatment with dabrafenib monotherapy or combination therapy was associated with significantly longer PPS duration.Trial registration number NCT01336634; Post-results.
Summary
Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression‐free survival benefit compared with placebo, bortezomib and ...dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1–4 due to dose adjustments for AEs. Exposure‐adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes.
This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to ...receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (
n
= 38) and combination (
n
= 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (
n
= 36), lapatinib + pazopanib (
n
= 38), and pazopanib (
n
= 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib–pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.
▪
Introduction: In the randomized placebo controlled phase 3 trial PANORAMA 1 the pan-deacetylase inhibitor (pan-DACi) panobinostat combined with bortezomib and dexamethasone (PAN-BTZ-Dex) led to a ...statistically significant and clinically relevant increase in progression free survival in patients (pts) with relapsed or relapsed and refractory multiple myeloma (Pbo-BTZ-Dex; 12.0 vs 8.1 months; hazard ratio 0.63, P<0.0001). Gastrointestinal (GI) toxicity, particularly diarrhea, a known class-effect of pan-DACi and BTZ, was the most common non-hematologic adverse event (AE) observed in both treatment arms, occurring at a higher incidence in the PAN-BTZ-Dex arm. Optimal management of GI toxicity, especially diarrhea-related AEs, in pts who receive PAN-BTZ-Dex could help maximize treatment outcomes. Here we present a detailed analysis of pts with diarrhea on the PANORAMA 1 study to inform strategies to reduce the effects of diarrhea and improve efficacy.
Methods: The PANORAMA 1 trial included 12 cycles of treatment with two treatment phases (TP1: eight 3-week cycles; TP2: four 6-week cycles). In TP1, pts were randomized to receive oral PAN (20 mg) or Pbo administered thrice weekly for the first 2 weeks, with intravenous BTZ (1.3 mg/m2) administered on days 1, 4, 8, and 11 and Dex (20 mg) administered orally on the days of and after BTZ. In TP2 (for pts demonstrating clinical benefit), PAN or Pbo were administered similarly but BTZ was administered once-weekly (days 1, 8, 22 and 29) with Dex on the day of and after BTZ. For each cycle, prevalence and incidence for diarrhea AEs were determined; these were characterized by grade, improvement in grade, worsening of grade, and resolution of diarrhea.
Results: In the PANORAMA 1 trial, a total of 260/381 (68.2%) pts treated with PAN-BTZ-Dex and 157/377 (41.6%) pts treated with Pbo-BTZ-Dex reported AEs of diarrhea; most were grade 1 or 2 (PAN-BTZ-Dex: 42.8% vs Pbo-BTZ-Dex: 33.7%). Grade 4 diarrhea was rare (PAN-BTZ-Dex: 1.3%; Pbo-BTZ-Dex: 0.5%). Dose adjustments/interruptions for diarrhea occurred in 26% on the PAN-BTZ-Dex arm and 9% on the Pbo-BTZ-Dex arm. Treatment discontinuation due to diarrhea occurred in 4.5% on the PAN-BTZ-Dex arm and 1.6% on the Pbo-BTZ-Dex arm. Serious AEs of diarrhea occurred in 11.3% on PAN-BTZ-Dex arm and 2.4% on Pbo-BTZ-Dex arm. There was no hemorrhagic diarrhea on the PAN-BTZ-Dex arm and in 1 pt in the Pbo-BTZ-Dex arm.
In the majority of pts (56.2%) in the PAN-BTZ-Dex arm, diarrhea occurred for the first time in cycles 1-4 and was primarily grade 1/2; first onset occurred rarely in TP2 (Figure). Cumulative incidence of diarrhea on the PAN-BTZ-Dex arm plateaued by cycle 6 (61.9% by cycle 6; 68.2% overall). The cumulative number of pts with complete resolution of diarrhea (defined as resolved diarrhea that did not recur on treatment) increased over the course of the study. During treatment, 67.7% (258/381) in PAN-BTZ-Dex arm had either no diarrhea or complete resolution of their diarrhea. Analysis of diarrhea management by grade and treatment phase revealed that most pts received medication to manage the diarrhea. Antidiarrheal medications were administered to 70.8% (184/260) pts with diarrhea across all grades; loperamide was used most commonly. However, many pts with grade 1/2 diarrhea had no action taken in TP1: grade 1 - 58% (115/198); grade 2 - 26% (33/127), suggesting suboptimal management of diarrhea.
Conclusions: These data demonstrate that diarrhea in pts who received PAN-BTZ-Dex occurs primarily in the first 1-4 cycles of treatment with cumulative incidence reaching a plateau around cycle 6. Majority of pts with diarrhea had complete resolution during treatment. Although diarrhea was commonly observed in pts who received PAN-BTZ-Dex in the PANORAMA 1 trial, it was manageable and seldom led to treatment discontinuation; however, some pts with grade 1/2 diarrhea did not receive proactive management. Optimal management of diarrhea with prompt intervention including antidiarrheal medication and dose holds/adjustments of BTZ and PAN at the first sign of loose stools may help to maintain pts on therapy and thus improve outcomes with PAN-BTZ-Dex. Future trials should seek to employ these strategies for pts who experience GI toxicity, and should consider subcutaneous administration of BTZ. In addition, studies using combinatorial agents with less overlapping GI toxicity with PAN may further improve safety in this setting.
Display omitted
Richardson:Takeda: Research Funding; Millennium: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees. Dimopoulos:Celgene: Consultancy, Honoraria. Jedrzejczak:Amgen, Novartis: Consultancy, Research Funding. Guenther:Novartis: Consultancy, Research Funding. Siritanaratkul:Novartis: Research Funding; Roche: Research Funding; Janssen: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Moreau:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Sanofi: Consultancy. Sopala:Novartis Pharma AG: Employment. Panneerselvam:Novartis: Employment, Equity Ownership. Redhu:Novartis: Employment. Corrado:Novartis Pharma AG: Employment. Binlich:Novartis Pharma SAS: Employment.
Introduction: Panobinostat (PAN) is a potent pan-deacetylase inhibitor (pan-DACi) that targets key aberrations in multiple myeloma (MM) cell biology, including protein metabolism and epigenetics. In ...a randomized phase 3 clinical trial in patients (pts) with relapsed or relapsed and refractory MM (PANORAMA 1), the addition of PAN to bortezomib (BTZ) and dexamethasone (Dex; PAN-BTZ-Dex) led to a clinically relevant and statistically significant increase in progression-free survival (PFS) of ≈ 4 months compared to placebo plus BTZ and Dex (Pbo-BTZ-Dex). PAN-BTZ-Dex was associated with a higher rate of adverse events (AEs) compared to Pbo-BTZ-Dex; however, a comparable number of pts completed the full duration of treatment on both treatment arms. Thus, we sought to determine the effect of treatment duration on the safety and efficacy of PAN-BTZ-Dex.
Methods: The PANORAMA 1 trial consisted of two treatment phases (TP1 and TP2) with a maximum of 12 cycles total. In TP1 (eight 3-wk cycles), pts were randomized to receive oral PAN (20 mg) or Pbo administered three times a wk for the first 2 wks, and intravenous BTZ (1.3 mg/m2) administered on days 1, 4, 8, and 11 with Dex (20 mg) administered orally on the days of and after BTZ. Pts demonstrating clinical benefit could proceed to TP2 (four 6-wk cycles), in which PAN was administered on a similar schedule but BTZ was administered once-wkly (days 1, 8, 22 and 29) with Dex administered on the days of and after BTZ. This analysis focused on safety and efficacy specifically associated with the two treatment phases. For efficacy outcomes (PFS and near complete response/complete response nCR/CR rate), pt groups were delineated by those who received treatment > 8 cycles (completed TP1, 24 weeks) and all 12 cycles (completed TP2, 48 weeks). Median PFS was calculated based on time averaged dose (cumulative dose in a time interval divided by the planned number of dosing days) of PAN received to determine the potential role of dose adjustments/interruptions on efficacy. PFS was analyzed by Kaplan-Meier estimates. A safety analysis was conducted of AEs for TP1/TP2 for pts who completed TP2. Due to interdependencies among outcomes, further investigations of these data are needed.
Results: Among the pts enrolled in the PAN-BTZ-Dex arm (N = 387), 169 (44%) completed TP1 and 102 (26.4%) completed TP2. Overall, pts who received a longer duration of treatment with PAN-BTZ-Dex demonstrated a longer PFS (Figure). Median PFS for pts who received PAN-BTZ-Dex and completed TP1 was 14.65 months (95% CI, 12.94, 16.85) and 17.64 months (95% CI, 15.90, 20.07) for those who completed TP2. In addition, nCR/CR rate was 52.9% for pts who completed TP2. Overall, the rates of commonly observed grade 3/4 AEs (≥ 20%) in the PAN-BTZ-Dex arm were thrombocytopenia (TCP, 57.0%), diarrhea (25.5%), and asthenia/fatigue (23.9%). Safety analysis for pts who completed TP2 demonstrated the higher rate of AEs in TP1 vs TP2 (excluding AEs that continued from TP1). For pts in the PAN-BTZ-Dex arm who completed treatment (n = 102), the rates of grade 3/4 events in TP1 and TP2 for common AEs were TCP (47.1% and 5.9%), diarrhea (25.5% and 8.8%), and asthenia/fatigue (19.6% and 5.9%). For pts in the Pbo-BTZ-Dex arm who completed treatment (n = 102), the rates for TP1 and TP2 were TCP (10.8% and 1.0%), diarrhea (5.9% and 0%), and asthenia/fatigue (7.8% and 0%). About half the pts (218/387; 56.3%) in the PAN-BTZ-Dex arm did not enter TP2 (112/218; 51.4% discontinued to due AEs). Analysis of time averaged dose of safety set pts on the PAN-BTZ-Dex arm demonstrated a median PFS of 12.71 (95% CI, 10.58, 14.19) months for pts who received >15-20 mg of PAN and 10.90 months (95% CI, 8.08, 12.71) for >10-15 mg.
Conclusions: These data highlight the PFS and nCR/CR rate among pts able to complete TP2 with PAN-BTZ-Dex. Furthermore, for pts who completed the entire treatment regimen, the incidence of new/worsening AEs in TP2 where BTZ was administered on a once weekly schedule was decreased. Pts who received a lower time averaged dose due to dose adjustments/interruption of PAN had a similar median PFS to pts who received a time averaged dose closer to the planned dose. Together, these data support the hypothesis that optimal management of AEs for pts receiving PAN-BTZ-Dex via dose adjustments including BTZ and/or concomitant medications, particularly earlier during their course of therapy, could increase treatment duration and maintain outcomes.
Display omitted
San Miguel:Millennium: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; MSD: Membership on an entity’s Board of Directors or advisory committees. Jedrzejczak:Amgen, Novartis : Consultancy, Research Funding. Guenther:Novartis: Consultancy, Research Funding. Siritanaratkul:Novartis: Research Funding; Roche: Research Funding; Janssen: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Sanofi: Consultancy. Sopala:Novartis Pharma AG: Employment. Redhu:Novartis : Employment. Paul:Novartis: Employment. Corrado:Novartis Pharma AG: Employment. Binlich:Novartis Pharma SAS: Employment. Richardson:Takeda: Research Funding; Millennium: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees.