Citations

Abstract Introduction. Efficacy and safety of daratumumab monotherapy (DARA mono) in relapsed/refractory multiple myeloma (rrMM) has been shown in the single-arm phase I/II trial GEN501 and the single-arm phase II trial SIRIUS (1, 2). Since then, several indirect treatment comparisons of DARA mono versus comparator therapies have been published showing consistent results with an overall survival benefit for DARA mono (3, 4, 5, 6). This analysis compares efficacy and for the first time also safety of DARA mono data versus an international historic control group, adjusting for differences in patient populations based on individual patient level data (IPD). Methods. IPD from the SIRIUS trial and from the International Myeloma Foundation (IMF)-cohort (7), a retrospective, multicenter cohort, were compared using a multivariate Cox proportional hazards model, on the endpoints of efficacy (overall survival (OS)) and safety (discontinuation due to adverse events (DISCONAE)). The IMF-cohort included patients with rrMM who received at least three prior lines of therapy, were refractory to both an immunomodulator (IMiD) and a proteasome inhibitor (PI), and were exposed to an alkylating agent. An inclusion criterion for the historic control group in this analysis was treatment with EU approved regimens. Baseline covariates adjusted for in the regression model included age, gender, prior lines of therapy, albumin, beta-2 microglobulin, prior exposure to pomalidomide and carfilzomib, and PI/IMiD refractory status. Several sensitivity analyses were run, including multiple imputation of missing values. Results. Data from 106 patients treated with DARA mono (16 mg/kg) were available from SIRIUS; 258 patients from the IMF chart review fulfilled the inclusion criteria; most frequent treatment regimens contained pomalidomide plus dexamethasone (PomDex) (n=172), bortezomib (n=31), carfilzomib (n=21), cyclophosphamide (n=14) and lenalidomide (n=9). The adjusted HR for OS was 0.41 [0.25, 0.69], p<0.001, and 0.23 [0.05, 1.00], p=0.050 for DISCONAE, in favor of daratumumab. Results were consistent across a range of sensitivity analyses and were similar when restricting the comparison to DARA vs. PomDex, with HR=0.35 [0.19, 0.64], p<0.001 for OS and 0.20 [0.03, 1.54], p=0.123 for DISCONAE. Conclusions. This comparison using real-world data of rrMM patients suggests improved efficacy and safety for DARA mono compared to approved therapy regimens used in clinical practice, including PomDex. References. Lokhorst, H. M., Plesner, T., Laubach, J. P., Nahi, H., Gimsing, P., Hansson, M., et al. Targeting CD38 With Daratumumab Monotherapy in Multiple Myeloma. The New England Journal of Medicine. 2015. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab Monotherapy in Patients with Treatment-Refractory Multiple Myeloma (SIRIUS): An Open-Label, Randomised, Phase 2 Trial. The Lancet. 2016. Usmani S, Ahmadi T, Ng Y, Lam A, Desai A, Potluri R, Mehra M. Analysis of Real-World Data on Overall Survival in Multiple Myeloma Patients With ≥3 Prior Lines of Therapy Including a Proteasome Inhibitor (PI) and an Immunomodulatory Drug (IMiD), or Double Refractory to a PI and an IMiD. The Oncologist. 2016. Van Sanden S, Ito T, Diels J, Vogel M, Belch A, Oriol A. Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low-Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison. The Oncologist. 2017. Usmani SZ, Diels J, Ito T, Mehra M, Khan I, Lam A. Daratumumab monotherapy compared with real-world historical control data in heavily pretreated patients with highly refractory multiple myeloma: An adjusted treatment comparison. American Journal of Heamtology. 2017. Jelínek T, Maisnar V, Pour L, Špička I, Minařík J, Gregora E, et al. Adjusted comparison of daratumumab monotherapy versus real-world historical control data from the Czech Republic in heavily pretreated and highly refractory multiple myeloma patients. Current Medical Research an Opinion. 2017. Kumar SK, Dimopoulos MA, Kastritis E, Terpos E, Nahi H, Goldschmidt H, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017. Disclosures Demmer: Janssen: Employment. Huschens:Janssen: Employment. Potthoff:Janssen: Employment. Tomeczkowski:Janssen: Employment. Englisch:Janssen: Employment. Thilakarathne:Janssen: Employment. Diels:Janssen: Employment. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Takeda: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Durie:Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Eisele:Janssen: Employment.

Abstract Background: Limited data exist regarding histological transformation in patients with Waldenström macroglobulinemia (WM). In this study, we present the disease characteristics, outcomes and risk factors for histological transformation in WM. Methods: Patients with WM seen at Mayo Clinic, Rochester, MN between January 1996 and December 2017 were included. Patients with aggressive non-Hodgkin lymphoma in the setting of WM were considered to have transformation. Univariate analysis for comparing baseline characteristics of transformed versus non-transformed WM was performed using Wilcoxon, Fisher's exact and Chi square tests, as appropriate. Multivariate analysis was performed using logistic regression analysis. Cox proportional hazard method was used to assess the impact on time-to-transformation. All time-to-event analyses were calculated by the Kaplan-Meier method. Results: Of 1014 patients with WM, 42 patients (4.1%) developed histological transformation. The median follow-up for the entire cohort was 9.5 years (95% CI: 8.8-10.5 years). The cumulative probability of transformation was 2.3% at 5 years, 5.3% at 10 years and 8.5% at 15 years from diagnosis of WM, respectively. There was no difference in the 5-year cumulative probability of transformation in patients with WM diagnosed between 1996-2000 (2.1%), 2001-2005 (2.9%), 2006-2010 (2.7%) and 2011-2015 (3.8%), p=0.61.The disease characteristics, laboratory parameters and histology at transformation are outlined in Table 1. In patients with DLBCL histology (n=39), Revised-International Prognostic Index was calculable in 28 patients, with 50% (n=14), 46% (n=13) and 4% (n=1) of DLBCL belonging to poor, good and very good risk groups, respectively. For DLBCL histology, 18 patients were classifiable using Hans algorithm into germinal center B-cell (GCB) type (n=3, 17%) and non-GCB type histology (n=15, 83%). The median lines of therapy received prior to transformation for the entire cohort was 2 (range 0-9), with 5 (11%) patients not having received any therapy for WM before transformation. Number of lines of alkylator-based therapy used prior to transformation [median 1 line (range 0-4)] was comparable to that used in patients in whom WM did not occur [median 1, (range 0-6); p=0.78]. The median time-to-transformation from diagnosis of WM was 4.8 years (95% CI: 2.6- 6.8 years). Overall survival (OS) from transformed disease was 3.2 years (95% CI 1.1-3.9 years). The 10-year OS of patients with WM who transformed was lower (46%) compared to patients without transformation (60%) with a trend towards statistical significance (p=0.08), Figure 1. The MYD88L265P mutation status was available in 333 patients in the entire cohort (22/42 pts in the transformed cohort and 311/972 in the non-transformed cohort. Of the 22 patients in the transformed WM cohort, 13 (59%) exhibited MYD88WT genotype and 9 (41%) exhibited MYD88L265P genotype. The risk of transformation was higher in patients with MYD88WT status [Odds ratio 6.3 (95% CI: 2.6-15.5); p<0.0001]. Additionally, serum lactate dehydrogenase (LDH) was higher at diagnosis of WM in patients who transformed, Table 2. On multivariate analysis, MYD88WT status remained an independent predictor of disease transformation [p=0.003; odds ratio 10 (95% CI: 2.1-48)]. On univariate Cox proportional hazard analysis for identifying predictors of time-to-transformation, only MYD88WT mutational status was associated with shorter time-to-transformation with a 5-year transformation rate of 15.5 % for MYD88WT versus 2.6 % with MYDL265P mutated patients [risk ratio 6.2 (95% CI: 2.5-16.4); p<0.0001]. Treatment-related details in the transformed cases were available for 37 (90%) patients; R-CHOP was the most common (41%) frontline therapy for transformation; 33% patients underwent autologous stem cell transplantation for transformed disease during their disease course. Conclusion: Histological transformation is an uncommon event in WM but confers poorer survival. MYD88WT genotype is independently associated with histological transformation a shorter time-to- transformation in patients with WM. Disclosures Ansell: Trillium: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Takeda: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Gertz:Apellis: Consultancy; Alnylam: Honoraria; spectrum: Consultancy, Honoraria; janssen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; celgene: Consultancy; Teva: Consultancy; Medscape: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

Abstract Introduction Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have significantly improved survival in patients with multiple myeloma (MM). Refractoriness to PIs and IMiDs results in poor outcomes with a median survival of about 13 months.Daratumumab and isatuximab are CD38-targeting monoclonal antibodies (MoABs) with remarkable activity in relapsed and refractory MM. The outcome of MM patients in US clinical practice who becomes refractory to CD38 MoABs is unknown. The aim of this multicenter, retrospective study is to investigate the natural history of patients with MM who become refractory to CD38 MoABs (Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure: MAMMOTH study). Methods We identified patients from 14 academic institutions in the US with diagnosis of active MM and refractory to daratumumab or isatuximab, administered alone or in combination. Patients were considered refractory to CD38 MoAB if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) while on therapy or within 60 days after last dose. The time when patients met the above criteria of progression was defined as time zero (T0). Data including patient-disease characteristics and all therapies administered before and after T0 were collected with an electronic platform and submitted to peer-based quality check for completeness and internal consistency. For survival outcome analysis, patients were classified into three groups: "Penta-refractory" (refractory to 1 CD38 MoAB + 2 PIs + 2 IMiDs), "Triple-refractory and quad-refractory" (refractory to 1 CD38 MoAB + 1 PI + 1/2 IMiDs, or 1 CD38 MoAB + 1/2 PIs + 1 IMiD), and "Not triple-refractory" (refractory to 1 CD38 MoAB, and not both of a PI and an IMiD). Responses were evaluated using the IMWG criteria. Results Two hundred and seventy-five patients were included in this study; median age at T0 was 65 years (range 27-90). Fifty five percent of patients were males, 52% had IgG isotype, 29% had ISS stage III disease, and 29% had high-risk cytogenetics at diagnosis. Median interval from diagnosis of MM to T0 was 50.1 months (mo) (range 2.5-230.1). Patients received a median of 4 lines of treatment (1-16) prior to the CD38 MoAB-containing regimen; 72% underwent prior autologous transplant. Daratumumab-refractory patients formed a majority (256, 93.1%) of this cohort. Most of the patients were refractory to lenalidomide (77%), pomalidomide (65%), bortezomib (68%), and carfilzomib (47%). Seventy patients (25.5%) were "penta-refractory" and 148 (53.8%) were "triple-refractory and quad-refractory". Median follow-up from T0 for survivors was 10.6 mo (range 1.9-42.3 mo). The median overall survival (OS) from T0 for the entire cohort was 8.6 mo (95% C.I. 7.2-9.9); OS for the groups based on refractoriness to prior treatments are shown (Figure). Two hundred and forty-nine patients (90.5%) received at least one line of treatment after T0, (median 2, range 1-10). The response rates and depth of responses to each line of treatment post T0 are shown (Table). Among patients who received ≥ 1 subsequent treatment, the median PFS and OS from T0 were 3.4 (95% C.I. 2.8-4.0) mo and 9.3 (95% C.I. 8.1-10.6) mo, respectively; the median OS for the 26 patients who received no further treatment was only 1.3 (95% C.I. 0.6-1.9) mo. By multivariate analysis, penta-refractoriness (HR 2.4, p <0.001), high-risk cytogenetics (HR 1.5, p=0.01), elevated LDH (HR 2, p<0.001) and creatinine > 2 (HR 2.4, p=0.01) at the onset of CD38-based therapy predicted inferior OS. Conclusions Patients with MM who become refractory to CD38 MoAB are increasingly less responsive to subsequent therapies. While survival is particularly dismal for penta-refractory patients, the outcomes are poor even for patients who are not refractory to other mainstream MM agents. The MAMMOTH study defines a MM population in urgent need for new therapies, and provides benchmark OS, PFS and response data for subsequent investigational therapies in this setting. Disclosures Malek: Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Paul:Bristol Myer Squibb: Other: Stock and pension plan (past employee). Neppalli:Amgen: Consultancy; Celgene: Consultancy. Liedtke:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; BlueBirdBio: Research Funding; celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees. Hari:Amgen Inc.: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Vij:Amgen: 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, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Costa:Karyopharm: Research Funding; Sanofi: Honoraria; Janssen: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Abstract From 2013-2017, numerous new approvals and expanded indications have dramatically changed the treatment (tx) landscape for MM. Since that time, experienced MM physicians from leading academic institutions and cancer centers (experts) have annually updated and contributed tx recommendations for an online decision support tool designed to provide healthcare providers (HCPs) with patient-specific tx guidance. This MM tool is freely available online at www.clinicaloptions.com/myelomatool and HCPs can use the tool to enter details of a patient case, indicate their intended tx plan, and then expert tx recommendations for that case are provided. Methods This study includes analysis of tx recommendations from 5 MM experts for 270 unique MM case scenarios made during development of the 2018 update to this tool. We also aim to compare the evolving tx recommendations among the experts over time, from 2013-2017, and to determine practice patterns of HCPs using the tool over the same time span. Results Based on analysis of these annually updated MM tools, consensus (≥ 3 of 5 experts choosing the same tx for the same case) among experts has been increasing for induction tx since 2013. In ASCT-eligible patients with no specific comorbidities, experts recommended bortezomib/lenalidomide/dexamethasone (VRd) in 100% and 90% of tool cases in 2018 and 2017, respectively, which increased from 65% to 75% consensus in 2013-2015. In previous analyses, the percentage of HCPs using VRd has also increased, albeit more slowly than with experts. In 2017, 42% of HCPs indicated that they are using VRd as induction in this setting compared with 22% in 2015-2016 and 9% in 2014-2015. For ASCT-ineligible patients with ECOG > 2 but no specific comorbidities, all 5 experts recommend triplet therapy for all cases regardless of risk in 2018, but in 2017, 3 of 5 recommended triplet therapy and 2 of 5 recommended doublets for normal-risk disease. Expert recommendations for induction change, however, based on specific patient comorbidities. For patients with peripheral neuropathy, 4 of 5 experts recommended carfilzomib/lenalidomide/dexamethasone instead of VRd. For patients with renal insufficiency, 4 of 5 experts recommended bortezomib/cyclophosphamide/dexamethasone. For patients with cardiac dysfunction, all 5 experts continue to recommend VRd for patients with ECOG ≤ 2 while 2 of 5 change from VRd to Rd for patients with ECOG > 2. For patients who achieve VGPR or better to induction, all 5 experts recommend lenalidomide maintenance for standard risk disease. But for patients with high risk disease who achieve VGPR or better to induction, 3 of 5 experts recommend bortezomib/lenalidomide combination maintenance therapy regardless of induction regimen, 1 expert recommends single-agent bortezomib regardless of induction regimen, and 1 expert recommends bortezomib after a PI-based induction regimen or lenalidomide for an IMiD or IMiD/PI-based induction regimen. In the 2018 tool update, the number of R/R case scenarios with 100% expert consensus increased over previous years: 20% of cases had all 5 experts agreeing on tx vs 12% in 2017. In addition, 29% of cases had 3 of 5 experts agreeing and 8% had 2 pairs of experts agreeing in 2018 vs none with 3 of 5 experts agreeing and 21% with 2 pairs of experts agreeing in 2017. In 2018, experts recommended daratumumab/pomalidomide/dexamethasone all cases with 100% consensus, which comprises patients who are refractory to multiple agents including lenalidomide, bortezomib, and/or carfilzomib. Overall, 23 different regimens were recommended for R/R MM; and additional majority expert consensus included daratumumab/lenalidomide/dexamethasone, daratumumab/carfilzomib/dexamethasone, and carfilzomib/pomalidomide/dexamethasone (Table 1). Conclusions Practice patterns are changing rapidly and are more complex, particularly in the R/R setting, in response to the evolving tx landscape for MM. This analysis highlights several areas of expert consensus, but disparities remain for select cases. The newest approved therapies continue to have a strong impact on experts' recommendations as they have been fully integrated into their tx approaches. These analyses provide a real-time assessment of changing tx patterns among experts as well as HCPs. We will present analyses of cases entered in the 2018 online tool by HCPs and detailed comparisons of expert and the intended tx of clinicians using the tool. Disclosures Ghobrial: Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; BMS: Consultancy. Lonial:Amgen: Research Funding. Raje:Research to Practice: Honoraria; Takeda: Consultancy; AstraZeneca: Research Funding; Celgene: Consultancy; BMS: Consultancy; Merck: Consultancy; Janssen: Consultancy; Amgen Inc.: Consultancy; Medscape: Honoraria. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Abstract Introduction Multiple myeloma (MM) is a result of a malignant transformation of plasma cells that is preceded by the presence of an asymptomatic clonal plasma cell expansion, a condition referred to as monoclonal gammopathy of undetermined significance (MGUS). We and others have shown familial aggregation of MM and MGUS. Evidence from epidemiologic, family and genome-wide association studies (GWAS) suggests a genetic component underlying MM etiology. GWAS have successfully established 17 common genetic risk loci for MM to date and recently, rare inherited susceptibility variants in the LSD1 / KDM1A and USP45 genes were identified in familial MM / MGUS kindreds. Family-based approaches may be used to elucidate genetic variation contributing to familial MM. Genetic linkage analysis has historically been used to detect the chromosomal location of disease genes. The objective of this study was to conduct a linkage analysis of MM / MGUS families to identify genomic regions for MM / MGUS. Methods Linkage analysis was performed on whole exome sequencing (WES) data generated from germline DNA extracted from peripheral blood from MM / MGUS families ascertained at four sites, of which 79 were selected with 2 or more affected members with any combination of MM or MGUS. Whole exome capture was performed using Agilent SureSelect 38 Mb paired end sequencing and ran on Illumina HiSeq 2000s/2500s; standard analyses for alignment (GRCh37) and quality control were conducted. The Genome Analysis Toolkit's (GATK) HaplotypeCaller in per-sample mode was used to jointly call all the samples together. Quality control included removing variants that had <75% call rate, <8x coverage, or minor allele frequency <0.01 (1KGenomes). The jointly called WES data from the 79 families consisted of 230 individuals, including 119 MM, 93 MGUS and 18 unaffected relatives. Additional early onset (defined as age <60) MM cases (n=400), sporadic MM cases (n=879) and controls (n=2389) were also included in the joint calling to be used for follow-up of linkage regions. We included independent variants defined as linkage disequilibrium (LD) r2 <0.05 using both PLINK 1.07's LD based variant pruner and also MERLIN's pairwise r2 cluster marker-marker modeling to ensure variant independence. After quality control and LD filtering: 12,946 variants remained. We conducted multipoint linkage analysis using MERLIN (Multipoint Engine for Rapid Likelihood Inference using the Lander-Green approach) and considered both non-parametric and parametric (dominant and recessive) models to test for co-segregation of chromosomal regions with MM / MGUS. A logarithm of the odds (LOD) score greater than 3.3 was significant evidence for linkage. Within the same families, we interrogated any suggestive regions by performing gene-level association tests using the PEDGENE R package to calculate burden and kernel statistics, accounting for family relationships. Follow-up of these genes in the early onset and sporadic MM cases and controls and interrogation of single variants driving the associations of these genes is ongoing. Results Among the 79 families, 28 consisted of two or more MM, 41 had two or more MM and MGUS cases and 10 had two or more MGUS. Analyses of the 79 MM / MGUS families identified chromosome 6 at 123420001-149070000 BP region, with evidence for linkage by the non-parametric model (LOD score=3.3) and supportive evidence for linkage by the dominant parametric model (LOD=2.5) (Figure). The chromosome 6 region, which is outside the HLA-region, contains a total of 72 genes. Using gene-level association tests, we identified four genes within the region (MOXD1, TRDN, ADAT2, LTV1) that were associated within MM / MGUS in the family cases (p<0.05). Discussion We found evidence for a locus on chromosome 6 linked to MM / MGUS. Four genes in this region may be associated with MM / MGUS in these families. Follow-up of these genes/variants in high-risk individuals (early-onset / age <60), sporadic cases and controls will help elucidate genetic mechanisms contributing to familial MM / MGUS. In addition, we demonstrate the benefit of applying a linkage analysis framework to familial WES data for discovery of genomic regions influencing MM / MGUS. Disclosures Dumontet: Roche: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Honoraria. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction: Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has demonstrated efficacy, as monotherapy and combined with proteasome inhibitor (PI) bortezomib, in relapsed/refractory (R/R) multiple myeloma (MM). We report preliminary safety and efficacy data for Ven combined with the second generation PI carfilzomib (K) and dexamethasone (VenKd) in R/R MM. Methods: In this ongoing phase 2, dose escalation study (NCT02899052), patients with R/R MM and no prior K exposure received VenKd on 28-d cycles in 4 dose finding and one expansion cohorts: Ven 400 mg/day + K 27 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 8, 15, 22 (Cohort 1), same regimen but with Ven 800 mg/day (Cohort 2), Ven 800 mg/day + K 70 mg/m2 Day 1, 8, 15 + dex 40 mg Day 1, 8, 15, 22 (Cohort 3/expansion cohort), or Ven 800 mg + K 56 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 2, 8, 9, 15, 16, 22, 23 (Cohort 4). Treatment continued until progressive disease (PD) or unacceptable toxicity. Results: As of June 11, 2018, 42 patients were enrolled. The median age was 66.5 years (min, max: 37, 79), 63% had ISS II/III disease, and 8 patients (19%) had t(11;14). Patients received a median of 2 prior therapies (range: 1 - 3), 93% had received prior PI (50% refractory), 62% were refractory to immunomodulatory therapies, and 33% double refractory. At the data cut off, 29 patients were still active and had completed ≥2 cycles and 13 patients discontinued with the primary reason being disease progression (n=4), death (n=3), physician decision (n=2), withdrawal of consent (n=2), lack of efficacy (n=1), and AE (n=1). All patients experienced at least one AE, and grade 3/4 AEs experienced by >10% of subjects included: decreased lymphocyte count (26%), decreased neutrophil count (14%), and hypertension (12%). Thirteen subjects experienced at least one serious AE. Maximum tolerated dose was not reached and Ven 800 mg/day + K 70 mg/m2 was selected for expansion. Ven mean (% coefficient of variation) maximum plasma concentration (Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24) on Cycle 1 Day 15 were 2.7 (57) mg/mL and 33.1 (54) mg×h/mL, respectively, at 400 mg venetoclax (n=4); and were 2.42 (53) mg/mL and 38.7 (51) mg×h/mL, respectively, at 800 mg venetoclax (n=13) in the dose escalation cohorts. The overall response rate (ORR) was 78% and the very good partial response (VGPR) or better rate was 56% (Table). Median time from first dose to the data cut or discontinuation was 5.7 months (range: 0.9 - 16.3) and the median time to first response was 1.9 months (95% CI: 0.9, 9.2). ORRs for subgroups of interest are reported in the Table. Conclusions: The combination of VenKd appears tolerable with no new safety signals or changes in Ven pharmacokinetics. VenKd shows promising preliminary efficacy in R/R MM patient subgroups. Response rates were comparable in all high risk subgroups and overall population. However, the subset of patients with t(11;14) had the highest response. Overall, these results demonstrate that VenKd is a safe and efficacious regimen in R/R MM and support the continued study of VenKd. Disclosures Costa: Abbvie: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Research Funding. Stadtmauer:Celgene: Consultancy; AbbVie, Inc: Research Funding; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kovacsovics:Amgen: Honoraria, Research Funding; Abbvie: Research Funding. Jakubowiak:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kaufman:Roche: Consultancy; BMS: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; Abbvie: Consultancy. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Freise:AbbVie, Inc: Employment, Equity Ownership. Ross:AbbVie, Inc: Employment, Equity Ownership. Pesko:AbbVie, Inc: Employment, Equity Ownership. Munasinghe:AbbVie, Inc: Employment, Equity Ownership. Gudipati:AbbVie, Inc: Employment, Equity Ownership. Mudd:AbbVie, Inc: Employment, Equity Ownership. Bueno:AbbVie, Inc: Employment, Equity Ownership. Kumar:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: Cardiac involvement is integral in staging and prognosis of immunoglobulin light chain (AL) amyloidosis. The N-terminal prohormone of brain natriuretic peptide (NT proBNP) is a cardiac biomarker used in screening for cardiac involvement and staging the disease. Transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) are the imaging modalities recommended to determine cardiac involvement and function. Methods: We conducted a retrospective review of all patients with biopsy proven systemic AL amyloidosis seen at the mayo clinic between Jan 1, 2006 and Dec 30, 2015. The aim of the study is to identify the nature of abnormalities in cardiac biomarkers and echocardiographic features in patients with AL amyloidosis and the ability of these investigations to diagnose cardiac involvement. We first identified all patients with AL amyloidosis that underwent endomyocardial biopsy for suspicion of cardiac involvement (Cohort 1). We then analyzed a cohort (Cohort 2) which consisted of patients who had serum NT proBNP and a comprehensive echocardiographic evaluation at time of diagnosis. Results: 179 patients with AL amyloidosis underwent endomyocardial biopsy (Cohort 1) of whom 173 had evidence of amyloid deposition. In this cohort, 159 patients had NT proBNP performed at the time of the procedure. The NT proBNP was elevated (>300) in all 159 patients with a median NT proBNP of 4917 (range 355-69541). The median left ventricular ejection fraction (LVEF), interventricular septal (IVS) thickness and strain rate were 54 (range 10-77), 15 (range 8-30) and -9 (range -21 to 0) respectively. CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. The LVEF, IVS thickness and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%) respectively. 95 patients with biopsy proven cardiac amyloidosis had complete echocardiogram data available on LVEF, IVS thickness and strain rate, with 97% (n=92) presenting with an abnormality in at least one of these variables . CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. Patients with a normal NT proBNP and normal echocardiogram were considered disease free (true negative), based on our initial analysis of these investigations in Cohort 1. Cohort 2 consisted of 342 consecutive patients. The median NT pro BNP was 1878 (25-48214). The median LVEF, IVS thickness and strain rate were 63 (22-90), 14 (6-25) and -13 (-25 to -3) respectively. 259 (76%) patients had a positive NT proBNP (above 300), of whom 237 (92%) had an abnormality detected on TTE. 83 patients had a negative NT proBNP, of whom 27 (33%) had an abnormality in either LVEF, IVS thickness or strain rate. 19 of these 27 patients had a borderline reduced strain rate between -17 and -18, whilst the remaining 8 patients had a strain between -14 and -15. Only 6/27 patients were considered to have possible early cardiac involvement and none have any other diagnostic or classical features of amyloidosis on TTE. Conclusion: The combination of NT proBNP and comprehensive echocardiographic evaluation provides substantial information to diagnose cardiac amyloidosis in a significant portion of patients negating the need for endomyocardial biopsy. A negative NT proBNP rules out clinically meaningful cardiac involvement and may obviate the routine use of TTE in patients with a low clinical suspicion of cardiac amyloidosis. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Amgen: Consultancy; Medscape: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; annexon: Consultancy; Apellis: Consultancy; Prothena: Honoraria. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: 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; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction: Immunoglobulin light chain (AL) amyloidosis is associated with significant morbidity and mortality. Several models were developed to allow survival prediction, but head-to-head model comparison is lacking. Patients and Methods: Five prognostic models were compared: Mayo 2004; Mayo 2012; 2013 European modification of Mayo 2004 (where Mayo 2004 stage 3 is subdivided into 3 subgroups based on NT-proBNP at 8500 ng/L and systolic blood pressure at 100 mmHg); 2015 European modification of Mayo 2004 (where Mayo 2004 stage 3 is subdivided into 2 subgroups based on NT-proBNP at 8500 ng/L); and organ model (a model based on number of involved organs). All patients with available baseline data for the 5 models were included in this study (n=1005). Improvements in predictive accuracy of the various models were determined by calculating a net improvement in survival prediction for each pair of prognostic models. Net improvement was considered as the proportion where model A outperforms model B minus the proportion where model B outperforms model A. Results: For all models, there was increasing risk for death with increasing stage. The organ model was the least powerful system with a hazard ratio of 2.8 for ≥4 organs compared to 1 involved organ. The organ model was consistently outperformed by the other 4 systems. In the cohort as a whole, the biomarker models (Mayo 2004; Mayo 2012; European 2013; European 2015) were comparable in ability to predict survival (Figure). However, a slightly superior performance of the European 2013 modification of the Mayo 2004 system was seen over the Mayo 2004 system in the group as a whole (net improvement 4.1%, P=0.023) and when restricted to non-ASCT population (net improvement 6.3% P=0.014). The European 2015 modification performed slightly better than the Mayo 2004 system in the ASCT population (net improvement 3.4%, P=0.025). 1-year mortality was better predicted by the European models (net improvement 11-14%, P<0.05), while the Mayo 2012 had better survival prediction to all other biomarker models in 3-year landmark comparison (net improvement 7-9%, P<0.05). Conclusion: Using biomarker based staging is a clear improvement over the organ staging system. The different biomarker staging systems' abilities to predict for survival were relatively comparable, solidifying the importance of soluble cardiac biomarkers and free light chain measurement as prognosticators in AL amyloidosis. Mayo 2004-based models better predict for early death while Mayo 2012 model has a better prediction for long-term survival. Figure. Figure. Disclosures Gertz: Ionis: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; janssen: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; annexon: Consultancy; Teva: Consultancy; Research to Practice: Consultancy; Apellis: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; Physicians Education Resource: Consultancy. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Introduction: Light chain burden in light chain (AL) amyloidosis is often low, making accurate response assessment challenging. Methods: AL amyloidosis patients achieving very good partial or complete response to first line therapy and had serial sFLC studies during and after completion of therapy were included (n=396). Involved free light chain (iFLC), difference in involved-to-uninvolved free light chains (dFLC) and sFLC ratio (sFLCR) were assessed at the end of first line therapy and at nadir iFLC. Survival analysis was done using the Kaplan-Meier method. Hematological progression-free survival (hemPFS) was defined as the time from diagnosis until hematological progression or death, where patients known to be alive and progression-free at the end of follow-up were censored. Hematological progression was defined according to consensus criteria or upon initiation of second line therapy, whichever came first. Results: The median iFLC and dFLC at the end of therapy was 1.7 mg/dL and 0.5 mg/dL, respectively. sFLCR normalization occurred in 70% of patients. iFLC ≤2 mg/dL and dFLC ≤0.5 mg/dL were associated with a longer hemPFS compared to their counterparts (Figure). Only iFLC ≤2 mg/dL was associated with a significantly longer overall survival (Figure). sFLCR normalization did not predict hemPFS or overall survival. Organ response was predicted by iFLC ≤2 mg/dL and dFLC ≤0.5 mg/dL (Table), with best discrimination seen with iFLC ≤2 mg/dL. Organ response was not predicted by sFLC normalization (Table). The median nadir iFLC was 1.4 mg/dL and was reached 3.9 months from the end of therapy, longer in transplanted patients compared to patients treated with non-transplant regimens (7.3 vs 1.8 months, respectively; P<0.001). iFLC ≤2 mg/dL at the completion of therapy and nadir iFLC reached >12 months from the end of therapy were favorable predictors of hemPFS/OS in a multivariate analysis. Conclusion: iFLC at the end of first line therapy better predicts for organ response and survival than dFLC among deep responders. Normalization of sFLCR does not predict for organ response or survival and should not be used as measure of therapeutic efficacy. Figure. Figure. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Alnylam: Honoraria; celgene: Consultancy; Ionis: Honoraria; Abbvie: Consultancy; annexon: Consultancy; janssen: Consultancy; spectrum: Consultancy, Honoraria; Research to Practice: Consultancy; Medscape: Consultancy; Apellis: Consultancy; Teva: Consultancy; Amgen: Consultancy; Prothena: Honoraria; Physicians Education Resource: Consultancy.

Abstract ATTRwt (formerly known as senile) amyloidosis and plasma cell disorders share a common demographic of occurrence with increasing prevalence with age. We aimed to identify the prevalence of plasma cell disorders in patients diagnosed with ATTRwt. We retrospectively reviewed all patients seen at Mayo Clinic Rochester between 1st January 2009 and 31st of December 2017 who were diagnosed with ATTRwt. The start date of the study was chosen to coincide with routine clinical availability of laser microdissection mass spectrometry (LCMS) for subtyping of amyloidosis. 492 patients with ATTRwt were evaluated during the study period. Serum immunofixation electrophoresis (SIFE), urine immunofixation electrophoresis (UIFE) and serum free light chain (FLC) assay testing was performed in 74% (n=362), 53% (n=261) and 79% (n=386) respectively. Of the 492 ATTRwt seen during this period, 139 (28%) had abnormal monoclonal protein studies, the vast majority (92%, n=128) of which were monoclonal gammopathy of undetermined significance (MGUS). Monoclonal protein testing in this cohort included SIFE, UIFE and FLC in 96% (n=134), 71% (n=99) and 99% (n=137) respectively. The non-MGUS diagnoses included smoldering multiple myeloma in <1%% (n=2), multiple myeloma (MM) in 6% (n=8), AL amyloidosis in 2% (n=3), and lymphoplasmacytic lymphoma (LPL) in 3% (n=4). MM and LPL developed after progression from MGUS in 2 and 3 patients respectively. Two patients with MGUS also had a diagnosis of low grade non Hodgkin lymphoma (chronic lymphocytic leukemia in one and marginal zone lymphoma in the other). The abnormal monoclonal protein studies included SIFE in 55%, UIFE in 26% and an abnormal serum free light chain ratio (FLCr) in 73%. The organ biopsied for the diagnosis of ATTRwt was heart in 43% (n=60), bone marrow in 24% (n=33), fat in 9% (n=12) and other sites in 5% (n=8, 3 lung, 2 lip, 2 bladder and 1 small bowel). LCMS confirmed the subtype of amyloidosis as ATTRwt in all patients with a biopsy positive for amyloidosis by congo red staining. 19% (n=26) of patients were diagnosed with ATTRwt based on clinical features and a strongly positive PYP scan. PYP scan was positive for ATTR in 55/56 patients in whom the test was performed. The most common monoclonal protein isotypes detected were light chain (45%) and IgG (28%). Light chain subtype was kappa in the majority of patients (80%). Plasma cell disorders are not uncommon in patients with ATTRwt amyloidosis. The diagnosis of a plasma cell disorder and ATTRwt are not mutually exclusive, and their coexistence can confuse the diagnosis if amyloid typing is not performed. Patients with ATTRwt may be misclassified as AL amyloidosis due to the presence of amyloid and a clonal plasma cell disorder with significant prognostic and therapeutic implications. Disclosures Kumar: Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Gertz:Ionis: Honoraria; Research to Practice: Consultancy; Amgen: Consultancy; Prothena: Honoraria; Alnylam: Honoraria; Medscape: Consultancy; celgene: Consultancy; Teva: Consultancy; Abbvie: Consultancy; janssen: Consultancy; spectrum: Consultancy, Honoraria; annexon: Consultancy; Apellis: Consultancy; Physicians Education Resource: Consultancy. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.