Citations

Abstract Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10−6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10−12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Abstract Background : Carfilzomib is an innovative second generation proteasome inhibitor (PI) that binds irreversibly and selectively to the proteasome. Carfilzomib exhibits sustained inhibition of the proteasome with minimal off-target activity. Kd was approved in 2016 as a treatment (Tx) option for R/RMM patients who have received one to three prior lines of therapy.In the ENDEAVOR phase 3, open label, multicenter randomized controlled trial assessing Kd vs Vd, median progression-free survival (PFS) was 18.7 months (95% CI:15.6 - could not be estimated) in the Kd group vs 9.4 months (8.4 - 10.4) in the Vd group at an a priori, pre-specified interim analysis (hazard ratio [HR]: 0.53 [95% CI: 0.44 - 0.65]; p<0.0001). OS data at the 1st interim analysis were immature. In the current study, we assessed the cost-effectiveness (CE) of Kd vs Vd from a US payer perspective using data from ENDEAVOR and long-term overall survival (OS) data from the Surveillance, Epidemiology, and End Results Program (SEER). Methods: A partitioned-survival model with a progression-free (PF), a post-progression (PP) and a death state was built with a 30 year horizon. PFS was modelled using separately fitted log-logistic parametric curves. In order to estimate measures of efficacy for OS and to incorporate treatment effect into the model, time-dependent multiple semiparametric Cox regression analyses were implemented for OS outcomes, which controlled for baseline covariates. OS for Vd in the base case was modelled with a separately fitted Weibull parametric curve, which was fitted to the Vd data. The time-dependent multiple Cox model generated a HR for 0 to 12 months and a HR beyond 12 months for Kd vs Vd, which were applied to model the Kd OS curve. The OS curves beyond 36 months were extrapolated with SEER data. A Weibull distribution was used for the extrapolation by matching the SEER registry data to the ENDEAVOR population, which was assumed to represent the Vd survival rate. To this extrapolated survival curve beyond 36 months, the OS treatment effect was applied in order to model the Kd curve. Grade ≥ 3 adverse events (AEs) with ≥ 2% incidence in any ENDEAVOR arm were included. Utilities were derived from the literature and adjusted for the treatment specific improvement in QoL observed when patients were PF in ENDEAVOR. Costs related to drug (WAC prices), administration, monitoring, AE management, and subsequent Tx were considered. The base case utilized OS results from an updated OS dataset (March 2016) that resulted in an ad hoc OS analysis. A 3% discount rate was applied to costs and health outcomes. Results: In the base-case, results from the model showed thatKd was more effective compared to Vd, providing 1.874 PfLY, 1.854 LY, and 1.654 QALY gains over the modelled horizon. Kd incurred $227,703 in total additional costs and the ICER vs Vd was 137,660$/QALY. Conclusions: The model predicts that Kd delivers 1.85 additional life years over the the comparator Vd. Per the base case, Kd is cost-effective vs Vd at generally accepted willingness-to-pay thresholds of $150,000/QALY and $300,000/QALY in the US. Based on the ENDEAVOR data, Kd is a superior PI-based doublet compared to Vd, and should be preferred whenever doublets are appropriate for the patient, Furthermore, this CE analysis shows that Kd delivers considerable incremental value to patients with relapsed or refractory MM and to payers who must allocate budgets for the treatment of patients. Table Table. Disclosures Jakubowiak: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Majer:Amgen Inc: Employment, Equity Ownership. Houisse:Amgen Inc: Consultancy. Benedict:Amgen Inc: Consultancy. Campioni:Amgen: Employment, Other: Holds Amgen Stock. Panjabi:Amgen Inc: Employment, Equity Ownership. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Background: Waldenstršms macroglobulinemia (WM) is an indolent B-lymphoplasmacytic lymphoma, which is highly sensitive to 20S proteasome inhibitors such as bortezomib. However, clinical resistance to the drug can be observed early at onset of therapy (primary or inherent resistance) or develop over time, through repeated exposure to the drug (acquired resistance). Although prior investigations into the biological mechanisms associated with bortezomib resistance (BR) have identified aberrations at the genomic (PSMB5 mutation) and transcriptional level (loss of XPB-1), there is limited data on the epigenetic abnormalities that support resistance to 20S proteasome inhibition. With this in mind, we conducted a comprehensive methylation and mRNA expression analysis in WM cells focusing on the molecular patterns that characterize inherent BR (iBR) as well as acquired BR (aBR). Materials and Methods: Bortezomib sensitive (BS) human WM cell lines, BCWM.1 and MWCL-1, the iBR WM cell line RPCI-WM1 (developed from a bortezomib-refractory WM patient) as well as aBR subclones (BCWM.1/BR, MWCL-1/BR) were used in the study. Methylation status of WM cells was profiled by Illumina Infinium 450k methylation array. Methylation IDAT files were background subtracted using GenomeStudio v1.9. Beta mixture quantile dilation (BMIQ) method in R watermelon package was used to adjust type II probes into distribution characteristic of type I probes. For each gene, probes were partitioned into 6 regions using R IMA package and the ones belonging to the same region were averaged, including transcription start sites (TSS; both 200 bp and 1500 bp upstream), 5' untranslated region (UTR), and 3'UTR, the first exon, and genebody. Gene regions showing a significant adjusted p-value and a beta difference of >0.1 or <-0.1 were selected for differential hypermethylation and hypomethylation, respectively. Correlation with gene expression was conducted only on genes showing >1.5 fold change in expression. Overview of methodology is shown in Figure 1. Results: We first assessed the differential methylation pattern (TSS, 200bp upstream of gene body) of bortezomib-sensitive (BS, BCWM.1, IC50 6nM) and iBR cells, (RPCI-WM1). A total of 3,801 hypermethylated and 1,865 hypomethylated DNA regions were observed in iBR cells relative to BS cells (Figure 2A). In iBR cells, a negative correlation between hypermethylated DNA and corresponding gene expression was found in 1,039 genes (Spearman r = -0.12) (Figure 2B). In parallel, we compared the methylation pattern (TSS 200bp) of BS WM cells (BCWM.1 and MWCL-1) with their aBR derivatives, which display ~20 – 50 fold resistance to bortezomib. aBR subclones showed differential hypermethylation of 1,521 DNA regions and hypomethylation of 651 genomic regions relative to BS WM cells. These findings were not unexpected as aBR cell lines, being derivatives of BS WM cells, are clonally related to the former, whereas iBR cells are derived from a different clone. Meta-analysis of iBR and aBR followed by pathway enrichment (NextBio, Illumina Inc), revealed a significant clustering of commonly hypermethylated genes within the Validated Transcriptional Targets of TP63 isoforms Canonical Pathway (p<1.9-E5, Figure 2C) and the CEBPA binding site Geneset 2 (p<8.2-E9, Figure 2D); pathways whose genes are actively involved in suppression of cell growth and differentiation. Further validation and functional relevance of candidate gene targets from this analysis, which are relevant to WM pathobiology, are currently being investigated. Conclusion: This is the first study to examine and correlate the global methylation and gene expression profiles in WM tumor cells that are inherently wired to resist 20S proteasome inhibition as well as tumor cells, which have acquired resistance through continuous exposure to bortezomib. Although considerable differences were observed in the methylation profiles of WM cells displaying inherent vs. acquired resistance, a number of common genes emerged and pointed towards transcriptional repressors, whose inactivation through methylation has been linked to other cancers. Altogether, these findings uncover cellular systems in WM cells, which are affected by DNA methylation, subsequent mRNA suppression and which may be associated as a whole with both inherent and acquired forms of bortezomib resistance. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Deubiquitinating enzyme (DUB) inhibitors are an emerging class of compounds, which are increasingly being regarded for their anti-cancer activity and therapeutic potential. The 19S regulatory particle of the proteasome contains two DUBs, USP14 and UCHL5, which are critical for the proper unfolding and deubiquitination of proteins prior to their entry into the 20S proteasome β-catalytic core. In B/plasma cell malignancies such as Waldenströms macroglobulinemia (WM) and multiple myeloma (MM), protein homeostasis and optimal proteasome functionality are paramount for tumor survival. This is evidenced by the success of 20S proteasome inhibition with bortezomib and carfilzomib, which have demonstrated remarkable clinical benefit in patients with WM or MM. As such, the proteasome degradation pathway represents a highly attractive and clinically validated, yet still largely unexplored therapeutic target. Here, we provide first evidence of the cytotoxic effects and molecular sequelae associated with a novel 19S proteasome DUB inhibitor, VLX1570, which selectively targets USP14 and UCHL5, in preclinical models of B/plasma cell cancers and their drug resistant tumor subclones. Materials: VLX1570 was obtained from Vivolux AB, Sweden. Bortezomib was purchased from Sellekchem, Houston TX. Human myeloma cell lines (OPM2, U266, KMS11), human WM cell lines (BCWM.1, MWCL-1 and RPCI-WM1), their respective bortezomib-resistant (BR) subclones as well as ibrutinib-resistant (IR) derivatives of BCWM.1 and RPCI-WM1 were used in experiments (total n=12). Peripheral blood mononuclear cells (PBMCs) from healthy donors were used to assess for cytotoxicity of VLX1570 in non-tumor cells. Results: A 72hr MTS assay first established sensitivity of plasma cell cancer models towards VLX1570, including drug resistant subclones (EC50 range, 20 – 90nM). Next we assessed whether loss of viability was due to apoptosis and observed dose-dependent annexin-V staining in ~50 – 70% of wild-type MM and WM cells, ~45 – 55% in corresponding BR models and ~50% in IR subclones when exposed to VLX1570 (100nm – 500nM) for 24hrs. VLX1570 was tested at similar concentrations in PBMCs and induced minimal cell death. To understand if VLX1570-induced apoptosis was mitochondrial mediated, we assessed mitochondrial outer membrane permeability (MOMP) in all plasma cell cancer models treated with the DUB inhibitor (100 – 500nM) and found a dose-dependent increase in MOMP (p<0.00025 – 0.000001). Activation of the mitochondrial/intrinsic apoptotic pathway was also evidenced by cleavage of caspase-9 and 3 on immunoblot analysis. As inhibition of protein deubiquitination results in accumulation of polyubiquitinated protein conjugates, we examined global ubiquitinated protein levels and found increasing amounts of high molecular weight poly-ubiquitinated protein in VLX1570 treated tumor cells in a dose-dependent manner. This prompted us to further delineate the potential cellular response mechanisms that relay the antitumor activity of VLX1570 in malignant plasma cells. Immunoblot analysis of drug sensitive and (bortezomib or ibrutinib) resistant MM and WM cell lines revealed several changes in ER stress response proteins, notably induction of HSP70 and splicing of XBP1; the latter event which was less prominent in BR cell lines treated with bortezomib. This suggested the ability of VLX1570 to overcome resistance through a rapid and potent proteotoxic effect, which overwhelmed the tumor cells stress response mechanisms beyond its capacity for survival. Finally, as abnormalities in the NFkB signaling pathway are implicated in malignant plasma cell survival, we found markedly decreased nuclear translocation of NFkB (p-P65) protein in tumor cells treated with VLX1570. Conclusions: The DUBs of the 19S proteasome cap offer an attractive target within the proteasome degradation system and whose inhibition by VLX1570 is able to circumvent mechanisms that support resistance to b-catalytic PI (bortezomib) or BTK inhibitor (ibrutinib) therapy. The studies undertaken thus far, coupled with more rigorous mechanistic and in vivo efficacy analyses currently underway, provides rational for the clinical development of DUB inhibitors for use in malignant B/plasma cell malignancies. Disclosures Martin: Janssen: Honoraria.

Abstract Background: NK/T cell non-Hodgkin lymphomas (NK/T NHL) are rare high-grade lymphomas that are diagnostically challenging and carry a poor prognosis. Incidence is notably higher in Asian countries as compared to North America and Europe. South Americans have an incidence similar to Asian countries though less well described. In this study we reviewed the incidence and outcomes of NK/T NHL in the US with a specific focus on patient race/ethnicity. Methods: Surveillance, Epidemiology and End Results (SEER) database was used to examine the standardized incidence rates (SIR) of NK/T cell NHL among adult (≥18 yrs) patients diagnosed between 1992-2013. Mutually exclusive race/ethnicity categories were: African-Americans (AA), Asians/Pacific Islanders (API), Hispanic whites (HW) and Non-Hispanic whites (NHW). Cases that received a diagnosis at death certificate/autopsy, no follow-up records, or lacking age at diagnosis, sex, or race/ethnicity documentation were excluded. Age adjusted incidence rates (AAIR) were calculated by race. Cox proportional hazards models, adjusted for confounding variables, were used to evaluate association between patient demographics and overall survival (OS). Results: A total of 706 cases met inclusion criteria. Of these, 64% were males and 36% females. AAIR was higher in males irrespective of race/ethnicity. Among different race/ethnic subgroups, API and HW had a higher AAIR than NHW and AA (0.2, 0.18, 0.05 and 0.04, respectively) (Figure 1). Median OS for males and females was similar (1.8 yr and 2 yr, respectively; p=0.76) There was a statistically significant difference in median OS by age for all patients with 4.3 yr for age 18-44 as compared with 0.8 yr for age >75 yr (p<0.001). Median OS by was different for HW (1.3 yr), API (1.8 yr), AA (2.3 yr) and HW (2.5 yr) but did not reach statistical significance (p=0.45). Median OS by stage varied as 7.3 yr for stage IE to 0.9 yr for all other stages combined (p<0.001) Cases with disease location as nasal cavity or sinus had a median OS of 3.5 yr as against 1.1 yr for those with all other sites (p<0.001) (Table 1). Conclusions: Significant disparities exist in the US for NK/T NHL incidence by race and gender, with highest AAIR among the racial minorities of API and HW, which are fastest and second fastest growing minority groups in the US respectively. Increasing age, advanced disease stage and site outside of the nasal cavity or sinus are independent predictors of poor prognosis. Some differences do exist in survival by race. These factors need to be considered for better resource allocation and utilization for this rare, often incurable and aggressive disease. Figure 1 Figure 1. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Kelly:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Abstract Background: Disparities in MM survival among different racial groups persist despite improvements in overall survival (OS). We report a comprehensive review of the SEER Medicare database to elucidate the causes of differences in disease presentation, management practices, cost of care and their relationships to outcomes among the MM patients (pts) from different racial groups. Methods: Pts diagnosed with MM between 1991-2010 with continuous Medicare coverage (1 year prior to diagnosis-date of death/end of 2012) were included. MM complications (MM-C); hypercalcemia (C), renal dysfunction (R), anemia (An), bone fractures (B), dialysis (D) occurring prior to/within 30 days of MM diagnosis (at diagnosis; AT-D), or any time later (after diagnosis; AF-D) were summarized. Demographics, survival (PEDSAF files) and disease characteristics, drug/stem cell transplant (SCT) utilization (NCH, OUTSAF, PDESAF files) were obtained. Trends in incidence of MM-C, treatment type over time (proportional odds) and their association with race (logistic regressions) were compared. Associations between race, MM-C AT-D and MM related death using Fine and Gray's competing risk methods were analyzed. Medicare claims adjusted for inflation (2013) within the first 6 months (mth)/total MM care were summed by drug and total charges. Median cost of care by race and year of diagnosis were evaluated by Kruskal-Wallis (univariate) and proportional odds models (multivariate). Results: A total of 35842 pts (52.1% males) with median age of 76 yr (range 18-104) were included. Mutually exclusive racial subgroups were: White (W, 72%), Hispanic (H: 7.3%), African-American (AA, 16.2%), Asian (A, 4.1%), other (0.3%). A significantly increasing trend in the prevalence of all MM-C AT-D was seen over time (all p<0.001). For AF-D, all MM-C initially increased but decreased from 2006-2010 except D that showed continued increase (Fig 1A). For race, MM-C were significantly different, with AA having the most C, R, An and D while W having the most B (Fig 1B). Inferior OS was seen with male gender (p=0.006), increasing age, earlier years of diagnosis, belonging to W or H race, C, R and B (all p<0.001), but not with An (p=0.298) or D (p=0.378). Trends in OS over time showed a significant interaction with race in 1991-1995 (p<0.001), 1996-2000 (p=0.004) and 2001-2005 (p<0.001) but not in 2006-2010 (p=0.182), possibly due to shorter follow up. Medicare claims analysis showed that pts receiving any treatment increased from 12.8% in 1991-1995 to 59.3% in 2006-2010 (p<0.001). Specific therapy utilization, including SCT and all drug classes/agents evaluated increased except for cytotoxic chemotherapy utilization (melphalan/cyclophosphamide), which decreased (Fig 2A). Any therapy utilization was significantly different by race (p<0.001) with highest for H (36.5%) and lowest for AA (31.6%). Specific treatments differed significantly by race (Fig 2B). Cost of care analysis showed significant increase over years for median drug claims (0.23k to 3.63k) and total claims (5.11k to 27.8k) during first 6 mth as well as for any time after MM diagnosis (drug: 1.3k to 9.9k, total: 21.9k to 84k) (p<0.001 for all). Median drug claims in first 6 mth were highest among AA (1.3k) and lowest among A (0.63k) (p<0.001). Same was true for total claims in first 6 mth (p<0.001). For any time after diagnosis, H had the highest drug (p<0.001) and total (p=0.081) claims. There were significant interactions between year of diagnosis, race and cost of care with H seeing the highest increase in drug claims in first 6 mth (p<0.001) and any time (p=0.002). Conclusion: MM-C have generally decreased AF-D due to improved therapeutics although AA continue to have the highest rates of MM-C. Our data shows that utilization and cost of MM care have increased tremendously with resulting improved outcomes, but significant racial disparities persist. These disparities may be in part due to impaired access to new agents from lack of supplemental insurance for certain racial groups. Drug utilization and cost of care disparities may also be due to differences in co-morbidities, MM-C or access leading to differential healthcare utilization and should be explored in order to ameliorate disparities in outcomes. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Background: As of 2013, approximately 558,340 people are living with non-Hodgkin lymphoma (NHL). Outcome disparities have been reported in lymphoid malignancies but a comprehensive analysis, especially with expanding ethnic minorities is necessary. We undertook a large Surveillance Epidemiology and End Results (SEER) based analysis to describe outcome disparities in different subgroups of T-cell and B-cell NHL patients (pts), with a focus on various ethnicities. Methods: The SEER 18 Registry data (1973-2011) was utilized for pts with a confirmed diagnosis of T-cell or B-cell NHL. Cases that received a diagnosis at death certificate or autopsy, no follow-up records, no documented age at diagnosis, sex, or race/ethnicity were excluded. Cox proportional hazards models, adjusted for gender, age, race, year (yr) of diagnosis, and stratified by SEER registries were used to evaluate association between pt characteristics and survival. All statistical tests were two-sided and utilized the SAS software (v9.4) with a two-sided significance level of 0.05. Results: The final analysis included 7,662 pts with T-cell NHL and 84,910 pts with B-cell NHL. The pt demographics are shown in Table 1. Pts were stratified based on yr of diagnosis to study the impact of therapeutic developments on pt outcomes (Table 1). Pts were also divided by T-cell NHL subtype: mature T-cell (9702/3) 51%, angioimmunoblastic T-cell (9705/3) 16%, anaplastic large cell (ALCL) (9714/3) 32%, and hepatosplenic gamma-delta cell (HSϒd) (9716/3) 0.8%. Median age at diagnosis was youngest for AA pts (54 yrs) and oldest for Asian pts (65 yrs) (Figure 1 A). Survival analysis revealed that females had a better median OS than males (3.3 yrs vs. 2.3 yrs, HR 0.876; 95% CI 0.824, 0.932; p<0.001). Increasing age was an independent predictor of worse overall survival, with pts age 18-44 having a median OS 9.4 yrs (HR 0.345; 95% CI 0.312, 0.382) and pts age ≥75 having a median OS of 1.0 yr (p<0.001). There was no statistically significant difference seen in median OS for pts with respect to yr of diagnosis (p=0.081). Among the different T-cell NHL subtypes, pts with ALCL had the best (3.8 yrs, HR 0.766; 95% CI 0.714, 0.822) and pts with HSϒd had the worst median OS (0.7 yrs HR 1.959; 95% CI 1.424, 2.695) (p<0.001). AA pts (1.7 yrs, HR 1.292; 95% CI 1.176, 1.419) and Hispanic pts (1.9 yrs, HR 1.215; 95% CI 1.087, 1.357) had significantly worse OS compared to White pts who had the longest median OS (3.1 yrs) (p<0.001) (Figure 1 B). To compare and contrast with aggressive B-cell NHL, similar analyses were performed using diffuse large B-cell (DLBCL) NHL (9680/3). DLBCL showed similar trends regarding sex, age and race. Ethnic minorities had significantly worse median OS including Hispanic (2.8 yrs, HR 1.154; 95% CI 1.111, 1.198) and AA pts (3.3 yrs, HR 1.261; 95% CI 1.212, 1.312) compared to White pts with a median OS of 5.8 yrs (p<0.001). B-cell NHL pts had a significant improvement in median OS over time with pts diagnosed in 2007-2011 having more than 3 times the median OS of pts diagnosed in 1973-1991 (7 yrs vs. 2.4 yrs; p<0.001). Conclusions: Studies of outcome disparities are important for evaluating disease characteristics and their relationship to specific pt populations over time. We have performed the largest population-based analysis for T-cell and B-cell NHL including various ethnicities in the novel therapeutic agent era. We observed that males, older pts and ethnic minorities had worse median OS for both T-cell and B-cell NHL. Despite novel therapeutics targeting T cells there has been no statistically significant improvement in OS over time. In contrast, significant improvement in B-cell NHL OS has been noted, presumably due to the advent of monoclonal antibodies. These results underline the urgency for the development of novel therapeutics as well as aggressive studies of disease biology and healthcare utilization for better triage of healthcare resources, especially for ethnic minorities. Table 1. Table 1. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Race/ethnicity is associated with disparate incidence and outcomes in MM, as seen in population-based studies. Their effect on outcomes has not been reported in prospective studies. Obesity is the most consistently associated modifiable risk factor for MM and is influenced by race/ethnicity but its association with outcomes has not been explored. We analyzed patient-level data from published ECOG-ACRIN/SWOG clinical trials in newly diagnosed MM (NDMM) patients (pts) to explore the interplay of race/ethnicity, obesity and outcomes. Methods: Pooled data from 9 ECOG-ACRIN/SWOG clinical trials (E1A06, E4A03, E1A00, E2A02, E5A93, E9486, S0204, S0232, S9321) in NDMM (1988-2011) were analyzed. Pts were divided by race: White (W), African-American (AA), other (O); race/ethnicity: Hispanic (H), non-Hispanic White (NHW), non-Hispanic AA (NHAA), non-Hispanic other (NHO); and body mass index (BMI): <25, 25-29.9, ≥30. Associations between these and baseline pt/disease characteristics were assessed using chi-square (categorical) and Wilcoxon rank sum (continuous) tests. Survival distributions were estimated with Kaplan-Meier method and compared between groups using log-rank test. Cox proportional hazards regression was used to estimate hazard ratios in univariate and multivariate models. Time to event data was censored at 6 yrs. Results: Pt distribution by race, race/ethnicity and BMI is shown in Table 1. Race: AA were younger than W (median 59 vs 62 yr), had significantly more females (48% vs 40%; p=0.001) and had a smaller proportion of pts ≥70 yr (18% vs 26%; p<0.001). Median BMI was highest in AA (27.2) and lowest in O (24) (p=0.001) but not significantly different categorically between W and AA only (p=0.908). AA had significantly more pts with hemoglobin (Hb) ≤10 g/dL than W (55% vs 36%; p<0.001). Median creatinine (Cr) was 1.3 mg/dL in O and 1.1 mg/dL in W (p=0.03). There were no differences by race for ECOG performance status (PS), MM stage, lytic lesions, paraprotein subtype, serum calcium (Ca) or β2-microglobulin (β2M). Enrollment to clinical trials over years was significantly different by race (p=0.009). The only study design showing different enrollment by race was with/out stem cell transplant (SCT) (p=0.03; 37% of AA vs 31% of W got SCT trials). Race/Ethnicity: NHO were the youngest (median 58 yr) and NHW the oldest (median 62 yr) subgroup (p<0.001). NHAA had the highest proportion of pts with BMI ≥30 (16%) and NHO the lowest (7%) (p=0.018). H had the smallest proportion of females (33%) while NHO had the largest (54%) (p=0.002). H had the highest number of pts ≥70 yr (28%) and NHAA the smallest (18%) (p=0.003). Anemia rates were significantly different (p<0.001) with Hb ≤10 g/dL in 36% NHW vs 56% in NHAA. No significant differences were seen for PS, MM stage, lytic lesions, paraprotein subtype or other lab parameters. H and NHAA were enrolled in larger numbers in 1992-2011 rather than prior or later years (p<0.001). Among the subgroups, H had largest proportion of patients (75%) on trials without novel agent vs 61.5% for NHW (p=0.047). NHAA had the highest proportion of patients on trials with SCT (38%) while NHO had the smallest (27.3%) (p=0.034). BMI: By gender, 30% of males and 39% of females having BMI <25 (p<0.001). BMI <25 had the highest proportion of pts with ISS stage III (31%) vs 21.5% for ≥30 (p=0.001). A similar trend was seen for DS stage (p=0.005). 64% of ≥30 pts had Hb >10 while 51% of <25 did (p=0.003). There was significant difference in continuous Cr distribution by BMI (p=0.004). Efficacy analysis did not show any significant difference in response rate by race (p=0.132), race/ethnicity (p=0.286) or BMI (p=0.896). In univariate/multivariate analysis, significantly worse overall survival (OS) was seen in males, age ≥70 yr, ECOG PS >0, ISS and DS stage III, presence of lytic lesions, Cr ≥2 mg/dL, Ca >12 mg/dL, Hb ≤10 g/dL. No significant difference was seen in OS or progression free survival by race, race/ethnicity or BMI (Figure 1). Conclusions: Significant differences exist in demographic and clinical characteristics of NDMM pts by race/ethnicity. Median OS was significantly associated with these characteristics but not with race/ethnicity itself. Observed racial/ethnic disparity in outcomes for MM pts may be overcome by access to comparable therapeutic options as seen in clinical trials. Obesity, while associated with MM incidence, does not seem to influence outcomes. Figure 1 Figure 1. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Stewart:Janssen Pharmaceuticals: Consultancy; Takeda Oncology: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy. Hussein:Celgene: Employment. Zonder:Takeda: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership; Prothena: Consultancy, Honoraria. Barlogie:Mount Sinai Hospital: Employment.

Abstract Background: There is a significant variation in disease incidence and outcomes among Multiple Myeloma (MM) patients (pts) from different ethnic backgrounds. Currently, there is a paucity of data regarding the influence of demographics and ethnicity on behavioral patterns of pts, their attitudes, beliefs, and knowledge about MM and its treatment, which could in turn affect outcomes. We conducted a questionnaire-based study to examine behavioral patterns of MM pts, especially focusing on ethnic minorities and how this may impact patient awareness and symptom complex related to the disease and its treatment. Methods: Apaper-basedquestionnaire consisting of 61 questions encompassing four broad categories was provided to participating pts at the University of Southern California Medical Centers. These included demographics, disease/treatment related quality of life (QoL), satisfaction regarding treatment, and satisfaction regarding treating physician/healthcare staff. Information on clinical characteristics and MM-related treatment was collected through an IRB-approved protocol. Pts were stratified by age, gender, and ethnicity (Hispanics vs. Non-Hispanics). Any missing patient responses were withdrawn from the final analysis of that question. Categorical and continuous variables were compared among groups using Chi-square and Kruskal-Wallis tests, respectively. All statistical analysis utilized SAS software (v9.3) with a two-sided significance level of 0.05. Results: A total of 89 pts (males: 40, females: 49) from March 2012 to October 2013 responded to the questionnaire of the 100 pts that were consented (81%). Median age was 59 (range: 23-81) years and 43 (48%) pts were Hispanic while 46 (52%) were Non-Hispanic. Baseline clinical characteristics are shown in Table 1A. As compared to Non-Hispanics, Hispanic pts were less likely to have completed college (70% vs. 30%, p<0.001), attend myeloma support groups (90% vs. 10%, p=0.026), feel they had sufficient disease/treatment-related information (72% vs. 22.5%, p<0.001). Hispanic pts were more likely to report being unemployed/without any income (57.5% vs. 9%, p<0.001), have 3-4 people living in the house (57.5% vs. 26 %, p=0.009), feeling ill (43% vs. 21%, p=0.029), have concern about deterioration in clinical condition (66% vs. 41%, p=0.022), and inability to work due to symptoms from MM or its treatment (38.6% vs. 11.9%, p=0.005) when compared to Non-Hispanics. With respect to MM treatment, Hispanic pts were less likely to report that side effects were as expected (34% vs. 57%, p=0.036) and believe that treating staff worked towards the same goal (88% vs. 100%, p=0.020) as them. Hispanic pts also reported a lower level of satisfaction with their doctor /treatment staff, as compared to Non-Hispanic pts and this difference was statistically significant as shown in Table 1B. Using gender as the stratification factor, we noted that female pts were more likely to report lack of energy (p=0.037), pain (p=0.010), satisfaction with discussion on emotional health (p=0.012) as compared to males. With age as the stratification factor, patients < 60 years of age were less likely to report expected effectiveness from treatment (p=0.031), satisfaction regarding appropriateness of treatment (p=0.008) or explanation of test results by their doctor (p=0.036), and were more likely to worry about deterioration in their condition (p=0.014). We did not find a statistically significant association between age, gender, or ethnicity and response to initial myeloma treatment. Conclusions: We found a significant association between MM patient ethnicity and the pts responses to questions pertaining to their QoL, satisfaction with treatment and treating physician. This difference in disease/treatment related knowledge and attitudes may be related to socio-cultural and behavioral patterns and may contribute to factors such as treatment compliance, effectiveness and symptom complex burden amongst others, that can impact outcomes among ethnic subgroups of MM pts. Efforts to mitigate these differences should focus on improving methods of patient education, spread more awareness among ethnic minorities, integration of psychosocial care into cancer therapy and promoting health psychology research. Disclosures No relevant conflicts of interest to declare.

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.