Colón‐Otero, Gerardo

749 Background: Solid Pseudopapillary Neoplasms (SPNs) of the pancreas are rare accounting for 1-2% of all pancreatic tumors. Previous studies had shown that a pathogenic mutation of the CTNNB1 gene is present in over 90% of the SPN tumors with very limited information available on the specific molecular changes present in SPN. Here we report the results of next generation genetic testing of a large series of SPN tumors from the Foundation Medicine database. Methods: Foundation Medicine database from 07/2012 to 04/2019 was reviewed. A total of 31 cases of SPN tumors were identified out of 12,892 cases of pancreatic cancers. Information collected included demographic information on the patients as well as tumor analysis for next generation genetic sequencing of 315 genes associated with cancer with FoundationOne or 324 genes associated with FoundationOneCDx. Microsatellite stability status and tumor mutation burden were determined. Results: Twenty nine out of 31 cases (93%) had a CTNNB1 mutation. Seventy percent of the CTNNB1 mutations were on position 32 (14 cases, 41%) or in position 37 (9 cases, 29%). Other sites of CTNNB1 mutations included position 34 (3 cases, 9.6%), position 2 (2 cases, 6.4%) and position 38 (1 case, 3.2%). Two cases did not have a CTNNB1 mutation, one had a CDKN2A mutation and the other had no detectable mutations. Most cases had additional mutations aside from the CTNNB1, the most common were TP53 (3 cases, 9.6%) and LRP1B (2 cases, 6.4%). Other accompanying mutations were seen just once. Twenty-five percent of these cases had actionable gene mutations, each found in one case including: MSH2, BRCA2, ATM, XRCC3, ATRX, PTEN, ESR1, CDKN2, and PIK3CA. Conclusions: Next generation genetic testing of SPN tumors is of clinical benefit since it identifies actionable mutations in 29% of the cases.

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.

PURPOSE Recent trials have shown potential benefit of extended adjuvant endocrine therapy and relatively high risk of recurrence (RoR) after 5 years in hormone receptor-positive (HR+) human epidermal growth factor receptor 2–negative (HER2−) breast cancer. Although risk of late relapse in HR+ HER2− breast cancer is fairly well defined, the risk in HER2-positive (HER2+) breast cancer treated with adjuvant trastuzumab-based chemotherapy remains largely unknown. METHODS We included 3,177 patients with HER2+ breast cancer treated with adjuvant chemotherapy alone or with trastuzumab from the North Central Cancer Treatment Group N9831 (ClinicalTrials.gov identifier: NCT00005970 ) and National Surgical Adjuvant Breast and Bowel Project B-31 (ClinicalTrials.gov identifier: NCT00004067 ) trials. RESULTS Overall, HR+ breast cancer was significantly associated with improved recurrence-free survival (RFS) during the first 5 years (hazard ratio, 0.65; 95% CI, 0.56 to 0.77; P < .001). Among patients treated with trastuzumab, cumulative hazard for RFS was lower in patients with HR+ HER2+ breast cancer during the first 5 years (10.96% v 17.48%; hazard ratio, 0.60; 95% CI, 0.45 to 0.79; P < .001). However, there was no significant difference in RFS based on HR status during years 5 to 10 (hazard ratio, 1.32; 95% CI, 0.93 to 1.88; P = .12). A comparable degree of trastuzumab benefit was observed in HR+ and HR− breast cancers ( P for interaction = .87). Furthermore, we observed low RoR in years 5 to 10 among patients with HR+ HER2+ breast cancer: 3.23% in patients without lymph node involvement (N0) and 6.39% in patients with involvement of one to three lymph nodes (N1). CONCLUSION The benefit of adjuvant trastuzumab persists for a long time. A distinct pattern of recurrence was observed between HR+ and HR− HER2+ disease but with similar degree of benefit from adjuvant trastuzumab. RoR in years 5 to 10 in HR+ HER2+ breast cancer is low, particularly in patients with N0 or N1 disease.

Abstract Background Waldenstršms macroglobulinemia (WM) is a rare and incurable indolent Non-Hodgkin's lymphoplasmacytic lymphoma. Rarity and limited availability of authentic preclinical models has been a major constraint in drug development for WM. We recently reported the establishment and characterization of a novel human WM cell line, RPCI-WM1. Thereafter we evaluated the tumorigenic potential of this unique WM cell line in a xenograft mouse model along with its ability to produce human IgM in vivo. Moreover, we assessed its potential as a possible model for enhanced understanding of WM cell biology in vivo and a mechanism to conduct functional studies and preclinical anti-WM drug evaluation. Aim The primary goal of this experiment was to develop and validate an in vivo WM model that can be used to investigate WM cell biology as well as drug evaluation. Methods The RPCI-WM1 cell line (1x106 cells) was injected both subcutaneously and via tail vein into female SCID mice. Engraftment was validated via detection of human IgM (ELISA) and tumor growth (as well as response to therapy) was monitored by weekly assessment of IgM levels and external tumor formation measurements. Results After subcutaneous injection (flank) into mice, the RPCI-WM1 cells developed localized tumors that secreted human IgM detectable in serum as early as 14 days. Progressive increase in IgM was measured in the serum and this corresponded with tumor growth in a time-dependent fashion. On average, tumor tissues grew to a median of 3 cm and IgM levels reached a median of 823 ng/mL by Day 30 post-implantation. We also assessed the practical utility of this xenograft mouse model for evaluation of therapeutics, using a compound X (propriety drug with demonstrable in vitro anti-WM effects). Eleven days post-implantation, the mice were randomized into 3 groups receiving either DMSO (n=6), 100 mg of compound X (n=7) or 200 mg/kg of compound X (n=7) every alternate day via intraperitoneal injection for 26 days. On Day 37, mice were sacrificed and tumor volume was measured. We observed a 48% reduction in tumor volume in the 100mg/kg cohort, with no additional anti-WM benefit noted in the 200mg/kg cohort. Human IgM secreted by the xenografted tumors was measured by ELISA and was significantly lower in mice treated with compound X versus the control group (Figure 1). We also conducted immunohistochemistry (IHC) analysis on tumor tissues obtained from 9 mice treated with compound X (both dose cohorts) or DMSO alone. IHC staining demonstrated changes in the known target proteins of compound X (such as BCL2, p53, Ki-67) between the treated and untreated mice. Summary Thus we demonstrate that the RPCI-WM1 cell line can be dependably used to induce tumor growth through xenotransplantation in SCID mice and this mimics the IgM secreting clinical disease model. This can then be used to serve as a platform for preclinical testing of novel anti-WM therapeutics and allow for subsequent correlative studies for pharmacodynamics purpose. Comprehensive data regarding this model its utility in evaluation of various biological questions such as those relevant to the tumor microenvironment as well therapeutic modeling will be presented. We are grateful to the Leukemia and Lymphoma Society and the International Waldenstršm Macroglobulinemia Foundation for their continued support. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Lenalidomide (Len) is clinically active in CLL patients (pts). Robust anti-leukemic immune response from Len is truncated by dysfunctional immune system in CLL and anti-apoptotic bcl-2 protein. We hypothesized that therapeutic downregulation of Bcl-2 may help enhance the killing potential of immune effector cells that are activated by Len. AT-101 is a novel, orally active BH3-mimetic that binds to antiapoptotic Bcl-2 family proteins (Bcl-2, Mcl-1 and Bcl-xL) and induces CLL cell death ex vivo (Masood et al British Journal of Haematology 2012). Encouraging efficacy and safety results of AT-101 alone or in combination with rituximab in CLL have been reported in Phase I/II studies. We have previously demonstrated that bcl-2 downregulation in CLL cells enhanced the killing potential of Len-activated immune cells. Conversely, pretreatment of CLL cells with Len enhanced AT-101 cytotoxicity in an immune cell independent manner (Masood et al British Journal of Haematology 2012). These preclinical findings formed the basis of a phase I/II clinical trial testing the combination of AT-101 and lenalidomide in relapsed B-CLL patients. Methods: The phase I portion of this study (NCT 01003769) utilizes a standard cohort of three design to determine the maximum tolerated dose (MTD) of the combination regimen. The MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients. Following the MTD determination, the phase 2 portion will assess the efficacy of this combination using a one-stage design with an interim analysis. Key inclusion criteria include adult CLL pts with relapsed disease who have received 1-4 prior lines of treatment (Rx) (phase I) or 1-2 lines of Rx (phase II), last dose > 4 weeks from enrollment, ECOG performance status 0-2, good renal/liver function, acceptable blood counts. Patients with known hypersensitivity to thalidomide/Len or prior use of gossypol/AT-101 were excluded. Cycle 1 Rx includes Len alone and cycles 2-12 includes Len and AT-101. Starting doses of Len and AT-101 are 5mg oral daily on days 1-21 and 40 mg oral twice daily (b.i.d) on days 1-3 of a 28-day cycle. Planned dose escalation is shown in Table 1. Three pts will be treated at each dose level and observed during the first cycle of the combination Rx. Dose limiting toxicity is defined as grade 4 anemia unrelated to disease, thrombocytopenia-grade 4 or grade 3 with bleeding/requiring platelets, ANC <500 for >14 days, febrile neutropenia , Grade 3/4 non-hematologic toxicity. Dose from Phase II will be based on MTD from phase I. Peripheral blood and bone marrow will be collected and analyzed for immune cellular microenvironment and effect of Len and AT-101 on molecular targets. Optional lymph node biopsy will be done at baseline and if tumor-flare reaction occurs. This study is expected to accrue a maximum of 26 pts in phase I and 34 pts in phase II, overall maximum sample size of 60 pts. Five pts in phase I have been accrued to date. Table 1 (* starting dose level) Table 1. (* starting dose level) Disclosures No relevant conflicts of interest to declare.

Abstract Background: Cost of cancer care is projected to reach $173 billion by 2020, a 39% increase from 2010. Several factors including psychiatric (psych) comorbidities contribute to this increase. Within the oncology setting, 29-38% of the patients (pts) are reported to have mood disorders and 15% have major depression. Depression alone is associated with increased healthcare utilization in pts with breast, colon, lung and prostate cancers. A 2015 report noted that the presence of at least one psychiatric comorbidity in 300 Leukemia pts was associated with an extra $55,000 per pt in just one year. Similarly, in pts treated with systemic steroids, the incidence of neuropsychiatric disorders can be as high as 75%. However, no such data is available for MM, where more than 90% of pts are treated with steroids, likely increasing risk for mood problems and impacting treatment cost. As such, the aim of our study was to analyze the SEER-Medicare database for healthcare utilization trends and acute cost of care (cost incurred during 6 months after MM diagnosis) in MM pts with or without psych comorbidities. 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. Pts were categorized as: MM with any psych disorder (MM+P), MM with depression (MM+D) and MM only. Presence of ³1 inpatient (ipt) or ³2 outpatient (opt) ICD9 diagnosis codes were used to assign pts to the psych categories. Within MM+P and MM+D groups were subdivided by presence of psych or depression diagnosis prior to MM (MM+P PRE or MM+D PRE). Medicare claims adjusted for inflation (2013) within the first 6 months (mth)/total MM care were summed by drug and total charges. Univariate and multivariate logistic regression models (adjusted for age, year, sex, race, and the Charlson Comorbidity Index; CCI) were performed to determine associations with ipt, opt, and any emergency department (ED) charges after MM diagnosis. Associations between psych conditions prior to MM diagnosis and costs of care after MM diagnosis were assessed using univariate and multivariate proportional odds models. Results: The study population included 36,007 eligible MM pts with a median follow-up of 1.8 years. 15168 (42%) pts had a psych condition at any time (MM+P), while 9355 (26%) were diagnosed prior to MM diagnosis (MM+P PRE). Depression was present in 8421 pts (23%), 4546 (13%) of those occurring prior to MM diagnosis. In comparison to MM pts, MM+P and MM+D pts tended to be female, White, and had a higher CCI (all p<0.001). When compared to MM pts, those with MM+P PRE and MM+D PRE had significantly higher incidence of MM-related complications (hypercalcemia, renal dysfunction, anemia, fractures and dialysis) at the time of or after MM diagnosis and also required increased overall care (all p<0.001). Both, MM+P and MM+D had higher odds of ipt visits (OR 1.48 and 1.41, resp., p<0.001), ED care (OR 1.48 and 1.37, resp., p<0.001) and opt visits (OR 1.25 and 1.22, resp., p<0.001) as compared to MM only pts. Cost of care analysis showed that MM+P and MM+D pts had a significantly higher cost of opt (OR 1.36 and 1.39, resp., p<0.001), ipt (OR 1.49 and 1.54, resp., p<0.001) and total care (OR 1.52 and 1.55, resp., p<0.001) as compared to MM only pts during first 6 mth after MM diagnosis (Figure 1). Total costs of care for MM+P and MM+D were also higher than MM only but the differences were less significant. Cost of care differences existed within first 6 mth of MM diagnosis by pt race as well with MM+P among Hispanic and Asian pts being more strongly associated with higher costs than Whites and African-Americans (AA) (p<0.001). MM+D had similar trends but not significant after adjustment for multiple comparisons. Conclusion: Psych comorbidities are associated with significant increase in healthcare utilization and cost of care in MM pts and may contribute to higher MM-related complications. More research is needed to study whether a multidisciplinary approach to identify and manage MM pts with psych conditions may help mitigate these trends. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Background: Patient (Pt) outcomes have improved significantly in multiple myeloma (MM) due to widespread use of novel therapeutic agents and stem cell transplant (SCT) butoutcome disparities among racial/ethnic groups exist. Differences in access to and utilization of novel therapeutics are likely contributing factors. We performed an analysis of the SEER-Medicare database to explore such differences. Methods: Pts with a confirmed MM diagnosis between 2007-2009 and continuous Medicare coverage from 1 year prior to diagnosis through end of 2012 were included. Medicare Part D data (oral medications) is not available prior to 2007 so utilization analysis of lenalidomide (LEN), thalidomide (THAL) and bortezomib (BORT) was performed from 2007-2009. Demographic/survival data (PEDSAF files) and drug/SCT utilization (NCH, OUTSAF, PDESAF files) were obtained (HCPCS/NCH codes). Categorical and continuous variables were compared using /Fisher tests and Wilcoxon tests, respectively. Gender, age, and year-adjusted p-values were calculated using logistic regression. A proportional odds model was used to detect time-dependent trends in drug usage within 12 months of MM diagnosis across year of diagnosis by race. Separate multivariate models were fit for each drug adjusting for gender, age, drug use and race. Associations between drug use and overall survival (OS) were examined using a time dependent proportional hazards model. Results: A total of 5358 MM pts were included (any Medicare claims) with 2733 (51%) males. Mutually exclusive race categories were White (W; 67%), African-American (AA; 18%), Hispanic (H; 10%) and Asian (A; 5%). Median follow up was 2.4 yrs. Baseline pt characteristics were significantly different for age with AA being the youngest at diagnosis (p<0.001) and for gender (p<0.001) with W having the largest (53.4%) and AA the smallest (45.2%) proportion of males. Medicare claims capture only pts without any supplemental insurance and so drug utilization in this database was much lower than expected for all subgroups. Year-wise comparison showed that LEN use within the first year of MM diagnosis increased from 2007 to 2009 (16.5% to 27.7%; p<0.001) and there was a significant decrease in median days to first dose (p=0.002). Over the same period, use of THAL decreased (26.6% to 14.6%; p<0.001) while use of BORT (7.8% to 15.4%; p<0.001), SCT (3.3% to 6.2%; p<0.001) and more than 1 novel agent (2.5% to 5.7%; p<0.001) increased significantly. Utilization patterns within first year of MM diagnosis were significantly different among racial subgroups for LEN, THAL, BORT, SCT and >1 novel agent use. (Figure 1) No significant difference was seen for days to first dose of LEN/THAL for any race but for BORT, H got first dose in median 117 days after diagnosis as compared to median 46-51 days for other races (p=0.025). During the first year after diagnosis, W and AA had higher BORT only usage while H and A had a higher LEN/THAL only usage (p<0.001). For drug use by year and race, a significant increase in LEN use was seen from 2007 to 2009 in W (p<0.001), AA (p=0.001) and A (p<0.001) but not H (p=0.26) while THAL use decreased significantly for all races. BORT use increased significantly for all except A (p=0.602) and SCT use increased significantly for all except AA (p=0.068). Inferior OS was significantly associated with older age (p<0.001) and males (p<0.001). LEN/THAL use within the first year of diagnosis did not affect OS while BORT use within the first year of diagnosis increased mortality risk (HR 1.18, p=0.021). SCT use improved OS (HR 0.52, p<0.001). Conclusions: In this comprehensive analysis of MM therapeutics utilization, we noted significant variability among different racial groups. The use of LEN, BORT and SCT has increased while THAL has decreased over time but disparities exist in utilization among different races, with lower use of LEN in AA, lower use of BORT in A and significantly delayed use of BORT in H, which are all notable since racial/ethnic minorities are fast growing in the US population mix and seem to have inequitable utilization and/or access. Inferior survival with early BORT use may represent selection bias of pts with more advanced/aggressive disease. These trends need to be examined in larger sample sizes especially from commercial payers to eliminate drug access and utilization disparities and achieve equitable benefit of therapeutic advances across all racial subgroups. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Background: The proteasome is an established and druggable target for the treatment of plasma cell-related malignancies including Waldenstrom macroglobulinemia (WM). WM cells as a consequence of high immunoglobulin production and increased B-cell receptor (BCR) mediated proliferation upregulate proteasome activity. Additionally, microenvironmental influence mediated through BCR signaling directly influences Bcl-2 and its BH3 family members, supporting tumor cell survival. Indeed, WM patients derive significant clinical benefit from proteasome-inhibitor (PI) based therapy with agents such as bortezomib and carfilzomib. However, resistance to PI develops over time and for these patients the optimal choice and sequence of therapy has yet to be determined. Using our WM models of PI-resistance we interrogated molecular events within the BCR and Bcl-2 pathways to determine therapeutic potential of targeting these crucial pathway in PI-resistance. Materials & Methods: WM cell lines (BCWM.1 and MWCL-1) and carfilzomib-resistant (CR) subclones (BCWM.1/CR and MWCL-1/CR) were used in experiments. Gene-expression and long-noncoding (LNC) RNA analysis was performed (Arraystar) and validated by real-time PCR. Bortezomib, carfilzomib, ABT199 and ibrutinib were purchased from Sellekchem. Results: To determine the functional impact of BCR and Bcl-2 signaling in PI-resistance, as well as therapeutic sensitivity of PI-resistant cells to their inhibitors (ibrutinib, ABT-199, respectively), we established and characterized WM cell lines resistant to carfilzomib. BCWM.1/CR cells showed approximately 20-fold resistance to carfilzomib (IC50 = 92.75nM) and MWCL-1/CR cells approximately 10-fold resistance (Fig. 1A). Both CR clones also displayed some cross-resistance to bortezomib. Gene expression and LNC-RNA profiling demonstrated several changes between carfilzomib-resistant vs. sensitive WM cells. Analysis of proteasome-related mRNA revealed downregulation of PSMB5, PSMB1, PSMB2 and PSMB8. Similarly, profiling of BCR-associated genes demonstrated decreased expression of several components, including BTK and SPI1. This observation functionally manifested as reduced sensitivity to the BTK-inhibitor ibrutinib, wherein CR cells displayed 1.5 - 2 fold growth resistance to ibrutinib on 72hr MTS assay. Next we examined the expression of Bcl-2 family members in CR cells. Intriguingly, we observed that Bcl-2 and Mcl-1 were significantly downregulated but XIAP (inhibitor of apoptosis) was significantly increased in CR cells vs. wildtype WM cells- both at transcriptional and translational levels. This suggested that upon acquisition of CR, a transcriptional shift towards XIAP occurs to accommodate sustained therapeutic stress from carfilzomib and maintain steady antiapoptotic composure. To test if the PI-resistant cells have moved away from their survival dependence on Bcl-2, we treated CR cells to increasing concentrations of the Bcl-2-specific inhibitor, ABT199, and as anticipated, CR cells displayed reduced apoptosis in presence of ABT199 compared to wildtype WM cells (32% annexin-V staining vs. 50%, respectively) (Fig. 1B). Conclusions: Our study sheds insight into the differential drivers of PI-resistance particularly towards carfilzomib, in WM cells. We demonstrate that acquisition of CR is associated with downregulation of Bcl-2 and Mcl-1, which is countered by upregulation of XIAP- an event that renders CR cells resistant to ABT199 (as it targets only Bcl-2). Likewise, downregulation of BCR-related components in CR cells was associated with reduced sensitivity towards ibrutinib. These observations suggest that acquisition of resistance to PI such as carfilzomib can impact future treatment with agents such as ibrutinib or ABT199. Our preclinical models provide rationale or early sequencing of ibrutinib or ABT199 in therapeutic planning of WM patients prior to induction of PI resistance. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Outcomes in multiple myeloma (MM) have significantly improved, leading to higher prevalence of this disease. Increasing efforts have been made by various agencies to educate patients (pts), manage quality of life (QoL) and survivorship. A global impact of these efforts including pt awareness, disease knowledge and participation in their care, as well as the physical and emotional impact of MM and its treatments (Rx) has not been assessed. We undertook an international, pt-reported survey to investigate these factors and understand any underlying disparities. Methods: A 61-question patient-reported questionnaire (MM-Q), addressing global aspects of MM pts care (components in Figure 1) was used. MM-Q was administered in collaboration with the International Myeloma Foundation (IMF). To limit responses by MM pt only, “SmartPatient” MM community members and IMF Support Group Leader list were invited to complete the survey. Some of the questions were mandatory, and those with missing responses were withdrawn from the final analysis of that pts MM-Q. Categorical and continuous variables were compared among groups using the Chi-square and Kruskal-Wallis tests, respectively using SAS software (v9.3) with a two-sided significance level of 0.05. Results: Survey responses are available from 894/1240 (72%) individuals thus far. Average survey completion time was 16 minutes. Data from 746 MM-Q was included in this analysis with 466 (62.5%) complete responses. Pts from United States (US) represented 85.7% of the responders (majority from New York State). Ethnicity (n=590) was reported as non-Latino by 97%, race (n=580) was reported as White by 95%, family history of MM was reported by 19 pts and 81 reported prior history of a primary malignancy (most common, 37% non-melanoma skin cancer). Living situation questions (n=538) revealed majority were in a household of 2 (62%), were unemployed/on public assistance (53.5%), travelled alone to medical appointments (74%), with travel times varying from <30 min (55%) to >1 hr (17%). Majority (83%) had no prior knowledge of MM, 63% were patient support group members, and 92% did MM-related research on internet. With respect to MM Rx (n=524), 70% had been on Rx within 3 months and 12% reported non-compliance. Prior Rx included thalidomide (30%), lenalidomide (66%), pomalidomide (11.5%), bortezomib (63.5%), carfilzomib (11%), steroids (100%), and clinical trial participation in 25% pts. Side effects from Rx/QoL in prior 3 months (n=403) are summarized in figure 2. Pts satisfaction with Rx/treating staff (n=378) revealed majority felt their Rx to be effective (92%), right for them (87%) and side effects were as expected (84%). In general, pts acknowledged positive attributes of the Rx staff (worked towards same goal; 91%, participated in decisions; 81%, honesty 89%, confidence; 92%), and their doctor's explanations regarding Rx (benefits; 84%, side effects; 74%, test results; 83%), with the exception of emotional effects of Rx (48%). 94% pts rated their care as good/excellent and 95% were willing to participate in a follow-up survey. Stratification of statistically significant responses by geographical categories, age and time since diagnosis are shown in table 1 and analysis by occupation and educational status is ongoing. Conclusions: We conducted a large patient-reported survey to understand the current state of awareness among MM pts and a global impact of the diagnosis and its Rx on them. We showed that majority of pts who accessed the survey responded (72%), which may be a product of literacy, education and access to technology. Majority of the pts were White and non-Latino, highlighting the possible role of access and awareness in ethnic minorities. We report the large prevalence of psychophysical burden of MM and its Rx in MM pts. In general, MM pts had a high rate of satisfaction related to the Rx and their healthcare providers, but the frequency of discussion regarding emotional effects of Rx between doctors and pts was conspicuously low (48%) and the more recently diagnosed pts were less likely to be satisfied with their treating staff. We also demonstrated significant behavioral pattern differences in geographical, age and time-since-diagnosis subgroups, some of which may be sociocultural, while others may be a result of more patient awareness and understanding of the disease. This knowledge will be very helpful in devising MM survivorship strategies. Disclosures No relevant conflicts of interest to declare.