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Supplementary Table S1. Sanger validated variants. Supplementary Table S2. Mutations in HSTL driver genes. Supplementary Table S3. Other mutations identified by exome sequencing. Supplementary Table S4. Copy number of HSTL patients and cell lines. Supplementary Table S5. Clinical and pathological characteristics of HSTL patients. Supplementary Tables S6, S7. Comparison to HSTL clinical data in the literature. Supplementary Table S8. Mutational frequencies in other lymphomas. Supplementary Table S9. HSTL mutations in other lymphoma driver genes. Supplementary Table S10. Gene set enrichment analysis of DERL2 SETD2 shRNA.

Supplementary Figure S1. Sanger sequencing chromatograms. Supplementary Figure S2. Cancer cell fraction for driver genes. Supplementary Figure S3. Ideogram with chromosome 7 alterations. Supplementary Figure S4. Examples of Exome Copy Number. Supplementary Figure S5. Exploratory Kaplan-Meier plots for clinical covariates. Supplementary Figure S6. Exploratory Kaplan-Meier plots for molecular covariates. Supplementary Figure S7. Sanger and exome sequencing validation of SETD2 biallelic mutation in one HSTL case. Supplementary Figure S8. SETD2 expression in mutant vs. wildtype cases. Supplementary Figure S9. Mutual exclusivity of STAT5B, PIK3CD, and STAT3 mutations.

A variety of organisms have been shown to have altered physiology or developed pathology due to gene transfer, but mammals have never been shown to do so. Here, we show that circulating tumor DNA (ct) can promote cell-specific horizontal gene transfer (HGT) between human cancer cells and explain the mechanisms behind this phenomenon. Once ctDNA enters the host cell, it migrates to the nucleus and integrates into the cell’s genome, thereby transferring its genetic information. We determine that retrotransposons of the ERVL, SINE, and LINE families are necessary for cell targeting and the integration of ctDNA into host DNA. Using chemically synthesized retrotransposons, we found that AluSp and MER11C reproduced multiple myeloma’s (MM) ctDNA’s cell targeting and integration into MM cells. We also discovered that ctDNA might, as a result of HGT, influence the treatment response of multiple myeloma and pancreatic cancer models. Overall, this is the first study to show that retrotransposon-directed HGT can promote genetic material transfer in cancer. There is, however, a broader impact of our findings than just cancer since cell-free DNA has also been found in physiological and other pathological conditions as well. Furthermore, with the discovery of transposons-mediated tissue-specific targeting, a new avenue for the delivery of genes and therapies will emerge.

Background Lack of health insurance coverage is associated with poor access and receipt of cancer care and survival in the United States. Disruptions in coverage are common among low-income populations, but little is known about associations of disruptions with cancer care, including prevention, screening, and treatment, as well as outcomes of stage at diagnosis and survival. Methods We conducted a systematic review of studies of health insurance coverage disruptions and cancer care and outcomes published between 1980 and 2019. We used the PubMed, EMBASE, Scopus, and CINAHL databases and identified 29 observational studies. Study characteristics and key findings were abstracted and synthesized qualitatively. Results Studies evaluated associations between coverage disruptions and prevention or screening (31.0%), treatment (13.8%), end-of-life care (10.3%), stage at diagnosis (44.8%), and survival (20.7%). Coverage disruptions ranged from 4.3% to 32.8% of patients age-eligible for breast, cervical, or colorectal cancer screening. Between 22.1% and 59.5% of patients with Medicaid gained coverage only at or after cancer diagnosis. Coverage disruptions were consistently statistically significantly associated with lower receipt of prevention, screening, and treatment. Among patients with cancer, those with Medicaid disruptions were statistically significantly more likely to have advanced stage (odds ratios = 1.2-3.8) and worse survival (hazard ratios = 1.28-2.43) than patients without disruptions. Conclusions Health insurance coverage disruptions are common and adversely associated with receipt of cancer care and survival. Improved data infrastructure and quasi-experimental study designs will be important for evaluating the associations of federal and state policies on coverage disruptions and care and outcomes.

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.

8023 Background: The introduction of novel oral immunomodulatory drugs has improved the overall survival rates of patients with multiple myeloma (MM). Poor adherence to oral therapies may lead to drug resistance, poor response to treatment and other downstream effects. It is unknown if socioeconomic status (SES) mediates adherence to oral MM agents. Methods: This is a retrospective review of newly diagnosed adult patients with MM with drug coverage through a large pharmacy benefit manager (PBM) who received oral MM agents between September 1, 2016 and September 1, 2020. Patients were excluded if they were not eligible for PBM benefits for the 6 months prior to or the 12 months after the index date and if they had a stem cell transplant based on a proxy signal. Adherence was defined as an annual medication possession ratio between 0.8 and 1.2. An SES composite index was developed using ZIP code level factors in a K-means clustering algorithm. Multivariable logistic regression for adherence was conducted using the SES-index and controlled for other patient-specific demographics. Results: In total, 6,602 patients were enrolled in the study, of which, 4,211 (64.5%) were defined as adherent. There were significant unadjusted differences in age (67.89 vs 64.06, p

Purpose: Multiple myeloma (MM) treatment has changed tremendously, with significant improvement in patient out-comes. One group with a suboptimal benefit is patients with high-risk cytogenetics, as tested by conventional karyotyping or fluorescence in situ hybridization (FISH). Methodology for these tests has been published, but not necessarily standardized. Methods: We address variability in the testing and reporting methodology for MM cytogenetics in the United States using the ongoing African American Multiple Myeloma Study (AAMMS). We evaluated clinical and cytogenetic data from 1,221 patients (1,161 with conventional karyotyping and 976 with FISH) tested between 1998 and 2016 across 58 laboratories nationwide. Results: Interlab and intralab variability was noted for the number of cells analyzed for karyotyping, with a significantly higher number of cells analyzed in patients in whom cytogenetics were normal (P 5.0025). For FISH testing, CD138-positive cell enrichment was used in 29.7% of patients and no enrichment in 50% of patients, whereas the remainder had unknown status. A significantly smaller number of cells was analyzed for patients in which CD138 cell enrichment was used compared with those without such enrichment (median, 50 v 200; P, .0001). A median of 7 loci probes (range, 1-16) were used for FISH testing across all laboratories, with variability in the loci probed even within a given laboratory. Chromosome 13–related abnormalities were the most frequently tested abnormality (n5956; 97.9%), and t(14;16) was the least frequently tested abnormality (n 5 119; 12.2%). Conclusions: We report significant variability in cytogenetic testing across the United States for MM, potentially leading to variability in risk stratification, with possible clinical implications and personalized treatment approaches.

PURPOSE: Oral anticancer medications (OAMs) offer convenient administration, reducing the burden of cancer treatment, but create challenges for patients and practitioners. Using data from the Quality Oncology Practice Initiative analysis, a baseline adherence rate of 30% was identified at a large public, academic hospital. To improve OAM adherence, a quality improvement initiative was conducted. METHODS: The aim was to increase OAM patient adherence by 30 percentage points. Through cause-and-effect analysis, adherence barriers were identified, leading to the development of 2 strategies: low-cost adherence tools and a pharmacist-led adherence program. Prescription refill data were collected before and after the intervention, using prescription-fill data and specialty pharmacy records. Adherence was defined as the patient having the drug available at least 80% to less than 120% of the days evaluated for 4 treatment cycles. Other indicators collected included the number of interventions, OAM-related toxicity, emergency room visits, and hospitalizations. RESULTS: OAM adherence increased from 37% to 85% (n = 20 of 54 v 44 of 52 patients; P < .0001) in 1 year. During the study, 655 interventions were documented by the pharmacist (adherence related, n = 331; treatment related, n = 324). The number of oncology-related emergency room referrals leading to hospitalization increased from 52% (n = 13 of 25) to 62% (n = 23 of 37) during the study period. CONCLUSION: A pharmacist-led adherence program, combined with low-cost adherence tools, exceeded the goal for the adherence initiative, suggesting that a multidisciplinary collaborative approach to OAM adherence can have a significant impact on outcomes.

Multiple myeloma (MM) is a heterogeneous malignant plasma cell disorder with complex molecular and genetic abnormalities. While current therapies have improved outcomes in MM, many patients relapse. Part of the development of the resistance to treatment relates to the genetic heterogeneity of tumors that allows for the development of resistant clones. Our laboratory demonstrated that MM circulating tumor DNA (ctDNA) serves as a mechanism for horizontal gene transfer between cancer cells. Using novel 3-D imaging analysis methodologies, we demonstrated that ctDNA target specifically cancer cells of similar tumor phenotype. Furthermore, using novel in vitro models and whole genome sequencing, we identify certain transposable elements (TE) responsible of allowing DNA insertion into cancer cells. Additionally, our analysis discovered a particular retro-transposon sequence unique of multiple myeloma (MM zip-code, MMZC). After chemically synthesizing the MMZC and using flow cytometry methods, we demonstrated that a MMZC was capable of targeting and internalizing within MM cells after 30 minutes of incubation when compared to a control non-carrying TE sequence. Moreover, after culturing for 24 hours, we observed an increase on the number of cells that have internalized the MMZC. To evaluate genome integration, we ligated the MMZC to a linearized CMV-GFP and a linearized CMV-mCherry fragment prior to adding to MM cell culture. Within 12 hours, live imaging showed expression of GFP and mCherry in MM cells. This results are being validated in single cell sequencing. To evaluate a potential therapeutic potential of MMZC cargo delivery, we ligated MMZC to HSV-Tk-GFP linearized vector and tested the cell specificity targeting and killing effect of MMZC-HSV-Tk-GFP in MM, Pancreatic cancer and colon cancer cell lines. MMZC-HSV-Tk-GFP did not elicit a reduction in cell viability. However, MMZC-HSV-Tk-GFP reduce MM cell viability when ganciclovir was added to the cell culture. The capacity of gene delivery has been validated in-vivo using a MM xenograft mice. PCR evaluating for MMZC-HSV-Tk-GFP after 48 hours of tail injection demonstrated that tumor, but not other organs, amplified HSV-Tk. Furthermore, tumor tissue expressed GFP. To our knowledge this is the first description of the use of humanized non-viral synthetic technology capable of delivering therapeutic cargo material into MM cell. Disclosures Martinez-Medina: Kodikaz Therapeutic Solutions: Current Employment. El-Rayes: Bayer: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Novartis: Research Funding; Boston biomedical: Research Funding; Bristol Myers Squibb: Research Funding; Astra Zeneca: Consultancy, Research Funding; exelixis: Consultancy; erytotech: Research Funding; dicephera pharmaceutical: Consultancy. Gries: Kodikaz Therapeutic Solutions: Current Employment; Feldan Therapeutics: Consultancy. Bernal-Mizrachi: Winship Cancer Institute of Emory University: Current Employment; Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kodikaz Therapeutic Solutions: Consultancy, Current holder of individual stocks in a privately-held company, Patents & Royalties; Bigene: Membership on an entity's Board of Directors or advisory committees.

Background: Use of long-term PI-based therapy can improve outcomes across treatment settings in MM. However, there are various physical, geographical, and/or socioeconomic barriers to prolonged therapy with parenteral PIs in community practice. The US MM-6 study (NCT03173092) is assessing in-class transition (iCT) from parenteral bortezomib (V)-based induction to all-oral ixazomib-based therapy with ixazomib-lenalidomide-dexamethasone (IRd) in the diverse US community population. The objective of the study is to increase the duration of PI-based treatment, while maintaining quality of life and improving outcomes. We previously reported efficacy and safety results for the first 101 US MM-6 patients (Girnius Blood 2020). Here we have analyzed updated data for this patient subset with an additional 11 months of follow-up to further evaluate efficacy and safety, and to determine reasons for premature (within 4 cycles of IRd) discontinuation. Methods: Transplant-ineligible/delayed-transplant (≥24 months) NDMM patients at US community sites, who had achieved stable disease or better after 3 cycles of V-based induction, received IRd (ixazomib 4 mg, days 1, 8, 15; lenalidomide 25 mg, days 1-21; dexamethasone 40 mg, days 1, 8, 15, 22) for up to 39 × 28-day cycles or until disease progression or unacceptable toxicity. The primary endpoint is 2-year progression-free survival (PFS). Rates of partial response (PR), very good PR (VGPR), and complete response (CR), and duration of therapy are key secondary endpoints. For the current analysis, sites with patients who discontinued US MM-6 were queried for more detailed information. Results: As of June 1, 2020, 101 patients had been enrolled and treated at 21 sites. Median age was 73 years (range, 48-90 years), with 81% aged >65 years; 97% had ≥1 comorbidity at the start of IRd therapy. Efficacy data after an additional 11 months of follow-up (data cut-off: May 4, 2021) showed that iCT to IRd improved responses (Table 1). Overall response rate (ORR) had improved from 65% (CR 9%, VGPR 25%, PR 32%), at the end of 3 cycles of V-based induction, to 78% (molecular CR [mCR] 1%, stringent CR [sCR] 3%, CR 32%, VGPR 25%, PR 17%) following iCT to IRd. Thirty-three patients (33%) were still ongoing on therapy at the latest data cut-off; median duration of IRd was 11.7 months and overall median duration of therapy (for all PI-based therapy, including V-based induction) was 14.6 months. At a median follow-up of 18.5 months, the 18-month PFS rate was 84%. The safety profile of IRd was consistent with previous clinical studies. Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 64% of patients and treatment-related serious TEAEs in 12% (including 4 on-study deaths), while 16% of TEAEs led to study drug discontinuation. Sixty-eight patients (67%) had completed or discontinued the study since first patient enrolment on November 15, 2017. Among these patients, 14 (21%) discontinued within 2 cycles of IRd and 27 (40%) discontinued within 4 cycles; reasons for discontinuation are presented in Table 2. Conclusions: With longer follow-up, use of iCT from V-based induction to IRd to achieve long-term PI-based therapy in NDMM patients demonstrates efficacy via improved response rates and acceptable PFS in this real-world setting. Over 80% of US MM-6 patients were aged >65 years and most had ≥1 comorbidity prior to study entry. The rate of patients discontinuing within 4 cycles of iCT (7 cycles of PI-based therapy in total) is concerning because these patients may not receive the full benefit of long-term PI-based treatment. To date, the majority of premature discontinuations were reported as being due to patient request (44%) followed by TEAEs (30%). Expanded site education and closer patient follow-up to reduce premature discontinuations will be addressed in the planned US MM7 iCT study in relapsed/refractory MM. Figure 1 Figure 1. Disclosures Rifkin: Coherus: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees. Noga: Takeda Oncology: Current Employment. Girnius: Beigene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Speakers Bureau; Genentech: Honoraria; Celgene: Speakers Bureau; BMS: Honoraria, Speakers Bureau. Bogard: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Whidden: Takeda Oncology: Current Employment. Birhiray: Bayer: Honoraria; Incyte: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Coheris: Honoraria; Kyte Pharma: Honoraria; Celgene: Honoraria; Helsin: Honoraria; Amgen: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Tessaro: Speakers Bureau; AstraZeneca: Speakers Bureau; Alexion: Consultancy; Abbvie: Consultancy, Honoraria; Lilly: Speakers Bureau; Exelexis: Speakers Bureau; Clovis Oncology: Speakers Bureau; Sanofi Oncology: Speakers Bureau; Genomic Health: Speakers Bureau; Puma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Jansen Bioncology: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Twumasi-Ankrah: Takeda: Current Employment. Guo: Takeda Oncology: Current Employment. Bernal-Mizrachi: Kodikaz Therapeutic Solutions: Consultancy, Current holder of individual stocks in a privately-held company, Patents & Royalties; Bigene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Winship Cancer Institute of Emory University: Current Employment. OffLabel Disclosure: Real-world evaluation of long-term use of the oral proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for the treatment of newly diagnosed multiple myeloma in non-transplant patients with stable disease after 3 cycles of a bortezomib-based induction

Multiple myeloma (MM) is a heterogeneous malignant plasma cell disorder with complex molecular and genetic abnormalities. Clonal evolution in MM is a hallmark of treatment failure. The origin of clonal evolution seems to result from the pressure induced by treatment, microenvironmental factors and immune response. In this work we identified that ctDNA may reshape tumor genetic landscape by horizontal gene transfer similar to what is seen in prokaryotes and some Eukaryotes. Our work demonstrated that ctDNA from treatment resistant patients can transmit the phenotype to MM cell lines. Using in vitro microscopy assays and whole genome sequencing methods, we identified that ctDNA preferentially target cells that resemble their MM cell of origin compared to other cancer cell types. The tropism for MM ctDNA to target MM cells was validated in in vivo xenograft mouse models, where ctDNA targeted tumor cells and spared other tissues or other tumor xenografts. To further understand, whether cell targeting was produced via a direct interaction of ctDNA with a receptor protein, we treated ctDNA with anti-DNA antibodies derived from lupus patients prior adding it to cell culture. Our results showed a significant reduction of ctDNA incorporation. Then, we treated cells with trypsin after 30 minutes incubation with ctDNA and showed a significant reduction of CY5-ctDNA cellular signal suggesting that ctDNA incorporation is mediated by a direct interaction of ctDNA with a receptor protein. Based on these findings, we performed mass spectrometry on proteins pulled from coculture of biotin labelled ctDNA and cell lysates derived from 3 different tumor types. Results identified eight proteins bound to ctDNA that were enriched compared to biotin or a CMV-GFP linearized control vector (HLA-A, CD41, Cd97, Integrin αVβ5, P14K2A, TMEM and PTK7A). The role of these proteins in ctDNA incorporation was evaluated by culturing cells with antibodies against these proteins prior to adding ctDNA. Integrin αVβ5 followed by PTK7A, P14K2A, TMEM and HLA-A were able to reduce ctDNA cell incorporation. These results are being confirmed using shRNA methods and results will be available at the time for the meeting. In summary, we have identified a novel mechanism by which MM cells share genetic material altering their genetic landscape and elucidated potential receptors mediating ctDNA recognition. Disclosures Vardarajan: Kodikaz Therapeutic Solutions, LLC: Consultancy. El-Rayes: exelixis: Consultancy; erytotech: Research Funding; dicephera pharmaceutical: Consultancy; Astra Zeneca: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Boston biomedical: Research Funding; Novartis: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Bayer: Research Funding. Martinez-Medina: Kodikaz Therapeutic Solutions: Current Employment. Gries: Kodikaz Therapeutic Solutions: Current Employment; Feldan Therapeutics: Consultancy. Bernal-Mizrachi: Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bigene: Membership on an entity's Board of Directors or advisory committees; Kodikaz Therapeutic Solutions: Consultancy, Current holder of individual stocks in a privately-held company, Patents & Royalties; Winship Cancer Institute of Emory University: Current Employment.

Introduction: Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for multiple myeloma (MM). The oral boron-containing selective and reversible proteasome inhibitor ixazomib has shown to induce deep and durable responses (Kumar RK et la, Blood 2016. 128(20):2415-2422). Triplets containing ixazomib, has shown to be more efficacious than doublet regimens in the relapse setting (Moreau P, et al. N Engl J Med 2016. 374:1621-1634).However, to date, there is not companion diagnostics capable of predicting PI response. We have recently discovered that MM patients resistant to PI lack of the ankyrin (ANK) and death domain (DD) present in the 3'-end of NFKB2. Loss of NFKB2 3'end frequently resulted from a structural rearrangements. We found that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation (unpublished data). Based on this findings, we designed this study to examine the efficacy of NFKB2 break apart FISH to predict the response to ixazomib and dexamethasone (Id) vs. ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients. Methods: In this phase 2 biomarker-driven open-label trial, relapsed patients with Results: At the moment of the interim analysis, 60 patients have achieved 4 cycles of treatment. All treatment groups (NFKB2 FISH [-] Id, n=27, NFKB2 FISH [+] Id, n=20 and IRd, n=19) received a median of 2 prior lines of therapy. A trend to higher ORR was observed in NFKB2 FISH negative treated with Id compared with NFKB2 FISH positive (41% CI:58%-97% vs. 30% CI:8%-60%, P=0.4, target p-value goal 0.15), including significantly higher rates of ≥ very good partial response, ≥ partial response, ≥ minimal response (15%, 25%, 15% vs. 4%, 25%, 10%, respectively). ORR for IRd arm is for now 57% CI:27%-80%. Interestingly, >G3 treatment related adverse events were higher in Arm A (15%) and Arm C (13%) vs Arm B (0%). The most common (≥10%) ≥ grade 3 include URI/pneumonia 16% and diarrhea 12% in Id NFKB2 FISH negative vs. neutropenia 18% and diarrhea (10%) in the IRd NFKB2 FISH positive arm. Treatment discontinuations only occurred in 3 NFKB2 FISH positive Id treated patient (13%). Conclusion: Interim analysis demonstrates a trend higher efficacy and ≥G3 toxicity of ixazomib with dexamethasone in MM patients with negative NFKB2 break-apart FISH compared to those with a positive test. Efficacy and toxicity of the triplet regimen are comparable to what is seen in the Tourmaline 1 trial. This study is registered clinicaltrials.gov# NCT02765854 Disclosures Bernal-Mizrachi: Kodikaz Therapeutic Solutions: Consultancy, Current holder of individual stocks in a privately-held company, Patents & Royalties; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Winship Cancer Institute of Emory University: Current Employment; Bigene: Membership on an entity's Board of Directors or advisory committees. Nooka: Takeda: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Other: Travel expenses; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Adaptive technologies: Consultancy; Karyopharm Therapeutics: Consultancy. Ye: Alexion, AstraZeneca Rare Disease: Other: Study investigator. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria. Hofmeister: Ohio State University: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: IP rights, Patents & Royalties; Medscape: Other: Non-pharma speaker for education, research, marketing; DAVA Oncology: Other: Non-pharma speaker for education, research, marketing; TRM Oncology: Other: Non-pharma speaker for education, research, marketing; Verascity: Other: Non-pharma speaker for education, research, marketing; Aptitude Health: Other: Non-pharma speaker for education, research, marketing; BlueBird Bio: Other: Non-CME speaker; Amgen: Other: Non-CME speaker; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Philips Gilmore: Other: CME speaker; Non-pharma speaker for education, research, marketing; BioAscend: Other: CME speaker; Imbrium: Membership on an entity's Board of Directors or advisory committees; Myeloma360: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Local PI of CST; Oncolytics: Other: National PI for CST; PI or co-PI IST; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; BMS/Celgene: Other: National PI for CST; PI or co-PI IST; Local PI of CST; Sanofi: Other: National PI for CST; PI or co-PI IST. Rushton: KSL: Current Employment. Lonial: Merck: Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Kaufman: Incyte, celgene: Consultancy; Genentech, AbbVie, Janssen: Consultancy, Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Heidelberg Pharma: Research Funding; Janssen: Honoraria; Novartis: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Fortis Therapeutics: Research Funding; BMS: Consultancy, Research Funding; Amgen: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding.

14-3-3 proteins are a family of master regulators of intracellular signaling, yet their impact on proteasome function is unknown. We demonstrate that 14-3-3ζ binds the 11S proteasome activator, limiting proteasome assembly and cellular capacity for protein degradation. To define the functional impact of 14-3-3ζ proteasomal binding in myeloma cells, silencing and overexpression experiments are performed. We find that downregulation of 14-3-3ζ impairs myeloma cell growth and confers resistance to clinically used proteasome inhibitors. In a large cohort of newly diagnosed myeloma patients, elevated expression of 14-3-3ζ is associated with high risk myeloma genetic subtypes and worse prognosis overall. Our work demonstrates the important role of 14-3-3ζ in regulating proteasome function, myeloma cell growth and sensitivity to therapeutics, and suggests regulation of 14-3-3ζ as a new approach in myeloma therapy.

PURPOSE: Pain and constipation are common among patients with cancer and remain inadequately controlled in many. The Quality Oncology Practice Initiative assessment of pain and constipation at the Georgia Cancer Center for Excellence at Grady Health System identified documentation to be below benchmark levels. A quality improvement initiative to improve pain and constipation management was conducted. METHODS: Given the low baseline documentation rates for pain (60%) and constipation (20%), we aimed for an increase of 20 percentage points within 1 year. On the basis of cause-and-effect analysis and provider questionnaires to understand fully the causal factors, our multidisciplinary team developed a new provider note template to integrate nurse’s assessment of pain and constipation into the provider’s documentation. A new order panel was developed in the electronic medical record to link appropriate orders with the pain and constipation plan. RESULTS: The integration of the initial nursing assessment into the provider note template increased pain score documentation from 66.7% to 100% ( P < .01), and the pain management plan improved from 65.3% to 86.4% ( P = .06). Similarly, constipation assessment documentation improved from 20.4% to 100% ( P < .01), and a documented constipation plan improved accordingly from 11.2% to 29.1% ( P < .01). As a result of this intervention, pain control at the third clinic visit improved from 61.5% to 86.8% ( P < .01). Emergency department visits related to pain and constipation decreased (16.2% to 14.9%; P = .19), and hospitalizations marginally increased (1.6% to 3.6%) during the study period ( P =.28). CONCLUSION: A standardized visit template and hardwired assessment of pain and constipation exceeded the goal for improvement in documentation and positively affected outcomes.

Objectives Examining the spatial patterns of diffuse large B-cell lymphoma (DLBCL) incidence and residential proximity to toxic release locations may provide insight regarding environmental and sociodemographic risk factors. Methods We linked and geocoded cancer incidence data for the period 1999-2008 from the Georgia Comprehensive Cancer Registry with population data from the US Census and the Environmental Protection Agency's Toxics Release Inventory. We conducted cluster analyses and constructed Poisson regression models to assess DLBCL incidence as a function of mean distance to the toxic release sites. Results In total, 3851 incident DLBCL cases occurred among adults residing in Georgia between 1999 and 2008. Significant focal clustering was observed around 57% of ethylene oxide sites, 5% of benzene sites, 9% of tetrachloroethylene sites, 7% of styrene sites, 10% of formaldehyde sites, 5% of trichloroethylene sites, and 10% of all release sites. Mean distance to sites was significantly associated with DLBCL risk for all chemicals. Conclusions Proximity to Toxics Release Inventory sites can be linked to increased DLBCL risk as assessed through focal clustering and Poisson regression, and confirmatory studies using geospatial mapping can aid in further specifying risk factors for DLBCL.

Diffuse large B-cell lymphoma is an aggressive, genetically heterogenerous disease and the most common type of non-Hodgkin lymphoma among adults. To gain further insights into the etiology of DLBCL and to discover potential disease-related factors, we performed a serum lipid analysis on a subset of individuals from a population-based NHL case-control study. An untargeted mass-spectrometry-based metabolomics platform was used to analyze serum samples from 100 DLBCL patients and 100 healthy matched controls. Significantly elevated levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), were detected in the serum of DLBCL patients (121%, P < 0.05). In the male controls, elevated 2-AG levels were observed in those who were overweight (BMI ≥ 25 - < 30 kg/m2; 108%, P < 0.01) and obese (BMI ≥ 30 kg/m(2); 118%, P < 0.001) compared to those with a BMI < 25 kg/m(2). DLBCL cell lines treated with exogenous 2-AG across a range of concentrations, exhibited heterogenous responses: proliferation rates were markedly higher in 4 cell lines by 22%-68% (P < 0.001) and lower in 8 by 20%-75% (P < 0.001). The combined findings of elevated 2-AG levels in DLBCL patients and the proliferative effects of 2-AG on a subset of DLBCL cell lines suggests that 2-AG may play a potential role in the pathogenesis or progression of a subset of DLBCLs.

Background Classical Hodgkin lymphoma (cHL) is one of the most common cancers among adolescents and young adults (AYA). Incidence rates vary by demographic factors, with the highest incidence in whites of high SES. Malignant Hodgkin Reed-Sternberg (HRS) cells comprise a small percentage of the tumor (about 1%), with the remainder composed of various immune cells (tumor microenvironment, TME). The TME in cHL predicts survival and response to treatment in NHW, but has not been examined in diverse populations. We implemented a study to examine the TME and survival by race/ethnicity and SES in a multiethnic, multicenter set of 1,536 U.S. cHL cases. We conducted an initial analysis of factors associated with EBV status in tumors. Methods FFPE tumor blocks for 649 cases diagnosed from 1996-2016 were identified to date. Diagnosis and histological subtype was confirmed by pathology review for 554. Tissue microarrays were constructed with two 2 mm cores from each case with 29 cases on each array. EBER was assessed using in situ hybridization and scored as negative, positive in HRS cells or positive in the surrounding normal infiltrate. Demographic and clinical information, including the anatomic site of the biopsy, subtype, race/ethnicity (Hispanic, African American [AA], Asian, Native American, NHW), age at diagnosis and gender was collected. Multiple logistic regression was conducted to assess the relationship between age at diagnosis, race/ethnicity, gender, subtype and EBV tumor status. Results Race data was available at this time for 549 cases including 153 NHW, 235 Hispanics, 110 AAs, 36 Asians, 2 Native Americans and 13 with unknown race. 260 (47%) were female. EBV prevalence was available for 393 cases, with 316 nodular sclerosis (NS), 52 mixed cellularity (MC), 8 lymphocyte depleted (LD), 3 lymphocyte rich (LR), and 14 not otherwise specified (NOS). Age at diagnosis ranged from 5-87 years of age, with 189 (48.09%) in AYA (15-35 y). EBV+ by histology was 12.5%% for LD, 33% for LR, 47% for MC, 25% for NS, and 29% for NOS. Histologic subtype was a statically significant predictor of EBV tumor status (p=.0007), even after adjusting for age, sex, and race/ethnicity (p=.0085). Among NS cases, EBV+ was similar across racial/ethnic groups. However, there was a much higher prevalence of EBV+ in AA (73%) compared to NHW and Hispanic (36-42%) MC cases. HIV/AIDS status was available for 40% of the AA cases but none were positive. There was no correlation between year of diagnosis and the presence of EBV in tumors (r=0.05, p=0.42), thus block storage time did not affect the results. Conclusions This is the largest study of the Hodgkin lymphoma TME in a racially and ethnically diverse population. In an initial analysis, histologic subtype was the strongest predictor of positive EBV tumor status. Unlike previous reports, EBV-positive tumors were not more common among non-whites, except for AA MC cases. We expect to confirm these results in a larger sample as more cases are accrued. Citation Format: Rachel Bolanos, Amie Hwang, Jose Aparicio, Chun Chao, Naba Qurashi, Christopher Flowers, Sheeja Pullarkat, David Conti, Sophia Wang, Karen Mann, Leon Bernal-Mizrachi, Joo Song, Christian Steidl, Imran Siddiqi, Wendy Cozen. Epstein-Barr virus prevalence in classical Hodgkin lymphoma tumors by race/ethnicity in a multiethnic U.S. population [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B092.

Background: Persons of African ancestry (AA) experience a 1.5-2-fold risk of multiple myeloma (MM) compared to persons of European ancestry (EA). We assembled a set of MM patients with self-reported AA in order to evaluate the contribution of genetics to etiology in this high-risk group. Methods: Here we present the results of a meta-analysis of two GWAS in 1,813 cases and 8,871 controls of AA. We also conducted an admixture mapping scan to identify risk alleles associated with local ancestry, 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. Finally, we conducted an eQTL analysis measuring gene expression in those genes harboring a risk variant in malignant plasma cells from 292 of the patients from a single site. Results: In GWAS analysis, we identified two suggestive novel loci located at 9p24.3 and 9p13.1 at P Conclusion: Our study shows that common genetic variation contributes to MM risk individuals of AA. This abstract is also being presented as Poster C040. Citation Format: Zhaohui Du, Niels Weinhold, Gregory Chi Song, Kristen A. Rand, David J. Van Den Berg, Amie E. Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William J. Blot, Graham Casey, Victoria L. Stevens, Rick Kittles, Phyllis J. Goodman, W. Ryan Diver, Anselm Hennis, Barbara Nemesure, Eric A. Klein, Benjamin A. Rybicki, Janet L. Stanford, John S. Witte, Lisa Signorello, Esther M. John, Leslie Bernstein, Antoinette Stroup, Owen W. Stephens, Maurizio Zangari, Frits Van Rhee, Andrew Olshan, Wei Zheng, Jennifer J. Hu, Regina Ziegler, Sarah J. Nyante, Sue Ann Ingles, Michael Press, John David Carpten, Stephen Chanock, Jayesh Mehta, Graham A Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Kenneth C. Anderson, Loic Le Marchand, Daniel Auclair, Brian C.-H. Chiu, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR05.

Introduction: Oral anticancer medications (OAMs) offer convenient administration but create new challenges with unique toxicity profiles, specific monitoring parameters and non-continuous dosing schedules. We evaluated provider compliance with US Food and Drug Administration (FDA) drug labeling-specified monitoring parameters for commonly dispensed OAMs at a public academic health system. Methods: A retrospective chart review of patients receiving OAMs was conducted at Grady Health System between July 2015 and June 2016. Patients included in the evaluation were dispensed one of the ten most common OAMs used in our cancer center. Laboratory data and provider documentation were collected and compared to FDA drug labeling-specified monitoring parameters, and the primary outcome was the percentage of fully-compliant cycles. Secondary outcomes included patient adherence assessed by provider documentation and fill history. Descriptive statistics were used to evaluate the data. Results: The initial report comprised 422 patients, of which 77 patients with a total of 349 treatment cycles were included for final analysis. One hundred twenty-six (36.1%) of the treatment cycles were fully compliant with the FDA drug labeling-specified monitoring parameters. Sixty-four of the 199 (32.2%) applicable clinic notes documented patient adherence, and 15 (39.5%) of 38 patients were adherent based on fill history. Conclusion: This study revealed low compliance with FDA-recommended monitoring parameters for commonly dispensed OAMs at our institution. In addition, this study confirmed national concerns about adherence to oral regimens. It also suggests that provider compliance with monitoring parameters is an area that needs to be addressed in order to improve the ambulatory OAM process.

Tumor necrosis factor receptor-associated factor 6 (TRAF6), an (K63) E3-ligase, plays a role in many biological processes and its activity is relevant in diffuse large B cell lymphoma (DLBCL) biology. Although molecules that trigger TRAF6 activation have been defined, those that stabilize TRAF6 and/or enhance TRAF6 function remain largely unclear. We found that TRAF6 amplifies pAKT signaling in DLBCL. Moreover, TRAF6 activation and stabilization of its ubiquitination profile are facilitated by smoothened (SMO), signal transducer of canonical Hedgehog signaling. Here, we report that SMO is needed to facilitate and maintain TRAF6-dependent elevated pAKT levels, and that the SMO/TRAF6 axis contributes to doxorubicin resistance in DLBCL. Mechanistically, we found that SMO, through its C-terminal tail, stabilizes and protects TRAF6 from degradation, an effect mediated by ubiquitin-specific protease-8. Moreover, this functional link between SMO and TRAF6 is reflected in DLBCL patients where high expression of both molecules correlates with poor prognosis. In summary, our study reveals a novel cell survival mechanism in which SMO stabilizes and protects TRAF6 from degradation. The axis SMO/TRAF6/AKT is highly relevant in the biology of DLBCL and is involved in doxorubicin resistance.

Disparities in clinical care have been described for patients with limited insurance coverage or social support. We hypothesized that patients with relapsed Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM) treated at an urban county hospital serving indigent and under-insured patients would face barriers for referral to a private academic transplant center for autologous stem cell transplantation (ASCT). Charts of patients with HL, NHL, or MM treated at Grady Memorial Hospital between 2007 and 2013 were reviewed, and 215 patients with diagnosis of HD (n=40), NHL (n=96), and MM (n=79). 55 patients were referred for ASCT consults and 160 patients were not referred. Reasons for transplant non-referral included established clinical criteria (64% of cases), poor performance status (13%), refusal (4%), moved/lost-to-follow-up (4%), medical non-compliance (3%), death (3%), or referral to another hospital (1%). Non-referral based upon socio-economic criteria included: lack of legal immigration status/insurance (2%), and lack of social support/substance abuse (2%). Among the 55 referred patients, 27 patients (49%) underwent ASCT. Median follow-up for all referred patients from the time of diagnosis was 3.9 [0.7-22.7] years. 5-year survival from the date of diagnosis for patients who received ASCT was 80.2% versus 65.7% for non-transplanted patients (log-rank test, p-value=0.11). While the referral process did not demonstrate significant barriers based upon insurance or social status, further evaluation is needed to identify modifiable factors that can improve referral and assess the impact of the Affordable Care Act on access to ASCT.

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369–79. ©2017 AACR. See related commentary by Yoshida and Weinstock, p. 352. This article is highlighted in the In This Issue feature, p. 339

Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF-κB sites to their promoter region. Overall, these results indicate that the noncanonical NF-κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach.

Mantle cell lymphoma (MCL) remains incurable with conventional chemotherapy without consensus on the optimal initial treatment. We examined our single center experience with frontline therapy for patients with MCL in consecutive cases diagnosed 1995-2011. Among 81 patients, median age was 59 (28% were ≥65 years of age), 95% had stage III/IV disease and 54% had a low risk MCL International Prognostic Index score. Thirty-five percent (n=28) received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and 65% received R-HCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate/cytarabine; n=53). Forty-one patients were consolidated with autologous stem cell transplant (ASCT). There were no significant differences in 2-year survival for R-CHOP versus R-HCVAD (p=0.10) or for ASCT versus observation (p=0.06). After controlling for clinical factors, R-HCVAD followed by ASCT was associated with superior progression-free survival (hazard ratio 0.26, 95% confidence interval 0.09-0.75).

As hyperphosphorylated paratarg-7 (pP-7) carrier state was shown to be the first molecularly defined autosomal dominantly inherited risk factor for monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma (MM) in a European population, the prevalence of pP-7 carrier state among African-Americans who have a significantly higher incidence of MGUS/MM is of interest. We therefore determined pP-7 carrier state and paraproteins with specificity for P-7 in African-American, European and Japanese patients with MGUS/MM and healthy controls. By isoelectric focusing and ELISA, a paratarg-7-specific paraprotein and the associated pP-7 carrier state was observed in 30/81 (37.0%) African-American, 42/252 (16.7%) European and 7/176 (4.0%) Japanese MGUS/MM patients (p < 0.001). A pP-7 carrier state was found in 11/100 (11.0%) African-American, 8/550 (1.5%) European and 1/278 (0.4%) Japanese healthy controls (p < 0.001), resulting in an odds ratio for MGUS/MM of 4.8 (p < 0.001) among African-American, 13.6 among European (p < 0.001) and 11.5 (p = 0.023) among Japanese carriers of pP-7. We conclude that pP-7 carriers are most prevalent among African-Americans, but a pP-7 carrier state is the strongest molecularly defined single risk factor for MGUS/MM known to date in all three ethnic groups. The high prevalence of pP-7 carriers among African-American patients emphasizes a predominant role of this genetic factor in the pathogenesis of these diseases. The large number of pP7 African-American patients and controls should facilitate the identification of the SNP or mutation underlying the pP-7 carrier state.

Spatial genetic heterogeneity is a characteristic phenomenon that influences multiple myeloma's (MM) phenotype and drug sensitivity (Rasche L. et al and Bolli N et al.). Hence, the branch model of tumor evolution is not sufficient to explain the disorganized architecture observed in MM. In this study, we investigated whether MM ctDNA horizontal gene transfer (HGT) affect tumor genetic architecture and drug sensitivity, resembling what is seen in prokaryotes, and elucidated the mechanisms involved in the mobilization of genetic material from one cell to another. We identified that plasma from patients with MM transmits drug sensitivity or resistance to cells in culture. This transmission of drug sensitivity is mediated by ctDNA transfer of oncogenes to a host cell. Importantly, in vitro and in vivo demonstrated that ctDNA mainly targets cells resembling the cell of origin (tropism). Karyotype spreads and whole genome sequencing demonstrated that once patients ctDNA encounters host cells, it migrates into the nucleus where it ultimately integrates into the cell's genome. Integration to the genome was confirmed to be targeted to myeloma cells. Further sequencing analysis of multiple MM samples identified ctDNA tropism and integration is dependent on the 5' and 3' end presence of transposable elements (TE), particularly of the MIR and ALUsq family. These results were further validated by TE mediated delivery of GFP into MM cells in vitro and HSVTK in tumors of mouse xenografts. In conclusion, this data indicates for the first time that TE mediates MM ctDNA HGT into homologous tumor cells shaping the hierarchical architecture of tumor clones and affecting tumor response to treatment. Therapeutically, this unique quality of ctDNA can be exploited for targeted gene therapeutic approaches in MM and potentially other cancers. Disclosures Bernal-Mizrachi: Kodikas Therapeutic Solutions, Inc: Equity Ownership; TAKEDA: Research Funding; Winship Cancer Institute: Employment, Patents & Royalties.

Introduction: Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for multiple myeloma (MM). The oral boron-containing selective and reversible proteasome inhibitor ixazomib has shown to induce deep and durable responses (Kumar RK et la, Blood 2016. 128(20):2415-2422). Triplets containing ixazomib, has shown to be more efficacious than doublet regimens in the relapse setting (Moreau P, et al. N Engl J Med 2016. 374:1621-1634).However, to date, there is not companion diagnostics capable of predicting PI response. We have recently discovered that MM patients resistant to PI lack of the ankyrin (ANK) and death domain (DD) present in the 3'-end of NFKB2. Loss of NFKB2 3'end frequently resulted from a structural rearrangements. We found that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation (unpublished data). Based on this findings, we designed this study to examine the efficacy of NFKB2 break apart FISH to predict the response to ixazomib and dexamethasone (Id) vs. ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients. Methods: In this phase 2 biomarker-driven open-label trial, relapsed patients with Results: At the moment of the interim analysis, 50 patients have achieved 4 cycles of treatment. All treatment groups (NFKB2 FISH [-] Id, n=24, NFKB2 FISH [+] Id, n=13 and IRd, n=12) received a median of 2 prior lines of therapy. A trend to higher ORR was observed in NFKB2 FISH negative treated with Id compared with NFKB2 FISH positive (48% CI:58%-97% vs. 23% CI:8%-60%, P=0.1), including significantly higher rates of ≥ very good partial response, ≥ partial response, ≥ minimal response (16%, 29%, 12.5% vs. 0.7%, 18%, 18%, respectively). ORR for IRd arm is for now 54% CI:27%-80%. Interestingly, >G3 treatment related adverse events were higher in Arm A (45%) and Arm C (60%) vs Arm B (15%). The most common (≥10%) ≥ grade 3 include URI/pneumonia 16% and diarrhea 12% in Id NFKB2 FISH negative vs. neutropenia 18% and diarrhea (10%) in the IRd NFKB2 FISH positive arm. Treatment discontinuations only occurred in 3 NFKB2 FISH positive Id treated patient (13%). Conclusion: Interim analysis demonstrates a trend higher efficacy and ≥G3 toxicity of ixazomib with dexamethasone in MM patients with negative NFKB2 break-apart FISH compared to those with a positive test. Efficacy and toxicity of the triplet regimen are comparable to what is seen in the Tourmaline 1 trial. This study is registered clinicaltrials.gov# NCT02765854 Disclosures Bernal-Mizrachi: TAKEDA: Research Funding; Winship Cancer Institute: Employment, Patents & Royalties; Kodikas Therapeutic Solutions, Inc: Equity Ownership. Nooka:GSK: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation. Ye:Portola Pharmaceuticals: Research Funding; MingSight: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Vij:Takeda: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria. Hofmeister:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Rushton:KSLBiomedical: Employment. Lonial:Genentech: Consultancy; Karyopharm: Consultancy; Celgene Corporation: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy. Kaufman:Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; AbbVie: Consultancy; Takeda: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria.

Multiple myeloma (MM) is a neoplasm thought to arise from a damaged germinal center B-cell that progresses to a plasma cell clone arising in bone marrow. MM comprises 20% of all hematologic cancer deaths. Persons of African ancestry (AA) have a 1.5 to 2-fold higher risk compared to individuals of European ancestry (EA). Genetically driven differences in hematopoiesis may lead to variation in the levels white blood cell (WBC) subsets which could, in turn, be associated with MM etiology. There are differences in genetic determinants of WBC traits between EA and AA populations, with possible implications for the racial disparity in risk. We tested the above hypothesis using Mendelian randomization (MR), an approach that leverages genetic determinants of specific traits (i.e. WBC counts) to estimate their effects on the risk of an outcome; and a transcriptome-wide association study (TWAS), which utilizes genetic predictors of gene expression to identify susceptibility genes. These analytic approaches were applied to data from the African American Multiple Myeloma Study (AAMMS) consisting of 1813 cases and 8871 AA cancer-free controls to examine how differences in heritable WBC gene expression profiles influence MM risk. Genetic determinants of variation in WBC subsets in AA were obtained from the literature and supplemented with new genome-wide association findings in AA subjects from the UK Biobank cohort (n=6108). Odds ratios (OR) for MM per 1 standard deviation (SD) increase in each WBC phenotype were estimated using independent (linkage disequilibrium (LD) r20.05 for each). However, when we applied genetic determinants of WBC identified in 330,000 cancer-free EA UK Biobank participants (P Next, we examined the association between WBC gene expression profiles and MM risk in AAMMS data. We applied published and validated ancestry-specific models developed using the PrediXcan approach, which leverage germline genetic and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (MESA) (Mogil et al. PMID: 30096133). The primary TWAS used gene expression models trained in AA subjects (n=233), with sensitivity analyses using models developed in AA and Hispanic subjects (n=585). The TWAS significance threshold was based on the number of genes with significant germline prediction models (p The expression of two genes was significantly associated with MM risk: KANK1at 9p24.3 (P = 1.01×10-5) and DNAJC27at 2p23.3 (P = 1.56×10-5). KANK1is a candidate tumor suppressor gene for renal cell carcinoma and has recently been associated with MM risk in AA [Du, Blood 2017 130:3058]. Here we provide additional evidence for its role in MM etiology via gene expression-mediated mechanisms. DNAJC27 (previously known as RBJ) is a novel MM risk gene linked to constitutive activation of ERK in solid tumors. We also identified two suggestively associated genes: PRR14 (P = 1.34×10-4; combined AA-Hispanic sample: P = 1.56×10-6), which has been linked to MM risk in EA populations, and PARP16 (P = 9.46×10-5). To our knowledge this is the first study to comprehensively examine variation in WBC traits and gene expression profiles with respect to MM risk in AA. Our TWAS analysis leveraged data from the largest collection of genetic and gene expression data in AA, enabling ancestry-matched inference and identification of two novel risk genes. Although the limited availability of genetic instruments for WBC limited the power of MR analysis, findings using variants identified in European populations may offer some insight into trans-ethnic etiologic pathways and contribute to risk stratification strategies using genetic and blood cell count biomarkers. Future studies, particularly with MGUS-free controls, are needed to validate these results. Disclosures Song: Millennium Pharmaceuticals Inc: Employment. Rand:Ancestry.com: Employment. Ailawadhi:Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy. Nooka:Takeda: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation. Singhal:Bureau of Millennium/Takeda, Celgene, Janssen, Celgene, Bristol-Myers Squibb and Bluebird: Speakers Bureau. van Rhee:Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy; Adicet Bio: Consultancy; Kite Pharma: Consultancy; Karyopharm Therapeutics: Consultancy. Mehta:Millennium/Takeda, Celgene; stock in Celgene, Bristol-Myers Squibb and Bluebird: Speakers Bureau. Wolf:Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Fiala:Incyte: Research Funding. Terebelo:Jannsen: Speakers Bureau; Celgene: Honoraria; Newland Medical Asociates: Employment. Anderson:Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi-Aventis: Other: Advisory Board. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding. Bernal-Mizrachi:TAKEDA: Research Funding; Kodikas Therapeutic Solutions, Inc: Equity Ownership; Winship Cancer Institute: Employment, Patents & Royalties. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Zonder:Celgene Corporation: Consultancy, Honoraria, 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, 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, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Huff:Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Karyopharm, Sanofi, MiDiagnostics: Consultancy. Lonial:Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Celgene Corporation: Consultancy, Research Funding; Genentech: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding.

192 Background: Pain and constipation are common among patients with cancer and remain inadequately controlled in many. Quality Oncology Practice Initiative (QOPI) assessment of pain and constipation at the Georgia Cancer Center for Excellence at Grady Health System identified documentation to be below benchmark levels. A quality improvement initiative to improve pain and constipation management was conducted. Methods: Given the low baseline documentation rates for pain (60%) and constipation (20%), we aimed for a 20-percentage point increase within one year. Based on cause and effect analysis and questionnaires to providers, our multidisciplinary team developed a new provider note template to integrate nurse’s assessment of pain and constipation into the provider’s documentation. A new order panel was developed in the electronic medical record (EPIC) to link appropriate orders with the pain and constipation plan. Results: Integrating the initial nursing assessment into the provider note template increased pain score documentation from 66.7% to 100%, P < 0.01 and pain management plan from 65.3% to 86.4%, P = 0.06. Similarly, constipation assessment documentation improved from 20.4% to 100%, P < 0.01 and a documented constipation plan improved accordingly from 11.2% to 29.1%, P < 0.01. As a result of this intervention, pain control at the 3rd clinic visit improved from 61.5% to 86.8%, P < 0.01. Emergency room visits related to pain and constipation decreased (16.2% to 14.9%, P = 0.19) and hospitalizations marginally increased (1.6% to 3.6%) during the study period. Conclusions: A standardized visit template and mandated assessment of pain and constipation exceeded the goal for improvement in documentation and positively impacted outcomes.

Epstein-Barr virus (EBV) is present in a varying proportion of classical Hodgkin lymphoma (cHL) tumors reportedly associated with age, sex, race/ethnicity and histologic subtype. As part of a study to examine the tumor microenvironment and survival in a multiethnic set of US cHL cases, we examined the distribution of EBV expression in tumor blocks from a subset of 269 of the available cases. We confirmed cHL diagnosis and histological subtype in H&E sections of FFPE tumor blocks of excisions and core biopsies from cases provided by Southern California Kaiser, Winship Cancer Center at Emory University, City of Hope National Medical Center, Grady Memorial Hosiptal, University of California Los Angeles and University of Southern California hospitals diagnosed from 1996-2016. Immunostain results were available for most cases. Tissue microarrays were constructed with two 2 mm cores from each case with 29 cases on each array. EBER was assessed using in situhybridization and scored as negative, positive in HRS cells or positive in the surrounding normal infiltrate. Demographic and clinical information, including the biopsy anatomic site, subtype, race/ethnicity (Hispanic, African American, Asian, non-Hispanic white), age at diagnosis and gender. Multiple logistic regression was conducted to assess the relationship between age, race/ethnicity, gender, subtype and EBV tumor status. Race/ethnicity data was available at this time for 237 cases. Of these, 186 were nodular sclerosis (NS), 53 were mixed cellularity (MC), 8 were lymphocyte depleted (LD), 3 were lymphocyte rich (LR), and 10 were not otherwise specified (NOS). Fifty-seven cases were African American, 48 were non-Hispanic white, 115 were Hispanic, 16 were Asian and one was other race. 106 were female (42%). Age at diagnosis ranged from 5-84 years, with 118 (50%) in the adolescent/young adult (AYA) range (15-35). EBV prevalence in HRS cells by subtype was 0% for LD, 47% for MC, 33% for LR, 23% for NS and 50% for NOS. When restricted to the two most common subtypes, NS and MC, histologic subtype alone was a statistically significant predictor of EBV tumor status (p=.0008) and when adjusting for age, sex, site and race/ethnicity (p=.0011). In NS cases, EBV HRS cell positivity was highest in non-Hispanic whites (31%), followed by Hispanics (23%) and African Americans (18%). Among MC cases, it was very high among African Americans (80%) compared to Hispanics and non-Hispanic whites (33-39%). The patterns were similar when restricted to the AYA age group. 6.5%, 4% and 20% of EBV-negative NS, MC and NOS cases, respectively, had EBV present in non-malignant lymphocytes but not in HRS cells. Histologic subtype was the strongest predictor of EBV HRS cell positivity in this set of multiethnic cHL patients. Unlike previous reports, EBV-positive tumors were not more common among non-whites, except for African American MC cases. Citation Format: Rachel Bolanos, Amie Hwang, Chun Chao, Christopher Flowers, Sheeja Pullarkat, Jose Aparicio, Sophia Wang, Karen Mann, Leon Bernal-Mizrachi, Joo Song, Christian Steidl, Christine Lee, Wendy Cozen, Iran Siddiqi. Epstein-Barr virus prevalence in classical Hodgkin lymphoma tumors is explained by histologic subtype, not race/ethnicity in a multiethnic US population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5053.

Background Despite prophylactic platelet transfusions, bleeding remains a significant problem in thrombocytopenic patients. Methods The antifibrinolytic agent epsilon aminocaproic acid (EACA) was administered to 44 chronically (median duration, 273 days) and severely (platelet count, 8 × 10(9)/L; range, 1 × 10(9)/L-19 × 10(9)/L) thrombocytopenic patients with hematological malignancies. Prophylactic EACA at a dose of 1 g twice daily was orally administered for a median duration of 47 days (range, 7 days-209 days) until the platelet count recovered to > 30; × 10(9) /L. Platelets were only transfused if bleeding occurred. Results While receiving EACA, 59% of the patients did not bleed, 25% had 19 episodes of spontaneously resolving minor bleeding that did not require platelet transfusion, and 16% received a median of 4 platelet transfusions (range, 1 transfusion-8 transfusions) for 1 major traumatic and 9 spontaneous grade 2 to grade 3 bleeding (based on the World Health Organization classification of idiopathic thrombocytopenic purpura). No EACA toxicities were noted, and venous thromboses were not observed. Conclusions EACA is well tolerated and is associated with a low risk of major bleeding in patients with hematological malignancies who are experiencing chronic severe thrombocytopenia.

Diffuse large B-cell lymphoma (DLBCL) has been categorized into two molecular subtypes that have prognostic significance, namely germinal center B-cell like (GCB) and activated B-cell like (ABC). Although ABC-DLBCL has been associated with NF-κB activation, the relationships between activation of specific NF-κB signals and DLBCL phenotype remain unclear. Application of novel gene expression classifiers identified two new DLBCL categories characterized by selective p100 (NF-κB2) and p105 (NF-κB1) signaling. Interestingly, our molecular studies showed that p105 signaling is predominantly associated with GCB subtype and histone mutations. Conversely, most tumors with p100 signaling displayed ABC phenotype and harbored ABC-associated mutations in genes such as MYD88 and PIM1. In vitro, MYD88 L265P mutation promoted p100 signaling through TAK1/IKKα and GSK3/Fbxw7a pathways, suggesting a novel role for this protein as an upstream regulator of p100. p100 signaling was engaged during activation of normal B cells, suggesting p100's role in ABC phenotype development. Additionally, silencing p100 in ABC-DLBCL cells resulted in a GCB-like phenotype, with suppression of Blimp, IRF4 and XBP1 and upregulation of BCL6, whereas introduction of p52 or p100 into GC cells resulted in differentiation toward an ABC-like phenotype. Together, these findings identify specific roles for p100 and p105 signaling in defining DLBCL molecular subtypes and posit MYD88/p100 signaling as a regulator for B-cell activation.

Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.

We performed a retrospective cohort analysis of 701 (533 white and 144 black) patients with diffuse large B-cell lymphoma (DLBCL) treated at two referral centers in southern United States between 1981 and 2010. Median age of diagnosis for blacks was 50 years vs. 57 years for whites (p < 0.001). A greater percentage of blacks presented with elevated lactate dehydrogenase levels, B-symptoms and performance status ≥ 2. More whites (8%) than blacks (3%) had a positive family history of lymphoma (p = 0.048). There were no racial differences in the use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; 52% black vs. 47% white, p = 0.73). While black race predicted worse survival among patients treated with CHOP (hazard ratio [HR] 1.8, p < 0.001), treatment with R-CHOP was associated with improved survival irrespective of race (HR 0.61, p = 0.01). Future studies should examine biological differences that may underlie the observed racial differences in presentation and outcome.

SummaryDiffuse large B-cell lymphoma (DLBCL) occasionally presents with circulat-ing malignant cells. The clinical characteristics and long-term outcomes ofthese patients have not been described. Twenty-nine newly diagnosedDLBCL presenting in leukaemic phase were identified between 1996 and2010, at two institutions. Median age was 48 years, and patients presentedwith leucocytosis, high lactate dehydrogenase levels, B symptoms, and highInternational Prognostic Index score. Extra nodal site involvement wasobserved in all patients and affected the bone marrow (100%), spleen(62%), pleura/lung (41%), liver (21%), bone (17%), bowels (7%) and cere-brospinal fluid (14%). Blood lymphomatous cells co-expressed CD19,CD20, CD22, CD38, CD45, HLA-DR and FMC7 in >90%, and kappa orlambda light chain restriction in >50%. Ninety per cent received rituximaband anthracycline-based chemotherapy. Overall, remission was complete in54% and partial in 31%; 15% had resistant disease. Median follow-up was47 months; 13 (45%) patients remain alive in complete remission. Medianprogression-free and overall survivals were 11·5 and 46·7 months, respec-tively. In summary, patients with DLBCL in leukaemic phase present withhigh tumour burden and frequent involvement of extra nodal sites. In thisuncommon DLBCL subgroup, anthracycline-based regimens with rituximabare associated with early morbidity and mortality, but yield approximately50% 4-year survival.Keywords: diffuse large B-cell lymphoma, leukaemic phase, outcomes,characteristics, treatment.

The inhibitors of apoptosis (IAP) are important regulators of apoptosis. However, little is known about the capacity of Smac mimetics (IAP inhibitor) to overcome virally associated-lymphoma's (VAL) resistance to apoptosis. Here, we explored the pro-apoptotic effect of a novel Smac mimetic, RMT5265.2HCL (RMT) in VAL cells. RMT improved the sensitivity to apoptosis in EBV- and to some extend in HTLV-1- but not in HHV-8-VAL. Furthermore, we identified that RMT promotes caspase 3 and 9 cleavage by inhibiting XIAP and inducing the mitochondrial efflux of Smac and cytochrome C. This investigation further support exploring the use of Smac inhibitors in VAL.

We investigated the clinical significance of leukopenia at the time of diagnosis in a cohort of 225 patients with newly diagnosed acute myeloid leukemia (AML) at a single institution. Leukocyte count was treated as a continuous variable and, using a receiver operating characteristic curve (ROC), a cutoff of 3,600/μL had the best sensitivity and specificity for remission (complete remission [CR]), relapse-free survival [RFS], and overall survival [OS]). In a multivariable model, leukopenia at diagnosis had no effects on CR (hazard ratio [HR] = 2.02; confidence interval [CI], 0.9-4.3; P = .07), RFS (HR = 0.93; CI, 0.5-1.5; P = .8), or OS (HR = 1.05; CI, 0.7-1.5; P = .7). No differential expression of cell surface molecules (CD34, c-Kit, CXCR4, PECAM, VLA2, VLA-, VLA4, VLA5, and FLT3) was observed on simultaneously obtained marrow and blood blasts in the high- vs. low-leukocyte groups. We conclude that leukopenia at diagnosis carries no prognostic significance in AML.

Introduction: Plasmablastic lymphoma (PL) is an aggressive variant of lymphoma, with strong association with HIV. Despite significant improvements in the survival of other lymphomas, PL has a short overall survival (14 months). The association with Epstein-Barr virus (EBV) infection and MYC chromosomal translocations are defining features of PL. However, the genetic causes and the role of specific mutation in PL are largely unknown. This limitation hinders the design of therapeutic approaches aimed to improve PL survival. Therefore, we performed a comprehensive analysis of the genetic landscape in PL. Methodology: Whole exon sequencing of 52 de novo PL tumors from HIV+ patients and matched normal tissues (15%) using high throughput sequencing on the Illumina platform. Of these 52 patient samples, 10 tumor and 4 normal control samples were removed due to poor sequencing quality. Mapping and variant calls were performed using BWA and Varscan softwares. Variants call filtering criteria include: exon location, minimum coverage of 5%, and onside T-test P value ≤ of 0.01 or 0.02). For immunohistochemistry, we use p-TAK1 Thr184-187 (Cell signaling) and p-BTK Tyr551(Termofisher) antibodies. Results: Analysis of exome sequencing data identified 1562 recurrent somatic mutations (p-value ≤0.01) in 711 genes, including 304 mutations previously identified in cancer driving genes. The most common recurrent pathways affected within the top 2000 gene mutations with p≤0.02 comprised mainly of NF-κB signaling followed by immune response (antigen presentation by MHC class II and the alternative and lectin induced complement pathways), reverse signaling by Ephrin B, mTOR/PTEN and EGFR/RAS pathways. Based on the lack of canonical NF-κB activation previously reported (Chapman J et al. Leukemia 2015; 29: 2270-2273) and the important role of MYD88-p100 signaling pathway in B cell differentiation into plasmablast (Guo et al. Oncogene 2016. 36(29):4224-4232), we investigated the status of p100 signaling in PL using a published gene expression dataset (Chapman J. et al Leukemia 2015). Our analysis demonstrated that most PL (70%) manifest constitutive p100 signaling. Therefore, we focused on mutations in genes involved in the NF-κB activation. Mutations in the NF-κB pathway were identified in all the analyzed cases with an average of 4 mutated genes in each tumor. Consistent with the previously reported downregulation in RNA expression of genes implicated in the BCR and canonical NF-κB signaling, we found deleterious mutations in genes in the BCR pathway that have been previously reported in lymphomas, including MATL1, FYN and SYK (24%, 16% and 15%, respectively). In contrast, we found frequent gene mutations in the MYD88-PI3P pathway that never have been reported in lymphomas, including SHIP2, DOCK8, PLCG2 in 50%, 39% and 37% of the cases, respectively. These findings are of relevance, as this mutations are expected to results in increased MYD88/TAK1 and BTK signaling (Shinners NP et al J. Imm. 2007, 179 (6) 3872-3880) and can be targeted by specific inhibitors. To evaluate the status of phosphorylation of TAK1 and BTK in these tumors, we performed immunohistochemistry analysis in 15 PL, demonstrating high levels of phosphorylation of these proteins in all tumors analyzed. Conclusion: To our knowledge, this is the first in-depth analysis of PL genome. Our data provide the most comprehensive genetic portrait of PL, provides potential genetic causes of this disease and identify potential druggable targets that deserve further clinical exploration. Disclosures Flowers: National Cancer Institute: Research Funding; Millennium/Takeda: Research Funding; Eastern Cooperative Oncology Group: Research Funding; OptumRx: Consultancy; Denovo Biopharma: Consultancy; Genentech/Roche: Research Funding; V Foundation: Research Funding; Abbvie: Consultancy, Research Funding; Acerta: Research Funding; Celgene: Research Funding; Pharmacyclics/ Janssen: Consultancy; Spectrum: Consultancy; Burroughs Wellcome Fund: Research Funding; Bayer: Consultancy; Karyopharm: Consultancy; Gilead: Research Funding; Genentech/Roche: Consultancy; Pharmacyclics: Research Funding; Janssen Pharmaceutical: Research Funding; Abbvie: Research Funding; BeiGene: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy. Lossos:Affimed: Research Funding. Bernal-Mizrachi:Takeda Pharmaceutical Company: Research Funding; Kodikaz Therapeutic Solutions: Consultancy, Equity Ownership.

Background: To address the current and long-term unmet health needs of the growing population of patients diagnosed with non-Hodgkin lymphoma (NHL) and NHL survivors, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/) with recruitment at eight centers (Cornell University, Emory University, Mayo Clinic, MD Anderson, University of Iowa, University of Miami, University of Rochester, and Washington University). Here we report on the first two years of enrollment. Methods: All patients ≥18 years with NHL (exclusive of chronic lymphocytic leukemia) newly diagnosed within 183 days of enrollment are eligible. LEO reviews all pathology diagnoses; annotates and harmonizes all cases with clinical, epidemiologic, pathology and treatment data; builds a NHL tumor bank that includes an H&E slide, a formalin-fixed, paraffin-embedded tissue sample and extracted tumor DNA and RNA; collects peripheral blood and banks DNA, serum, plasma and buffy coat in a central biorepository; and prospectively follows patients regularly to ascertain disease progression/relapse, retreatment, transformation, second cancers, survival, updated exposures, and patient-reported outcomes. We examined the demographics, clinical characteristics, and NHL subtypes for patients enrolled in the first two years (2015-2017) in LEO Cohort and compared these characteristics to population-based registry data from the United States Surveillance, Epidemiology, and End Results (SEER) Program for 2011-2015. We also examined baseline body mass index (BMI), comorbidities and quality of life (QOL) measured with the Functional Assessment of Cancer Therapy - General (FACT-G) scores (0-100 scale) overall and by NHL subtype that were collected in LEO but not available in SEER or any other large, prospective US NHL cohort. Results: From 2015-2017, LEO enrolled 3244 NHL patients across 47 states (Figure) with a median age at diagnosis of 62 years (range, 18-94 years) and 55.9% male. Based on self-identified race/ethnicity, 85% of the participants were White, 7.4% were Black/African American, 2.6% were Asian, and 3.5% other or more than one race; 9.9% were Hispanic (regardless of race). The most common subtypes were diffuse large B-cell (DLBCL, 33.9%), follicular (FL, 22.2%), mantle cell (MCL, 9.3%), marginal zone (MZL, 8.3%), T-cell (TCL, 10.9%), and all other NHL subtypes (other NHL, 15.3%). These distributions were all within 5% of SEER data, except that 6.8% of participant in LEO were in the age 80+ years group compared to 18.5% in SEER (Table). The overall prevalence of self-reported comorbidities at enrollment was 13.5% for heart disease (range, 12.1% for FL to 16.6% for MCL), 8.8% for diabetes (range, 7.1% for FL to 9.8% for DLBCL), 4.6% for osteoporosis (range, 3.0% for MCL to 6.3% for MZL), and 5.9% for autoimmune disease (range, 2.0% for MCL to 12.6% for MZL). The median BMI was 27.9 kg/m2 (range, 26.7 kg/m2 for TCL to 28.3 kg/m2 for MZL). A total of 2151 participants completed the FACT-G with a median score of 78.7 (range, 75.9 for TCL to 83.3 for MZL). Complete IPI data were available on 2296 participants: 40.4% IPI 0-1, 32.7% IPI 2, 18.3% IPI 3, 8.7% IPI 4-5. Overall, 73.7% of participants were initially treated with systemic therapy (range, 40.0% for MZL and 91.8% for DLBCL); 14.5% were initially managed with observation (range, 1.4% DLBCL and 31.8% for FL); and 2.0% were initially manage with radiotherapy (range, 0.2% for MCL and 3.8% for DLBCL). Outcomes are being prospectively collected. Conclusions: LEO is a large and diverse cohort of newly diagnosed NHL patients and the first two years of enrollment reflects the broader United States NHL population. Enrollment is ongoing. This unique resource will enable examination of the interactions among a broad array of clinical and molecular factors and their impact on multiple outcomes, to improve prognostication, identify new approaches to improve outcomes and survivorship, and facilitate clinical trials using this infrastructure. Disclosures Flowers: Acerta: Research Funding; Pharmacyclics/ Janssen: Consultancy; OptumRx: Consultancy; Janssen Pharmaceutical: Research Funding; V Foundation: Research Funding; Burroughs Wellcome Fund: Research Funding; Spectrum: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Consultancy; Millennium/Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Gilead: Consultancy; BeiGene: Research Funding; Karyopharm: Consultancy; Denovo Biopharma: Consultancy; Genentech/Roche: Consultancy; Gilead: Research Funding; Genentech/Roche: Research Funding; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding. Nastoupil:TG Therappeutics: Research Funding; Merck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech: Honoraria, Research Funding; Karus: Research Funding; Novartis: Honoraria; Juno: Honoraria. Kahl:Acerta: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Juno: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy. Casulo:Celgene: Research Funding; Gilead: Honoraria. Friedberg:Bayer: Honoraria. Lossos:Affimed: Research Funding. Martin:Seattle Genetics: Consultancy; Kite: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy. Leonard:Bayer: Consultancy; Celgene: Consultancy; Biotest: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; MEI Pharma: Consultancy; Juno: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Novartis: Consultancy. Bernal-Mizrachi:Kodikaz Therapeutic Solutions: Consultancy, Equity Ownership; Takeda Pharmaceutical Company: Research Funding. Maurer:Morphosys: Research Funding; Nanostring: Research Funding; Celgene: Research Funding. Cerhan:Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding.

Introduction: Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for multiple myeloma (MM). The oral boron-containing selective and reversible proteasome inhibitor ixazomib has shown to induce deep and durable responses (Kumar RK et la, Blood 2016. 128(20):2415-2422). Triplets containing ixazomib, has shown to be more efficacious than doublet regimens in the relapse setting (Moreau P, et al. N Engl J Med 2016. 374:1621-1634).However, to date there is not companion diagnostics capable of predicting PI response. We have recently discovered that MM patients resistant to PI lack of the ankyrin (ANK) and death domain (DD) present in the 3'-end of NFKB2. Loss of NFKB2 3'end frequently resulted from a structural rearrangements. We found that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation. Activation of this caspase resulted from NFKB2 interaction with FADD/caspase-8/p62 (unpublished data). Based on this findings, we design this study to examine the efficacy of NFKB2 break apart FISH to predict the response to the duplet ixazomib and dexamethasone (Id) vs ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients (1-3 lines of therapy). Methods: In this phase 2 biomarker driven open label trial, relapse patients with Results: At the moment of interim analysis, 26 patients have achieved 4 cycles of treatment. All treatment groups (NFKB2 FISH [-] Id, n=16, NFKB2 FISH [+] Id, n=6 and IRd, n=4) received a median of 2 prior lines of therapy. A higher ORR was observed in NFKB2 FISH negative treated with Id compared with NFKB2 FISH positive (56.3% CI:29.9%-80.3% vs. 16.7% CI:0.4%-64.1%, P=0.16), including significantly higher rates of ≥very good partial response, ≥ partial response, ≥ minimal response (12%, 37.5%, 6% vs. 0%, 0%, 16%, respectively). ORR for IRd arm is for now 25% CI:0.6%-80.6%. Patients that continue treatment after cycle 4 that achieve minimal response or better improved their depth of response in 6% in Id treated NFKB2 FISH negative patients and 25% of IRd treated NFKB2 FISH negative patients. The most common (≥10%) grade 2/4 include pneumonia 20% (Id treated NFKB2 FISH negative), thrombocytopenia 16% (Id NFKB2 FISH positive), neutropenia 60% (IRd NFKB2 FISH positive. Treatment discontinuations only occurred in 1 Id treated patient (5%). Conclusion: Interim analysis demonstrate a trend higher efficacy of ixazomib with dexamethasone in MM patients with negative NFKB2 break-apart FISH compared to those with a positive test. Efficacy and toxicity of the triplet regimen are comparable to what is seen in Tourmaline 1 trial. This study was registered at www.clinicaltrials.gov as # NCT02765854. Disclosures Bernal-Mizrachi: Takeda Pharmaceutical Company: Research Funding; Kodikaz Therapeutic Solutions: Consultancy, Equity Ownership. Cole:Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees; University of Michigan: Employment. Heffner:ADC Therapeutics: Research Funding; Kite Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: 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; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kelkar:Empire Genomics: Employment. Lonial:Amgen: Research Funding. Kaufman:Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Roche: Consultancy; BMS: Consultancy; Janssen: Consultancy.

Multiple myeloma (MM) is twice as common in African Americans (AA) compared to European Americans (EA). The reported familial clustering and the elevated MM risk among first-degree relatives of cases implicate genetic susceptibility. Previous genome-wide association studies (GWAS) in EA have identified 16 novel risk loci. In this study, we tested the generalizability of the established risk alleles to AA and conducted a meta-GWAS analysis using two sets of AA to identify additional novel common MM risk variants. In the first study, we genotyped 1,305 incident AA MM cases from the African American Multiple Myeloma Study (AAMMS) using the Illumina HumanCore GWAS array and compared them to 7,078 AA controls from the African Ancestry Prostate Cancer Consortium (AAPC) and African Ancestry Breast Cancer Consortium (AABC) using the Illumina 1M-Duo. In the second study, 95 additional AAMMS cases and 435 AA MM cases from the University of Arkansas for Medical Sciences (UAMS) were genotyped using the Illumina MegaBead Chip and compared to 2,390 AA controls from the Multiethnic Cohort. The Haplotype Reference Consortium (HRC) was used to impute the overlapping typed SNPS from each GWAS case and control set together. Per-allele risk associations were tested for 8,715,278 overlapping genotyped and imputed variants with >1% frequency and >0.8 imputation score using unconditional logistic regression in both sets, and the combined effects were estimated using a fixed-effect meta-analysis. Of the 16 reported risk loci discovered in EA, directional consistency was present for 15 variants; eight of these replicated at nominal significance p Citation Format: Zhaohui Du, Chi Song, Kristin Rand, Niels Weinhold, David Van Den Berg, Amie Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward S. Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William Blot, John David Carpten, Antoinette Stroup, Andrew Olshan, Wei Zhang, African Ancestry Breast & Prostate Consortium, Stephen Chanock, Jayesh Mehta, Graham A. Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Loic LeMarchand, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association studies of multiple myeloma among African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 223.

6596Background: Cancer patients commonly suffer from pain and constipation, and a high number of patients have inadequate control of these symptoms. At the Cancer Center for Excellence at Grady Hea...