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Abstract Background: Pomalidomide is an immunomodulatory agent (IMiD®) that has been approved for treatment of relapsed and refractory multiple myeloma (MM). Combinations of IMiDs and proteasome inhibitors offer the potential for deeper and more durable responses due to enhanced efficacy. Preliminary results of a phase 1 study of twice weekly bortezomib with pomalidomide have been reported with promising results (Richardson, ASH 2012). This phase I/II trial was designed to evaluate the maximum tolerated doses (MTD) as well as safety and efficacy of the combination of pomalidomide, once weekly bortezomib and dexamethasone (PVD) in patients with relapsed, lenalidomide refractory, MM. Patients and methods: We included patients with relapsed MM who had 1-4 prior lines of therapy and were resistant or refractory to lenalidomide. In the phase I portion of the trial, dose level 1 consisted of pomalidomide 4 mg days 1-21 PO, bortezomib 1.0mg/m2 days 1,8,15, and 22 IV or SQ and dexamethasone 40 mg days 1,8,15, and 22 PO, given every 28 days. Bortezomib was increased to 1.3mg/m2 for dose level 2 and and was adopted for the phase 2 portion. The primary aim of the phase I cohort was to determine the MTD of the combination, and for the phase II cohort was to evaluate the confirmed response rate (PR, VGPR, or CR) in relapsed refractory MM. Response was assessed by the IMWG criteria and toxicity was graded using the CTCAE v4.0. Results: 50 patients were accrued between March 2012 and July 2014 (dose level (DL)1: 3, DL 2: 6, Phase II: 41). We describe results in 47 patients treated at MTD and phase II. Median age was 66, 51% were female and median time from diagnosis to study was 46 months (15-142). Twenty five percent had mSMART defined high-risk status. Median number of prior regimens was 3. All patients had prior lenalidomide, 68% had stem cell transplant, 17% received thalidomide, 56% had alkylators and 57% had bortezomib. With median follow up of 9 months, 72% remain progression free, 96% are alive and 66% remain on treatment. The most common AEs at least possibly attributable to the combination were anemia, fatigue, leukopenia and thrombocytopenia; however, the majority of these were grade 1-2. Grade ≥3 AEs (regardless of attribution) that occurred in at least 3 patients included neutropenia (29), leukopenia (15), lung infection (6), lymphopenia (8) dyspnea (3) and syncope (3). DVT/PE occurred in one patient. Among the 42 patients who were evaluable, confirmed responses (PR, VGPR, or CR) were seen in 34 (81%) including sCR (3), CR (5), VGPR (8), PR (18). Confirmed responses were seen in 9 of 11( 82%) high risk patients. Median progression free survival was 17.7 months (95%CI: 9.5-NA). Conclusions: PVD is a highly effective combination in patients refractory to lenalidomide with confirmed responses in over 80%. Weekly administration of bortezomib enhanced the tolerability and convenience of this regimen. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy or DVT. PVD is a highly attractive option in patients with relapsed and refractory MM. Disclosures Lacy: Celgene: Research Funding. Lust:Senesco: PI Other. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Stewart:Celgene: Consultancy; Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.

Abstract Multiple myeloma (MM) is a malignancy of plasma B-cells that is invariably preceded by monoclonal gammopathy of undetermined significance (MGUS), a pre-neoplastic plasma cell proliferative disorder. C57Bl/KaLwRij (KaLwRij) is a spontaneous inbred mouse strain predisposed to benign idiopathic paraproteinemia (BIP), a plasma cell dyscrasia that parallels many features of human pathology including progression to myeloma. In both humans and mice, the genetic basis for MGUS/MM risk is unknown. We sought to identify the genetic basis for MGUS/MM risk in KaLwRij mice to shed light on genes or pathways that mediate disease risk in humans. Using an integrative approach, we combined KaLwRij x B6 haplotype analysis (418 genes) and a MM patient association study (180 genes) to identify five candidate genes likely to contribute to both murine BIP-susceptibility and human MM risk. Surprisingly, we found KaLwRij mice had homozygous germline deletion of one of the five candidate genes, Samsn1, a putative negative regulator of B-cell activation. Consistent with the reported inhibitory function of SAMSN1 in B-cells, KaLwRij mice had enhanced naïve B-cell response in vitro following stimulation with IL4 and LPS and in vivo following immunization. We found that re-expression of Samsn1 in KaLwRij-derived myeloma cell line 5TGM1 decreased MM tumor growth in vitro, suggesting that loss of Samsn1 contributes to tumor growth in part through a cell intrinsic mechanism. Importantly, germline risk alleles may also influence cell types beyond the pre-malignant B-cells. It is established that the host environment also plays a critical role in supporting myeloma growth in KaLwRij mice. We found that Samsn1 is highly expressed in macrophages, but not in other MM-supportive cell types including osteoclasts and bone marrow stromal cells. Myeloma-associated macrophages play critical roles in supporting tumor growth and are broadly classified as anti-tumor M1 macrophages and tumor-promoting M2 macrophages. Microarray analysis of macrophages from B6 and KaLwRij mice prior to onset of BIP revealed three differentially expressed genes, but only one, Samsn1, is conserved in the human genome. We found that both unpolararized primary peritoneal and MCSF cultured bone marrow macrophages from healthy KaLwRij mice had markedly elevated expression of pro-tumorigenic M2 macrophage markers FIZZ1 and YM1 compared to B6 controls, despite the absence of activating cytokines. To confirm that loss of Samsn1 influenced macrophage activation and M2 polarization, we obtained bone marrow macrophages from mice with a targeted deletion of Samsn1 and found that unpolarized Samsn1-/- cells had similarly increased pro-tumor M2 macrophage marker expression. To evaluate the biologic significance of Samsn1 loss in macrophages on MM tumor growth, we established 5TGM1 MM tumors and injected M2 polarized macrophages from B6, KaLwRij, or Samsn1-/- mice. We found that MM tumor burden was markedly enhanced by the addition of a Samsn1-/- or KaLwRij macrophages compared to wild type macrophages. Thus, we found that loss of Samsn1 in macrophages enhances M2 polarization, prior to MGUS/MM development and can promote established myeloma tumor growth. Together, this data suggests that Samsn1 is a gene contributing to BIP-susceptibility in KaLwRij mice through mutually exclusive functions in multiple cell types including B-cells and macrophages. It is likely that SAMSN1 and its pathway members contribute to human MM progression, and may represent a point for preventative therapeutic intervention. Disclosures No relevant conflicts of interest to declare.

Abstract BACKGROUND: While hematologic cancers comprise only 10% of all malignancies, they are divided into >100 distinct World Health Organization subtypes. It is known that higher volume of care is generally associated with better clinical outcomes. However, such a volume-outcome relationship in the medical management of hematologic cancers has not been rigorously explored. The American Society of Clinical Oncology (ASCO) National Census of Oncology Practices shows that the majority of hematologist-oncologists in the United States (US) have a combined hematology-oncology practice (J Oncol Pract 2013). In this study, we estimated the annual number of new and established patients with major hematologic cancers seen on average by a hematologist-oncologist in the US. METHODS: We estimated the number of hematologist-oncologists working in the US using the ASCO workforce information system data from 2011. We utilized statistics from the Surveillance Epidemiology and End Results (SEER) Program to determine the incidence and 37-year limited prevalence of hematologic cancers in 2011. We used 'first malignant tumor per site' statistics as the tumor inclusion method. For potentially curable hematologic cancers (acute lymphocytic leukemia, acute myeloid leukemia, Burkitt lymphoma, diffuse large b-cell lymphoma, Hodgkin lymphoma, and marginal zone lymphoma), we used the estimated 1-5 year survival rates from SEER and excluded patients who survived >5 years, since relapses are rare afterwards. Because prevalence estimates of chronic myelomonocytic leukemia, myelodysplastic syndromes, and certain subtypes of non-Hodgkin lymphoma are unavailable, we were unable to calculate the number of annual established cases. For myeloproliferative neoplasms, we obtained the prevalence estimate from Mehta J, et al (Leuk Lymphoma 2014). We derived the distribution of major non-Hodgkin lymphoma subtypes from the National Cancer Data Base (NCDB) Participant User File. RESULTS: The ASCO workforce information reported a total of 13,084 hematologist-oncologists working in the US in 2011. The Table summarizes the average number of specific hematologic cancer cases seen per hematologist-oncologist in 2011. CONCLUSION: Hematologic cancers are relatively rare but complex. In the US, a hematologist-oncologist on average cares for only 1-2 new patients of any subtype of hematologic cancers annually. The number of established patients is correspondingly low. These numbers are expected to vary by practice setting and disease specialization. As the diagnosis and management of hematologic cancers becomes more sophisticated, future research should explore the potential of a volume to clinical outcome relationship for these providers. Table. Hematologic Cancer Average Annual Number of Cases per Hematologist-Oncologist in the US New Cases Established Cases All Cases Acute lymphocytic leukemia 0.4 1.4 1.8 Acute myeloid leukemia 1 1.5 2.5 Chronic lymphocytic leukemia 1.1 10.7 11.8 Chronic myeloid leukemia 0.4 2.7 3.1 Chronic myelomonocytic leukemia 0.1 - - Hodgkin lymphoma 0.7 2.7 3.4 Multiple myeloma 1.6 6.3 7.9 Myelodysplastic syndromes 1.2 - - Myeloproliferative neoplasms 0.6 22.2 22.8 Non-Hodgkin lymphoma 5.1 - - Anaplastic large cell 0.1 - - Burkitt 0.1 0.3 0.4 Diffuse large B-cell 2 6 8 Follicular 1.1 - - Hairy cell leukemia 0.1 - - Lymphoplasmacytic 0.1 - - Mantle-cell 0.3 - - Marginal zone 0.5 2.1 2.6 Peripheral T-cell, not otherwise specified 0.1 - - Disclosures No relevant conflicts of interest to declare.

Abstract Background: There has been major improvement in the survival of patients diagnosed with multiple myeloma (MM) over the past two decades. Such improvement has been attributed to the broader use of hematopoietic progenitor cell transplantation and novel drugs that prolong initial remission and more successfully treat relapsed disease. Early mortality (EM), here defined as death in the first year after diagnosis, is uncommon in modern MM trials. The magnitude of EM in unselected patients with MM and its impact on overall outcomes in this disease is unknown Methods: We analyzed EM in MM utilizing data from the Surveillance Epidemiology and End Result Program (SEER-13). Patients diagnosed with MM as first malignant neoplasm between 1993 and 2010 (follow up until end of 2011) were included. Cases reported from death certificate or autopsy only were excluded, along with patients recorded as alive but with no survival time (<1% of total). Relative EM rates (1 – relative survival) used data from the US population in 2000 as reference. We described EM for different population groups, changes over time and performed multivariate analysis (binary logistic regression) to assess risk factors for EM in MM. To assess the impact of factors other than reduction in EM in the increased survival of MM, we performed a landmark survival analysis including only those patients who survived at least 1 year after diagnosis. Results: There were 30,324 patients in the analysis, 11,439 diagnosed at age < 65 and 18,885 at age ≥ 65. Absolute EM was 17.6% and 35.3% while relative EMwas 16.9% and 31.7% for the younger and the older groups respectively. There was decline of relative EM rates that occurred in both age groups but only became evident among older patients after 2005 (Figure 1). In multivariate analysis, factors associated with increased risk of EM were male sex, age ≥65 years , diagnosis in 1993-2001, presence of primary plasma cell leukemia, low household income and residence in the coverage area of certain SEER registries (Table 1). Landmark analysis of 1-year survivors demonstrated increased survival from 1993-2001 to 2002-2010 for patients < 65 (median 58 vs. 85 months, P<0.001) and for patients ≥ 65 (median 38 vs. 48 months, P<0.001, Figure 2). Conclusions: Reduction in EM partially explains population improvements in MM overall survival. EM remains high in MM and a major barrier for continued improvement in survival outcomes. Table 1 Factor Reference OR 95% C.I. P Female sex Male 0.90 0.85-0.95 <0.001 Year of diagnosis 1993-2001 2002-2010 1.16 1.10-1.22 <0.001 Plasma Cell Leukemia Multiple Myeloma 5.62 4.17-7.58 <0.001 Age ≥65 years < 65 years 2.56 2.42-2.72 <0.001 Race-ethnicity <0.001 NHB NHW 0.97 0.90-1.04 0.39 Hispanic NHW 1.04 0.95-1.14 0.41 AIAN NHW 0.90 0.63-1.28 0.56 API NHW 0.84 0.75-0.94 0.004 Median household income# 0.91 0.87-0.95 <0.001 SEER registry <0.001 Alaska Los Angeles 1.37 0.62-3.02 0.43 Atlanta Los Angeles 1.003 0.89-1.14 0.96 Connecticut Los Angeles 0.83 0.75-0.93 0.002 Detroit Los Angeles 1.06 0.96-1.16 0.23 Hawaii Los Angeles 1.21 1.01-1.45 0.04 Iowa Los Angeles 0.89 0.80-0.99 0.03 New Mexico Los Angeles 0.88 0.77-1.01 0.07 Rural Georgia Los Angeles 1.10 0.76-1.58 0.63 San Francisco-Oakland Los Angeles 0.99 0.86-1.11 0.87 San Jose-Monterey Los Angeles 1.05 0.87-1.12 0.51 Seattle-Puget Sound Los Angeles 0.91 0.83-1.01 0.08 Utah Los Angeles 1.13 0.98-1.29 0.08 NHB= non-Hispanic Blacks;, NHW= non-Hispanic Whites; AIAN= American Indian, Alaska Natives; API= Asian and Pacific Islanders; #Per US$ 10,000 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

Background Current treatment guidelines strongly recommend statin therapy for secondary prevention. However, it remains unclear whether patients’ perceptions of cardiovascular risk, beliefs on cholesterol, or the intensity of prescribed statin therapy differs for patients with coronary artery disease ( CAD ) versus cerebrovascular disease (Ce VD ) versus both CAD and Ce VD ( CAD &Ce VD ). Methods and Results The PALM (Patient and Provider Assessment of Lipid Management) registry collected data on statin use, intensity, and core laboratory low‐density lipoprotein cholesterol levels for 3232 secondary prevention patients treated at 133 US clinics. Among individuals with Ce VD only (n=403), CAD only (n=2202), and Ce VD & CAD (n=627), no significant differences were observed in patient‐perceived cardiovascular disease risk, beliefs on cholesterol lowering, or perceived effectiveness and safety of statin therapy. However, patients with Ce VD only were less likely to receive any statin therapy (76.2% versus 86.2%; adjusted odds ratio 0.64, 95% CI 0.45–0.91), or guideline‐recommended statin intensity (34.6% versus 50.4%; adjusted odds ratio 0.60, 95% CI 0.45–0.81) than those with CAD only. Individuals with Ce VD only were also less likely to achieve low‐density lipoprotein cholesterol <100 mg/ dL (59.2% versus 69.7%; adjusted odds ratio 0.79, 95% CI 0.64–0.99) than individuals with CAD alone. There were no significant differences in the use of any statin therapy or guideline‐recommended statin intensity between individuals with CAD &Ce VD and those with CAD only. Conclusions Despite lack of significant differences in patient‐perceived cardiovascular risk or statin beliefs, patients with Ce VD were significantly less likely to receive higher intensity statin or achieve low‐density lipoprotein cholesterol <100 mg/ dL than those with CAD only.