African American Multiple Myeloma Research Articles

Exploring the Link Between High-Risk Cytogenetics and Skeletal Lytic Lesions in African American (AA) Multiple Myeloma (MM) Patients: Insights From a Decade-Long Study

Exploring the Link Between High-Risk Cytogenetics and Skeletal Lytic Lesions in African American (AA) Multiple Myeloma (MM) Patients: Insights From a Decade-Long Study

CT-448 Academic Center Outreach to Community Practices Increases Transplant Referrals and Possibly Reduces Racial Disparities

Racial disparities are evident in transplant utilization rates. Outcomes improve for multiple myeloma (MM) with an autologous stem cell transplant (autoSCT) but despite the guidelines, African Americans (AA) receive fewer autoSCT when compared to whites (W). Multiple single-institution studies have confirmed that rates of autoSCT for MM in AA are similar to W when patients are referred for evaluation. Lower referral to a transplant center may contribute to these disparities. Emphasis on physician communication to facilitate an improved referral network represents an intervention to overcome this disparity. We reviewed our center data to assess the impact of outreach on transplant referrals and impact on race. We reviewed transplants (both autoSCT and alloSCT) performed at Augusta University between fiscal years 2015 to 2021. Patients were divided into two cohorts (cohort A: FY2014-17 and cohort B: FY2019-21) based on initiation of physician outreach by our program. FY2018 was used in our analysis for a year of outreach which included visiting practices within catchment area. In addition, two outreach clinics were established in collaboration with large community practice sites. Statistics are descriptive. 389 transplants analyzed included patients age >18 years with 52% males and 45% age ≥ 61 years. Cohort B had a significant increase with 266 vs 123 in cohort A, a 116% increase. There was increased median distance travelled to our center from 15.2 to 52.3 miles. Considering 15 miles as our urban area, >60% of transplants in cohort B were from outside our area. The increase in median distance travelled was found in both autoSCT and alloSCT (15.2 vs 40.3 and 15.2 vs 79.3, respectively). More significantly, cohort B had a 147% increase in AA compared to 96% in W. The distance travelled to our center was higher for W but also increased for AA at 15.4 vs 69.3 and 15.2 vs 34.8 miles, respectively. Of note, review of regional transplant center data suggests the increased volume at our center is not related to redistribution between programs across GA and SC. Our model confirms that academic outreach increases transplant referrals. The increase includes patients of minority thus may be an effective model to reduce healthcare disparities.

A Meta-Analysis of Genome-Wide Association Studies of Multiple Myeloma in Persons of African Ancestry [African-American Multiple Myeloma Study (AAMMS)] Identifies Suggestive Risk Variants

Background: Multiple myeloma (MM) is 2-3 times more common among persons of African ancestry (AA) compared to those of European ancestry (EA). The 2-3-fold increased risk among family members of cases suggests a genetic contribution to risk. Genome-wide association studies (GWAS) in EA populations have identified 16 novel risk loci. We previously showed that 5 of these replicated in populations of AA (Rand et al., CEBP, 2016). In order to increase the power to identify additional novel common genetic risk variants, we conducted a GWAS meta-analysis using two sets of AA MM patients recruited into the African American Multiple Myeloma Study (AAMMS) and the University of Arkansas for Medical Sciences (UAMS)) Myeloma Institute.Methods: The first GWAS included 1,305 incident AA MM cases enrolled in AAMMS, recruited from 10 clinical centers and population-based cancer registries in the NCI SEER Program from 2011 to 2013 and genotyped using the Illumina HumanCore GWAS array. Control data were obtained from 4425 male controls from the African Ancestry Prostate Cancer Consortium (consisting of 14 independent studies) and 2632 female controls from a breast cancer GWAS of African-American women (consisting of 9 independent studies) and genotyped using the Illumina 1M-Duo. The second GWAS included 95 additional AAMMS patients and 435 AA MM patients enrolled from UAMS, genotyped using the Illumina MegaBead Chip and compared to 2,390 AA controls from the Multiethnic Cohort. Both GWAS were imputed with the CAAPA Haplotype Reference panel on the University of Michigan Imputation Server http://www.caapa-project.org/. Single nucleotide polymorphisms (SNPs) with a minor allele frequency of less than 0.01 and an imputation score of less than 0.8 were excluded. Associations between SNPs and MM risk in each GWAS were calculated using unconditional logistic regression adjusted for sex, age at diagnosis (cases) or cohort sample collection (controls), and the first 10 genetic ancestry principal components. A meta-analysis of the two GWAS was conducted using a fixed effects model.Results: There were 8,715,278 overlapping SNPs in the meta-analysis with a lambda (inflation) = 1.066. Seven loci were associated with MM risk at p<10-6, but none reached genome-wide significance. We found several novel SNPs at the previously reported locus 6p21.33, with odds ratios (ORs) ranging from 1.20-1.28 and p-values ranging from 3.72-8.46 x 10-7 (Figure 1). We also identified six additional suggestive novel loci at chr4q32.1, chr9p24.3, chr12q12, chr12p13.3, chr16p12.2, chr18q12.1 with ORs ranging from 1.27-2.13 and p-values from 1.2x10-7-9.39x10-7.Of the 16 known risk loci in EA MM patients, eight replicated at p<0.05 in the AA MM GWAS meta-analysis. We previously reported better localized signals in AA patients for 7 of these known risk SNPs; five of these replicated at p< 0.05 in this meta-analysis. The highest p-value for the previously identified EA or AA SNPs was 1.90 x10-5.Conclusions: We have found suggestive loci associated with MM risk in AA's that appear distinct from risk loci identified in EA's, that may explain some of the disparity for MM risk in these two populations. Further follow-up with replication is warranted.Figure 1. A Manhattan plot showing results of a fixed effects meta-analysis of two genome wide association scans based on a total of 1,835 multiple myeloma patients and 9,468 controls of African ancestry, with genome-wide significance of p= 5x10-8 (red line). Y-axis= -Log10 of the p-value; X-axis= chromosomes; green dots= previously reported risk loci, excluding those with imputation scores<0.8 and a minor allele frequency of <1%. [Display omitted] DisclosuresAilawadhi:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Research Funding. Nooka:Amgen, Novartis, Spectrum, Adaptive: Consultancy. Anderson:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; MedImmune: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Other: scientific founder; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopep: Other: scientific founder. Vij:Amgen: Honoraria, Research Funding; Jazz: Honoraria; Konypharma: Honoraria; Bristol-Meyers-Squibb: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Research Funding. Zonder:Prothena: Consultancy; Pharmacyclics: Other: Data Safety Monitoring Committee; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Orlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees.

African American Patients With Multiple Myeloma: Optimizing Care to Decrease Racial Disparities.

The incidence of multiple myeloma in African Americans is two to three times higher than in other ethnicities and is the leading hematologic malignancy in African Americans. Despite the high incidence of multiple myeloma in African American individuals, a vast majority experience delays in diagnosis and reduced usage of effective therapies, including stem cell transplantation, as well as low participation in clinical trials. Racial disparities, social and financial health disparities, and barriers to earlier access to care can lead to poorer patient outcomes. There are also unique characteristics in the disease manifestation in African Americans with multiple myeloma that are imperative for oncology nurses to understand and recognize to provide optimal care.

Variability in Cytogenetic Testing for Multiple Myeloma: A Comprehensive Analysis From Across the United States.

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. 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. 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%). 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.

Comprehensive Investigation of White Blood Cell and Gene Expression Profiles As Risk Factors for Multiple Myeloma in African Americans

Comprehensive Investigation of White Blood Cell and Gene Expression Profiles As Risk Factors for Multiple Myeloma in African Americans

Abstract 223: A meta-analysis of genome-wide association studies of multiple myeloma among African Americans

Abstract 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 &amp;gt;1% frequency and &amp;gt;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&amp;lt;0.05, with the most statistically significant variant being rs4487645 at 7p15.3 (OR=1.38, p=3.56×10-6). AA individuals with polygenic risk scores from these 16 variants (PRS) in the top 10% stratum had a 1.44-fold increased MM risk compared to those with a PRS in the 25th -75th percentiles. Additionally, we identified three suggestive novel loci located at 12q12, 9p24.3 and 9p13.1 at p&amp;lt;1×10-6, with ORs ranging from 1.25-1.55, but none reached genome-wide significance. The variant at 9p24.3 is located in an intron in the KANK1 gene and a correlated SNP in EAs (r2=0.5) is strongly associated with gene expression in neoplastic plasma cells (unpublished, Weinhold and Morgan). Our study replicated most of the reported risk loci discovered among EA, demonstrated that a PRS constructed using the 16 reported risk alleles was associated with MM risk, and provides suggestive evidence for additional loci associated with MM risk in AAs. 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 &amp; 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.

163 - Improved Survival in African American Patients Undergoing Autologous Transplant for Multiple Myeloma in the Chemotherapy and Novel Agent Era

African Americans (AA) have a 2- to 3-fold higher incidence of multiple myeloma (MM) when compared to other racial groups. Evidence suggests that there may be differences in the biology of MM, which confer a more favorable prognosis in AA patients. Prior studies are conflicted as to whether AA patients achieve equal or improved outcomes compared to non-African American (non-AA) patients. Our purpose was to evaluate the impact of AA race on outcomes of MM patients undergoing ASCT at a single center in both the chemotherapy and novel agent era. One hundred and twenty-nine patients who received melphalan 200 mg/m2 and ASCT between 2000 and 2013 were included in the analysis. Sixty-one (47%) patients were African-American and 68 (53%) were non-AA. Baseline characteristics including age, FISH, cytogenetics, paraprotein subtype, median number of prior therapies and International Staging System (ISS) stage were similar between racial groups. Overall, 77 (60%) patients received any novel agent prior to transplant and 52 (40%) received only chemotherapy. More non-AA patients were male (59% vs. 38%, p=0.02), received initial induction with a proteasome inhibitor (59% vs. 28%, p=0.0007), and were treated with post-ASCT maintenance therapy (41% vs. 23%, p=0.008). Time from diagnosis to ASCT in AA patients was 10 (range: 4-144) versus 8 (range: 3-54) months in non-AA patients (p=0.01). The ASCT hospital course was similar between both groups with no significant differences in time to neutrophil and platelet engraftment as well as the duration of hospitalization. Additionally, there was no significant difference in the extra-hematologic toxicity between the two groups including the incidence of diarrhea, mucositis, and infection. Response was measured using the International Myeloma Working Group criteria and was assessed immediately prior to transplant and between 90 to 180 days after transplant. No differences were observed in pre-transplant (p=0.13) or post-transplant (p=0.28) response rates between the two groups. African American patients had a significantly improved median OS compared to non-AA patients (not reached vs. 108 months, p=0.03). We further stratified analyses of OS by those treated in the chemotherapy versus novel agent era. Improved OS was observed in both the chemotherapy (93 vs. 68 months, p=0.02) and novel agent (not reached vs. 79 months, p=0.01) treatment era. In a multivariate Cox proportional hazards model, AA race was associated with improved overall survival (adjusted HR 0.30, 95% CI 0.11 to 0.81; p=0.017). Multiple myeloma has one of the most apparent ethnic disparities in incidence and outcomes among cancers. In our study, AA patients had a longer time to transplant and received less proteasome inhibitor-based induction and post-ASCT maintenance suggesting disparities in access to care. Despite these differences in treatment, we observed improved overall survival after ASCT compared to non-AA patients. We demonstrated this improved OS in patients who had received either chemotherapy or novel agents prior to ASCT. These findings provide further evidence for more favorable outcomes among AA patients. One explanation could be a difference in disease biology that may result in a lower risk disease. Investigation of these biologic differences between AA and non-AA MM patients may increase our understanding of the pathogenesis and future treatments of myeloma. Disclosures No relevant conflicts of interest to declare.

Fluorescence in Situ Hybridization (FISH) abnormalities and Baseline Clinical Features at Diagnosis in African American Multiple Myeloma Patients

BACKGROUND: Multiple myeloma (MM) is the most common hematologic malignancy in the African American (AA) population with an incidence more than 2-3 times higher than Caucasians [Landgren O et al Blood 2006]. In the pre-novel therapy era, SEER data [1975-2008] indicated better survival outcomes for AA patients with MM. However, with the recent advent of novel drugs for treatment of MM, the survival gap for Caucasian patients with MM has closed [Ailawadhi S et al Br J Haematol 2012]. A recent pooled analysis of diagnostic cytogenetics in 292 AA MM patients [Greenberg et al Blood Cancer J 2015] reported on differences in commonly observed baseline cytogenetic abnormalities (CA) between AA and Caucasian MM patients. The large and diverse population of patients with MM at our institution prompted us to examine diagnostic cytogenetics in our MM patients along with other clinical features.PATIENTS & METHODS: The MM database was interrogated for all patients presenting with MM between January 2012 and February 2016. Baseline clinical and pathology variables were compared between the AA and Caucasian cohorts. Continuous variables were compared using nonparametric rank tests, while incidences and proportions (e.g. CAs including t(11;14), t(4;14), t(14;16), t(14:20), amplification 1q21, monosomy13/del13q and del17p) were compared using Fisher’s exact tests.RESULTS: A total of 398 patients were identified for the analysis (African Americans n = 168, Caucasian n = 230). The median age of AA MM patients was significantly younger than Caucasian MM patients (median age 63 years vs. 68 years, p<0.0001), with a similar sex distribution. There was no significant difference in the degree of anemia, renal insufficiency, serum LDH levels, bone marrow flow cytometry, bone marrow cellularity or plasmacytosis in the two cohorts. Although there was a trend toward more ISS I amongst Caucasian MM patients, there was no statistical difference in ISS stages (p = 0.126) and no significant difference in R-ISS stage between the cohorts (p = 0.361). There was 72.7% agreement between the ISS and R-ISS staging (88 of 121 evaluable subjects had the same stage by ISS and R-ISS staging criteria), while 27.3% of the patients were upstaged from Stage I or II by ISS criteria to Stage III by R-ISS criteria. Of those upstaged, 19 patients were in the Caucasian cohort and 14 were in the AA cohort. The magnitude of this upstaging was significant when evaluated with a Generalized McNemar’s test (p < 0.001). Additionally, there was a similar incidence of common FISH abnormalities in the AA cohort compared to the Caucasian cohort [Table 1].CONCLUSIONS: This is the largest single institution report of FISH data in AA MM patients. Unlike previous reports, we show similar clinical, pathological, and cytogenetic features between AA and Caucasian patients with MM at presentation. It is possible that molecular abnormalities not detectable by FISH in our patient cohort could account for differences in our data and the published literature. [Display omitted] DisclosuresBhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Symanowski:Eli Lilly & Co: Consultancy; Ra Pharma: Consultancy; Caris Life Sciences: Consultancy; Endocyte: Consultancy. Avalos:Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees. Usmani:Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Skyline: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Pharmacyclics: Research Funding; BioPharma: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Novartis: Speakers Bureau.

Outcomes in Transplant Eligible Multiple Myeloma African American Patients Appear Similar to Caucasian Patients

Background: SEER Data from 1975-2008 show a stark disparity in the incidence of multiple myeloma (MM) in African Americans (AA) compared to Caucasians, with a 2-3 times higher incidence in AA. Differences in the incidence appear to be genetically driven, but remain poorly understood. Although AA patients appear to have a lower incidence of high risk cytogenetics [Greenberg G et al, Blood Cancer J 2015], their outcomes have not improved in the novel era therapy compared to Caucasian patients [Ailawahdi S et al, Blood Cancer J 2016]. Access to specialized disease-specific care (including access to a transplant center) due to socioeconomic status and lack of social support have been proposed as impediments to optimal care for AA MM patients. We prospectively examined newly diagnosed transplant eligible AA and Caucasian patients with MM at our institution to assess their transplant outcomes.Methods: The MM database was interrogated from March 2014-December 2015 for all autologous stem cell transplant (ASCT) eligible patients with MM. Clinical features, induction regimens, treatment responses and ASCT outcomes were compared between AA and Caucasian patients. Continuous variables were compared using nonparametric rank tests, while incidences and proportions were compared using Fisher's exact tests.Results: A total of 73 consecutive ASCT eligible MM patients were identified (32 AA, 41 Caucasian). There was no significant difference in sex distribution between the cohorts (p > 0.999). However, AA patients were significantly younger at the time of diagnosis with a median age of 56 years compared to a median age of 61 years in the Caucasian cohort (p = 0.008). Except for lower hemoglobin levels among AA patients, there were no statistically significant differences in any other clinical variable at diagnosis (lab features, serum LDH levels, ISS staging, IMWG risk stratification, cytogenetics, etc.) between the patient cohorts. Analysis of pre- and post- ASCT data showed similar response rates to induction therapy and outcomes with no statistically significant differences observed in pre-ASCT and post-ASCT depth of response (assessed by IMWG criteria) or 1-year progression free survival between the two cohorts.Conclusions: At our institution, AA patients with MM presented at a younger age than Caucasians. However, no significant differences in disease features were observed between the two groups at the time of initial presentation. A much higher proportion of AA MM patients (44%) underwent ASCT at our institution compared to other academic centers. Although longer follow-up is required, our data suggest that when AA patients with MM are provided similar access to care as Caucasian patients with MM, similar response rates to induction therapy and ASCT can be achieved. DisclosuresBhutani:Prothena: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda Oncology: Research Funding, Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Symanowski:Caris Life Sciences: Consultancy; Ra Pharma: Consultancy; Eli Lilly & Co: Consultancy; Endocyte: Consultancy. Avalos:Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees. Usmani:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Skyline: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; BioPharma: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Novartis: Speakers Bureau.

HLA Haplotypes Are Associated with Multiple Myeloma Risk in the African American Multiple Myeloma Study (AAMMS)

Background: Persons of African ancestry (AA) have a 2-3-fold higher risk of multiple myeloma (MM) than persons of European ancestry (EA). Like other B-cell malignancies, genome-wide association scans (GWAS) have identified MM risk variants in the HLA region in persons of EA. We conducted a case-control analysis with data from the National Marrow Donor Program (NMDP)1comprising MM patients typed for bone marrow transplant to donor controls matched by race-ethnicity, and found associations between specific HLA alleles/haplotypes and MM risk that varied by race and ethnicity. To confirm our results and identify additional novel signals, we have now investigated associations between HLA alleles and haplotypes and MM risk in the African American Multiple Myeloma Study (AAMMS) Cohort. Methods: The source of subjects was the AAMMS, in which AA MM patients were identified from 10 cancer centers and 4 Surveillance, Epidemiology and End-Results (SEER) Program cancer registries in order to identify genetic risk factors for MM among AAs. A GWAS was conducted using the Illumina Human Core BeadChip array on DNA samples from 1,305 AA MM patients in the AAMMS comparing results to those from 7,078 AA controls with GWAS data generated from the Illumina 1MDuo2. The major histocompatibility complex (MHC) region single nucleotide polymorphisms (SNPs) were imputed to classical HLA variants using HIBAG. Unconditional logistic regression was used to estimate HLA associations, adjusting for sex, age and the first 2 principal components. P-values were adjusted for false discovery rate (FDR) for each locus group. Results: We did not identify any single HLA alleles associated with MM risk among AAs. However, several B*07:02-containing haplotypes were associated with MM risk (odds ratios [OR] ranging from 2.38 to 2.64 and FDR P-values ranging from 1.43 x 10-6 to 3.57 x 10-8). We found associations between MM risk and genotypes containing DRB3*02:02, including DRB3*02:02~DRB1*11:01+ DRB3*02:02~DRB1*11:01 (OR=1.93, PFDR= 9.36 x 10-5) similar to those observed in the NMDP study1. Novel findings included associations between MM risk and HLA Class I haplotypes B*53:01+ B*57:01 (OR=1.94, PFDR= 0.003) and C04:01~B*53:01+C*06:02~B*57:01 (OR=1.96, PFDR= 0.0050). Results from an ongoing meta-analysis between the two data sets (one based on an imputed GWAS and one based on NMDP HLA typing) will be presented.Conclusions: This study is the second to examine HLA alleles and risk of MM among AA's and is by far the largest. We confirmed a previously observed association between an HLA Class II DRB3 variant and MM risk and confirmed an association with B*07 haplotypes previously observed among EAs1. We also identified novel associations between other HLA Class I haplotypes and MM risk in AA's. Because HLA is highly polymorphic, many HLA alleles are rare variants for which genetic associations are difficult to detect without very large sample sizes. Further investigation with large sample sizes will be necessary to refine these associations in order to better identify the underlying causal alleles and determine the functional significance of these HLA associations. 1Beksac M, Gragert L, Fingerson S, et al.: HLA polymorphism and risk of multiple myeloma.Leukemia. 2016 Jul 27. doi: 10.1038/leu.2016.199.2Rand KA, Song C, Hwang AE, et al. Genetic susceptibility markers of multiple myeloma in African-Americans. Abstract # 2030, 56th Annual American Society of Hematology Meeting, San Francisco, California, 2014. DisclosuresAilawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Nooka:Spectrum, Novartis, Onyx pharmaceuticals: Consultancy. Zonder:Pharmacyclics: Other: DSMC membership; Prothena: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Lonial:BMS: Consultancy; Novartis: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Onyx: Consultancy.

Improved Survival in African American Patients Undergoing Autologous Transplant for Multiple Myeloma in the Chemotherapy and Novel Agent Era

African Americans (AA) have a 2- to 3-fold higher incidence of multiple myeloma (MM) when compared to other racial groups. Evidence suggests that there may be differences in the biology of MM, which confer a more favorable prognosis in AA patients. Prior studies are conflicted as to whether AA patients achieve equal or improved outcomes compared to non-African American (non-AA) patients. Our purpose was to evaluate the impact of AA race on outcomes of MM patients undergoing ASCT at a single center in both the chemotherapy and novel agent era.One hundred and twenty-nine patients who received melphalan 200 mg/m2 and ASCT between 2000 and 2013 were included in the analysis. Sixty-one (47%) patients were African-American and 68 (53%) were non-AA. Baseline characteristics including age, FISH, cytogenetics, paraprotein subtype, median number of prior therapies and International Staging System (ISS) stage were similar between racial groups. Overall, 77 (60%) patients received any novel agent prior to transplant and 52 (40%) received only chemotherapy. More non-AA patients were male (59% vs. 38%, p=0.02), received initial induction with a proteasome inhibitor (59% vs. 28%, p=0.0007), and were treated with post-ASCT maintenance therapy (41% vs. 23%, p=0.008). Time from diagnosis to ASCT in AA patients was 10 (range: 4-144) versus 8 (range: 3-54) months in non-AA patients (p=0.01). The ASCT hospital course was similar between both groups with no significant differences in time to neutrophil and platelet engraftment as well as the duration of hospitalization. Additionally, there was no significant difference in the extra-hematologic toxicity between the two groups including the incidence of diarrhea, mucositis, and infection.Response was measured using the International Myeloma Working Group criteria and was assessed immediately prior to transplant and between 90 to 180 days after transplant. No differences were observed in pre-transplant (p=0.13) or post-transplant (p=0.28) response rates between the two groups. African American patients had a significantly improved median OS compared to non-AA patients (not reached vs. 108 months, p=0.03). We further stratified analyses of OS by those treated in the chemotherapy versus novel agent era. Improved OS was observed in both the chemotherapy (93 vs. 68 months, p=0.02) and novel agent (not reached vs. 79 months, p=0.01) treatment era. In a multivariate Cox proportional hazards model, AA race was associated with improved overall survival (adjusted HR 0.30, 95% CI 0.11 to 0.81; p=0.017).Multiple myeloma has one of the most apparent ethnic disparities in incidence and outcomes among cancers. In our study, AA patients had a longer time to transplant and received less proteasome inhibitor-based induction and post-ASCT maintenance suggesting disparities in access to care. Despite these differences in treatment, we observed improved overall survival after ASCT compared to non-AA patients. We demonstrated this improved OS in patients who had received either chemotherapy or novel agents prior to ASCT. These findings provide further evidence for more favorable outcomes among AA patients. One explanation could be a difference in disease biology that may result in a lower risk disease. Investigation of these biologic differences between AA and non-AA MM patients may increase our understanding of the pathogenesis and future treatments of myeloma. DisclosuresNo relevant conflicts of interest to declare.

Abstract B41: Distribution of cytogenetic abnormalities in African American multiple myeloma patients may be unique for different geographic regions

Abstract Background: Multiple myeloma (MM) is the most common hematologic malignancy in the African American population, with an incidence more than 2 times higher than Caucasian population [Landgren O et al Blood 2006]. Historically, the African American MM patients have had better outcomes compared with other races [Ailawadhi S et al Br J Haematol 2012], but no biologic explanations exist for this observation. Greenberg et al [Blood Cancer J 2015] have recently reported on differences in commonly observed baseline cytogenetic abnormalities (CA) between African American and Caucasian MM patients seen at Mayo Clinic (Rochester, MN), Cook County Hospital (Chicago, IL) and University of Maryland (Baltimore, MD). We examined the MM cohort at our referral center to validate these observations. Patients and Methods: The Levine Cancer Institute MM database was interrogated for all patients presenting with MM between January 2012 and April 2015. Baseline clinical and pathology variables were compared between the African American and Caucasian cohorts. Continuous variables were compared using nonparametric rank tests, while incidences and proportions (e.g. CAs including t(11;14), t(4;14), monosomy13/del13q and del17p) were compared using Fisher's exact tests. Results: A total of 662 patients were identified; excluding those with MGUS classification, 368 patients were included in the analysis (African Americans n = 130, Caucasian n = 238). The median age of African American MM patients was significantly younger than Caucasian MM patients (median age 60 years vs. 65 years, p=0.010), with similar gender distribution. There was a numerically larger proportion of African American patients with anemia (40.8% vs 30.8%, p =0.166), however, there was no significant difference in degree of BM plasmacytosis amongst the two groups. The overall distribution of MM patients by IMWG risk stratification (Chng et al, Leukemia 2013) was also similar between the two groups. The African American MM patients had a numerically higher incidence of a metaphase abnormality on conventional cytogenetics (21.7% vs. 13.9%, p =0.154). They had a significantly lower incidence of t(11;14) [7.7% vs. 16%, p=0.024], a numerically higher incidence of t(4;14) [6.2% vs. 3.8%, p=0.309], and similar incidence of deletion 13/del13q [22.3% vs. 18.9%, p=NS] and del17p [7.7% vs. 7.6%, p=NS]. Conclusions: The present dataset is the largest single institution report on CA racial differences in MM patients. We observed that unlike previous reports of lower incidence of t(4;14) or del17 p in African American MM patients by Greenberg et al, we have observed a higher incidence of t(4;14) and similar incidence of del17p in our experience compared to Caucasian MM patients. The different pattern of CA distribution compared to published literature may represent geographic heterogeneity and potentially influence survival outcomes. Citation Format: Preeya Patel, Manisha Bhutani, Kyle Madden, Myra R. Robinson, Rupali Bose, James Symanowski, Saad Z. Usmani. Distribution of cytogenetic abnormalities in African American multiple myeloma patients may be unique for different geographic regions. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B41.

Abstract IA07: Outcome disparities in multiple myeloma: The role of race/ethnicity

Abstract Approximately 27,000 new cases of multiple myeloma (MM) will be diagnosed and more than 11,000 deaths will occur from it in 2015. Overall, 5-year relative survival rates have improved from 26.5% in 1975 to 44.9% in 2010, and this has been attributed to the introduction of novel therapeutic agents, widespread utilization of autologous stem cell transplant (ASCT), and improvement in supportive care modalities. However, studies evaluating the role of race/ethnicity in MM have shown marked disparities in incidence and outcomes of MM among patients of different racial subgroups. Traditionally, it has been known that African-Americans (AA) have a higher incidence of MM than Whites and that it occurs in AA at a younger age. Despite this difference in incidence, AA patients are known to have a better overall survival (OS) than Whites. Recent population-based outcomes analyses of MM patients beyond just Whites and AA has shown that Asians have the best median OS, while Hispanics have the worst, in a population that is more representative of the current US racial/ethnic mix. Additionally, the cumulative survival benefit over time as per a recent report was most pronounced among Whites (1.3 years) and least among Asians (0.5 years), suggesting a possible differential access as well as utilization of therapeutic modalities. Thus, despite overall improvement in MM outcomes over years, racial disparities exist. While majority of the data so far has reported the existence of these outcome disparities, a few reports have explored the potential causes of these differences. With regards to disease biology, there is some data suggesting that MM patients belonging to different races may have variability in the incidence of high-risk mutations, with AA MM patients having a lower incidence of such mutations, supporting the better OS seen in AA patients as compared to Whites. Another suggestion supporting differences in an interaction between biologic and environmental factors in MM patients is the variability in incidence of second primary malignancies in patients after they have developed MM, which may affect their outcome and OS. Other causes of outcome disparities may include a differential access to certain treatment options, especially more complex ones like stem cell transplants, as well as certain novel therapeutic agents that may depend on the patient's insurance payer status, which brings up differences in socioeconomic status, education level and barriers in accessing healthcare. It has also been reported recently that access to comprehensive cancer centers has benefitted Whites more than racial minorities. While access issues are being reported for MM patients belonging to different races, it has been suggested that outcome disparities by race are not noted in equal access healthcare systems. The potential shortcomings for these studies in equal access healthcare systems though, have been small size, mostly single-institution and focusing primarily on Whites and AA, without much representation yet of Hispanics and Asians, despite these two racial subgroups being the fastest growing ones in the US. Outcome disparities in MM by patient race have been established. The factors affecting these outcome disparities may be complex and interrelated, making it difficult to identify specific factors that may be modifiable. Yet, it is important to explore outcome disparities and their potential causes, especially in large cohorts prospectively, so that healthcare resources may be utilized efficiently and furthermore, the disadvantaged population subgroups may be benefitted by targeted interventions. Citation Format: Sikander Ailawadhi. Outcome disparities in multiple myeloma: The role of race/ethnicity. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA07.

In-Depth Molecular Profiling of Multiple Myeloma in African Americans

Introduction: Multiple Myeloma (MM) is a complex malignancy of plasma cells well-described hyperdyploidy, and immunoglobulin gene rearrangements. To promote rapid advances in the field, Multiple Myeloma Research Foundation (MMRF) initiative is an intensive and comprehensive longitudinal study (CoMMpass) designed to create a rich discovery ecosystem to through in-depth clinical and molecular profiling to understand the molecular perturbations of the disease in the context of therapy. The large study population empowered us to stratify mutational landscapes among different ethnicities to influence on broader disparities in tumor dynamics.Methods: Clinical data, tumor/normal sample collection, and mutational landscape analysis described in this abstract are derived from MMRF CoMMpass IA7 release that is composed of self-identified 93 African American (AA) and 377 European American (EA). The post-processing and primary analysis was done on baseline samples only. Whole exome sequencing was analyzed for the detection of somatic events. Secondary analysis was performed using MutSigCV (Mutation Significance) algorithm and GISTIC (The Genomic Identification of Significant Targets in Cancer) to determine the significance of coding mutations and copy number events.Results: Our preliminary comparison analysis of CoMMpass IA7 data demonstrated that overall there was no statistical difference (p=0.5973) in nonsilent mutation burden between the two stratified groups, AA (μ=63.9 mutations/patient) vs EA (μ=73.7 mutations/patient). However, we have observed several notable differences. The most notable population difference (p<0.0001) was TP53 mutation occurrence, which was more common in EA 5.6% (21/377) compared AA 2.1% (2/93).Furthermore, MutSig analysis also revealed a novel candidate PTCHD3 (p = 7.07E-06, q = 3.33E-02) with 6% occurrence in AA compared to only 0.04% in EA. Furthermore, we looked at mutation occurrence difference of at least 5 fold between the two stratified populations. We have identified several additional genes that have higher mutation frequencies in tumors from AA patients including: ANKRD26, BCL7A, BRWD3. Interestingly, majority is implicated in epigenetic regulatory mechanisms.Moreover, despite the complex karyotype in MM translocations, our analysis demonstrated a lower frequency of 14q32 translocations in tumors from AA patients (10%) compared to tumors from EA patients (37%). These data would independently validate our previously reported differences in 14q32 breakpoints between these two populations.Conclusion: Data from this comprehensive diverse multi-institutional longitudinal study has afforded us the opportunity to study population differences among MM patients in an unprecedented way. Taking advantage of high quality, high-resolution whole exome and whole-genome data has allowed us to identify potential differences in the genomic and molecular landscape of MM from AA and EA patients. These data may help us further understand the incidence and outcomes among patients from these populations. As CoMMpass continues to mature these datasets will be retested that may result in some of these preliminary reported events to either level off, or increase in power. DisclosuresMulligan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lonial:Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Keats:Translational Genomic Research Institute: Employment.

Distribution of Cytogenetic Abnormalities in African American Multiple Myeloma Patients May be Unique for Different Geographic Regions

BACKGROUND: Multiple myeloma (MM) is the most common hematologic malignancy in the African American population, with an incidence more than 2 times higher than Caucasian population [Landgren O et al Blood 2006]. Historically, the African American MM patients have had better outcomes compared with other races [Ailawadhi S et al Br J Haematol 2012], but no biologic explanations exist for this observation. Greenberg et al [Blood Cancer J 2015] have recently reported on differences in commonly observed baseline cytogenetic abnormalities (CA) between African American and Caucasian MM patients seen at Mayo Clinic (Rochester, MN), Cook County Hospital (Chicago, IL) and University of Maryland (Baltimore, MD). We examined the MM cohort at our referral center to validate these observations.PATIENTS & METHODS: The Levine Cancer Institute MM database was interrogated for all patients presenting with MM between January 2012 and April 2015. Baseline clinical and pathology variables were compared between the African American and Caucasian cohorts. Continuous variables were compared using nonparametric rank tests, while incidences and proportions (e.g. CAs including t(11;14), t(4;14), monosomy13/del13q and del17p) were compared using Fisher's exact tests.RESULTS: A total of 662 patients were identified; excluding those with MGUS classification, 368 patients were included in the analysis (African Americans n = 130, Caucasian n = 238). The median age of African American MM patients was significantly younger than Caucasian MM patients (median age 60 years vs. 65 years, p=0.010), with similar gender distribution. There was a numerically larger proportion of African American patients with anemia (40.8% vs 30.8%, p =0.166), however, there was no significant difference in degree of BM plasmacytosis amongst the two groups. The overall distribution of MM patients by IMWG risk stratification (Chng et al, Leukemia 2013) was also similar between the two groups. The African American MM patients had a numerically higher incidence of a metaphase abnormality on conventional cytogenetics (21.7% vs. 13.9%, p =0.154). They had a significantly lower incidence of t(11;14) [7.7% vs. 16%, p=0.024], a numerically higher incidence of t(4;14) [6.2% vs. 3.8%, p=0.309], and similar incidence of deletion 13/del13q [22.3% vs. 18.9%, p=NS ] and del17p [7.7% vs. 7.6%, p=NS ].CONCLUSIONS: The present dataset is the largest single institution report on CA racial differences in MM patients. We found that unlike previous reports of lower incidence of t(4;14) or del17 p in African American MM patients by Greenberg et al, we have observed a higher incidence of t(4;14) and similar incidence of del17p in our experience compared to Caucasian MM patients. The different pattern of CA distribution compared to published literature may represent geographic heterogeneity and potentially influence survival outcomes. DisclosuresCogdill:Celgene: Speakers Bureau; Onyx: Speakers Bureau; Millennium: Speakers Bureau; Novartis: Speakers Bureau. Usmani:Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Janssen Oncology: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pharmacyclics: Research Funding; Millennium: Honoraria, Speakers Bureau; Array BioPharma: Honoraria, Research Funding.

Genetic Susceptibility Markers of Multiple Myeloma in African-Americans

Multiple myeloma (MM) is 2-3 times more common among African-Americans compared to non-Hispanic whites. The 2-3-fold increased risk among family members of cases suggests a genetic contribution to risk. Genome-wide association studies (GWAS) in populations of European ancestry have identified seven novel risk loci at 2p23.3 (rs6746082), 3q26.2 (rs10936599), 3p22.1 (rs1052501), 6p21.32 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077) and 22q13.1 (rs877529) (Broderick, et al. Nat Genet, 2011, Chubb, et al. Nat Genet, 2013), three of which were replicated in another European series (Martino et al., Br J Haematol, 2012). Here we examined the index signals and conducted fine-mapping for each locus in a case-control study of 1,049 multiple myeloma cases and 7,084 controls of African ancestry to identify better markers of risk and novel independent loci in seven previously reported regions in this high risk population.Incident cases were recruited from 10 clinical centers and SEER cancer registries from 2011 to 2013 and genotyped using the Illumina HumanCore GWAS array. Control data were obtained from previous genome-wide studies of breast and prostate cancer, genotyped using the Illumina 1M-Duo in 4425 male controls from the African Ancestry Prostate Cancer Consortium (consisting of 14 independent studies) and 2632 female controls from a breast cancer GWAS of African-American women (consisting of 9 independent studies). Imputation to 1000 Genomes (March 2012 release) was conducted for regions around six of the previously identified single nucleotide polymorphisms [SNPs] (the HLA region harboring rs2285803 is still being imputed, results will be presented). A case-control analysis of SNPs/indels >1% frequency within 250 kb of each index variant was conducted using unconditional multivariable logistic regression adjusting for age, sex and five leading principal components. Region-specific alpha levels were determined through permutation tests. The minimum alpha level across the six regions was α=0.002.All previously reported risk variants were common in African-Americans (minor allele frequency [MAF] >0.05). For five of the six SNPs, we had ≥94% power to detect the same effect observed in non-Hispanic whites, and 64% power for the less common variant rs10936599 (MAF=0.07). We observed directionally consistent effects (odds ratio [OR]>1) for the six risk variants tested, with three replicating at p≤0.05 (7p15.3, p=1.4x10-7; 17p11.2, p=0.05; 22q13.1, p=0.02). For three of the six regions, we observed better markers of risk in African-Americans that were correlated with the index SNP in Europeans (7p15.3, rs56333627, p=1.5x10-5, r2=0.89; 17p11.2, rs34562254, p=2.9x10-3, r2=0.90; 22q13.1, rs2092410, p=1.1x10-4 r2=.71). The missense variant identified in the 17p11.2 region (rs34562254, Pro251Leu) is located in TNFRSF13B, which encodes the protein TACI, a B cell surface receptor which plays a role in B cell maturation, apoptosis and antibody production by inducing activation of transcription factors including NFAT and NFκβ. In addition, there is evidence suggesting that TACI is involved in MM pathogenesis.Our results demonstrate that many of the risk loci for MM found in European ancestry populations are also risk loci in men and women of African ancestry and that by fine-mapping, we are able to identify variants that better capture risk in populations of African ancestry. DisclosuresTerebelo:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Abstract 3852: Obesity is associated with clinical characteristics in African American multiple myeloma patients

Abstract African-American ethnicity, male sex, older age and obesity are accepted risk factors for multiple myeloma (MM). Obesity early in life is a risk factor for many cancers, including MM; most studies have focused on populations of European origin. African-Americans have a higher prevalence of obesity than other populations, and may have a distinct genetic contribution to this condition. We established a multi-center study to investigate possible explanations for the excess risk of MM among African-Americans. The aim of the present case-case analysis was to determine whether body mass index (BMI) was associated with clinical characteristics at presentation in African-American MM patients. 1,065 patients diagnosed with active MM from January 1, 2009 through September 30, 2013 were recruited through nine outpatient centers at academic medical centers and 3 SEER population-based cancer registries. Information on weight and height at 20 years of age and at 5 years prior to diagnosis was obtained from questionnaires. Clinical information collected from the medical records and interviews included age at diagnosis, stage, percent plasmacytosis on bone marrow biopsy, B2 microglobulin level, immunoglobulin class and presence of lytic bone lesions. Molecular profiling abstracted from pathology reports included chromosomal gain/deletions (1P-, 1Q+, +3, +5, +7, +9, +11, 12P-, Del(13), +15, Del(17P), Del(17P13)), translocations (4;14), (11;14), and (14;16 ). Analysis of Variance (ANOVA) was used to test the null hypothesis that age at diagnosis was similar across BMI categories. A T-test was used to test the null hypothesis that the mean age at diagnosis in underweight/normal patients was not different than that for overweight and obese patients. The Mantel-Haenszel Chi square test for trend was used to test the null hypothesis that the proportion of cytogenetic and molecular abnormalities was similar across BMI categories. The study population consists of 306 African American male and 396 African American female MM patients. In both, obesity at 20 years of age was associated with younger age at diagnosis, compared to a normal/underweight (p=0.0015). Among males only, obesity at 5 years prior to diagnosis was also associated with younger age at diagnosis (p=0.03). A trend between increasing BMI and molecular characteristics associated with a poor prognosis was suggested. We observed a strong association between obesity at age 20 and younger age at diagnosis among males and females, and in males only at 5 years prior to diagnosis. Obesity is one of the few known potentially modifiable risk factors for MM. Younger age at diagnosis reflects an earlier accumulation of either or both genetic and environmental risk factors. We also observed a link between obesity at each of the two time points and specific molecular markers of poor prognosis. Additional studies are needed to determine biological significance of the results. Citation Format: Amie E. Hwang, Sikander Ailwadhi, Carol Ann Huff, Leon Bernal-Mizrachi, Christopher A. Haiman, Edward Peters, Seema Singhal, Karen Pawlish, Cathryn Bock, Todd Zimmerman, David J. Van Den Berg, David V. Conti, Brenda B. Birmann, Jayesh Mehta, John J. Graff, Daniel O. Stram, Niquelle Brown, Yang Yu, Moosa Azadian, Laurence Kolonel, Brian E. Henderson, Ann Mohrbacher, Graham Colditz, Brian-C Chiu, Michael Tomasson, Jeffrey Zonder, Robert Z. Orlowski, Sagar Lonial, Wendy Cozen. Obesity is associated with clinical characteristics in African American multiple myeloma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3852. doi:10.1158/1538-7445.AM2014-3852

Obesity In Young Adulthood Is Associated With Early Onset Multiple Myeloma In African Americans

IntroductionAfrican-American ethnicity, male sex, older age and obesity are accepted risk factors for multiple myeloma (MM). Obesity early in life is a risk factor for many cancers, including MM; most studies have focused on populations of European origin. African-Americans have a higher prevalence of obesity than other populations, and may have a distinct genetic contribution to this condition. We established a multi-center collaborative study to investigate possible explanations for the excess risk of MM among African-Americans. The aim of the present case-case analysis was to determine whether body mass index (BMI) was associated with risk factors and clinical characteristics at presentation in African-American MM patients. MethodsPatients diagnosed with active MM since January 1, 2009 were recruited from nine outpatient centers and three Surveillance, Epidemiology, End-Results Program (SEER) population-based cancer registries. Information on weight and height at 20 years of age and at 5 years prior to diagnosis was obtained from questionnaires. Clinical information collected included age at diagnosis, stage, percent plasmacytosis on bone marrow biopsy, β2 microglobulin level, Ig serotype, light vs. heavy chain disease, and presence of lytic bone lesions. BMI (ht/wt2) was categorized into 3 levels (normal <25, overweight 25-29, obese >30) according to World Health Organization standard. The Pearson chi-square test was used to test the association between BMI category, and risk factors and clinical characteristics. Mean ages at diagnosis across BMI categories were compared using linear regression and a t-test for trend calculated. ResultsTo date, 1,044 African-American MM patients have been enrolled and of those, 1,014 provided a DNA sample. At present, 970 patients have completed a questionnaire, clinical records have been abstracted for 823 patients, and 509 patients have some information on gender, age at diagnosis, weight, height and clinical characteristics.The mean age at diagnosis was 59. Increasing BMI at age 20 was associated with younger age at diagnosis (p= 0.0004), whereas BMI at 5 years prior to diagnosis was not associated with age at diagnosis (p=0.9477). Among men, mean age at diagnosis decreased with increasing BMI at age 20 (p= 0.0125) (Table 1a) and at 5 years prior to diagnosis (p=0.0252) (Table 1b). Among women, the trend was signficant at age 20 (p=0.0018) (Table 1a) but not at 5 years prior to diagnosis (p= 0.7094) (Table 1b). Increasing BMI was not significantly associated with any other clinical characteristics.Table 1aAssociation of body mass index (BMI) at age 20 with age at diagnosis among African-American multiple myeloma patients.MenWomenTotalBody Mass Index (ht/wt2)NMean Age at DiagnosisNMean Age At DiagnosisNMean Age At Diagnosis< 2512160.723160.135260.425-306457.93257.49657.7> 301855.22352.944153.9Total203286489P for trendP= 0.0125P= 0.0018P<0.0001Table 1bAssociation of body mass index (BMI) at 5 years prior to age at diagnosis among African-American multiple myeloma patients.MenWomenTotalBody Mass Index (ht/wt2)NMean Age at DiagnosisNMean Age At DiagnosisNMean Age At Diagnosis< 254661.77859.312460.225-308859.79859.018659.3> 307757.412259.819958.9Total211298509P for trendP= 0.0252P= 0.7094P= 0.3063 Conclusion/DiscussionIn a large collection of African-American MM patients, we observed a strong association between increasing BMI at age 20 and younger age at diagnosis. A similar trend was observed in men only at 5 years prior to diagnosis, consistent with previous reports. Obesity is one of the few known potentially modifiable risk factors for MM. Younger age at diagnosis reflects an earlier accumulation of either or both genetic and environmental risk factors. Obesity at an early age may influence MM risk through shared biological pathways such as interleukin-6 and insulin-like growth factor, by contributing to chronic B-cell activation, thereby increasing susceptibilty for MM later in life. The significance of the gender difference for the association closer to diagnosis is unclear and requires additional study. Disclosures:Terebelo:Amgen: Honoraria; Millennium: Honoraria. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Zonder:Skyline: Consultancy. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Lonial:Celgene Corporation: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Investigation Of The Genetic Disparities Between African Americans and Causasians Utilizing Gene Expression Profiles (GEP) Of Purified Plasma Cells (PC) and Whole Bone Marrow Biopsies (BMBx)

MGUS and Multiple Myeloma (MM) are two to three times more common in African Americans (AA) compared to Caucasians (CAU). They also differ in many disease characteristics, most notably the better disease specific survival of AA compared to CAU. Recent improvements in outcomes have helped the CAU population, not benefitting the AA to the same degree. Although this disparity is well appreciated, little is know regarding the associated molecular differences.Availability of large sample sizes of GEPs from CD138+ selected PC offered the opportunity to investigate whether race related differences in PC-GEP exist. The training set included 467 Caucasians and 43 African Americans, and the test set included 209 CAU and 13 AA. A model was developed based on the 27 most differentially expressed probesets (by q-value) in the training set (ROC-AUC, 0.999), and was validated in the test set (ROC-AUC, 0.979). These data were further corroborated in a validation set of asymptomatic MM (AMM) (63CAU/7AA, ROC-AUC, 0.941). Heatmaps of the 27-gene model for the training, test and validation sets are shown in Figure 1a -c. Performance analysis of this 27-gene model revealed a sensitivity of 69.2% and 90.9%, a specificity of 99.1% and 98.1% and a positive predictive value of 99.2% and 96.4% in the MM test set (table 1) and AMM validation set (table 2) respectively. [Display omitted] [Display omitted] [Display omitted] Table 1Summary measures of the 27-gene model, test setMeasureValueSensitivity9/13 (69.2%)Specificity205/209 (98.1%)Positive Predictive Value214/222 (96.4%)Table 2Summary measures of the 27-gene model, AMM validation setMeasureValueSensitivity5/7 (71.4%)Specificity62/63 (98.4%)Positive Predictive Value67/70 (95.7%)The bone marrow microenvironment (ME) has a significant impact on the behavior of myeloma cells. We therefore also sought to investigate the differences in the bone marrow ME between AA and CAU. Using a set of 783 probesets that are unique to the bone marrow microenvironment, we analyzed GEPs of whole bone marrow biopsies in a training set of 250 CAU and 22 AA patients, identifying only 7 probesets with a false discovery rate <0.1. A score created based on these 7 genes had a sensitivity of only 66.7%, a specificity of 76.5% and a positive predictive value of 76.1%.In summary we identified a list of genes, which are differentially expressed between AA and CAU and have developed a model that can accurately identify race based on the expression of 27 genes. With the data available we were not able to develop a suitable model that identified differences of the bone marrow ME between AA and CAU. Correlation of the gene expression differences of plasma cells with clinical characteristics and outcome will provide us with a better understanding of the pathophysiology of MM in AA and will hopefully be the basis of individualized therapy that also takes ethnicity into consideration. Disclosures:No relevant conflicts of interest to declare.