Increased Risk Of Multiple Myeloma Research Articles

Association between BCL2 interacting protein 3 like (BNIP3L) genetic polymorphisms and the risk of multiple myeloma in China

ABSTRACT Background: The BCL2 interacting protein 3-like (BNIP3L) protein is involved in multiple myeloma (MM) development and progression. This study aims to explore the connection between BNIP3L single-nucleotide polymorphisms (SNPs) and MM. Methods: SNaPshot was used to examine six SNP loci of the BNIP3L gene in enrolled subjects. The relationship between these loci and MM susceptibility and prognosis was explored. Survival analysis was used to evaluate the impact of different factors on patient survival. Results: The rs2874670 AA genotype and A allele were associated with increased MM risk (P < 0.05). The CCACAC haplotype had a higher frequency in MM, while CCGCAC had a higher frequency in normal patients (all P < 0.05). Patients with R-ISS stage I and II had higher survival rates than those with stage III (P < 0.05). Patients, who received chemotherapy followed by autologous stem cell transplantation, had longer survival time than those who only received chemotherapy (P < 0.05). Low levels of LDH and β2-MG were associated with better survival rates (P < 0.05). Cox regression identified that LDH levels, β2-MG levels, and R-ISS staging were the risk factors for the death of MM. Mann-Whitney U test found a significant difference in survival time between MM patients with different BNIP3L rs2874670 genotypes after BD chemotherapy (P < 0.05). Conclusion: To our knowledge, this is the first study to find that BNIP3L rs2874670 could increase MM susceptibility in China. Different BNIP3L rs2874670 genotypes may affect the prognosis of MM patients receiving BD chemotherapy.

Pre-diagnosis dietary patterns and risk of multiple myeloma in the NIH-AARP cohort.

10635 Background: Despite patient interest in knowing whether diet is linked to multiple myeloma (MM), there is limited research on dietary patterns and MM risk (Malik et al. BCJ 2022). Two studies have assessed this risk, albeit with a small number of MM cases. The EPIC-Oxford cohort and Oxford Vegetarian study (65 MM cases) showed that fish eaters, vegetarians and vegans had significantly reduced MM risk compared to meat eaters (Key et al. AJCN 2014). The Nurses’ Health Study and Health Professionals Follow-up Study (478 MM cases) showed a significantly increased MM risk in men with Empirical Dietary Inflammatory Pattern (Lee et al. JNCI Can Spectr 2019). To our knowledge, this is the largest epidemiologic study to date assessing pre-diagnosis dietary patterns and MM risk. Methods: The NIH-AARP Diet and Health study is a prospective cohort of 567,169 persons who completed a food frequency questionnaire in 1995-1996 and were followed until December 2011. Healthy Eating Index-2015 (HEI-2015), Healthy Diet Score (HDS), alternate Mediterranean Diet (aMED) and healthful Plant-based Diet Index (hPDI) scores were calculated using a priori defined methods and grouped into quartiles, with higher scores reflecting healthier eating patterns. We prospectively evaluated the association between pre-diagnosis dietary patterns and MM incidence in this cohort. Hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated using multivariate Cox proportional hazards models adjusted for age at study entry, sex, race, body mass index, education, and total energy intake (by residual method). Sensitivity analysis was conducted to assess reverse causality by excluding MM cases diagnosed within one year of follow-up. Results: Among 392,589 participants (after exclusions), a total of 1,366 MM cases (59% males; 92% non-Hispanic whites) were identified during the follow-up period. Analysis revealed a significant association between hPDI scores and reduced MM risk (highest vs lowest quartile, HR 0.85; 95%CI 0.73-1.0; p=0.043) (Table). In sensitivity analysis (1,302 MM cases), the association was no longer significant (HR 0.87; 95%CI 0.74-1.03; p 0.09) but trended in the same direction. This may be due to small sample size, given MM is a rare disease. HEI-2015, HDS and aMED scores were not associated with MM risk. Conclusions: A healthful plant-based diet was associated with reduced MM risk in the NIH-AARP cohort. These results will help oncologists and patients make informed choices about their diet. [Table: see text]

Abstract 2962: Investigation of the relationship between obesity, weight cycling, and tumor progression in a murine myeloma model

Abstract Background: The purpose of this study was to investigate physiologic effects of body weight regulation patterns and myeloma progression in vivo. Obesity and obesogenic behaviors are positively associated with both monoclonal gammopathy of unknown significance and multiple myeloma (MM). As the only known modifiable risk factor, this association has emerged as an optimal target for MM prevention, but little is known about the mechanistic relationship of weight patterns with MM progression. In two large prospective cohorts, we have reported an association of episodes of weight cycling (WC), e.g., intentional weight loss followed by unintentional weight gain, with increased MM risk compared to weight-stable individuals (Marinac et al. JNCI Cancer Spectrum, 2019). Experimental Procedures: We used two murine MM models (C57BL/6J Vk*Myc and SCID-Beige MM.1Sluc+ xenograft); male mice were fed a control diet (CD; 10% kcal from fat), high fat diet (HFD; 60% kcal from fat), or a diet cycling regimen (DC; 4 weeks on CD then 4 weeks on HFD) for 16 weeks and thereafter injected them intravenously with tumor cells (1x106 Vk*Myc or 2x106 MM.1S). Body composition was assessed via PIXIMUS-DEXA (SCID-Beige) or NMR (C57BL/6J). Tumor burden was assessed via CD138+ FACS (Vk*Myc) or in vivo bioluminescent imaging (IVIS; MM.1S). Results: The C57BL/6J mice (n=20) on HFD consistently gained weight and sustained the gains throughout the study duration; mice on the DC regimen exhibited dramatic weight cycling responses to diet switching. We observed significant differences in body fat (%) between HFD and CD mice, as assessed by NMR (p&amp;lt;= 0.0001), while body fat fluctuated with diet in the DC mice. At the time of tumor cell injection, HFD mice had higher body weights versus CD (p&amp;lt;0.000001) and DC (p&amp;lt;0.000001) mice; however, weights of DC mice were comparable to CD despite weight fluctuation throughout the study. Three weeks after MM inoculation, we detected elevated tumor burden in DC mice vs. CD mice (n-10, p=0.0061) and a trend toward elevated tumor burden in HFD mice (p=0.145). C57BL/6J mice on the DC regimen also had greater Vk*Myc tumor burden (p=0.0413) within the bone marrow (BM), specifically. In the SCID-Beige MM.1Sluc+ model (n=10), we observed similar trends for weight gain and cycling, and greater early tumor burden in both the HFD (p&amp;lt;0.0001) and DC (p=0.0214) groups compared to CD. Tumor burden was also elevated (p=0.0004) in the heaviest mice (vs. the lightest), regardless of diet, later in the SCID-Beige study. Conclusions: Combined, these results suggest that HFD and WC may contribute to MM risk via changes in the BM microenvironment that affect MM cell homing, engraftment and early expansion. This study lays the groundwork for the future characterization of the relationship between weight patterns, the BM, and MM pathogenesis, which may affect MM prevention and treatment strategies. Citation Format: Heather Fairfield, Catherine Marinac, Mariah Farrell, Brenda Birmann, Michaela Ruth Reagan. Investigation of the relationship between obesity, weight cycling, and tumor progression in a murine myeloma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2962.

Abstract PR05: A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans

Abstract 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&amp;lt;1 × 10-6, but 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. 20 of the 23 known EA risk variants showed directional consistency and 9 replicated at P&amp;lt;0.05 in AA individuals. In eight regions, we identified markers that better capture MM risk in persons of AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95%CI: 1.56, 2.11) increased MM risk compared to 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). 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.

A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry

AbstractPersons 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.

MicroRNA-146b overexpression associates with deteriorated clinical characteristics, increased International Staging System stage, cacoethic chromosome abnormality, and unfavorable prognosis in multiple myeloma patients.

BackgroundMicroRNA‐146b (miR‐146b) is a critical regulator and prognosis biomarker in several hematological malignancies, whereas its role in multiple myeloma (MM) was unclear. Therefore, this study aimed to investigate the significance of miR‐146b in MM patients.MethodsThe plasma cells were separated from bone marrow samples of 180 symptomatic MM patients (before treatment) and 50 healthy controls (HCs), and subsequently detected by reverse transcription‐quantitative polymerase chain reaction for miR‐146b expression.ResultsMiR‐146b was increased in MM patients compared with HCs (P < .001), and it predicted increased MM risk (area under curve (AUC): 0.879, 95% confidence interval (CI): 0.822‐0.936). For clinical parameters, miR‐146b was positively correlated with serum creatinine (P = .047), beta‐2‐microglobulin (P < .001), lactate dehydrogenase (P < .001), bone lesion (P = .027), International Staging System (ISS) stage (P < .001), and t (4; 14; P = .006), while negatively correlated with albumin (P = .004) in MM patients. For prognosis, miR‐146b was decreased in complete response (CR) patients compared with non‐CR patients (P = .025), as well as in overall response rate (ORR) patients compared with non‐ORR patients (P = .036), and it discriminated CR patients from non‐CR patients (AUC: 0.610, 95% CI: 0.523‐0.698) and distinguished ORR patients from non‐ORR patients (AUC: 0.602, 95% CI: 0.501‐0.703) in MM patients. Moreover, miR‐146b was correlated with worse progression‐free survival (P = .007) and overall survival (P = .014) in MM patients.ConclusionMiR‐146b was overexpressed in MM patients and predicted increased MM risk; meanwhile, it correlated with deteriorated clinical properties, increased ISS stage, cacoethic chromosome abnormality, and worse prognosis in MM patients.

Abstract 2686: Associations between a polygenic risk score and risk of multiple myeloma and its precursor

Abstract Genome-wide association studies (GWAS) conducted among populations of European ancestry (EA) have identified 23 common single nucleotide polymorphisms (SNPs) associated with multiple myeloma (MM) risk. We hypothesize that the combination of these SNPs in a polygenic risk score (PRS) is likely to be a strong risk factor for MM. However, it is unclear whether the genetic variation associated with MM susceptibility also predisposes to monoclonal gammopathy of undetermined significance (MGUS). Thus, we calculated a PRS and evaluated the association with risk of MM and its precursor, MGUS. We pooled genotype data for 2434 MM and 3446 controls from ten MM GWAS of individuals of EA within the Interlymph Consortium, for 23 MM risk SNPs identified by prior GWAS. An additional 754 MGUS cases were ascertained from Mayo Clinic and MD Anderson clinical practices. To calculate the PRS, we used the risk estimates corresponding to the 23 SNP associations from the largest published MM GWAS. The log of the odds ratio (OR) for each SNP was multiplied by the respective number of risk alleles and summed to generate a PRS for each individual. The PRS was examined continuously, per one standard deviation (SD), and as quintiles, based on the PRS distribution in the controls. Associations of PRS with MM and MGUS risk were examined separately, using multivariable logistic regression assuming an additive model to assess ORs and 95% confidence intervals adjusted for age, sex, and site. We also evaluated age and sex stratified models. The distribution of sex within MM cases, MGUS cases and controls were each ~60% male and ~40% female. The median age was 61, 66, and 66 years for MM cases, MGUS cases and controls, respectively. PRS ranged from 1.52-4.91, with a median PRS of 3.21 for MM cases, 3.19 for MGUS cases, and 3.05 for controls. PRS was significantly associated with MM risk when assessed continuously (OR=1.19 per SD, p=2.2x10-16) and categorically; compared with the middle quintile (Q3), individuals in the highest quintile (Q5) had a 66% increased MM risk (OR=1.66, p=2.3x10-9) and those in the lowest quintile (Q1) had a 38% decreased MM risk (OR=0.62, p=1.3x10-6). PRS was also significantly associated with MGUS risk (OR=1.19 per SD, p=1.7x10-11); individuals with the highest PRS (Q5) had a 77% increased risk (OR=1.77, p=4.0x10-4) and those with lowest PRS (Q1) had 30% decreased risk (OR=0.70, p=0.04), compared with Q3. When stratified by age and sex, similar associations and trends were found. Using an independent sample of MM / MGUS cases and controls, we showed that a PRS constructed from 23 common genetic variants for MM risk is associated with risk of both MM and MGUS, regardless of age or sex. A future direction of this work is testing associations with PRS and clinical characteristics of the MM cases, as well as differences between MGUS cases that progress and those that do not. Our results suggest that common genetic variation may predispose to MGUS as the precursor to MM. Citation Format: Alyssa I. Clay-Gilmour, Michelle A. Hildebrandt, Nicola J. Camp, Elad Ziv, Elizabeth E. Brown, Jonathan N. Hofmann, John J. Spinelli, Graham G. Giles, Parveen Bhatti, Wendy Cozen, Xifeng Wu, Dennis P. Robinson, Aaron D. Norman, Jason P. Sinnwell, Shaji K. Kumar, S Vincent Rajkumar, Susan L. Slager, Celine M. Vachon. Associations between a polygenic risk score and risk of multiple myeloma and its precursor [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 2686.

Elucidating Under-Studied Aspects of the Link Between Obesity and Multiple Myeloma: Weight Pattern, Body Shape Trajectory, and Body Fat Distribution.

BackgroundAlthough obesity is an established modifiable risk factor for multiple myeloma (MM), several nuanced aspects of its relation to MM remain unelucidated, limiting public health and prevention messages.MethodsWe analyzed prospective data from the Nurses’ Health Study and Health Professionals Follow-Up Study to examine MM risk associated with 20-year weight patterns in adulthood, body shape trajectory from ages 5 to 60 years, and body fat distribution. For each aforementioned risk factor, we report hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MM from multivariable Cox proportional-hazards models.ResultsWe documented 582 incident MM cases during 4 280 712 person-years of follow-up. Persons who exhibited extreme weight cycling, for example, those with net weight gain and one or more episodes of intentional loss of at least 20 pounds or whose cumulative intentional weight loss exceeded net weight loss with at least one episode of intentional loss of 20 pounds or more had an increased MM risk compared with individuals who maintained their weight (HR = 1.71, 95% CI = 1.05 to 2.80); the association was statistically nonsignificant after adjustment for body mass index. We identified four body shape trajectories: lean-stable, lean-increase, medium-stable, and medium-increase. MM risk was higher in the medium-increase group than in the lean-stable group (HR = 1.62, 95% CI = 1.22 to 2.14). Additionally, MM risk increased with increasing hip circumference (HR per 1-inch increase: 1.03, 95% CI = 1.01 to 1.06) but was not associated with other body fat distribution measures.ConclusionsMaintaining a lean and stable weight throughout life may provide the strongest benefit in terms of MM prevention.

Anthropometric characteristics, physical activity and risk of hematological malignancies: A systematic review and meta-analysis of cohort studies.

Overweight/obesity, adult attained height and physical activity are possible risk factors for hematological malignancies. This meta-analysis aims to evaluate the associations between these factors and hematological cancer risk in adults. Eligible cohort studies were sought in PubMed up to May 31, 2016; overall, 44 studies were included in the present analyses. Pooled relative risk estimates were calculated using random-effects models; separate analyses were conducted for non-Hodgkin lymphoma (NHL) and subtypes (diffuse large B-cell lymphoma, DLBCL; follicular cell lymphoma; small lymphocytic lymphoma/chronic lymphocytic leukemia, SLL/CLL), Hodgkin lymphoma (HL), multiple myeloma (MM), leukemia and subtypes (acute lymphoblastic leukemia, acute myeloid leukemia, AML). Obesity was associated with increased risk of NHL, HL, MM, leukemia overall and AML in both sexes, as well as with higher DLBCL risk in women; the dose-response meta-regression analysis confirmed these associations. Less pronounced effects were observed regarding overweight, as it was associated with increased MM risk in both sexes, NHL risk in males, DLBCL and overall leukemia risk in females. Taller men presented with significantly higher risk of NHL and taller women were affected by higher risk of NHL, DLBCL, FL, CLL/SLL, MM, leukemia and AML. On the other hand, physical activity and abdominal fatness were not associated with the risk of hematological malignancies. In conclusion, this meta-analysis highlights the pivotal role of anthropometric measures in shaping the risk of hematological malignancies in adults. Additional, well-designed studies stemming from all the continents are needed for the further substantiation and generalization of the results.

Epidemiology and etiopathogenesis of multiple myeloma and monoclonal gammapathy of undetermined significance

Multiple myeloma (MM) accounts for about 13% of haematological malignancies. Etiopathogenesis is still not fully understood. Confirmed risk factors include the following: age, male sex, black race and MM among first-degree relatives. MM may be preceded by monoclonal gammapathy of undetermined significance (MGUS). The risk of progression is about 1% per year. Genetic changes, proinflammatory and proangiogenic cytokines and some infections may play a role in this risk. With regard to lifestyle risk factors, only obesity and overweight were associated with increased MM incidence and elevated risk for transformation of MGUS to MM. Regarding occupational exposure, there is an increased risk of MM among farmers, firefighters and hairdressers. As far as autoimmune diseases are concerned, only ankylosing spondylitis and pernicious anemia are associated with significantly increased MM risk. Increased risk of MM was also reported in relatives of MM patients, especially in first-degree relatives and in African-American families. The risk of MGUS is elevated in both first-degree relatives of MM and MGUS patients. Data from genetic analysis indicated translocations involving immunoglobulin heavy chain (IGH) loci, hyperphosphorylation of several proteins which are the targets for paraproteins produced by malignant plasma cells and single nucleotide polymorphisms (susceptibility loci) as the potential genetic predisposition to multiple myeloma. The mechanism of heterogeneity of clinical manifestations of MM is not known. Anemia is less frequent in patients whose relatives were diagnosed with hematologic malignancy compared to those with a negative family history. In patients from a younger age group, osteolytic bone lesions were more common than in older patients. In conclusion, environmental exposures modify the genetic predisposition to MM and MGUS.

Association of VEGF and VDR gene- gene and gene- smoking interaction on risk of multiple myeloma in Chinese Han population.

AimsTo investigate the association of several single nucleotide polymorphisms (SNPs) within vascular endothelial growth factor (VEGF) and vitamin D receptor (VDR) gene polymorphisms and additional gene- gene and gene- smoking interaction with multiple myeloma (MM) risk in Chinese population.MethodsGeneralized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among SNPs and smoking. Logistic regression was performed to investigate association between 6 SNPs within VEGF and VDR gene, additional gene- gene and gene- smoking interaction on MM risk.ResultsMM risk is significantly higher in carriers with the rs699947- A allele within VEGF gene than those with CC genotype (CA+ AA versus CC), adjusted OR (95%CI) =1.72 (1.19-2.33), and higher in carriers with rs2228570- T allele within VDR gene than those with CC genotype (CT+ TT versus CC), adjusted OR (95%CI) = 1.68 (1.26-2.17). We also found a significant two-locus model (p=0.0010) involving rs699947 and rs2228570, and a significant two-locus model (p=0.0107) involving rs2228570 andsmoking. Participants with rs699947- CA+AA and rs2228570- CT+TT genotype had the highest MM risk, compared to participants with rs699947- CC and rs2228570- CC genotype, OR (95%CI) = 3.12 (1.82 -4.61). Smokers with rs2228570- CT+TT genotype had the highest MM risk, compared to never- smokers with rs2228570- CC genotype, OR (95%CI) = 3.27 (1.74-4.86).ConclusionsWe found that the A allele of rs699947 within VEGF and T allele of rs2228570 within VDR gene, interaction between rs699947 and rs2228570, rs2228570 andsmoking were all associated with increased MM risk.

Pesticide exposures and the risk of multiple myeloma in men: An analysis of the North American Pooled Project.

Multiple myeloma (MM) has been consistently linked with agricultural activities, including farming and pesticide exposures. Three case-control studies in the United States and Canada were pooled to create the North American Pooled Project (NAPP) to investigate associations between pesticide use and haematological cancer risk. This analysis used data from 547 MM cases and 2700 controls. Pesticide use was evaluated as follows: ever/never use; duration of use (years); and cumulative lifetime-days (LD) (days/year handled × years of use). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression adjusted for age, province/state of residence, use of proxy respondents and selected medical conditions. Increased MM risk was observed for ever use of carbaryl (OR = 2.02, 95% CI = 1.28-3.21), captan (OR = 1.98, 95% CI = 1.04-3.77) and DDT (OR = 1.44, 95% CI = 1.05-1.97). Using the Canadian subset of NAPP data, we observed a more than threefold increase in MM risk (OR = 3.18, 95% CI = 1.40-7.23) for ≤10 cumulative LD of carbaryl use. The association was attenuated but remained significant for >10 LD of carbaryl use (OR = 2.44; 95% CI = 1.05-5.64; ptrend = 0.01). For captan, ≤17.5 LD of exposure was also associated with a more than threefold increase in risk (OR = 3.52, 95% CI = 1.32-9.34), but this association was attenuated in the highest exposure category of >17.5 LD (OR = 2.29, 95% CI = 0.81-6.43; ptrend = 0.01). An increasing trend (ptrend = 0.04) was observed for LD of DDT use (LD > 22; OR = 1.92, 95% CI = 0.95-3.88). In this large North American study of MM and pesticide use, we observed significant increases in MM risk for use of carbaryl, captan and DDT.

Association between hepatitis B virus infection and risk of multiple myeloma: a systematic review and meta-analysis.

Hepatitis B virus (HBV) infection is a major global public health concern. Although recent findings suggest an inverse relationship between HBV infection and multiple myeloma (MM), the true relationship between these two conditions remains unclear. The primary aim of this meta-analysis was to evaluate the association between HBV infection, defined as hepatitis B surface antigen positivity, and the incidence of MM. We searched the PubMed/Medline, Cochrane Library and EMBASE databases from January 1975 to July 2014 and reviewed the reference lists of all retrieved articles. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using fixed- and random-effects models. We identified nine case-control studies involving 30,646 patients with MM and 379,837 controls. HBV infection was not significantly associated with the development of MM (OR = 1.3; 95% CI: 0.92-1.82; P = 0.14). A similar risk of developing MM was present in different HBV-prevalent countries. However, significant heterogeneity was observed among studies (P = 0.01). A statistically significant relationship between HBV infection and increased MM risk was detected in sub-analyses evaluating high-quality studies and those with hospital-based controls (P < 0.05). HBV infection may be associated with an increased risk of MM. However, confirmation of this relationship and the specific molecular mechanisms involved in the association between HBV infection and the development of MM require further exploration.

Tumor Necrosis Factor-Alpha Inhibitor Medications for Inflammatory Conditions and Incidence of Multiple Myeloma

PurposeTumor necrosis factor-alpha (TNF-α) is a pleiotropic cytokine that regulates a wide variety of cellular responses including proliferation and differentiation. This potent mediator of inflammation and bone resorption is elevated in plasma of multiple myeloma (MM) patients, and inhibition of TNF-α is hypothesized to enhance the effects of MM treatments. However, the effects of TNF-α inhibitors on incidence of MM have not been fully characterized. Some reports indicate a possible increased risk of hematological malignancies with anti-TNF therapies. The purpose of this study was to examine incidence of MM among adults with inflammatory conditions treated with anti-TNF monoclonal antibodies and TNF fusion protein.Patients and MethodsWe conducted a retrospective cohort study of new users of TNF-α inhibitors from 2009-2013 using the Truven Health MarketScan Database. Patients were required to be 20+ years old and have 12 months of continuous enrollment prior to first TNF-α inhibitor use. Exclusion criteria included presence of the following in the year prior to first TNF-α inhibitor use: any malignancy, HIV+, and hematopoietic stem cell transplant.We used longitudinal pharmacy claims data to measure continuous use of infliximab, adalimumab, golimumab, certolizumab and etanercept, as well as other immunosuppressive medications. MM cases were identified using a validated algorithm for administrative claims data and ICD-9 diagnosis codes. Data from the year prior to first TNF-α inhibitor use were also used to calculate Charlson comorbidity index scores and document diagnoses of inflammatory conditions, including rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory bowel disease (Crohn's disease, ulcerative colitis) and ankylosing spondylitis. Incidence rates of MM per 100,000 person-years (PY) with 95% confidence intervals (CI) were calculated for the cohort with stratification by gender, age group (20-49, 50-64, 65+ years) and type of TNF-α inhibitor (anti-TNF antibody, TNF fusion protein). Observed rates were compared to MM incidence rates from Surveillance, Epidemiology and End Results Program registries in the same time period and geographic regions. Standardized incidence ratios (SIR) and exact 95% CIs were calculated for those strata using Poisson regression.ResultsAmong 114,045 incident users of TNF-α inhibitors, 82,003 (72%) used anti-TNF antibodies and 41,468 (36%) used TNF fusion protein alone or consecutively (after switching) during median follow up of 27 months and 205,635 PY overall. Rheumatoid arthritis (47%), psoriasis (21%) and inflammatory bowel disease (22%) were the most prevalent indications for TNF-α inhibitors, while fewer had psoriatic arthritis (15%) and ankylosing spondylitis (6%). There were 51 patients that developed MM during follow up, for a crude incidence rate (25 per 100,000 PY) that was higher than the expected rate (9 per 100,000 PY, age-standardized). TNF-α inhibitor users that developed MM were older (median: 57 vs. 49 years in non-cases) and had more concurrent treatment with corticosteroids (84% vs. 56%).The overall age-standardized incidence ratio for MM was SIR=3.2 (95% CI 2.4-4.2), with even higher than expected incidence in younger age groups (20-49 years: SIR=5.5, 95% CI 2.5-10.5; 50-64 years: SIR=8.0, 95% CI 5.1-11.5) but not in older patients (65+ years: SIR=1.8, 95% CI 1.0-3.1). Estimates were slightly higher for anti-TNF antibodies (SIR=3.6, 95% CI 2.6-5.0) vs. TNF fusion protein (SIR=2.8, 95% CI 1.6-4.5) and slightly lower in females (SIR=3.0, 95% CI 2.0-4.3) vs. males (SIR=3.5, 95% CI 2.3-5.2).ConclusionsIn this large sample of patients treated with TNF-α inhibitors, we observed a higher incidence of MM diagnoses than would be expected from a similarly aged population. Other than a causal association between TNF-α inhibitors and increased MM risk, a possible explanation for these findings could be the relationship between the underlying autoimmune, inflammatory conditions and myeloma etiology, particularly with the greater disease severity that would warrant these medications vs. other, non-biologic disease-modifying antirheumatic drugs (DMARDs). Future research on the comparative safety with long-term use of TNF-α inhibitors and other DMARDs that can incorporate clinical information on disease severity is needed to better understand these conditions, their treatment and subsequent MM risk. DisclosuresNo relevant conflicts of interest to declare.

The International Multiple Myeloma Research (IMMEnSE) Consortium: Genetics of Multiple Myeloma Risk and Prognosis

We established the IMMEnSE (International Multiple Myeloma rESEarch) consortium, to increase our understanding of the genetic determinants of multiple myeloma (MM) risk, response to therapy and survival. At present we have DNA samples of over 3200 MM cases and 3000 healthy controls from 10 countries, mainly in Europe. For the majority of the cases clinical data on known prognostic factors, therapy outcome and survival have been also collected.We already performed several association studies in the context of the IMMEnSE consortium. In particular, associations were found between MM risk and SNPs in the ABCB1 gene, which encodes for an efflux pump that has a key role in protecting cells from chemical damage (rs10264990: odds ratio (OR) =0.79, 95% confidence interval (CI) 0.68-0.91; p=0.001, and rs17327442: OR=1.99; 95%CI 1.32-3.02; p=0.001). We also investigated the 8q24 region, which has been shown to harbor multiple loci of susceptibility to various cancers, and found an association between a SNP mapping in this region and MM risk (rs2456449: OR=1.37; 95%CI 1.12-1.68; p=0.0022). In addition, IMMEnSE cases and controls were also genotyped for three MM risk SNPs from the first genome-wide association study (GWAS), and the association of two of them (rs4487645 on chromosome 7p15.3 and rs6746082 on chromosome 2p23.3) was confirmed. Finally, SNPs of key telomere-related genes were genotyped and telomere length was measured in MM cases and controls, and a pleiotropic and functional variant of the TERT gene was found to be associated with reduced MM risk (rs2242652: OR=0.81; 95%CI 0.72-0.92; p=0.001). A suggestive association between longer telomeres and increased MM risk was also found (ptrend=0.01).We will study new SNPs emerging as promising candidates from ongoing GWAS on MM risk and survival, as well as SNPs of key genes involved in the pathogenesis of MM. Finally, we plan to study methylation status of key genes involved in MM etiology, and mitochondrial copy number. The role of all these factors will be investigated in relation to MM risk and prognosis.Collection of samples and data of MM cases and controls is ongoing, as well as of subjects with monoclonal gammopathy of undetermined significance (MGUS).Table 1MM cases and healthy controls collected in the IMMEnSE consortiumCountryCasesMedian age(5th-95th percentile)ControlsMedian age(5th-95th percentile)Control typeItaly23263 (46-78)23759 (42-76)General populationPoland1,28663 (42-82)20068 (43-79)Blood donorsSpain32264 (46-82)1,13166 (43-84)Hospitalized subjectsFrance64257 (37-68)19148 (18-63)Blood donorsPortugal7068 (45-82)10058 (53-79)Blood donorsHungary14868 (34-90)10574 (55-87)Hospitalized subjectsDenmark34856 (43-65)1,00063 (52-73)Blood donorsIsrael10960 (41-77)95-Blood donorsCanada6258 (42-70)---Japan5166 (47-84)---Total3,27063 (37-84)3,05963 (18-92) [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Medication use and multiple myeloma risk in Los Angeles County.

The role of medication use in multiple myeloma (MM) risk remains unclear. The Los Angeles County Multiple Myeloma Case-Control Study, comprising 278 MM cases and individually matched neighborhood controls, provided data to assess associations between medication use and MM risk. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Erythromycin (ever) use was associated with increased MM risk (OR 1.85, 95% CI 1.13-3.03). This association was restricted to men (OR 3.77, 95% CI 1.72-8.29) and was especially apparent among men who took two or more courses of erythromycin (OR 4.68, 95% CI 1.70-12.87). Compared to females, males have lower levels of cytochrome P450 3A4 (CYP3A4), for which erythromycin is both a substrate and inhibitor. Use of CYP3A4-inhibiting drugs such as erythromycin in men may thus result in even lower levels of CYP3A4 and, consequently, higher levels of CYP3A4-metabolized substances. These results could potentially provide clues to explain discrepancies in MM incidence by sex. Consortial efforts to confirm these associations are warranted.

Anthropometric, behavioral, and female reproductive factors and risk of multiple myeloma: a pooled analysis.

Risk of developing multiple myeloma (MM) rises with age and is greater among men and blacks than among women and whites, respectively, and possibly increased among obese persons. Other risk factors remain poorly understood. By pooling data from two complementary epidemiologic studies, we assessed whether obesity, smoking, or alcohol consumption alters MM risk and whether female reproductive history might explain the lower occurrence of MM in females than in males. The Los Angeles County MM Case-Control Study (1985-1992) included 278 incident cases and 278 controls, matched on age, sex, race, and neighborhood of residence at case's diagnosis. We estimated MM risk using conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). In the prospective California Teachers Study (CTS), 152 women were diagnosed with incident MM between 1995 and 2009; we calculated hazard ratios using Cox proportional hazards analysis. Data from the two studies were pooled using a stratified, nested case-control sampling scheme (10:1 match) for the CTS; conditional logistic regression among 430 cases and 1,798 matched controls was conducted. Obesity and smoking were not associated with MM risk in the individual or combined studies. Alcohol consumption was associated with decreased MM risk among whites only (pooled OR = 0.66, 95% CI = 0.49-0.90) for ever versus never drinking. Higher gravidity and parity were associated with increased MM risk, with pooled ORs of 1.38 (95 % CI = 1.01-1.90) for ≥3 versus 1-2 pregnancies and 1.50 (95% CI = 1.09-2.06) for ≥3 versus 1-2 live births. Female reproductive history may modestly alter MM risk, but appears unlikely to explain the sex disparity in incidence. Further investigation in consortial efforts is warranted.

Multiple Myeloma and lifetime occupation: results from the EPILYMPH study

BackgroundThe EPILYMPH study applied a detailed occupational exposure assessment approach to a large multi-centre case–control study conducted in six European countries. This paper analysed multiple myeloma (MM) risk associated with level of education, and lifetime occupational history and occupational exposures, based on the EPILYMPH data set.Methods277 MM cases and four matched controls per each case were included. Controls were randomly selected, matching for age (+/− 5 years), centre and gender. Lifetime occupations and lifetime exposure to specific workplace agents was obtained through a detailed questionnaire. Local industrial hygienists assessed likelihood and intensity for specific exposures. The odds ratio and 95% confidence intervals (OR, 95% CI) were calculated for level of education, individual occupations and specific exposures. Unconditional logistic regression models were run for individual occupations and exposures.ResultsA low level of education was associated with MM OR=1.68 (95% CI 1.02-2.76). An increased risk was observed for general farmers (OR=1.77; 95% CI 1.05-2.99) and cleaning workers (OR=1.69; 95% CI 1.04-2.72) adjusting for level of education. Risk was also elevated, although not significant, for printers (OR=2.06; 95% CI 0.97-4.34). Pesticide exposure over a period of ten years or more increased MM risk (OR=1.62; 95% CI 1.01-2.58).ConclusionThese results confirm an association of MM with farm work, and indicate its association with printing and cleaning. While prolonged exposure to pesticides seems to be a risk factor for MM, an excess risk associated with exposure to organic solvents could not be confirmed.

Thyroid Hormones Antagonize and Tetrac, a Deaminated T4 Analog, Sensitizes Bortezomib Action in Multiple Myeloma Cells

Abstract 2867 Background:Multiple myeloma (MM) is a highly resistant hematological neoplasia that remains an incurable disease. A leading drug in MM treatment is bortezomib, a selective proteasome inhibitor. Current treatment protocols have extended the overall survival of patients with MM, however, ultimately the disease becomes refractory to all forms of treatments and therefore drugs with new mechanisms of action are urgently needed.Experimental and clinical observations suggest that thyroid hormones (T3 and T4) modulate neoplastic cells and activate MAPK pathway through binding to αv β3 integrin, commonly overexpressed in cancer. Tetraiodothyroacetic acid (tetrac), a non-agonist T4 analog, selectively blocks T3 and T4 binding to αv β3 receptor site. MM cells interact with αv β3 for invasion/growth and thyroid diseases were associated with increased MM risk. We recently demonstrated the thyroid hormones- αv β3-MAPK axis in myeloma cells. In the current study we further show that T3 and T4 antagonize bortezomib action via MAPK activation and that in the presence of tetrac bortezomib action is significantly enhanced. Methods:Cell lines: MM cell lines (RPMI-8226, ARK, ARP-1, U266 and CAG) are cultured in RPMI 1640 supplemented with 10% heat-inactivated FBS/antibiotics. Before addition of T3 or T4, cells are grown for 48 hours without serum. Bone marrow (BM) aspirates were obtained from patients with MM treated at the Meir Medical Center. Signed institutional review board–approved written informed consent was obtained from all patients. Primary MM cells were separated on Ficoll gradient and were cultured in RPMI 1640. Reagents and chemicals: T3, T4, tetrac, MAPK inhibitor (U0126), autophagy inhibitor (3MA) and pan caspase inhibitor, Z-VAD. Cells were treated with T3 or T4 (1nM-100nM and 1μM) in the presence/absence of tetrac (100nM and 1μM) and/or bortezomib (25nM) and tested by several methods: Cell number. Cell proliferation assay: WST-1 (10% final concentration) is incubated at 37°C for 2 h and read using microELISA reader at 440nm. Cell cycle: Cells are harvested, fixed and stained with DNA propidium iodide (PI) (50 μg/ml) /RNAse A (10mg/ml) and analyzed for DNA content by FACS. Analysis of apoptosis/necrosis: Cells (105) are incubated with 5 μl Annexin V (FITC conjugated)/5 μl PI and analyzed by FACS. Expression of apoptotic genes (real-time PCR). Results were repeated 2–3 times in triplicates and were analyzed using unpaired students t test.Results and discussion: Results demonstrate that T3 and T4 at near physiological and supra physiological levels, increased myeloma cell viability by 15–50% and cell number by 30%-60%. This increased viability was blocked by U0126, indicating involvement of the MAPK pathway. In parallel a 20–25% reduction in cell death and of pro-apoptotic genes expression was documented following treatment with the hormones. Co-treatment of myeloma cell lines with T3 or T4 reduced bortezomib cytotoxicity and increased cell survival in a MAPK-dependent manner. Pretreatment of MM cell lines and primary cells from MM patients with tetrac, 48 hours before the addition of bortezomib, resulted in a synergistic cytotoxic effect. The effect of tetrac was blocked using a pan-caspase inhibitor (Z-VAD) but not by an autophagy inhibitor (3MA), suggesting apoptosis-related cell death. Conclusions:We present here novel data demonstrating that T3 and T4 may oppose bortezomib action via MAPK activation. Blocking the thyroid hormones- αv β3 axis using tetrac, promotes bortezomib cytotoxicity, suggesting this approach as a promising adjunct therapy in MM. Disclosures:No relevant conflicts of interest to declare.

Blocking Thyroid Hormones Induced MAPK Activation -Novel Target for Therapy In Myeloma

AbstractAbstract 2964 Background:Basic/epidemiological/clinical data has established that thyroid hormones (T3/T4) may modulate neoplastic cells and T3/T4 deprivation removes this stimulus. Recently, growing body of epidemiological and clinical evidence suggests improved survival in individuals with primary/secondary hypothyroidism in a variety of tumor types, e.g., breast, lung, renal, prostate, head and neck, glioblastoma and more. On the other hand, hyperthyroidism was associated with an increased risk of lung and prostate cancers in a large-based population study as well as in pancreatic and ovarian cancers. Finally, enhanced response rates to chemo/radiation therapy in hypothyroidism patients have also been reported in preclinical/clinical studies. Taken together, these observations suggest a role for T3 and T4 in tumor growth and a protective effect of hypothyroidism in various cancer types.T3/T4 affects cell division/angiogenesis by activating MAPK/PI3K pathways through binding integrin αvβ3, an integrin over-expressed on many cancer cells. Thyroid binding site upon the integrin is at close proximity to its well known RGD recognition site and is blocked by tetrac, a natural analog of T4. Interestingly, in multiple myeloma (MM), a highly resistant hematological malignancy, the tumor cells interact with αvβ3 for their invasion/proliferation and thyroid diseases were associated with increased MM risk. As most MM patients still resist treatment, drugs with new mechanisms of action are urgently needed.We have recently demonstrated that, similar to results obtained from other cancer types, thyroid hormones induce myeloma cell viability and proliferation through MAPK activation. In the current study, we further studied the ability of thyroid hormones to induce MAPK activation in myeloma cells. We show that this MAPK induction is quick, specific and is initiated through thyroid hormones binding to the integrin αvβ3 receptor site and propose ways to block this potent action. Methods:Cell lines: MM cell lines, RPMI 8226 and CAG are cultured in RPMI 1640 supplemented with 10% heat-inactivated FBS/antibiotics. Reagents and chemicals: T3, T4, tetrac, RGD and RGE peptides, αvβ3 monoclonal antibodies (LM609), phosphorylated and total MAPK ERK1/2 antibodies. Cell proliferation assay: WST-1 (10% final concentration) is incubated at 37°C for 2 h and read using microELISA reader at 440nm. Flow cytometry: Cell cycle: Cells are harvested, fixed and stained with DNA propidium iodide (PI) (50 μ g/ml)/RNAse A (10mg/ml) and analyzed for DNA content by FACS. Analysis of apoptosis/necrosis: Cells (105) are incubated with 10 μ l Annexin V (FITC conjugated)/5 μ l PI and analyzed by FACS. Western blotting: Whole cell lysates were separated on 8–12% polyacrylamid gels and analyzed by western blot using above indicated antibodies. Results were repeated 2–4 times, in triplicates and were analyzed using unpaired students t test. Results and Discussion:Results demonstrate that physiological T3 and T4 concentrations (1nM and 100nM respectively), induce within minutes MAPK activation in myeloma cells, lasting up to 24 hours. This induction is completely blocked by a selective MAPK inhibitor, U0126. We further show that this thyroid-induced MAPK activation is initiated through αvβ3 integrin site, by using specific functional antibody to the integrin (LM609), as well as blocking the binding site using RGD but not RGE peptides. In addition, by using a T4 analog, tetrac, that selectively blocks thyroid hormones binding to the integrin site, we demonstrate a novel and specific way to block the induction of MAPK by T3 and T4. We present here indications that thyroid hormones induce a quick and potent MAPK activation in myeloma cells, similar to reports from other cancer types. This MAPK activation can be blocked using several inhibitors, including tetrac, previously demonstrated by us as a sensitizer of bortezomib action in myeloma. Conclusions:In order to surpass myeloma cancer treatment resistance, new mechanisms of action are urgently needed. Our unique approach, by inhibiting thyroid-induced MAPK pathway initiated at the αvβ3 integrin site, may potentially become a new promising chemosensitizing treatment in this disease. Disclosures:No relevant conflicts of interest to declare.