Risk Of Multiple Myeloma Research Articles

Genetically determined telomere length and multiple myeloma risk and outcome

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the “teloscore” in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36–2.11; P = 2.97 × 10−6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86–0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.

Germline variants at SOHLH2 influence multiple myeloma risk

Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10−14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.

Recommendations on eliminating racial disparities in multiple myeloma therapies: a step toward achieving equity in healthcare.

African Americans are at higher risk of multiple myeloma (MM) yet underrepresented in clinical trials and reap less benefits from novel therapies of the disease. To improve representation of African Americans in MM clinical trials, researchers, providers, patients, industry partners and regulators at the FDA-AACR workshop developed recommendations to all stakeholders. The outlined principles offer a roadmap to addressing disparities broadly in clinical trials.

Lipid Level, Lipid Variability, and Risk of Multiple Myeloma: A Nationwide Population-Based Study of 3,527,776 Subjects.

Simple SummaryThere is preclinical evidence that abnormalities in lipid metabolism promote cancer development, and a few studies show the association between lipid levels and multiple myeloma (MM). However, to our knowledge, the role of lipid variability as a risk factor for MM has not been evaluated. We investigated whether lipid level and its variability are associated with the development of MM at a population level. Lower baseline lipid levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, and high variability in high-density lipoprotein cholesterol were all associated with increased risk of developing MM. These findings support the role of lipid metabolism in MM risk.(1) Background: There is evidence that abnormality in lipid metabolism promotes cancer development. This study investigated whether lipid level and its variability are associated with the development of MM at a population level. (2) Methods: A retrospective cohort study included a total of 3,527,776 subjects aged 40 and above who participated in ≥3 health examinations within the previous five years, including the index year (2012–2013). Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) were measured, and visit-to-visit lipid variability were calculated by variability independent of the mean (VIM) method. The study population was followed from the health examination date in the index year until the diagnosis of MM, death, or the last follow-up date (31 December 2017). (3) Results: During a median (5–95%) 5.1 years of follow-up, 969 subjects developed MM. A lower risk of MM was observed with higher quartiles of baseline lipid levels compared to the lowest quartile group (Q4 vs. Q1: adjusted hazard ratios (aHRs) 0.51, 95% confidence interval (CI) (0.42–0.61) for TC; 0.50 (0.41–0.61) for HDL-C; 0.65 (0.54–0.77) for LDL-C; and 0.72 (0.60–0.87) for TG in model (3). Among all lipid measures, only variability in HDL-C was associated with risk of MM: aHRs (95% CI) were 1.12 (0.91–1.38), 1.19 (0.97–1.46), and 1.34 (1.09–1.65) in the Q2, Q3, and Q4, respectively, compared to the Q1 of VIM of HDL-C. (4) Conclusions: This study shows that patients with lower lipid levels and high HDL-C variability are at increased risk of developing MM.

Long non-coding RNA ANRIL and its target microRNAs (microRNA-34a, microRNA-125a and microRNA-186) relate to risk stratification and prognosis in multiple myeloma

ABSTRACT Objective This study aimed to investigate the correlations of long non-coding RNA ANRIL (lncRNA ANRIL), microRNA (miR)-34a, miR-125a and miR-186 with disease risk, clinical features and prognosis of multiple myeloma (MM). Method Totally, 87 MM patients and 30 controls were recruited. LncRNA ANRIL and its target miRNAs (miR-34a, miR-125a and miR-186) in bone marrow derived plasma cells were detected by RT-qPCR. Treatment response was assessed and survivals were calculated in MM patients. Results LncRNA ANRIL expression was increased, while miR-34a, miR-125a and miR-186 expressions were reduced in MM patients compared with controls. Meanwhile, lncRNA ANRIL negatively correlated with miR-34a and miR-125a but not miR-186 in MM patients, while did not correlate with miR-34a, miR-125a or miR-186 in controls. In MM patients, lncRNA ANRIL high expression associated with higher beta-2-microglobulin (β2-MG) and more advanced international staging system (ISS) stage; miR-125a high expression associated with lower β2-MG, less advanced ISS stage and less t (14; 16) abnormality; miR186 high expression associated with increased albumin; while miR-34a did not associate with any clinical features. Furthermore, lncRNA ANRIL high expression associated with decreased complete response (CR), while miR-34a high and miR-125a high expression associated with increased CR and objective response rate. Additionally, lncRNA ANRIL high expression associated with shorter progression-free survival (PFS), while miR-34a high expression associated with prolonged overall survival (OS), and miR-125a high expression associated with longer PFS and OS. Conclusion LncRNA ANRIL and its target miRNAs might serve as biomarkers for assisting with personalized treatment and prognosis improvement of MM.

Risk and Response-Adapted Treatment in Multiple Myeloma.

Simple SummaryTherapeutic strategies in multiple myeloma have been adapted only to age and comorbidities for a long time. Given the currently available therapeutic and technologic arsenal, the time may have come to refine this adaptation. First, high-risk patients should benefit from the most intensive and efficient combinations from diagnosis. Here, we review these different strategies and how to define and identify high-risk myeloma patients in current clinical practice. In addition, the advent of technologies detecting minimal residual disease gives us this opportunity to define the quality of response to treatment with an unpreceded sensitivity and adapt treatment accordingly. Finally, even if molecular targeting is still nascent in myeloma, some molecular features are interesting to detect at relapse to determine optimal salvage treatments.Myeloma therapeutic strategies have been adapted to patients’ age and comorbidities for a long time. However, although cytogenetics and clinical presentations (plasmablastic cytology; extramedullary disease) are major prognostic factors, until recently, all patients received the same treatment whatever their initial risk. No strong evidence allows us to use a personalized treatment according to one cytogenetic abnormality in newly diagnosed myeloma. Retrospective studies showed a benefit of a double autologous transplant in high-risk cytogenetics according to the International Myeloma Working Group definition (t(4;14), t(14;16) or del(17p)). Moreover, this definition has to be updated since other independent abnormalities, namely gain 1q, del(1p32), and trisomies 5 or 21, as well as TP53 mutations, are also prognostic. Another very strong predictive tool is the response to treatment assessed by the evaluation of minimal residual disease (MRD). We are convinced that the time has come to use it to adapt the strategy to a dynamic risk. Many trials are ongoing to answer many questions: when and how should we adapt the therapy, its intensity and duration. Nevertheless, we also have to take into account the clinical outcome for one patient, especially adverse events affecting his or her quality of life and his or her preferences for continuous/fixed duration treatment.

Common gene variants within 3′‐untranslated regions as modulators of multiple myeloma risk and survival

We evaluated the association between germline genetic variants located within the 3'-untranlsated region (polymorphic 3'UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3'-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.

Assessment of Discordance Among Smoldering Multiple Myeloma Risk Models

This cohort study assesses the concordance of 3 models to stratify risk for progression to multiple myeloma in an independent cohort of patients with smoldering multiple myeloma.

Multiple myeloma and cardiovascular risk (a literature review)

Multiple myeloma is a plasma cell clonal malignancy that accounts for 10 % of hematological cancers. It predominantly affects elderly people; median age at diagnosis is 70 years. Consequently, many patients with MM have cardiovascular comorbidities or risk factors. MM can cause cardiac comorbidities such as cardiomyopathy and heart failure caused by cardiac amyloidosis and/or anemia. Heart dysfunction occuring after cytostatic drugs and monoclonal antibodies intake may act as a limiting factor in multiple myeloma treatment. Side effects of chemotherapy include hypotension, hypertension, arrhythmias, conduction disturbances, pericarditis, thromboembolic events, heart failure, death. Advances in pharmacotherapy for MM, such as the introduction of immunomodulators, proteasome inhibitors, and monoclonal antibodies, have dramatically improved life expectancy, but new agent classes are associated with adverse effects, including cardiovascular events. The risk of cardiotoxicity may be increased by some factors that include drug exposure, age, history of heart diseases, arterial hypertension, drug combination, previous radiotherapy or chemotherapy. However, with careful risk assessment, monitoring, and prophylactic therapy, many of these cardiovascular complications can be managed or treated successfully. It is important to detect cardiovascular toxicity before clinical signs of heart and vessel disturbance appear. The role of markers in elicitation of cardiovascular events risk group is still uncertain. Early definition of risk factors for prognosis of cardiovascular events appearing after polychemotherapy of multiple myeloma is an important and yet unsolved problem.

Association between Clinical Presentation of Multiple Myeloma, Immunoglobulin Isotypes, and Cytogenetic Risk Groups

Introduction: In multiple myeloma (MM), chromosomal abnormalities (CAs) are valuable in risk stratifying patients and predicting disease free survival. While immunoglobulin isotypes have historically contributed to MM staging, more recently established classifications of CAs have allowed for a revised staging system that better predicts disease behavior. In this retrospective study, we hypothesized that CAs correlate with disease characteristics including immunoglobulin heavy chain isotype, degree of bone marrow infiltration (PC%), and end-organ damage. Methods: MM patients diagnosed between 2013 to 2019 were included in this retrospective chart review using electronic records from two distinct sources: (1) 442 patients from an independent pathology database and (2) a validation cohort composed of 110 patients from our institution. CAs were stratified by Mayo mSMART 2.0 criteria into standard, intermediate, and high-risk groups (Mikhael et al. Mayo Clin Proc 2013). End-organ damage was defined as the presence of lytic bone lesions, anemia, hypercalcemia, or renal failure on clinical presentation. Within each cohort, associations between categorical variables were made using the chi-squared test or Fisher's exact test, as deemed appropriate. The Mann-Whitney test was used to compare between groups for continuous variables. A result was considered statistically significant at the p<0.05 level of significance. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: 552 MM patients were included in the study. Multi-variate analysis revealed that del(13q14), dup(1q21), t(4;14), trisomy (11q13), del(16q23), and hypodiploidy were associated with a significantly higher PC%, whereas kappa light chain only (LCO) disease was associated with a lower PC%. Higher median PC% was found when comparing the intermediate to standard CA risk group. IgA isotype was associated with intermediate risk CAs including del(13q) and standard risk CAs including t(11;14), while IgG isotype was associated with dup(1q21), and kappa LCO disease correlated with a higher rate of higher risk CAs including deletion of p53 at 17p13 and dup(1q21). With regard to clinical presentation, lytic lesions were more frequent in patients with normal cytogenetics and trisomy 11 and less frequent in IgA isotype, whereas the presence of anemia on presentation correlated with IgA isotype. Renal failure was associated with MAF translocations including t(14;16), a high-risk CA. Conclusions: We demonstrate that a relationship exists between specific CAs, immunoglobulin isotypes, and clinical presentations in MM. Our data indicate that IgA isotype is significantly associated with intermediate-risk cytogenetics including del(13q) and anemia on presentation, and that light chain disease and renal failure correlate with high risk CAs including del(17p13). These associations between biological and clinical features further support the concept of divergent cytogenetic evolution in MM as being an underlying factor leading to distinctive disease presentations. Disclosures Braunstein: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Tumor of proximal clavicle-solitary plasmacytoma of bone, an extremely rare case

Solitary plasmacytoma of bone (SPB) was defined as solitary osteolytic bone lesion with plasma cells collection, and lack of evidence of systemic myeloma. SPB has a higher risk of multiple myeloma (MM) progression and lower survival rate compared to extramedullary plasmacytoma, which is another form of plasmacytoma with soft tissue infiltration. Most of the SPB were discovered at axial skeletons and diaphysis of long bones which red marrow is predominant. Thoracic and lumbar vertebrae are the most frequent disease distribution, while clavicle involvements were rarely seen. We reported a case of solitary plasmacytoma of proximal clavicle, an extremely rare presentation, sustained a pathologic fracture under a low-energy trauma mechanism treated with tumor excision, plate fixation, and adjuvant radiotherapy, and showed excellent stability and functional outcome in 1 year follow-up.

Tattoos and Hematologic Malignancies in British Columbia, Canada.

Tattoos may cause a variety of adverse reactions in the body, including immune reactions and infections. However, it is unknown whether tattoos may increase the risk of lymphatic cancers such as non-Hodgkin lymphoma (NHL) and multiple myeloma. Participants from two population-based case-control studies were included in logistic regression models to examine the association between tattoos and risk of NHL and multiple myeloma. A total of 1,518 participants from the NHL study (737 cases) and 742 participants from the multiple myeloma study (373 cases) were included in the analyses. No statistically significant associations were found between tattoos and risk of NHL or multiple myeloma after adjusting for age, sex, ethnicity, education, body mass index, and family history. We did not identify any significant associations between tattoos and risk of multiple myeloma, NHL, or NHL subtypes in these studies. Though biologically plausible, tattoos were not associated with increased risk of NHL or multiple myeloma in this study. Future studies with greater detail regarding tattoo exposure may provide further insights.

Low high-density lipoprotein and increased risk of several cancers: 2 population-based cohort studies including 116,728 individuals

BackgroundIncreasing evidence suggests that high-density lipoprotein (HDL) may play a role in cancer development. We tested the hypothesis that low HDL levels are associated with increased risk of cancer.MethodsIndividuals from two population-based cohorts, the Copenhagen General Population Study (2003–2015, N = 107 341), and the Copenhagen City Heart Study (1991–1994, N = 9387) were followed prospectively until end of 2016 to assess low plasma HDL cholesterol and apolipoprotein A1 as risk factors for cancer using Cox proportional hazard regression.ResultsDuring up to 25 years follow-up, we observed 8748 cancers in the Copenhagen General Population Study and 2164 in the Copenhagen City Heart Study. In the Copenhagen General Population Study and compared to individuals with HDL cholesterol ≥ 2.0 mmol/L (≥ 77 mg/dL), multivariable adjusted hazard ratios (HRs) for any cancer were 1.13 (95% confidence interval 1.04–1.22) for individuals with HDL cholesterol of 1.5–1.99 mmol/L (58–77 mg/dL), 1.18 (1.08–1.30) for HDL cholesterol of 1.0–1.49 mmol/L (39–58 mg/dL), and 1.29 (1.12–1.48) for individuals with HDL cholesterol < 1.0 mmol/L (< 39 mg/dL). Correspondingly, compared to individuals with apolipoprotein A1 ≥ 190 mg/dL, HRs for any cancer were 1.06 (0.96–1.17) for individuals with apolipoprotein A1 of 160–189 mg/dL, 1.18 (1.07–1.30) for apolipoprotein A1 of 130–159 mg/dL, and 1.28 (1.13–1.46) for individuals with apolipoprotein A1 < 130 mg/dL. Among 27 cancer types, low HDL cholesterol and/or apolipoprotein A1 were associated with increased risk of multiple myeloma, myeloproliferative neoplasm, non-Hodgkin lymphoma, breast cancer, lung cancer, and nervous system cancer. Results were overall similar in women and men separately, and in the Copenhagen City Heart Study.ConclusionsLow HDL levels were associated with increased risk of several cancers. Increased risk was most pronounced for hematological and nervous system cancer, and to a minor extent for breast and respiratory cancer.

Role of MIF-173G/C and Mbl2 Codon 54A/B Variants in the Risk of Multiple Myeloma: An Association Study

Multiple myeloma (MM) is a malignant disease manifested by the clonal proliferation of atypical plasma cells. Macrophage inhibitory factor (MIF) is one of the pleiotropic regulators in various biological and cellular processes. Mannose-binding lectin (MBL) is a crucial protein involved in the lectin pathway of the immune system. We aimed to assess whether variants of MIF and MBL2 genes are associated with MM among a Turkish population. We analyzed the MIF-173G/C (rs755622) and MBL2 codon 54A/B (rs1800450) variants in 200 patients with MM and 200 healthy control subjects using a polymerase chain reaction (PCR) followed by restriction endonuclease digestion. There was also an evaluation of the patients undergoing autologous stem-cell transplantation (ASCT) for these variants. AA and BB genotypes of MBL2 codon 54A/B increased in the patients as compared to the controls (p=0.008, p=0.001, respectively). The subjects carrying AA and BB genotypes of MBL2 were at high risk of development of susceptibility to MM by 7.377 and 8.812 times, respectively. The distribution of MBL2 codon 54A/B alleles was similar between the groups (p&gt;0 .05). There was no statistical difference between the patients and controls in the genotype and allele frequencies of the MIF- 173G/C variant (p&gt;0 .05). The patients undergoing ASCT, MBL2 codon 54A/B AA and BB genotypes also showed association with increased risk for MM (p=0.004, p=0.001, respectively). As far as we know, this is the first report of the study on an association between these variants and MM in our population. Our results indicate that the MBL2 codon 54A/B variant may be associated with susceptibility to MM.

HIV and lymphoma: from oncological futility to treatment

Cancer and HIV have been inextricably linked since the first report in 1982 of biopsy-confirmed Kaposi's sarcoma among previously healthy homosexual men living in Los Angeles and Orange counties, California, USA. 1 Centers for Disease ControlA cluster of Kaposi's sarcoma and pneumocystis carinii pneumonia among homosexual male residents of Los Angeles and Orange counties, California. MMWR Morb Mortal Wkly Rep. 1982; 31: 305-307 PubMed Google Scholar The cases established concerns for what later would be defined as AIDS. The report speculated: “One hypothesis consistent with the observations reported here is that infectious agents are being sexually transmitted among homosexually active males. Infectious agents not yet identified may cause the acquired cellular immunodeficiency that appears to underlie KS [Kaposi's sarcoma] and/or PCP [Pneumocystis carcinii pneumonia] among homosexual males.” The discovery of HIV proved it to be the aetiological agent. Given the known association between immunodeficiency and cancer and oncogenic virus and cancer, the discovery of human herpesvirus 8 (also known as Kaposi's sarcoma-associated herpesvirus) completed the puzzle on the mysterious outbreak of Kaposi's sarcoma. 2 Chang Y Cesarman E Pessin MS et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994; 266: 1865-1869 Crossref PubMed Scopus (4973) Google Scholar Epidemiology of haematological malignancies in people living with HIVPeople living with HIV or AIDS are at increased risk of Hodgkin and non-Hodgkin lymphoma compared with HIV-negative individuals. Data on the risk of multiple myeloma or leukaemia are inconsistent and of low quality but the risk does not seem to be increased. Specific haematological malignancies occur in different contexts of age, CD4 cell count, HIV control, viral co-infections, or chronic inflammation, and the expansion of combination antiretroviral therapy has led to varied demographic and epidemiological shifts among people with HIV. Full-Text PDF CAR T-cell therapy for cancer and HIV through novel approaches to HIV-associated haematological malignanciesPeople living with HIV are a global population with increased cancer risk but their access to modern immunotherapies for cancer treatment has been limited by socioeconomic factors and inadequate research to support safety and efficacy in this population. These immunotherapies include immune checkpoint inhibitors and advances in cellular immunotherapy, particularly chimeric antigen receptor (CAR) T-cell therapy. Despite the field of cancer immunotherapy rapidly expanding with ongoing clinical trials, people with HIV are often excluded from such trials. Full-Text PDF Haemopoietic cell transplantation in patients living with HIVHaemopoietic cell transplantation is established as a standard treatment approach for people living with HIV who have haematological malignancies with poor prognosis. Studies with autologous and allogeneic haemopoietic cell transplantation suggest that HIV status does not adversely affect outcomes, provided that there is adequate infection prophylaxis. Attention to possible drug–drug interactions is important. Allogeneic haemopoietic cell transplantation substantially reduces the long-term HIV reservoir when complete donor chimerism is established. Full-Text PDF Treatment management of haematological malignancies in people living with HIVAlthough the incidence of HIV-associated lymphomas decreased after the introduction of effective combination antiretroviral therapy, they became the most common AIDS-related cancer in high-income countries. Moreover, as people living with HIV live longer, a wide range of non-AIDS-related cancer has emerged, including other haematological malignancies. Nonetheless, combination antiretroviral therapy has offered people with HIV the opportunity to receive the same therapies as those provided to the general population, and intensive curative therapies have become the standard. Full-Text PDF

Evaluating polygenic risk scores in assessing risk of nine solid and hematologic cancers in European descendants.

Genome-wide association studies (GWAS) have identified many genetic risk variants for cancers. The utility of these variants in assessing risk of esophageal, gastric and endometrial cancers, as well as melanoma, glioma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphoid leukemia and multiple myeloma, has not been adequately investigated. We constructed a site-specific polygenic risk score (PRS) for each of these nine cancers using their GWAS-identified risk variants. Using data from 400 807 participants of European descent in the UK Biobank, a population-based cohort study, we estimated the hazard ratios of each cancer associated with its PRS using Cox proportional hazard models. During a median follow-up of 5.8 years, 3905 incident cases of these nine cancers were identified in the cohort. The area under the receiver operating characteristic curve ranged from 0.53 to 0.69 for these cancers. Except for esophageal cancer, significant dose-response associations were observed between PRS and cancer risk. Compared to individuals in the middle quintile (40%-60%) at an average risk, those among the highest 5% of the PRS had a twofold elevated risk of melanoma, glioma, follicular lymphoma or multiple myeloma, and a fourfold elevated risk of chronic lymphoid leukemia. Using PRS, 63.0% of the participants could be classified as having an over twofold elevated risk for at least one cancer. The PRS derived using risk variants identified to date by GWAS showed the potential in identifying individuals at a significantly elevated risk of cancer for prevention.

Long non-coding RNA NEAT1 serves as a novel biomarker for treatment response and survival profiles via microRNA-125a in multiple myeloma.

BackgroundThe present study aimed to explore the association of long non‐coding RNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) with multiple myeloma (MM) risk and further investigate its correlation with clinical features, treatment response, survival profiles, and its interaction with microRNA‐125a (miR‐125a) in MM patients.MethodsTotally, 114 de novo symptomatic MM patients and 30 healthy donors (as controls) were recruited. Their bone marrow samples were collected before treatment (MM patients) and at enrollment (healthy donors), respectively. Subsequently, plasma cells were isolated from bone marrow for detection of lncRNA NEAT1 and miR‐125a expression via reverse transcription quantitative polymerase chain reaction.ResultslncRNA NEAT1 was upregulated in MM patients compared with healthy donors and presented with excellent value in distinguishing MM patients from healthy donors. In MM patients, lncRNA NEAT1 positively associated with International Staging System (ISS) stage, beta‐2 microglobulin (β2‐MG), and lactate dehydrogenase (LDH), but not correlated with core cytogenetics and other clinical features. Furthermore, lncRNA NEAT1 negatively associated with complete remission (CR), overall remission rate (ORR), progression‐free survival (PFS), and overall survival (OS). Moreover, lncRNA NEAT1 negatively associated with miR‐125a in MM patients. MiR‐125a was downregulated in MM patients compared with healthy donors, and it negatively associated with ISS stage, β2‐MG, and LDH, but positively correlated with CR, ORR, PFS, and OS in MM patients.ConclusionlncRNA NEAT1 might interact with miR‐125a, and serves as a novel biomarker for treatment response and survival profiles in MM, indicating its clinical value for MM management.

Statin use and the risk of multiple myeloma: a PRISMA-compliant meta-analysis

Previous studies exploring associations between statin use and risk of multiple myeloma (MM) showed inconsistent results. We searched for articles published in English in databases (PubMed, Web of Science, EMBASE, Medline, and Google Scholar) before October 2019. The multivariate odds ratio (OR)/relative risk (RR) and 95% confidence intervals (CI) were computed to explore associations between statin use and risk of MM. The study indicated that statin users showed significantly lower risks of MM with a random effects model (OR/RR = 0.77, 95% CI 0.63 to 0.95, I2 = 63.1%, p for Q test = 0.001). Subgroup analyses showed that statin users showed significantly lower risks of MM in Caucasian populations with a fixed effects model (OR/RR = 0.72, 95% CI 0.59 to 0.88, I2 = 43.5%, p for Q test = 0.060), whereas no significant association was shown between statin use and risks of MM in Asian populations with a random effects model. Additionally, Subgroup analyses showed that statin users showed significantly lower risks of MM in cohort studies with a fixed effects model (RR = 0.83, 95% CI 0.74 to 0.93, I2 = 0.0%, p for Q test = 0.429), whereas no significant association was shown between statin use and risks of MM in case-control studies with a random effects model. In conclusion, the present study indicated that statin use might be a protective factor for MM incidence. However, the relationship between statin use and MM risk requires repeated and large prospective studies to be verified.

Erythrocyte levels of cadmium and lead and risk of B-cell non-Hodgkin lymphoma and multiple myeloma.

Cadmium and lead are persistent environmental toxins that are known or probable carcinogens, based on evidence for causality for nonhematologic cancers. Associations of these metals with risk of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are unknown but biologically plausible. To examine the associations of circulating levels of lead and cadmium exposure with risk of B-cell NHL (B-NHL) and multiple myeloma, we conducted a nested case-control study among 299 incident B-cell NHLs and 76 MM cases within the Cancer Prevention Study-II Nutrition Cohort (CPS-II NC). Each case was incidence-density matched to two eligible controls on age, race, sex and blood draw date. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) for lymphoid malignancies overall and stratified by subtype. We observed a significant positive association between high erythrocyte lead concentration and risk of lymphoid malignancies overall (RR = 1.16, 95% CI: 1.02-1.33 per 17.6 μg/L (1 standard deviation [SD])) and follicular lymphoma in particular (RR = 1.80, 95% CI: 1.15-2.80 per SD). In contrast, there was no association between erythrocyte cadmium and risk of B-NHL (RR = 0.89, 95% CI: 0.75-1.06 per 0.37 μg/L [1 SD]), or any B-NHL subtypes; but a strong inverse association with MM risk (RR = 0.59, 95% CI: 0.38-0.89, per SD). Results from our study suggest a positive association between erythrocyte lead level and risk of lymphoid malignancies and a possible inverse association between cadmium and myeloma. Additional research is needed to confirm and further explore these findings.

Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance

AbstractSo far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.