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Telomere dysfunction is a notable event observed in many cancers contributing to their genomic instability. A major factor controlling telomere stability is the human telomerase reverse transcriptase catalytic subunit (hTERT). Telomere shortening has been observed in multiple myeloma (MM), a plasma cell malignancy with a complex and heterogeneous genetic background. In the present study, we aimed to analyse telomere length and hTERT genetic variants as potential markers of risk and survival in 251 MM patients. We found that telomere length was significantly shorter in MM patients than in healthy individuals, and patients with more advanced disease (stage III according to the International Staging System) had shorter telomeres than patients with less advanced disease. MM patients with hTERT allele rs2736100 T were characterized with significantly shorter progression-free survival (PFS). Moreover, allele rs2736100 T was also found to be less common in patients with disease progression in response to treatment. hTERT rs2853690 T was associated with higher haemoglobin blood levels and lower C-reactive protein. In conclusion, our results suggest that telomere length and hTERT genetic variability may affect MM development and can be potential prognostic markers in this disease., (© 2023. Springer Nature Limited.)

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10 -9 ) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46 , IKBKE , PARK2 , ULK4 , ATG5 , and CDKN2A associated with MM risk ( p = 4.47 × 10 -4 -5.79 × 10 -14 ). Mechanistically, we found that the ULK4 rs6599175 SNP correlated with circulating concentrations of vitamin D3 ( p = 4.0 × 10 -4 ), whereas the IKBKE rs17433804 SNP correlated with the number of transitional CD24 + CD38 + B cells ( p = 4.8 × 10 -4 ) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 ( p = 3.6 × 10 -4 ). We also found that the CD46 rs1142469 SNP correlated with numbers of CD19 + B cells, CD19 + CD3 - B cells, CD5 + IgD - cells, IgM - cells, IgD - IgM - cells, and CD4 - CD8 - PBMCs ( p = 4.9 × 10 -4 -8.6 × 10 -4 ) and circulating concentrations of interleukin (IL)-20 ( p = 0.00082). Finally, we observed that the CDKN2A rs2811710 SNP correlated with levels of CD4 + EMCD45RO + CD27 - cells ( p = 9.3 × 10 -4 ). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3 - , MCP-2 - , and IL20-dependent pathways.

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10 -8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10 -7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival., Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed., Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P &lt; 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant., Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS., Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma., (©2022 American Association for Cancer Research.)

There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 × 10 -15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 × 10 -13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population., (© 2021. The Author(s).)

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10 -7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

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., (© 2020 Union for International Cancer Control.)

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.

Myeloproliferative neoplasms (MPNs) are a group of diseases that cause myeloid hematopoietic cells to overproliferate. Epidemiological and familial studies suggest that genetic factors contribute to the risk of developing MPN, but the genetic susceptibility of MPN is still not well known. Indeed, only few loci are known to have a clear role in the predisposition to this disease. Some studies reported a diagnosis of MPNs and multiple myeloma (MM) in the same patients, but the biological causes are still unclear. We tested the hypothesis that the two diseases share at least partly the same genetic risk loci. In the context of a European multicenter study with 460 cases and 880 controls, we analyzed the effect of the known MM risk loci, individually and in a polygenic risk score (PRS). The most significant result was obtained among patients with chronic myeloid leukemia (CML) for PS0RS1C1-rs2285803, which showed to be associated with an increased risk (OR = 3.28, 95% CI 1.79-6.02, P = .00012, P = .00276 when taking into account multiple testing). Additionally, the PRS showed an association with MPN risk when comparing the last with the first quartile of the PRS (OR = 2.39, 95% CI 1.64-3.48, P = 5.98 × 10 -6 ). In conclusion, our results suggest a potential common genetic background between MPN and MM, which needs to be further investigated., (© 2020 UICC.)

Multiple myeloma (MM) is a heterogeneous bone marrow cancer characterized by proliferation of malignant plasma cells in the bone marrow. One of its major symptoms are hypercalcaemia and bone lesions, which may result in pathologic bone fractures. Receptor activator for nuclear factor κB (RANK) and its ligand, RANKL, are part of an activation pathway for osteoclasts and are thus responsible for bone resorption. Furthermore, RANKL expression is increased in multiple myeloma. In the present study, we investigated the role of single nucleotide polymorphisms (SNPs) in the genes coding for RANK (rs1805034, rs8086340), RANKL (rs7325635, rs7988338), and TACI (rs34562254), a receptor for osteoclast-derived pro-survival factors. The study involved 222 patients and 222 healthy individuals, and the analysis included disease susceptibility, survival, bone lesions, calcium levels, and vascular endothelial growth factor levels. Patients with allele RANK rs1805034 C had higher survival (p = .003). This relationship was especially evident in women (p = .006). Furthermore, allele rs1805034 C was associated with slightly lower median age at diagnosis (64.0 vs. 65.5, p = .008). Allele RANKL rs7325635 A correlated with lower progression-free survival (p = .027), and with lack of early progression (p = .023). Additionally, women with allele rs7325635 G were found to have higher calcium blood concentration (p = .040). Allele TACI rs34562254 A was more common in MM patients in more advanced stages (II and III stage International Staging System) at diagnosis (p = .017), and the SNP showed a slight trend towards association in a multivariate analysis (p = .084). Taken together, our results suggest that RANK rs1805034 and RANKL rs7325635 may have a role in MM development and progression., (© 2020 Wiley Periodicals LLC.)

Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms (SNPs) in the CRBN gene may influence response to lenalidomide in multiple myeloma (MM). Fourteen tagging SNPs covering the genetic variability in the CRBN gene region were genotyped in 167 Polish patients with refractory/relapsed MM treated with lenalidomide-based regimens. We found that carriers of minor alleles of two studied CRBN SNPs rs1714327G > C (OR = 0.26; 95% CI = 0.1-0.67; p  = .0055, Bonferroni corrected p  = .033) and rs1705814T > C (OR = 0.22; 95% CI = 0.07-0.65; p  = .0063, Bonferroni corrected p  = .037) were significantly associated with lower probability of achievement at least partial remission while treated with lenalidomide-based regimens, using the dominant inheritance model. Moreover, one of these SNPs, namely rs1705814T > C, was correlated with shorter progression-free survival (HR = 2.49; 95%CI = 1.31-4.74, p  = .0054, Bonferroni corrected p  = .033). It is suggested that selected germline CRBN allelic variants (rs1714327G > C and rs1705814T > C) affect lenalidomide efficacy in patients with relapsed/refractory MM.

Genetic variants in genes acting during the maturation process of immature B-cell to differentiated plasma cell could influence the risk of developing multiple myeloma (MM). During B-cell maturation, several programmed genetic rearrangements occur to increase the variation of the immunoglobulin chains. Class switch recombination (CSR) is one of the most important among these mechanisms. Germline polymorphisms altering even subtly this process could play a role in the etiology and outcome of MM. We performed an association study of 30 genetic variants in the key CSR genes, using 2632 MM patients and 2848 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the Heidelberg MM Group and the ESTHER cohort. We found an association between LIG4 -rs1555902 and decreased MM risk, which approached statistical significance, as well as significant associations between AICDA- rs3794318 and better outcome. Our results add to our knowledge on the genetic component of MM risk and survival.

Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Multiple myeloma is a hematological malignancy, which sometimes creates difficulties in diagnosis, based on the presence of monoclonal protein in serum/urine and plasmocyte infiltration in the bone marrow, and on the other hand, synchronous cancers are also a diagnostic challenge. We present a case report of a patient with concurrent breast cancer and multiple myeloma. A 68-year-old woman was admitted to the hospital with diagnosis of left breast cancer in first stage of the disease. In the past, she had had several episodes of thrombocytopenia, leucocytosis, and mild anaemia, which were followed by hematologist in outpatient setting. She was operated and started adjuvant chemotherapy. During treatment, episodes of hematological abnormalities were observed. After completion of the chemotherapy for breast cancer, the patient was observed and short time after that multiple myeloma was diagnosed as a synchronous cancer. Patient was first treated for breast cancer, then subsequently for multiple myeloma (2 lines therapy: CTD and VMP). We describe diagnostic problems with multiple myeloma; however, they could be caused by curation of breast cancer, which might have supressed the proliferation of plasmocytes and could delay the diagnosis. All symptoms of multiple myeloma were interpreted as a secondary effect of chemotherapy. Review of the literature shows the clinical approaches in such situations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background/aim: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) play an important role in the initiation of angiogenesis. We aimed to assess whether polymorphisms within the genes coding for these angiogenic activators (VEGF (rs3025039;C>T) and bFGF (rs308395;G>C)) contribute to susceptibility and/or progression in multiple myeloma patients (MM) and to chemotherapy., Patients and Methods: One hundred and thirty-two patients with MM and 122 controls were genotyped for the VEGF and bFGF alleles by the PCR-RFLP technique. Genotyping results were compared regarding progression, risk of disease and response to treatment., Results: Patients in stage I-II disease (Durie-Salmon criteria) more frequently carried the bFGF -921G allele compared to patients in stage III (p=0.053) and healthy controls (OR=2.010, p=0.040). Progression after first-line chemotherapy was more frequent among patients carrying this variant (p=0.022)., Conclusion: Our results imply that the course of disease in MM patients is associated with a polymorphism within the bFGF gene., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3'UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk., (© 2016 UICC.)

Multiple myeloma (MM) is a plasma-cell malignancy derived from an early precursor of the B-cell lineage characterised by bone-marrow infiltration, lytic bone lesions, and the presence of a monoclonal protein in serum and/or urine. Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B-cell development and function that is required during immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Immunomodulatory drugs, derivatives of thalidomide, are commonly used in therapy against MM. They are known to target a protein called cereblon (CRBN); however, the exact mechanism remains unknown. The present study aimed to assess the association of two (rs12203592 and rs872071) polymorphisms within the IRF4 gene and two (rs711613 and rs1045433) in the CRBN gene with MM susceptibility, progression, and response to treatment. For this purpose, 144 MM patients and 126 healthy individuals were genotyped for the IRF4 and CRBN alleles. The presence of the IRF4 (rs872071) G allele was more frequently detected in patients than healthy individuals (OR 1.78; P = 0.034), and this relationship was especially pronounced in women (OR 2.83; P = 0.012). The CRBN (rs711613) A allele-carriers were better responders to the treatment (P = 0.012), in particular to thalidomide including therapy (P = 0.023). These results underline the prognostic significance of the IRF4 and CRBN polymorphisms in patients with MM.

Recent studies have suggested that cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide, and that dysregulation of Wnt/β-catenin pathway may be one of possible reasons of lenalidomide resistance. This prompted us to analyze the effect of polymorphisms within the genes coding for cereblon (CRBN (rs121918368 C>T)) and β-catenin (CTNNB1 (rs4135385 A>G; rs4533622 A>C)). MM patients (n=142) and healthy individuals (n=123) were genotyped using the Light SNiP assays. The presence of the CTNNB1 (rs4533622) A allele was more frequently detected in patients presented with stage II-III disease according to International Staging System (63/82 vs. 26/44, p=0.043) and Durie-Salmon criteria (75/99 vs. 14/26, p=0.049). The CTNNB1 (rs4135385) AA homozygosity was more frequent among patients with better response to CTD, i.e., cyclophosphamide-thalidomide-dexamethasone (18/23 vs. 32/60, p=0.047). Patients carrying the CTNNB1 (rs4533622) AA genotype were better responders to the first line therapy with thalidomide containing regimens (p<0.05). No significant association was observed between the effect of lenalidomide therapy and polymorphisms studied. However, the occurrence of neutropenia during lenalidomide therapy was more frequent among the CTNNB1 (rs4135385) AA carriers (p=0.019), while the CTNNB1 (rs4533622) AA homozygosity characterized patients with high grade (3-4) neutropenia (p=0.044). No association was found for the CRBN polymorphism. These results suggest that the CTNNB1 polymorphisms may affect the clinical course and response to chemotherapy in patients with multiple myeloma., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Multiple myeloma (MM) is a plasma cell malignancy characterized by bone marrow infiltration and the presence of a monoclonal protein in serum and/or urine. CXCR4 and its ligand CXCL12 are essential for neoplastic cell homing to bone marrow in haematological malignancies. The JAK2/STAT3 pathway, which is activated after CXCL12 binding to CXCR4, takes part in many signalling cascades which are linked to cell proliferation and cell survival. Constitutive activation of this pathway plays an important role in tumourigenesis and malignant transformation. The present study aimed to determine the association between the polymorphic features located within the CXCR4 (rs2228014) and CXCL12 (rs1801157) encoding genes and disease susceptibility and progression. For this purpose 172 individuals including 54 patients with MM and 118 healthy controls were typed for the CXCL12 (A/G) and CXCR4 (C/T) alleles using the PCR-RFLP technique. The CXCL12 alleles and genotypes segregated similarly among patients and controls while the CXCR4 T variant was less frequently represented among patients (OR=0.074, p<0.001). All patients with the CXCR4 T allele and 16 out of 48 with wild type genotype presented with grade III of MM according to the International Staging System (ISS) (p=0.047). The CXCL12-3'A variant was more frequently detected in patients with less advanced MM (9/17 vs. 7/38, p=0.012 for patients in stage IA or IIA vs. IIB, IIIA and IIIB, respectively). Moreover, patients lacking the CXCL12-3'A variant more frequently presented with ISS II-III (32/38 vs. 5/13, p=0.003 for patients lacking CXCL12-3'A with ISS>I vs. ISS=I). This favourable effect of the CXCL12-3'A allele was also seen in the analysis of patient survival (p<0.05). The impact of the CXCL12-3'A allele was confirmed by multivariate analyses. In conclusion, these results imply that the CXCL12-3'A allele plays a favourable role in patients with multiple myeloma., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The amyloidoses are group of heterogeneous disorders, in which synthesized and secreted proteins, as a soluble molecules, are formed into insoluble, fibrillar tissue deposits, leading to organ dysfunction. Classification now is based on the chemical nature of the fibrillar component of the deposits. One of these is light-chain amyloidosis (AL). The aim of the study was to describe of multiple myeloma patients and amyloidosis. The study group consisted of 45 patients (16 men and 29 women). The diagnosis was made by fine-needle aspiration of subcutaneous fat and then staining the tissue with Congo red. We also analyse the concentration of the serum SAA. We analyse the most characteristic features of AL as hearth failure, proteinuria, renal failure, carpal tunnel syndrome, hepatosplenomegaly, macroglossia and orthostatic hypotension. Among the multiple myeloma patients we found 17 with AL amyloid and 35 persons with elevated concentration of the serum SAA. The most frequent symptoms were related with renal failure and heart failure.

Multiple myeloma (MM) is a plasma cell malignancy characterised by bone marrow infiltration and the presence of a monoclonal protein in serum and/or urine. Interleukin-6 (IL-6) has been identified as one of the most important cytokines that contributes to myeloma cell survival and proliferation. Recent investigations suggest involvement of another cytokine, IL-10, in the activation of MM cells. The present study aimed to determine whether there is an association between the polymorphic features located within the promoter regions of IL-6 and IL-10 genes and progression the disease. IL-6 (-174 G/C) and IL-10 (-1082 A/G, -819 C/T, -592 A/C) promoter single nucleotide polymorphisms (SNPs) were determined by PCR-SSP technique using commercial primers. Our single centre results were compared with the data from literature and combined in cumulative analysis employing the Mantel-Haenszel method. In univariate analysis, only IL-10 ACC genotype tended to prevail in our (Polish) group of patients. None of IL-6 genotypes or IL-10 (-1082) alleles was found to associate with MM disease either in our single centre or in cumulative study. Among patients who died within 36 months of diagnosis, a significant prevalence (P < 0.05) of IL-6 heterozygous cases as opposed to IL-6 homozygotes was observed. IL-6 and IL-10 promoter gene polymorphisms were not found to associate with the susceptibility to the development of MM. However, the IL-6 polymorphic features appeared as factors that might affect the survival of MM patients. The latter observation warrants further study.

A total of 34 multiple myeloma (MM) patients (17 recently diagnosed and 17 in progression of the disease) treated at the Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation Medical University in Wrocław were studied. Among the 19 females and 15 males, aged 31-72 years, there were 17 IgG, 9 IgA and 1 IgM, one with plasma cell leukaemia and 6 with light chain disease. Staging according to Durie and Salmon disclosed: 7--IIA stage, 15--IIIA and 12--IIIB. Blood hyperviscosity symptoms (HS) developed in 9 patients, and precomatic state or coma was observed in four of them. Control group was constituted of 14 healthy subjects--10 women and 4 men aged 32-51 years. Vascular endothelial growth factor (VEGF) serum concentration in MM patients varied from 0 pg/ml to 760 pg/ml, mean 148.75 pg/ml, SD = 204.4 and in controls 0 pg/ml--164 pg/ml, mean 31.5, SD = 23.3; p < 0.05. The mean VEGF level in recently diagnosed patients was higher than in progression of the disease, mean 188.6 pg/ml, SD = 230.6 and mean 110.9 pg/ml, SD = 177.9; respectively, but the difference was not statistically significant. The patients with stage III had significantly (p < 0.05) higher VEGF level than those in stage II (mean 303.1 pg/ml, SD = 302.2 and mean 89.0 pg/ml SD = 121.6) respectively. The group of MM patients with renal failure (creatinine level > 2 mg%) had higher VEGF level than those with normal renal function: mean 199.9 pg/ml, SD = 235, and mean 46.9 SD = 47 respectively, p < 0.01. Elevated VEGF level was also present in comatic and precomatic patients when compared with hyperviscosity patients without these symptoms (p < 0.05). In multiple myeloma patients no correlation was found between the serum VEGF level and percentage of bone marrow plasma cells, serum beta-2-m and monoclonal Ig levels, levels of Hb, albumine and LDH. Median survival time (M-ST) of patients with VEGF higher than 71, 0 pg/ml was 32 months, M-ST of patients with VEGF below 71 pg/ml was 52 months. In summary: serum level of VEGF in advanced state of multiple myeloma was elevated and correlated with clinical state. An elevated serum level of VEGF is associated with a poor prognosis.

Multiple myeloma (MM) is a plasma-cell malignancy derived from an early precursor of the B-cell lineage characterised by bone-marrow infiltration, lytic bone lesions, and the presence of a monoclonal protein in serum and/or urine. Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B-cell development and function that is required during immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Immunomodulatory drugs, derivatives of thalidomide, are commonly used in therapy against MM. They are known to target a protein called cereblon (CRBN); however, the exact mechanism remains unknown. The present study aimed to assess the association of two (rs12203592 and rs872071) polymorphisms within the IRF4 gene and two (rs711613 and rs1045433) in the CRBN gene with MM susceptibility, progression, and response to treatment. For this purpose, 144 MM patients and 126 healthy individuals were genotyped for the IRF4 and CRBN alleles. The presence of the IRF4 (rs872071) G allele was more frequently detected in patients than healthy individuals (OR 1.78; P = 0.034), and this relationship was especially pronounced in women (OR 2.83; P = 0.012). The CRBN (rs711613) A allele-carriers were better responders to the treatment ( P = 0.012), in particular to thalidomide including therapy ( P = 0.023). These results underline the prognostic significance of the IRF4 and CRBN polymorphisms in patients with MM. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are short RNA molecules that can suppress gene expression as part of epigenetic regulatory mechanisms. Many miRNAs were found to be involved in various diseases, including haematological malignancies. Single nucleotide polymorphisms (SNPs) located in and around genes coding for these miRNAs can affect their expression. In the present study, we aimed to analyse three SNPs associated with miR-196a-2 (rs11614913 C>T), miR-146a (rs2910164 C>G), and miR-9-3 (rs4335754 A>G) in the context of multiple myeloma. For this purpose, we used DNA samples from 253 multiple myeloma patients and genotyped them for the three SNPs. We found patients with allele rs4335754 G were characterized by longer overall survival (p = 0.009) and lower calcium blood levels (p = 0.048) than patients lacking this allele. Additionally, patients with complete/partial remission after first line of treatment were more likely to carry rs4335754 G than those with minor/no response (p = 0.024), whereas among patients treated with CTD regimen as first line therapy, those with remission or stable disease were more likely to carry allele rs11614913 C than those with progression (p = 0.048). As for the miR-146a rs2910164 SNP, a trend was observed for better progression-free survival in patients with allele rs2910164 G (p = 0.056). These results suggest that alleles rs4335754 G and rs11614913 C may be associated with longer overall survival and better response to treatment in patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis (neovascularization) is a multistep process in which new blood vessels grow from existing vessels. Angiogenesis is associated with the growth, dissemination, and metastasis of solid tumors. There is increasing evidence that neovascularization may be important in hematological malignancies. Several studies suggest that vascular endothelial growth factor (VEGF) is one of the most important cytokines responsible for the development, maintenance, and progression of multiple myeloma (MM) by promoting bone marrow angiogenesis. A high serum concentration of VEGF has been reported in MM patients. The aim of this study was to evaluate the expression of VEGF in the bone marrow of MM patients. Methods: Eighteen paraffin-embedded bone marrow core biopsy specimens from newly diagnosed patients with MM were evaluated. In addition, 10 bone marrow core biopsy specimens from adult patients without evidence of malignancy were used as controls. Bone marrow sections were stained immunohistochemically for VEGF. Results: Our data show that multiple myeloma is associated with an increased expression of VEGF in the bone marrow. Conclusions: Our observation supports previous studies suggesting that angiogenesis may play a role in the pathophysiology of hematopoietic malignancies. The clinical significance of this phenomenon needs further investigation. However, this study provides rationale for the use of angiogenesis inhibitors in MM therapy. [Copyright &y& Elsevier]

Multiple myeloma (MM) is a haematologic malignancy characterized by the presence of atypical plasma cells. Basigin (BSG, CD147) controls lactate export through the monocarboxylic acid transporter 1 (MCT1, SLC16A1) and supports MM survival and proliferation. Additionally, BSG is implicated in response to treatment with immunomodulatory drugs (thalidomide and its derivatives). We investigated the role of single nucleotide polymorphisms (SNPs) in the gene coding for BSG and SLC16A1 in MM. Following an in silico analysis, eight SNPs (four in BSG and four in SLC16A1) predicted to have a functional effect were selected and analyzed in 135 MM patients and 135 healthy individuals. Alleles rs4919859 C, rs8637 G, and haplotype CG were associated with worse progression-free survival (p = 0.006, p = 0.017, p = 0.002, respectively), while rs7556664 A, rs7169 T and rs1049434 A (all in linkage disequilibrium (LD), r2 > 0.98) were associated with better overall survival (p = 0.021). Similar relationships were observed in thalidomide-treated patients. Moreover, rs4919859 C, rs8637 G, rs8259 A and the CG haplotype were more common in patients in stages II–III of the International Staging System (p < 0.05), while rs8259 A correlated with higher levels of β-2-microglobulin and creatinine (p < 0.05). Taken together, our results show that BSG and SLC16A1 variants affect survival, and may play an important role in MM. [ABSTRACT FROM AUTHOR]