[show abstract][hide abstract] ABSTRACT: Background: Genetic background plays a role in multiple myeloma (MM) susceptibility. Several single nucleotide polymorphisms (SNPs) associated with genetic susceptibility to MM were identified in the last years, but only few of them were validated in independent studies. Methods: With the aim to conclusively validate the strongest associations so far reported, we selected the polymorphisms rs2227667 (SERPINE1), rs17501108 (HGF), rs3136685 (CCR7), rs16944 (IL1B), rs12147254 (TRAF3), rs1805087 (MTR), rs1800629 (TNF-α), rs7516435 (CASP9), rs1042265 (BAX), rs2234922 (mEH), and rs1801133 (MTHFR). We genotyped them in 1498 MM cases and 1934 controls ascertained in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium, and meta-analyzed our results with previously published ones. Results: None of the selected SNPs were significantly associated with MM risk (p-value range: 0.055 - 0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women. Conclusions: We can exclude that the selected polymorphisms are major MM risk factors. Impact: Independent validations studies are crucial to identify true genetic risk factors. Our large-scale study clarifies the role of previously published polymorphisms in MM risk.
Cancer Epidemiology Biomarkers & Prevention 02/2014; · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: The exposure to pesticides and toxic compounds in xenobiotic transport and metabolism genes has been shown to affect risk of developing multiple myeloma (MM). Therefore, we hypothesized that genetic variations in xenobiotic transport and metabolism regulator genes PXR (NR1I2) and CAR (NR1I3) could determine a difference in MM susceptibility. Ten tagging single-nucleotide polymorphisms (SNPs) for PXR and seven for the CAR genes were selected and genotyped in 627 MM cases and 883 controls collected in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium. None of the 17 SNPs investigated showed significant association with MM risk either alone or when combined in haplotypes. Significant SNP-SNP interactions were not found, neither with 58 previously genotyped polymorphisms in ABC transporters. We can therefore exclude that common genetic variants in the xenobiotic transport and metabolism regulator genes PXR and CAR affect MM risk.Journal of Human Genetics advance online publication, 10 January 2013; doi:10.1038/jhg.2012.149.
Journal of Human Genetics 01/2013; · 2.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: We conducted a retrospective study to compare thalidomide, bortezomib and dexamethasone (VTD) with thalidomide plus doxorubicin and dexamethasone (TAD). Until now, first-line treatment with these combinations has not been reported in any comparative study. The principal objective of this study was to determine whether VTD would improve the complete response (CR) and CR plus very good partial response rates compared with TAD. Second, using additional methods, such as flow cytometric assays and polymerase chain reaction technology, we evaluated the molecular residual disease in the subgroup of patients that obtained CR. Our study shows that VTD is a superior induction regimen compared with TAD, with a higher response rate after induction, translating into greater CR plus very good partial response.
[show abstract][hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have shown that the 8q24 region harbours multiple independent cancer susceptibility loci, even though it is devoid of genes. Given that no GWAS data are currently available for multiple myeloma (MM), we tested the hypothesis that genetic variants in this region could play a role in MM risk. We genotyped 20 single nucleotide polymorphisms of 8q24 in 1188 MM cases and 2465 controls and found a statistically significant (P = 0·0022) association between rs2456449 and MM risk. These data provide further evidence that the genetic variability in the 8q24 region is associated with cancer risk, particularly haematological malignancies.
British Journal of Haematology 05/2012; 157(3):331-8. · 4.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cytokines play a central role in multiple myeloma (MM) pathogenesis thus genetic variations within cytokines coding genes could influence MM susceptibility and therapy outcome. We investigated the impact of 8 SNPs in these genes in 202 MM cases and 235 controls also evaluating their impact on therapy outcome in a subset of 91 patients. Despite the overall negative findings, we found a significant age-modified effect of IL6 and TNF-α SNPs, on MM risk and therapy outcome, respectively. Therefore, this observation suggests that genetic variation in inflammation-related genes could be an important mediator of the complex interplay between ageing and cancer.
Leukemia research 03/2012; 36(5):594-7. · 2.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is strong evidence suggesting the presence of a genetic component in the aetiology of multiple myeloma (MM). However no genetic risk factors have been unequivocally established so far. To further our understanding of the genetic determinants of MM risk, a promising strategy is to collect a large set of patients in a consortium, as successfully done for other cancers. In this article, we review the main findings in the genetic susceptibility and pharmacogenetics of MM and present the strategy of the IMMEnSE (International Multiple Myeloma rESEarch) consortium in contributing to determine the role of genetic variation in pharmacogenetics and in MM risk.
International Journal of Oncology 12/2011; 40(3):625-38. · 2.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: The control of nausea and vomiting induced by chemotherapy is paramount for overall treatment success in cancer patients. Antiemetic therapy during chemotherapy in lymphoma patients generally consists of anti-serotoninergic drugs and dexamethasone. The aim of this trial was to evaluate the efficacy of a single dose of palonosetron, a second-generation serotonin type 3 (5-HT(3)) receptor antagonist, in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy (MEC) containing steroids.
Patients received a single intravenous bolus of palonosetron (0.25 mg) before administration of chemotherapy. Complete response (CR) defined as no vomiting and no rescue therapy during overall phase (0-120 h) was the primary endpoint. Complete control (CC) defined as CR and only mild nausea was a secondary endpoint.
Eighty-six evaluable patients entered in the study. A CR was observed in 74 patients (86.0%) during the overall phase; the CR during the acute (0-24 h) and delayed (24-120 h) phases was 90.7% and 88.4%, respectively. CC was 89.5% during the acute and 84.9% during the delayed phase; the overall CC was 82.6%.
This was the first trial, which demonstrated the efficacy of a single dose of palonosetron in control CINV in patients with aggressive non-Hodgkin's lymphoma receiving MEC regimen containing steroids.
Supportive Care in Cancer 10/2011; 19(10):1505-10. · 2.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Several trials comparing the efficacy of standard melphalan and prednisone (MP) therapy with MP plus thalidomide (MPT) in elderly patients with multiple myeloma (MM) have been reported, with inconsistent results. The primary goal of our study was to evaluate the efficacy and toxicity of MP versus MPT in newly diagnosed patients with MM who were transplant-ineligible or over age 65. A total of 135 patients were enrolled. Either minimal response or better or partial response or better were more frequent with MPT treatment (p = 0.001). After a median follow-up of 30 months, median progression-free survival (PFS) and overall survival (OS) were 33 and 52 months for MPT versus 22 and 32 months for MP, respectively. The comparison showed a significant advantage for MPT versus MP in PFS (p = 0.02) and only a trend for OS (p = 0.07). Severe adverse events were observed more frequently with MPT. In conclusion, our results show an improved activity of MPT at a cost of increased toxicity. We believe that MPT can be considered one of the new standard of care for elderly or transplant-ineligible patients with MM.
[show abstract][hide abstract] ABSTRACT: The aim of this study was to show a lower incidence of febrile episodes in multiple myeloma patients receiving lenograstim vs. filgrastim after high-dose cyclophosphamide for stem cell mobilization. Patients treated with cyclophosphamide were randomly assigned to receive filgrastim or lenograstim. Primary endpoint was the incidence of febrile episodes. 5.1% patients developed a febrile episode, 9.1% with filgrastim and 1.1% with lenograstim. Lenograstim group presented a significantly higher absolute CD34+ cell number compared with the filgrastim group but no differences were detected for collection efficacy. The study demonstrated a lower incidence of febrile episodes with lenograstim compared to filgrastim.
Leukemia research 12/2010; 35(7):899-903. · 2.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Single nucleotide polymorphisms (SNPs) in the multiple drug resistance protein 1 (MRP1) and P-glycoprotein 1 (MDR1) genes modulate their ability to mediate drug resistance. We therefore sought to retrospectively evaluate their influence on outcomes in relapsed and/or refractory myeloma patients treated with bortezomib or bortezomib with pegylated liposomal doxorubicin (PLD). The MRP1/R723Q polymorphism was found in five subjects among the 279 patient study population, all of whom received PLD + bortezomib. Its presence was associated with a longer time to progression (TTP; median 330 vs. 129 days; p = 0.0008), progression-free survival (PFS; median 338 vs. 129 days; p = 0.0006), and overall survival (p = 0.0045). MDR1/3435(C > T), which was in Hardy-Weinberg equilibrium, showed a trend of association with PFS (p = 0.0578), response rate (p = 0.0782) and TTP (p = 0.0923) in PLD + bortezomib patients, though no correlation was found in the bortezomib arm. In a recessive genetic model, MDR1/3435 T was significantly associated with a better TTP (p = 0.0405) and PFS (p = 0.0186) in PLD + bortezomib patients. These findings suggest a potential role for MRP1 and MDR1 SNPs in modulating the long-term outcome of relapsed and/or refractory myeloma patients treated with PLD + bortezomib. Moreover, they support prospective studies to determine if such data could be used to tailor therapy to the genetic makeup of individual patients.
Annals of Hematology 11/2010; 89(11):1133-40. · 2.87 Impact Factor