J F San Miguel

Centro de Investigación del Cáncer, Helmantica, Castille and León, Spain

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Publications (635)3341.56 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We have evaluated the use of CD138+ positively selected bone marrow samples to identify a molecular target for minimal residual disease assessment by polymerase chain reaction (PCR) in 25 untreated patients with multiple myeloma. A fraction of each sample was used for CD138+ selection, and the rest served as a reference control. VDJH, DJH, and Kde gene rearrangements were tested for amplification according to the BIOMED-2 Concerted Action. PCR products were directly sequenced in an automated ABI 3130 DNA sequencer using Big-Dye terminators. Within the CD138+ selected group, VDJH rearrangements were detected in all cases (100 %), DJH in 16 (64 %), and Kde in 18 (72 %) cases; whereas in the control samples, VDJH, DJH, and Kde rearrangements were detected in 19 (76 %), 11 (44 %), and 12 (48 %) cases, respectively. After sequencing, 24 (96 %) cases within the CD138+ group had a PCR target for MRD detection compared with 15 (60 %) cases in the control group. We conclude that the use of CD138+ positively selected bone marrow samples increases the applicability of minimal residual disease studies by PCR in patients with multiple myeloma.
    Annals of Hematology 09/2012; · 2.40 Impact Factor
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    ABSTRACT: Background. Cytogenetic studies in clonal plasma cell diseases have mainly been done in whole bone marrow or CD138+ microbead-enriched plasma cells and suggest that recurrent immunoglobulin heavy chain translocations - e.g. t(4;14) - are primary oncogenetic events. The aim of this study is to determine cytogenetic patterns of highly purified aberrant plasma cells (median purity ≥98%) in different clonal plasma cell diseases. Design and Methods. We analyzed aberrant plasma cells from 208 patients with multiple myeloma (n=148) and monoclonal gammopathy of undetermined significance (n=60) for the presence of del(13q14), del(17p13) and t(14q32) using multicolor interphase fluorescence in situ hybridization. Additionally, analysis of immunoglobulin heavy chain gene arrangements and complementarity determining region 3 sequencing was carried out in a subset of patients and combined multicolor interphase fluorescence in situ hybridization/immunofluorescent protein staining analyses were performed in selected cases to confirm clonality and cytogenetic findings. Results. At diagnosis, 96% of multiple myeloma versus 77% of monoclonal gammopathy of undetermined significance cases showed at least one cytogenetic alteration and/or hyperdiploidy. The cytogenetic heterogeneity of individual cases reflected coexistence of cytogenetically-defined aberrant plasma cell clones, and led to assume that karyotypic alterations were acquired stepwise. Multiple myeloma and monoclonal gammopathy of undetermined significance cases frequently showed different but related cytogenetic profiles when other cytogenetic alterations such as deletions/gains of the immunoglobulin heavy chain and the fibroblast growth factor receptor 3 were additionally considered. Interestingly, in 24% of multiple myeloma versus 62% of monoclonal gammopathy of undetermined significance patients aberrant plasma cells with and without t(14q32) coexisted in the same patient. Conclusions. Our data suggest that recurrent immunoglobulin heavy chain translocations might be absent in the primordial plasma cell clone in a significant proportion of patients with clonal plasma cell diseases carrying these cytogenetic alterations.
    Haematologica 08/2012; · 5.94 Impact Factor
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    ABSTRACT: Background. Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two these life-threatening complications in these complex patients are currently not well defined. Design and Methods. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Results. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft versus host disease to be the only independent prognostic risk factor. By contrast, eight factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III - IV graft versus host disease and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (p = 0.856). However, significant clinical bleeding was associated with inferior survival (p < 0.001). Conclusions. In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.
    Haematologica 08/2012; · 5.94 Impact Factor
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    ABSTRACT: Melphalan 200 mg/m(2) (MEL200) is the standard conditioning regimen administered to newly diagnosed patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). Few alternatives have been explored in order to improve the antimyeloma activity of this conditioning. We compare i.v. busulfan (BU) 9.6 mg/kg and MEL 140 mg/m(2) (MEL140) versus MEL200 mg/m(2) as a conditioning regimen before ASCT for newly diagnosed patients with MM. For this purpose, 51 patients receiving i.v. BU plus MEL were compared to 102 patients receiving MEL200 mg/m(2) in a 1:2 matched control analysis. Matching criteria included age, clinical stage at diagnosis, and response to induction therapy. No differences in the overall and complete response (CR) rates were observed after ASCT between both groups. After a median follow-up of 63 and 50 months in control and BU plus MEL groups, progression-free survival (PFS) was 24 and 33 months, respectively (P = .10). Most frequent toxicities included mucositis and febrile neutropenia in both groups. No case of sinusoidal obstruction syndrome was observed. Transplant-related mortality was 4% and 2% in BU plus MEL and control groups, respectively. ASCT conditioned with i.v. BU plus MEL may be considered an effective and well-tolerated alternative to a MEL-only approach as a conditioning regimen for patients with MM who are candidates for ASCT. (Clinicaltrials.gov identifier: NCT00560053 and NCT00804947.).
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 08/2012; · 3.15 Impact Factor
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    ABSTRACT: Several studies have evaluated the prognostic value of the individual expression of certain genes in patients with myelodysplastic syndromes (MDS). However, none of them includes their simultaneous analysis by quantitative polymerase chain reaction (PCR). We evaluated relative expression levels of 14 molecular markers in 193 peripheral blood samples from untreated MDS patients using real-time PCR. Detectable WT1 expression levels, low TET2, and low IER3 gene expression were the only markers showing in univariate analysis a poor prognostic value for all treatment-free (TFS), progression-free (PFS), and overall survival (OS). In multivariate analysis, molecular parameters associated with a shorter TFS were: WT1 detection (p = 0.014), low TET2 (p = 0.002), and low IER3 expression (p = 0.025). WT1 detection (p = 0.006) and low TET2 (p = 0.006) expression were associated with a shorter PFS when multivariate analysis was carried out by including only molecular markers. Molecular values with an independent value in OS were: WT1 detection (p = 0.003), high EVI1 expression (p = 0.001), and undetectatable p15-CDKN2B (p = 0.037). WT1 expressers were associated with adverse clinical-biological features, high IPSS and WPSS scoring, and unfavorable molecular expression profile. In summary, detectable WT1 expression levels, and low TET2 and low IER3 expression in peripheral blood showed a strong association with adverse prognosis in MDS patients at diagnosis. However, WT1 was the only molecular marker displaying an independent prognostic value in both OS and TFS.
    Annals of Hematology 08/2012; · 2.40 Impact Factor
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    ABSTRACT: The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65 years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81(+) MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05 <65 years trial. Moreover, CD81(+) SMM (n=34/56, 57%) patients had a shorter time to progression to MM (P=0.02). Overall, our results show that CD81 may have a relevant role in MM pathogenesis and represent a novel adverse prognostic marker in myeloma.
    Leukemia 08/2012; 26(8):1862-9. · 9.38 Impact Factor
  • S Vincent Rajkumar, Giampaolo Merlini, Jesus F San Miguel
    Nature Reviews Clinical Oncology 07/2012; 9(9):494-6. · 15.03 Impact Factor
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    ABSTRACT: Minimal residual disease (MRD) assessment by PCR in multiple myeloma (MM) has several shortcomings, including the lack of a suitable target. Kappa deleting element (KDE) rearrangements occur in virtually all Ig-lambda B-cell malignancies and in 1/3 of Ig-kappa are not affected by somatic hypermutation and, as in ALL, could be used as PCR targets. We have first investigated the incidence, gene segment usage, and CDR3 composition of IGK-KDE rearrangements in 96 untreated myeloma patients. Second, we tested 16 KDE gene rearrangements as molecular targets for MRD assessment by RQ-PCR using a germline reverse primer and a germline Taqman probe in combination with allele-specific oligonucleotides (ASO) as forward primers. Monoclonal KDE rearrangements were amplified in 45% (43/96) of cases, monoallelic in 2/3 of them (29 cases), and biallellic in the remaining 14 cases. Overall, 88% of cases were successfully sequenced, KDE being equally frequently rearranged with VK and with intron-Recombination signal sequence (RSS). Median numbers of inserted and deleted nucleotides in the junctional region were one and five, respectively. Using KDE rearrangements as additional PCR target for MRD assessment in MM improves the applicability of these studies in 9% of cases overall and in 20% of lambda cases. Its use in the latter subset could represent a significant advance.
    European Journal Of Haematology 07/2012; 89(4):328-35. · 2.41 Impact Factor
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    ABSTRACT: The Spanish Myeloma Group conducted a trial to compare bortezomib/thalidomide/dexamethasone (VTD) versus thalidomide/dexamethasone (TD) versus vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib (VBMCP/VBAD/B) in patients aged 65 years or younger with multiple myeloma. The primary endpoint was complete response (CR) rate postinduction and post-autologous stem cell transplantation (ASCT). Three hundred eighty-six patients were allocated to VTD (130), TD (127), or VBMCP/VBAD/B (129). The CR rate was significantly higher with VTD than with TD (35% vs 14%, P = .001) or with VBMCP/VBAD/B (35% vs 21%, P = .01). The median progression-free survival (PFS) was significantly longer with VTD (56.2 vs 28.2 vs 35.5 months, P = .01). In an intention-to-treat analysis, the post-ASCT CR rate was higher with VTD than with TD (46% vs 24%, P = .004) or with VBMCP/VBAD/B (46% vs 38%, P = .1). Patients with high-risk cytogenetics had a shorter PFS and overall survival in the overall series and in all treatment groups. In conclusion, VTD resulted in a higher pre- and posttransplantation CR rate and in a significantly longer PFS although it was not able to overcome the poor prognosis of high-risk cytogenetics. Our results support the use of VTD as a highly effective induction regimen prior to ASCT. The study was registered with http://www.clinicaltrials.gov (NCT00461747) and Eudra CT (no. 2005-001110-41).
    Blood 07/2012; 120(8):1589-96. · 9.78 Impact Factor
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    ABSTRACT: Introduction The RAS/RAF/MEK/ERK signaling pathway plays an important role in osteoclast (OC) differentiation and survival mediated by macrophage-colony stimulating factor (M-CSF). Also, vascular endothelial growth factor (VEGF) may greatly influence OC formation and resorption through VEGFR1 and VEGFR2. RAF265 is a novel, orally bioavailable dual inhibitor of RAF kinase and VEGFR2. Methods Effect of RAF265 on osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) and OC resorption on calcium-coated wells was assessed by appropriate in vitro assays. Immunoblotting, real-time RT-PCR and flow cytometry were used to evaluate RAF265 mechanism of action. Results RAF265 significantly impaired in vitro differentiation of PBMCs to OCs induced by receptor activator of NF-kB ligand (RANKL) and M-CSF (IC(50) ≅ 160 nM). In parallel, RAF265 exerted a potent inhibition of OC resorptive capacity (IC(50) ≅ 20 nM). RAF265 treatment led to ERK inhibition and diminished expression of c-fos and NFATc1 (nuclear factor of activated T cells, calcineurin-dependent 1), which would likely account for inhibition of osteoclastogenesis. The reduced gene expression of aVb3 integrin, CCR1, cathepsin K, carbonic anhydrase II, matrix metalloproteinase 9, urokinase and tissue-type plasminogen activators, vacuolar H(+)-ATPase subunit (ATP6V1A) and Rab7 GTPase would probably mediate RAF265 hindered resorption. RAF265 inhibitory effect on VEGFR2 (noticeable at 10-50 nM) was also found to be implicated in the potent inhibition of this agent on OC function. Conclusions We have found a new therapeutic application for RAF265 as an inhibitory agent of osteoclastogenesis and OC function, which might be useful for the treatment of skeletal disorders associated with increased bone resorption.
    Investigational New Drugs 07/2012; · 3.50 Impact Factor
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    ABSTRACT: Background. Multiple myeloma remains largely incurable. However, a few patients experience ≥10-years relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with complete response, since some revert into an MGUS profile. Design and Methods. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of long-term disease control multiple myeloma (n=28) vs. both newly-diagnosed MGUS (n=23) and symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Results. Similarly to MGUS and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8+T-cells and NK-cells. However, bone marrow Tregs were reduced in long-term disease control vs. symptomatic multiple myeloma. Noteworthy, B-cells were depleted in MGUS and symptomatic multiple myeloma, while recovered in long-term disease control patients in both bone marrow and peripheral blood, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B-cells. The number of bone marrow dendritic cells and tissue macrophages significantly differed between long-term disease control and symptomatic multiple myeloma with a recovery trend in the former patient population towards levels similar to those found in healthy adults.Conclusions. In summary, our results indicate that long-term disease control multiple myeloma patients have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting an improved immunesurveillance.Keywords: myeloma, long term follow-up, immunesurveillance, T-cells, Tregs, B-cells.
    Haematologica 07/2012; · 5.94 Impact Factor
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    ABSTRACT: Proteasome inhibitors (PIs), namely bortezomib, have become a cornerstone therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting pathologic bone destruction. In clinical trials, carfilzomib, a next generation epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. Interactions between myeloma cells and the bone marrow (BM) microenvironment augment the number and activity of bone-resorbing osteoclasts (OCs) while inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth and osteolytic lesions. At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzomib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.Leukemia advance online publication, 27 July 2012; doi:10.1038/leu.2012.183.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; · 10.16 Impact Factor
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    ABSTRACT: Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these "second-generation" PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade.
    Blood 05/2012; 120(5):947-59. · 9.78 Impact Factor
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    ABSTRACT: Genetic events mediating transformation from premalignant monoclonal gammopathies (MG) to multiple myeloma (MM) are unknown. To obtain a comprehensive genomic profile of MG from the early to late stages, we performed high-resolution analysis of purified plasma cells from 20 MGUS, 20 smoldering MM (SMM) and 34 MM by high-density 6.0 SNP array. A progressive increase in the incidence of copy number abnormalities (CNA) from MGUS to SMM and to MM (median 5, 7.5 and 12 per case, respectively) was observed (P=0.006). Gains on 1q, 3p, 6p, 9p, 11q, 19p, 19q and 21q along with 1p, 16q and 22q deletions were significantly less frequent in MGUS than in MM. Although 11q and 21q gains together with 16q and 22q deletions were apparently exclusive of MM status, we observed that these abnormalities were also present in minor subclones in MGUS. Overall, a total of 65 copy number-neutral LOH (CNN-LOH) were detected. Their frequency was higher in active MM than in the asymptomatic entities (P=0.047). A strong association between genetic lesions and fragile sites was also detected. In summary, our study shows an increasing genomic complexity from MGUS to MM and identifies new chromosomal regions involved in CNA and CNN-LOH.Leukemia advance online publication, 19 June 2012; doi:10.1038/leu.2012.128.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2012; · 10.16 Impact Factor
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    ABSTRACT: Background We have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reduce-graft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. DESIGN AND METHODS: We evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. RESULTS: The combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN γ, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. Conclusions The current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.
    Haematologica 04/2012; 97(9):1329-37. · 5.94 Impact Factor
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    ABSTRACT: Bone loss, in malignant or non-malignant diseases, is caused by increased osteoclast resorption and/or reduced osteoblast bone formation, and is commonly associated with skeletal complications. Thus, there is a need to identify new agents capable of influencing bone remodeling. We aimed to further pre-clinically evaluate the effects of dasatinib (BMS-354825), a multitargeted tyrosine kinase inhibitor, on osteoblast and osteoclast differentiation and function. For studies on osteoblasts, primary human bone marrow mensenchymal stem cells (hMSCs) together with the hMSC-TERT and the MG-63 cell lines were employed. Osteoclasts were generated from peripheral blood mononuclear cells (PBMC) of healthy volunteers. Skeletally-immature CD1 mice were used in the in vivo model. Dasatinib inhibited the platelet derived growth factor receptor-β (PDGFR-β), c-Src and c-Kit phosphorylation in hMSC-TERT and MG-63 cell lines, which was associated with decreased cell proliferation and activation of canonical Wnt signaling. Treatment of MSCs from healthy donors, but also from multiple myeloma patients with low doses of dasatinib (2-5 nM), promoted its osteogenic differentiation and matrix mineralization. The bone anabolic effect of dasatinib was also observed in vivo by targeting endogenous osteoprogenitors, as assessed by elevated serum levels of bone formation markers, and increased trabecular microarchitecture and number of osteoblast-like cells. By in vitro exposure of hemopoietic progenitors to a similar range of dasatinib concentrations (1-2 nM), novel biological sequelae relative to inhibition of osteoclast formation and resorptive function were identified, including F-actin ring disruption, reduced levels of c-Fos and of nuclear factor of activated T cells 1 (NFATc1) in the nucleus, together with lowered cathepsin K, αVβ3 integrin and CCR1 expression. Low dasatinib concentrations show convergent bone anabolic and reduced bone resorption effects, which suggests its potential use for the treatment of bone diseases such as osteoporosis, osteolytic bone metastasis and myeloma bone disease.
    PLoS ONE 04/2012; 7(4):e34914. · 3.53 Impact Factor
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    ABSTRACT: Increased risk of acute myeloid leukemia/myelodysplastic syndromes following treatment has been reported in multiple myeloma, but whether dysplastic features are already present at diagnosis remains to be investigated. Using multiparameter flow cytometry, we analyzed the distribution and phenotype of bone marrow hematopoietic cells from 47 multiple myeloma patients (15 symptomatic and 32 high-risk smoldering). From the 32 smoldering myeloma patients, 18 were studied at baseline and 22 after nine cycles of lenalidomide/dexamethasone treatment following the QUIREDEX trial (including 8 from baseline). Phenotypic alterations of bone marrow cells of 7 (47%) symptomatic and 6 (33%) smoldering myeloma patients were detected at baseline; there was no difference in the frequency and extent of phenotypic alterations between symptomatic versus smoldering cases. Likewise, no difference was seen between smoldering myeloma patients studied at baseline versus after lenalidomide/dexamethasone treatment. Our results suggest that phenotypic alterations of bone marrow hematopoietic cells are often present in newly diagnosed symptomatic and smoldering multiple myeloma patients. QUIREDEX trial (NCT00480363).
    Haematologica 04/2012; 97(10):1608-1611. · 5.94 Impact Factor
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    ABSTRACT: PRAME is a tumor associated antigen (TAA) of particular interest since it is widely expressed by lymphoid and myeloid malignancies. Several studies have associated high PRAME RNA levels with good prognosis in acute myeloid leukemia (AML). PRAME expression is regulated at the epigenetic level. For this reason inhibitors of DNA methylation, such as 5-azacytidine, can modulate the expression of this TAAs. In the current study we analyzed the effect of 5-azaC on the expression of PRAME in blasts versus CD34+ cells from healthy donors in an attempt to increase its expression, thus inducing a potential target for therapeutic strategies.
    Leukemia research 04/2012; 36(7):895-9. · 2.36 Impact Factor
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    ABSTRACT: The phase 3 VISTA study (ClinicalTrials.gov NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone (VMP; nine 6-wk cycles) vs. melphalan-prednisone (MP) but also increased toxicity. Health-related quality of life (HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). The phase 3 VISTA study (ClinicalTrials.gov NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone (VMP; nine 6-wk cycles) vs. melphalan-prednisone (MP) but also increased toxicity. Health-related quality of life (HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). EORTC QLQ-C30 was administered at screening, on day 1 of each cycle, at the end-of-treatment visit, and every 8 wk until progression. EORTC QLQ-C30 scores were evaluated among patients with a valid baseline and at least one post-baseline HRQoL assessment. At baseline, domain scores were similar between arms. By cycle 4, mean differences were clinically meaningful for most domains, indicating poorer health status with VMP. From cycle 5 onwards, improvements relative to baseline/MP were observed for all domains with VMP. Mean scores were generally improved by the end-of-treatment assessment vs. baseline in both arms. Among responding patients, mean scores generally improved from time of response to end-of-treatment assessment, substantially driven by patients achieving complete response (CR). Multivariate analysis showed a significant impact of duration of response/CR on improving global health status, pain, and appetite loss scores. Analyses by bortezomib dose intensity indicated better HRQoL in patients receiving lower dose intensity. These findings demonstrate clinically meaningful, transitory HRQoL decrements with VMP and relatively lower HRQoL vs. MP during early treatment cycles, associated with the expected additional toxicities. However, HRQoL is not compromised in the long term, recovering by the end-of-treatment visit to be comparable vs. MP.
    European Journal Of Haematology 04/2012; 89(1):16-27. · 2.41 Impact Factor
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    Marìa-Victoria Mateos, Jesús F San Miguel
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    ABSTRACT: The discovery of the ubiquitin-proteasome pathway first, and the proteasome inhibitors thereafter were not made in the hope of improving the treatment of malignant diseases. However, bortezomib, the first in class proteasome inhibitor introduced in the clinical practice has contributed to improve the outcome of patients with multiple myeloma, at relapse or disease progression as well as upfront. The results observed in a large randomized trial (APEX) comparing bortezomib and high-dose dexamethasone demonstrated a significant benefit for bortezomib in terms of response rate, progression-free and overall survival. These results led to bortezomib being approved for use in relapsed and/or refractory myeloma patients. Subsequent studies demonstrated that its activity could be enhanced in combination with other drugs; and the next step was to move to the newly diagnosed patient population; in fact, bortezomib-melphalan-prednisone (VMP) is approved as a standard of care for newly diagnosed elderly patients. However, toxicity, especially peripheral neuropathy, as well as the intravenous route required for its administration are the two most significant bortezomib-related issues. To try to reduce the peripheral neuropathy, new guidelines for its management and the introduction of weekly schedules of administration have contributed to significantly decrease its incidence and the subcutaneous administration has been recently introduce to avoid the intravenous (IV) route. Results obtained in phase I/II and III studies have confirmed that subcutaneous administration is feasible and represents an additional step towards the optimization of bortezomib use, resulting in a probably more convenient method than the IV route that is at least as effective.
    Therapeutic advances in hematology. 04/2012; 3(2):117-24.

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17k Citations
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  • 2002–2014
    • Centro de Investigación del Cáncer
      Helmantica, Castille and León, Spain
    • Hospital Universitario de La Princesa
      Madrid, Madrid, Spain
  • 2013
    • Clínica Universidad de Navarra
      Madrid, Madrid, Spain
  • 1984–2013
    • Hospital Universitario de Salamanca
      Helmantica, Castille and León, Spain
    • Flinders Medical Centre
      Tarndarnya, South Australia, Australia
  • 1983–2013
    • Universidad de Salamanca
      • Department of Medicine
      Helmantica, Castille and León, Spain
  • 2012
    • Roswell Park Cancer Institute
      Buffalo, New York, United States
    • Centre Hospitalier Universitaire de Nantes
      Naoned, Pays de la Loire, France
    • Mayo Clinic - Scottsdale
      Scottsdale, Arizona, United States
  • 2011–2012
    • Universitair Ziekenhuis Leuven
      Louvain, Flanders, Belgium
    • Athens State University
      Athens, Alabama, United States
    • Mayo Clinic - Rochester
      • Department of Hematology
      Rochester, Minnesota, United States
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 2008–2012
    • Mayo Foundation for Medical Education and Research
      • Division of Hematology
      Scottsdale, AZ, United States
    • Emory University
      Atlanta, Georgia, United States
    • Arbor Research Collaborative for Health
      Ann Arbor, Michigan, United States
  • 1996–2012
    • Hospital Clínic de Barcelona
      • Servicio de Hematología
      Barcino, Catalonia, Spain
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 2010
    • National and Kapodistrian University of Athens
      Athínai, Attica, Greece
  • 2003–2010
    • Hospital Universitario 12 de Octubre
      Madrid, Madrid, Spain
  • 2009
    • Spanish National Research Council
      Madrid, Madrid, Spain
    • Alexandra Regional General Hospital
      Athínai, Attica, Greece
    • University of Pennsylvania
      • "Abramson" Cancer Center
      Philadelphia, PA, United States
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, MA, United States
  • 1996–2008
    • Hospital Clínico Universitario de Valencia
      Valenza, Valencia, Spain
  • 2007
    • Institut Claudius Regaud
      Tolosa de Llenguadoc, Midi-Pyrénées, France
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      Chapel Hill, NC, United States
  • 2006
    • Newcastle University
      Newcastle-on-Tyne, England, United Kingdom
    • University of Alcalá
      Cómpluto, Madrid, Spain
    • Institute for Plant Molecular and Cell Biology
      Valenza, Valencia, Spain
    • Universidad de Navarra
      • Center for Applied Medical Research (CIMA)
      Pamplona, Navarre, Spain
    • Centre Hospitalier de Luxembourg
      Letzeburg, Luxembourg, Luxembourg
    • Hospital Francesc De Borja De Gandia
      Gandía, Valencia, Spain
  • 2002–2005
    • Hospital de la Santa Creu i Sant Pau
      • Hematology Clinic Services
      Barcino, Catalonia, Spain
  • 2004
    • Hospital General De Segovia
      Segovia, Castille and León, Spain
  • 2001
    • Centro Hospitalar de Coimbra
      Coímbra, Coimbra, Portugal
    • Erasmus Universiteit Rotterdam
      • Department of Immunology
      Rotterdam, South Holland, Netherlands
  • 1999–2001
    • Instituto Português de Oncologia
      • Department of Hematology
      Oporto, Porto, Portugal
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 1998–2001
    • Hospital Universitari Germans Trias i Pujol
      Badalona, Catalonia, Spain
  • 2000
    • Hospital Universitario Madrid Montepríncipe
      Madrid, Madrid, Spain
    • Karolinska University Hospital
      Tukholma, Stockholm, Sweden
  • 1997–2000
    • Hospital Universitario Ramón y Cajal
      Madrid, Madrid, Spain
  • 1995
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1989
    • Hospital Universitari i Politècnic la Fe
      • Department of Hematology
      Valenza, Valencia, Spain