Jesús F San Miguel

Universidad de Navarra, Iruña, Navarre, Spain

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Publications (359)2348.57 Total impact

  • Jesús F San Miguel

    No preview · Article · Jan 2014 · Haematologica
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    ABSTRACT: To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice.
    Full-text · Article · Jan 2014 · Journal of Clinical Oncology
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    ABSTRACT: Various translocations and mutations have been identified in myeloma and certain aberrations, such as t(4;14) and del17, are linked with disease prognosis. To investigate mutational prevalence in myeloma and associations between mutations and patient outcomes, we tested a panel of 41 known oncogenes and tumor suppressor genes in tumor samples from 133 relapsed myeloma patients participating in phase 2 or 3 clinical trials of bortezomib. DNA mutations were identified in 14 genes. BRAF as well as RAS genes were mutated in a large proportion of cases (45.9%) and these mutations were mutually exclusive. New recurrent mutations were also identified, including in the PDGFRA and JAK3 genes. NRAS mutations were associated with a significantly lower response rate to single-agent bortezomib (7% versus 53% in patients with mutant versus wild-type NRAS, P = .00116, Bonferroni-corrected P = .016), as well as shorter time-to-progression in bortezomib-treated patients (P = .0058, Bonferroni-corrected P = .012). However, NRAS mutation did not impact outcome in patients treated with high-dose dexamethasone. KRAS mutation did not reduce sensitivity to bortezomib or dexamethasone. These findings identify a significant clinical impact of NRAS mutation in myeloma and demonstrate a clear example of functional differences between the KRAS and NRAS oncogenes.
    Full-text · Article · Dec 2013 · Blood
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    María-Victoria Mateos · Jesús F San Miguel
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    ABSTRACT: Multiple myeloma (MM) is the second most frequent hematological disease. Two-thirds of newly diagnosed MM patients are more than 65 years of age. Elsewhere in this issue, McCarthy et al discuss the treatment of transplantation candidates; this chapter focuses on the data available concerning therapy for non-transplantation-eligible MM patients. Treatment goals for these non-transplantation-eligible patients should be to prolong survival by achieving the best possible response while ensuring quality of life. Until recently, treatment options were limited to alkylators, but new up-front treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) plus alkylating agents have significantly improved outcomes. Other nonalkylator induction regimens are also available and provide a novel backbone that may be combined with novel second- and third-generation drugs. Phase 3 data indicate that maintenance therapy or prolonged treatment in elderly patients also improves the quality and duration of clinical responses, extending time to progression and progression-free survival; however, the optimal scheme, appropriate doses, and duration of long-term therapy have not yet been fully determined. The potential for novel treatment regimens to improve the adverse prognosis associated with high-risk cytogenetic profiles also requires further research. In summary, although we have probably doubled the survival of elderly patients, this group requires close monitoring and individualized, dose-modified regimens to improve tolerability and treatment efficacy while maintaining their quality of life.
    Preview · Article · Dec 2013 · Hematology
  • María-Victoria Mateos · Jesús F San Miguel

    No preview · Article · Dec 2013
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    ABSTRACT: Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six elderly (>65 years) newly diagnosed MM patients from 6 European randomized trials were retrospectively analyzed and matched for age, albumin and beta2-microglobulin at diagnosis, 296 patients were selected from the VMP groups and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P=0.007). After a median follow-up of 34 months (range, 1-92), VMP significantly prolonged both PFS (median 32.5 vs 22.9 months, HR 0.65; 95% CI 0.52-0.82; P<0.001) and OS (median 79.7 vs 45.1 months, HR 0.44; 95% CI 0.32-0.59; P<0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status or serum creatinine, but not among patients ≥75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control-case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT.
    No preview · Article · Nov 2013 · American Journal of Hematology
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    ABSTRACT: Treatment in medical oncology is gradually shifting from the use of non-specific chemotherapeutic agents towards an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation- proteasome inhibitors, immunomodulatory agents (IMIDs) and alkylators). Then we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAb), cell cycle specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors, and kinase inhibitors. Among this plethora of new agents or mechanisms some are specially promising: Anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Also the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, that has produced exciting results in the relapsed/refractory setting.Leukemia accepted article preview online, 20 November 2013. doi:10.1038/leu.2013.350.
    No preview · Article · Nov 2013 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K

  • No preview · Article · Nov 2013 · European Journal of Cancer
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    ABSTRACT: Minimal residual disease monitoring is becoming increasingly important in multiple myeloma (MM), but multiparameter flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) techniques are not routinely available. This study investigated the prognostic influence of achieving molecular response assessed by fluorescent-PCR (F-PCR) in 130 newly diagnosed MM patients from Grupo Español Multidisciplinar de Melanoma (GEM)2000/GEM05 trials (NCT00560053, NCT00443235, NCT00464217) who achieved almost very good partial response after induction therapy. As a reference, we used the results observed with simultaneous MFC. F-PCR at diagnosis was performed on DNA using three different multiplex PCRs: IGH D-J, IGK V-J and KDE rearrangements. The applicability of F-PCR was 91·5%. After induction therapy, 64 patients achieved molecular response and 66 non-molecular response; median progression-free survival (PFS) was 61 versus 36 months, respectively (P = 0·001). Median overall survival (OS) was not reached (NR) in molecular response patients (5-year survival: 75%) versus 66 months in the non-molecular response group (P = 0·03). The corresponding PFS and OS values for patients with immunophenotypic versus non-immunophenotypic response were 67 versus 42 months (P = 0·005) and NR (5-year survival: 95%) versus 69 months (P = 0·004), respectively. F-PCR analysis is a rapid, affordable, and easily performable technique that, in some circumstances, may be a valid approach for minimal residual disease investigations in MM.
    No preview · Article · Oct 2013 · British Journal of Haematology
  • María-Victoria Mateos · Enrique M Ocio · Jesús F San Miguel
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    ABSTRACT: The activity observed with proteasome inhibitors and immunomodulatory drugs (IMIDs) in multiple myeloma (MM) has prompted the development of second- and third-generation agents with similar, but not exactly the same, mechanisms of action as their predecessors. This review summarizes the mechanism of action and the available data on the clinical activity of novel proteasome inhibitors (carfilzomib, oprozomib, ixazomib, and marizomib) and novel IMIDs (pomalidomide), stressing the similarities and differences with bortezomib, and with thalidomide and lenalidomide, respectively. In summary, these novel agents have shown clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their parental drugs; moreover, they may even overcome resistance, indicating that there are some differences in their mechanisms of action and resistance. These data indicate that both the inhibition of the proteasome and the modulation of the immune system are good strategies to target MM tumor cells and this, along with the absence of complete cross-resistance observed among these drugs, open new avenues to optimize their use through the most appropriate sequencing and combinations.
    No preview · Article · Oct 2013 · Seminars in Oncology
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    ABSTRACT: Circulating myeloma tumor cells (CTCs) as defined by the presence of peripheral blood (PB) clonal plasma cells (PCs) are a powerful prognostic marker in multiple myeloma (MM). However, the biological features of CTCs and their pathophysiological role in MM remains unexplored. Here, we investigate the phenotypic, cytogenetic and functional characteristics as well as the circadian distribution of CTCs vs. paired bone marrow (BM) clonal PCs from MM patients. Our results show that CTCs typically represent a unique subpopulation of all BM clonal PCs, characterized by down-regulation (P<.05) of integrins (CD11a/CD11c/CD29/CD49d/CD49e), adhesion (CD33/CD56/CD117/CD138), and activation molecules (CD28/CD38/CD81). FISH analysis of FACS-sorted CTCs also unraveled different cytogenetic profiles versus paired BM clonal PCs. Moreover, CTCs were mostly quiescent and associated with higher clonogenic potential when co-cultured with BM stromal-cells. Most interestingly, CTCs showed a circadian distribution which fluctuates in a similar pattern to that of CD34(+) cells, and opposite to SDF1 plasma levels and corresponding surface expression of CXCR4 on clonal PCs, suggesting that in MM, CTCs may egress to PB to colonize/metastasize other sites in the BM during the patients' resting period.
    Full-text · Article · Sep 2013 · Blood
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    ABSTRACT: Few effective treatments exist for patients with refractory or relapsed and refractory multiple myeloma not responding to treatment with bortezomib and lenalidomide. Pomalidomide alone has shown limited efficacy in patients with relapsed multiple myeloma, but synergistic effects have been noted when combined with dexamethasone. We compared the efficacy and safety of pomalidomide plus low-dose dexamethasone with high-dose dexamethasone alone in these patients. This multicentre, open-label, randomised phase 3 trial was undertaken in Australia, Canada, Europe, Russia, and the USA. Patients were eligible if they had been diagnosed with refractory or relapsed and refractory multiple myeloma, and had failed at least two previous treatments of bortezomib and lenalidomide. They were assigned in a 2:1 ratio with a validated interactive voice and internet response system to either 28 day cycles of pomalidomide (4 mg/day on days 1-21, orally) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally) or high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20, orally) until disease progression or unacceptable toxicity. Stratification factors were age (≤75 years vs >75 years), disease population (refractory vs relapsed and refractory vs bortezomib intolerant), and number of previous treatments (two vs more than two). The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with, number NCT01311687, and with EudraCT, number 2010-019820-30. The accrual for the study has been completed and the analyses are presented. 302 patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone and 153 high-dose dexamethasone. After a median follow-up of 10·0 months (IQR 7·2-13·2), median PFS with pomalidomide plus low-dose dexamethasone was 4·0 months (95% CI 3·6-4·7) versus 1·9 months (1·9-2·2) with high-dose dexamethasone (hazard ratio 0·48 [95% CI 0·39-0·60]; p<0·0001). The most common grade 3-4 haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups were neutropenia (143 [48%] of 300 vs 24 [16%] of 150, respectively), anaemia (99 [33%] vs 55 [37%], respectively), and thrombocytopenia (67 [22%] vs 39 [26%], respectively). Grade 3-4 non-haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups included pneumonia (38 [13%] vs 12 [8%], respectively), bone pain (21 [7%] vs seven [5%], respectively), and fatigue (16 [5%] vs nine [6%], respectively). There were 11 (4%) treatment-related adverse events leading to death in the pomalidomide plus low-dose dexamethasone group and seven (5%) in the high-dose dexamethasone group. Pomalidomide plus low-dose dexamethasone, an oral regimen, could be considered a new treatment option in patients with refractory or relapsed and refractory multiple myeloma. Celgene Corporation.
    No preview · Article · Sep 2013 · The Lancet Oncology
  • María-Victoria Mateos · Jesús F San Miguel
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    ABSTRACT: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by the presence of one or both features of serum M-protein ≥ 30 g/L and bone marrow plasma cell infiltration ≥ 10 %. However, myeloma-related symptomatology is absent from this condition. The risk of progression to active MM is not uniform, and several markers are useful for identifying SMM patients at high risk of progression to active MM. These include the size of the M-protein and the infiltration in the bone marrow, the serum-free light-chain ratio, the presence of immunoparesis and percentage of plasma cell with aberrant phenotype by flow cytometry, or the presence of focal lesions in magnetic resonance imaging. Overall, the presence of these factors identifies patients who have a 50 % probability of progression at 2 years, and the forthcoming challenge will be to identify ultra-high-risk patients who have an 80 % risk of progression at 2 years. The current standard of care is not to treat until progression to symptomatic disease occurs. Several trials of melphalan, thalidomide and bisphosphonates have been conducted in the overall SMM patient population to examine the delay in time to progression (TTP) to symptomatic disease, but these have shown no significant benefit. However, a randomized trial that focused on high-risk SMM patients allocated to receive early treatment with lenalidomide plus dexamethasone versus observation did report a significant benefit with respect to TTP and overall survival. In summary, high-risk SMM patients should be targetted for early treatment, and more so efforts should be made to identify the ultra-high-risk subgroup within the high-risk SMM patient population which may be considered as early MM and thereby candidates for receiving therapy before they develop myeloma-related symptomatology.
    No preview · Article · Aug 2013 · Current Hematologic Malignancy Reports
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    ABSTRACT: The gene expression profiles (GEPs) of 96 selected genes were analysed by real-time quantitative polymerase chain reaction (qPCR) with a TaqMan low-density array card in isolated tumour plasma cells (PCs) from 157 newly diagnosed multiple myeloma (MM) patients. This qPCR-based GEP correctly classified cases following the Translocation-cyclin D classification. Classic prognostic parameters and qPCR-based GEP predicted MM patient outcome and, although multivariate analyses revealed that cytogenetic risk (standard vs. high risk) was the variable that most strongly predicted prognosis, GEP added significant information for risk stratification. Considering only the standard risk cytogenetic patients, multivariate analyses revealed that high β2-microglobulin, low CDKN1A and high SLC19A1 gene expression levels independently predicted a short time-to-progression (TTP), while high International Staging System stage, low CDKN2B and high TBRG4 gene expression predicted poor overall survival (OS). A gene expression risk score enabled the division of standard risk patients into two groups with different TTPs (83% vs. 38% at 3 years, P < 0·0001) and OS rates (88% vs. 61% at 5 years; P = 0·003). This study demonstrates that quantitative PCR is a robust, accurate and feasible technique for implementing in the daily routine as a surrogate for GEP-arrays.
    No preview · Article · Aug 2013 · British Journal of Haematology
  • Javier Pardo · Alejandro Martín · Inmaculada Galindo · Jesús F. San Miguel

    No preview · Article · Aug 2013 · Medicina Clínica
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    ABSTRACT: Multiple myeloma (MM) remains an incurable disease. New approaches to develop better tools for improving patient prognostication and monitoring treatment efficacy are very much needed. In this study, we aimed to evaluate the potential of metabolomics by 1H-NMR to provide information on metabolic profiles that could be useful in the management of MM. Serum samples were collected from MM patients at the time of diagnosis and after achieving complete remission. A matched control set of samples was also included in the study. The 1H-NMR measurements used to obtain the metabolic profile for each patient were followed by the application of univariate and multivariate statistical analyses to determine significant differences. Metabolic profiles of MM patients at diagnosis exhibited higher levels of isoleucine, arginine, acetate, phenylalanine and tyrosine, and decreased levels of 3-hydroxybutyrate, lysine, glutamine, and some lipids compared with the control set. A similar analysis performed in MM patients after achieving complete remission indicated that some of the metabolic changes (i.e., glutamine, cholesterol, lysine) observed at diagnosis displayed a variation in the opposite direction upon responding to treatment, thus contributing to MM patients having a closer metabolic profile to those of healthy individuals after the disappearance of major disease manifestations. The results highlight the potential that metabolic profiles obtained by 1H-NMR in identifying MM biomarkers that may be useful to objectively discriminate individuals with and without MM, and monitor response to treatment.
    Full-text · Article · Jul 2013 · Clinical Cancer Research
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    ABSTRACT: We have analyzed the applicability, sensitivity and prognostic value of Allele Specific Oligonucleotide Real time Quantitative Polymerase Chain Reaction (ASO RQ-PCR) as method for minimal residual disease (MRD) assessment in patients with multiple myeloma (MM), comparing the results with those of Multiparameter Flow Cytometry (MFC). 170 patients enrolled in 3 consecutive Spanish trials achieving at least partial response after treatment were included. Lack of clonality detection (n=31), unsuccessful sequencing (n=17), and suboptimal ASO performance (n=51) limited the applicability of PCR to 42% of cases. MRD was finally investigated in 103 patients (including 32 previously studied) with persistent disease identified by PCR and MFC in 54% and 46% of cases, respectively. A significant correlation in MRD quantitation by both techniques was noted (r=0.881, P<0.001) being reflective of treatment intensity. Patients with <10(-4) residual tumor cells showed longer progression free survival compared to the rest (not reached vs 31 months, P=0.002), with similar results observed with MFC. Among complete responders (n=62), PCR discriminated two risk groups with different PFS (49 vs 26 months, P=0.001) and OS (NR vs. 60 months, P=0.008). Thus, although less applicable than MFC, ASO RQ-PCR is a powerful technique to assess treatment efficacy and risk stratification in MM.Leukemia accepted article preview online, 17 July 2013. doi:10.1038/leu.2013.217.
    No preview · Article · Jul 2013 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by several genetic and environmental factors. The key role of the Human Leukocyte Antigen (HLA) system in tumor antigen presentation could be involved in susceptibility and disease control. We have analyzed the phenotypic frequencies of HLA-A, -B, -C, -DRB1 and -DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using CHOP-like without (n=64, 26%) or with Rituximab (n=153, 61%). Our data reveal that DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs. 19.5%, P=0.0008, Pc=0.0104) and a lower frequency of HLA-C*03 (6.4% vs. 17.9%, P<0.0005, Pc=0.007) compared with healthy individuals. Irrespective of the aaIPI, those patients receiving a CHOP-like plus Rituximab regimen and carrying the HLA B44-supertype had worse 5-year PFS (54% vs. 71%, P=0.019), and 5-year OS (71% vs. 92%, P=0.001), compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect.
    Full-text · Article · Jul 2013 · Blood
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    ABSTRACT: The mechanisms involved in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole genome sequencing on a series of MGUS (n=4), high risk (HR)-SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors which drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.Leukemia accepted article preview online, 2 July 2013; doi:10.1038/leu.2013.199.
    Full-text · Article · Jul 2013 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: The current study was designed to assess the safety and efficacy of bortezomib in combination with fludarabine and melphalan as reduced intensity conditioning before allogeneic stem cell transplantation in patients with high risk multiple myeloma. Sixteen patients were evaluable. The median number of previous line of treatment was 3; all patients had relapsed following a prior autograft and 13 had previously received bortezomib. Fifteen of them either remained stable or improved disease status at day +100 post-transplant, including 11 patients with active disease. More specifically, nine patients (56%) and five patients (31%) reached complete remission and partial response, respectively. 25% developed grade III acute graft-versus-host disease. The cumulative incidence of non-relapse mortality, relapse and overall survival were 25%, 54% and 41%, respectively, at 3 years. Regarding the non-haematological toxicity (grade>2), two patients developed peripheral neuropathy, two patients liver toxicity and 1 pulmonary toxicity early post-transplant. The haematological toxicity was only observed during the first three cycles mostly related to low haemoglobin and platelet levels. The current trial is the first one evaluating the safety and efficacy of bortezomib as part of a reduced intensity conditioning regimen among patients with high risk multiple myeloma.
    No preview · Article · Jun 2013 · British Journal of Haematology

Publication Stats

17k Citations
2,348.57 Total Impact Points


  • 2013-2015
    • Universidad de Navarra
      Iruña, Navarre, Spain
    • Clínica Universidad de Navarra
      Madrid, Madrid, Spain
  • 1987-2015
    • Hospital Universitario de Salamanca
      Helmantica, Castille and León, Spain
  • 2014
    • Centro Nacional de Investigaciones Oncológicas
      Madrid, Madrid, Spain
  • 1991-2014
    • Universidad de Salamanca
      • Department of Medicine
      Helmantica, Castille and León, Spain
  • 2012
    • Hospital Universitario Marques de Valdecilla
      • Servicio de Anatomía Patológica
      Santander, Cantabria, Spain
  • 2011
    • Royal Prince Alfred Hospital
      • Institute of Haematology
      Camperdown, New South Wales, Australia
  • 2010
    • Cornell University
      Итак, New York, United States
  • 2002-2010
    • Centro de Investigación del Cáncer
      Helmantica, Castille and León, Spain
    • Hospital de Jerez
      Jerez, Andalusia, Spain
  • 2009
    • Alexandra Regional General Hospital
      Athínai, Attica, Greece
  • 2006
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
  • 2003
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2001
    • Hospital Clínico, Maracaibo
      Maracaibo, Zulia, Venezuela
  • 2000
    • Hospital Universitario 12 de Octubre
      Madrid, Madrid, Spain
  • 1995
    • Leiden University
      Leyden, South Holland, Netherlands