Nuestros investigadores

Paula Rodríguez Otero

Publicaciones científicas más recientes (desde 2010)

Autores: Rodriguez, Paula; Mateos, M. V.; Martinez-Lopez, J.; et al.
ISSN 0887-6924  Vol. 33  Nº 4  2019  págs. 1056 - 1056
Following the publication of this article, the author notes that the following information was missed from the acknowledgments section.
Autores: Chari, A., (Autor de correspondencia); Martinez-Lopez, J.; Mateos, M. V.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 134  Nº 5  2019  págs. 421 - 431
Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomiderefractory patients were eligible. Carfilzomib- and daratumumab-naive patients (n 5 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m(2) initial dose, escalated to 70 mg/m(2) thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide.
Autores: Moreno, Laura; Zabaleta, Aintzane; et al.
ISSN 1078-0432  Vol. 25  Nº 10  2019  págs. 3176 - 3187
Purpose: Knowledge about the mechanism of action (MoA) of monoclonal antibodies (mAb) is required to understand which patients with multiple myeloma (MM) benefit the most from a given mAb, alone or in combination therapy. Although there is considerable research about daratumumab, knowledge about other anti-CD38 mAbs remains scarce. Experimental Design: We performed a comprehensive analysis of the MoA of isatuximab. Results: Isatuximab induces internalization of CD38 but not its significant release from MMcell surface. In addition, we uncovered an association between levels of CD38 expression and different MoA: (i) Isatuximab was unable to induce direct apoptosis on MM cells with CD38 levels closer to those in patients with MM, (ii) isatuximab sensitized CD38(hi) MMcells to bortezomib plus dexamethasone in the presence of stroma, (iii) antibody-dependent cellular cytotoxicity (ADCC) was triggered by CD38(lo) and CD38(hi) tumor plasma cells (PC), (iv) antibody-dependent cellular phagocytosis (ADCP) was triggered only by CD38(hi) MM cells, whereas (v) complement-dependent cytotoxicity could be triggered in less than half of the patient samples (those with elevated levels of CD38). Furthermore, we showed that isatuximab depletes CD38(hi) B-lymphocyte precursors and natural killer (NK) lymphocytes ex vivo-the latter through activation followed by exhaustion and eventually phagocytosis. Conclusions: This study provides a framework to understand response determinants in patients treated with isatuximab based on the number of MoA triggered by CD38 levels of expression, and for the design of effective combinations aimed at capitalizing disrupted tumor-stroma cell protection, augmenting NK lymphocyte-mediated ADCC, or facilitating ADCP in CD38(lo) MM patients.
Autores: Rodriguez, Paula; Mateos, M. V. ; Martinez-Lopez, J.; et al.
ISSN 2044-5385  Vol. 9  Nº 4  2019  págs. 36
Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) >= 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb >= 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years.
Autores: Martínez, Nicolás, (Autor de correspondencia); Rodriguez, Paula; et al.
ISSN 0390-6078  Vol. 103  Nº 7  2018  págs. E318 - E321
Autores: Sanoja-Flores, L.; Flores-Montero, J. ; Garcés, Juan-José; et al.
ISSN 2044-5385  Vol. 8  2018  págs. 117
Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p < 0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p < 0.0001) and a shorter survival in MM patients with active disease requiring treatment (p <= 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.
Autores: Rodriguez, Paula; Mateos, M. V.; Martinez-Lopez, J.; et al.
ISSN 0887-6924  Vol. 32  Nº 11  2018  págs. 2427 - 2434
Although survival of elderly myeloma patients has significantly improved there is still a subset of patients who, despite being fit and achieving optimal responses, will die within 2 years of diagnosis due to myeloma progression. The objective of this study was to define a scoring prognostic index to identify this group of patients. We have evaluated the outcome of 490 newly diagnosed elderly myeloma patients included in two Spanish trials (GEM2005-GEM2010). Sixty-eight patients (13.8%) died within 2 years of diagnosis (early deaths) due to myeloma progression. Our study shows that the use of simple scoring model based on 4 widely available markers (elevated LDH, ISS 3, high risk CA or >75 years) can contribute to identify up-front these patients. Moreover, unsustained response (<6 months duration) emerged as one important predictor of early myeloma-related mortality associated with a significant increase in the risk of death related to myeloma progression. The identification of these patients at high risk of early death is relevant for innovative trials aiming to maintain the depth of first response, since many of them will not receive subsequent lines of therapy.
Autores: Mateos, M. V. ; Rocafiguera, A. O. ; Rodriguez, Paula; et al.
ISSN 0390-6078  Vol. 103  Nº Supl. 1  2018  págs. 32 - 32
Autores: Rodriguez, Paula; Mateos, M. V.; Lopez, J. M.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018  págs. 4503
Autores: Tamariz-Amador, L.E; Hernández-Santamaría, T. ; et al.
ISSN 0390-6078  Vol. 103  Nº Supl. 2  2018  págs. 118 - 118
Autores: Richardson, P. ; Ocio, E.; Oriol, A. ; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 132  Nº Supl. 1  2018 
Autores: Rodriguez, Paula, (Autor de correspondencia)
ISSN 0390-6078  Vol. 103  Nº Supl. 1  2018  págs. 8 - 8
Autores: Rodriguez, Paula; Lourenco, Bruno David; Engelhardt, M. ; et al.
ISSN 0390-6078  Vol. 102  Nº 3  2017  págs. 423 - 432
Immune escape and impaired immune surveillance have been identified as emerging hallmarks of cancer.(1) Multiple myeloma represents a genuine example of disrupted immune surveillance characterized by: impaired antibody production, deregulation of the T and natural killer cell compartment, disruption of antigen presentation machinery, upregulation of inhibitory surface ligands, and recruitment of immunosuppressive cells. Although the potential value of immunotherapeutic interventions had a clear antecedent in the graft-versus-myeloma effect induced by allogeneic stem cell transplant and donor lymphocyte infusions, it is only recently that this field has faced a real revolution. In this review we discuss the current results obtained with immune approaches in patients with multiple myeloma that have placed this disease under the scope of immuno-oncology, bringing new therapeutic opportunities for the treatment of multiple myeloma patients.
Autores: Lapa, C. ; Garcia-Velloso, Maria Jose; Lückerath, K.; et al.
ISSN 1838-7640  Vol. 7  Nº 11  2017  págs. 2956 - 2964
C-11-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to F-18-2'-deoxy-2'-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET-and FDG-PET/computed tomography (CT) at the University Centers of Wurzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases. MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (kappa=0.82 vs kappa=0.72). This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra-and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM.
Autores: Kumar, S. K., (Autor de correspondencia); Dimopoulos, M. A.; Kastritis, E.; et al.
ISSN 0887-6924  Vol. 31  Nº 11  2017  págs. 2443 - 2448
Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T-0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T-0 was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T-0 was 3.1 years. The median number of lines of therapy before T-0 was 4 (range 3-13). The median overall survival (OS) from T-0 for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T-0 in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T-0 of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated.
Autores: Morales, María Isabel; García, Berta; et al.
ISSN 2253-654X  Vol. 36  Nº Supl 1  2017  págs. 10
n pacientes con mieloma múltiple el FDG-PET/CT es una herramienta sensible en la valoración de respuesta, permite la detección de enfermedad extramedular y complementa la valoración de la enfermedad mínima residual. La persistencia de captación de FDG en pacientes en RC puede predecir la recaída
Autores: Rodriguez, Paula; Mateos, M. V.; Orlowski, R. ; et al.
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 319
Autores: Rodriguez, Paula; Mateos, M. V.; Joaquin, M. L.; et al.
ISSN 0390-6078  Vol. 102  Nº Supl.2  2017  págs. 274 - 275
Autores: Mateos, M. V. ; Martinez-Lopez, J.; Hernandez, M.; et al.
ISSN 0390-6078  Vol. 102  Nº Supl. 2  2017  págs. 143
Autores: Garcia-Sanz, R.; Jimenez, C.; Puig, N.; et al.
ISSN 1532-1924  Vol. 29  Nº 2  2016  págs. 136 - 147
Waldenstrom's macroglobulinaemia (WM) is an MYD88(L265P)-mutated lymphoplasmacytic lymphoma that invades bone marrow and secretes monoclonal immunoglobulin M (IgM). WM cells are usually unable to undergo class switch recombination, and have mutated IGHV, with a typical immunophenotype CD19(+)/CD22(low+)/CD23(-)/CD25(+)/CD27(+)/CD45(+)/CD38(low+)/SmIgM(+) (negative for CD5, CD10, CD11c, CD103). This immunophenotype matches memory B cells (smIgM(-/+)/CD10(-)/CD19(+)/CD20(+)/CD27(+)/CD38(low+)/CD45(+)), representing 30% of B cells in the blood. Fifty percent of them have not undergone class switch recombination and are IgM(+). These cells have suffered somatic hypermutation as WM cells. Genetic abnormalities do not abrogate the capacity to progress to plasma cells that usually belong to the clonal WM compartment, with a normal immunophenotype and functional characteristics. However, some WM cells are CD27(-), MYD88(WT), without somatic hypermutation, or with class switch recombination capable of reactivation. Thus, most data support a B-memory-cell origin for WM, but a small fraction of cases may have a different origin.
Autores: Moreno, L.; Zabaleta, Aintzane; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: Figueroa, Rocío; Marcos-Jubilar, María; García, Berta; et al.
ISSN 0390-6078  Vol. 101  Nº Supl. 1  2016  págs. 524
Autores: Burgos, Leire; Garcés, Juan-José; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 128  Nº 22  2016 
Autores: San José, Edurne; Agirre, X; Rodriguez, Paula; et al.
ISSN 1750-1911  Vol. 5  Nº 5  2013  págs. 525 - 538
Acute lymphoblastic leukemia (ALL) is a heterogeneous cancer that is characterized by rapid and uncontrolled proliferation of immature B- or T-lymphoid precursors. Although ALL has been regarded as a genetic disease for many years, the crucial importance of epigenetic alterations in leukemogenesis has become increasingly evident. Epigenetic mechanisms, which include DNA methylation and histone modifications, are critical for gene regulation during many key biological processes. Here, we review the cell signaling pathways that are regulated by DNA methylation or histone modifications in ALL. Recent studies have highlighted the fundamental role of these modifications in ALL development, and suggested that future investigation into the specific genes and pathways that are altered by epigenetic mechanisms can contribute to the development of novel drug-based therapies for ALL.
Autores: Rodriguez, Paula; Román-Gómez, J.; et al.
ISSN 0007-1048  Vol. 155  Nº 1  2011  págs. 73 - 83
The role of epigenetic mechanisms in the regulation of microRNAs (miRNAs) with a tumour-suppressor function in human neoplasms has recently been established. Several miRNAs have been found to be inappropriately regulated by DNA methylation in patients with acute lymphoblastic leukaemia (ALL). We analysed the methylation status of the three members of the MIR9 family (MIR9-1, MIR9-2 and MIR9-3) in a uniformly treated cohort of 200 newly diagnosed ALLs. MIR9 was methylated in 54% of the patients and was associated with downregulation of MIR9 (P < 0.01). Hypermethylation of MIR9 was an independent prognostic factor for disease-free survival, overall survival and event-free survival in a multivariate analysis (P < 0 01). Epigenetic downregulation of MIR9 induced upregulation of its targets, FGFR1 and CDK6, while treatment of ALL cells with FGFR1 (PD-173074) and CDK6 (PD-0332991) inhibitors induced a decrease in cell proliferation and an increase in apoptosis of ALL cells. Our results indicate that the MIR9 family is involved in the pathogenesis and clinical behaviour of ALL and provide the basis for new therapeutic strategies in the treatment of ALL, targeting the epigenetic regulation of miRNAs and/or the FGFR1 or CDK6-RB pathway directly
Autores: Agirre, X; Martín-Palanco, V.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 6  Nº 2  2011  págs. e17012
Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n¿=¿48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2'-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p¿=¿0.001) and mortality (p<0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p¿=¿0.006) and overall survival (OS) (p¿=¿0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL.
Autores: Gállego, Jaime; et al.
ISSN 0167-594X  Vol. 103  Nº 3  2011  págs. 603 - 609
Central nervous system (CNS) prophylaxis is required during initial treatment of non-Hodgkin lymphoma (NHL) subtypes that carry a high risk of CNS involvement. Intrathecal (IT) liposomal cytarabine, a formulation with prolonged half-life, has been shown to be safe and effective in the treatment of meningeal disease in patients with high-grade lymphoma. We retrospectively reviewed all adult patients with high-grade NHL that received prophylactic therapy with IT liposomal cytarabine and developed neurologic complications in our institution between April 2007 and May 2009. We recorded information on hospital admission, chemotherapy regimens, clinical features, neuroimaging, cerebrospinal fluid, neurophysiology data, and outcome. Neurotoxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Four of fourteen patients (28%) developed moderate or severe neurotoxicity (grades 2 and 3 of the NCI-CTC), manifested as conus medullaris/cauda equine syndrome or pseudotumour cerebri-like syndrome, after a median of 3.5 IT courses of liposomal cytarabine. All patients had received corticosteroids to prevent arachnoiditis. Liposomal cytarabine given via the IT route, even with concomitant corticosteroid administration, can result in significant neurotoxicity in some patients. We discuss the potential pathogenesis of these effects and suggest hypothetical therapeutic measures to prevent these complications. Specialists should be aware of these possible complications when administering prophylactic IT liposomal cytarabine in high-grade NHL patients, and additional prospective studies should be conducted to more clearly delineate the frequency and characteristics of these complications.