P. Rodriguez-Otero - Academia.edu (original) (raw)

Papers by P. Rodriguez-Otero

$Research paper thumbnail of Melphalan flufenamide for relapsed/refractory multiple myeloma$

$Research paper thumbnail of S188: Teclistamab in Combination with Daratumumab, a Novel, Immunotherapy-Based Approach for the Treatment of Relapsed/Refractory Multiple Myeloma: Updated Phase 1B Results$

$Research paper thumbnail of P898: Comparison of Teclistamab with Belantamab Mafodotin in Patients with Triple-Class Exposed Relapsed/Refractory Multiple Myeloma Using Matching-Adjusted Indirect Treatment Comparison$

$Research paper thumbnail of S180: RG6234, a Novel GPRC5D T-Cell Engaging Bispecific Antibody, Induces Rapid Responses in Patients with Relapsed/Refractory Multiple Myeloma: Preliminary Results from a First-In-Human Trial$

$Research paper thumbnail of P1463: Phase I Dose Escalation of LAVA-051, a Novel Bispecific Gamma-Delta T-Cell Engager (Gammabody™), in Relapsed/Refractory Hematological Malignancies$

$Research paper thumbnail of B04: Combination of Subcutaneous Teclistamab with Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Results from a Phase 1B Multicohort Study$

$Research paper thumbnail of P13: Can Patient-Reported Ocular Symptoms Guide Dose Modifications in Patients with Relapsed/Refractory Multiple Myeloma Receiving Belantamab Mafodotin?$

HemaSphere

anti-CD38 antibodies (15%). Median OS was 9.79 months (95% CI: 7.79, 12.22), median PFS was 3.42 ... more anti-CD38 antibodies (15%). Median OS was 9.79 months (95% CI: 7.79, 12.22), median PFS was 3.42 months (95% CI: 2.79, 4.27), and median TTNT was 3.61 months (95% CI: 3.09, 4.57). The following factors were prognostic for worse outcomes for OS (Figure) and PFS: higher refractory status (p<0.001), being male (p=0.001), older age (p<0.001), shorter duration of prior lines (p<0.001), shorter TTP in prior line (p=0.025), and higher lactate dehydrogenase levels (p<0.002). Conclusions: Real-world outcomes (OS, PFS, and TTNT) were poor in tri-exposed patients with RRMM. The wide variety of treatment regimens used in clinical practice confirms the absence of a clear SOC for these patients. These real-world data from patients in Belgium are consistent with those from other countries, underscoring the high unmet medical need for new and effective treatments for patients with RRMM.

Prognostic scores are often constructed to classify patients in prognostic groups thanks to pre-t... more Prognostic scores are often constructed to classify patients in prognostic groups thanks to pre-treatment characteristics easily accessible. Once constructed, scores are applied to new patients. Scores are helpful in identifying patients with advanced stage, selecting the appropriate treatmen to individual patients, and in stratifying patients in prospective trials. Models selection is usually based on adequation to initial sample data. Thus prediction on initial data overestimates prediction on new patients. This difference between predictions, so called model optimism, has to been taken into account when studying predictive ability of models for new patients. The methodology used to build two prognostic scores is presented. Similar constraints were stated at the beginning (£5 variables in the final score, 3-risk-group score). For follicular lymphomas (Solal-Céligny, 2004), 8 variables were significantly associated with overall survival. The best model including 5 variables was sel...

British Journal of Haematology, 2020

Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for mu... more Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/ prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd, n = 67; D-VMP, n = 67; D-Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71Á6% [90% confidence interval (CI) 61Á2-80Á6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88Á1% (90% CI 79Á5-93Á9%) and 90Á8% (90% CI 82Á6-95Á9%). With longer median follow-up for D-VMP and D-Rd (14Á3 and 14Á7 months respectively), responses deepened (ORR: 89Á6%, 93Á8%; ≥VGPR: 77Á6%, 78Á5%), and minimal residual disease-negativity (10-5) rates were 16Á4% and 15Á4%. Infusion-related reactions across all cohorts were infrequent (≤9Á0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard-of-care regimens demonstrated comparable clinical activity to DARA IV-containing regimens, with low infusion-related reaction rates and reduced administration time.

Blood Cancer Journal, 2019

Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patien... more 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 posttreatment biomarkers helpful in predicting the likelihood of disease control at 5 years.

$Research paper thumbnail of Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial$

The Lancet Haematology, 2019

Blood Cancer Journal, 2018

Here, we investigated for the first time the frequency and number of circulating tumor plasma cel... more 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.

Advances in hematology, 2009

CD57+ T cells increase in several viral infections like cytomegalovirus, herpesvirus, parvovirus,... more CD57+ T cells increase in several viral infections like cytomegalovirus, herpesvirus, parvovirus, HIV and hepatitis C virus and are associated with several clinical conditions related to immune dysfunction and ageing. We report for the first time an expansion of CD8+ CD57+ T cells in a young patient with an acute infection with Toxoplasma gondii. Our report supports the concept that CD8+ CD57+ T cells could be important in the control of chronic phase of intracellular microorganisms and that the high numbers of these cells may reflect the continuing survey of the immune system, searching for parasite proliferation in the tissues.

PLoS ONE, 2011

Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphobla... more 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-29-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.

Molecular Cancer, 2009

The development of Imatinib Mesylate (IM), the first specific inhibitor of BCR-ABL1, has had a ma... more The development of Imatinib Mesylate (IM), the first specific inhibitor of BCR-ABL1, has had a major impact in patients with Chronic Myeloid Leukemia (CML), establishing IM as the standard therapy for CML. Despite the clinical success obtained with the use of IM, primary resistance to IM and molecular evidence of persistent disease has been observed in 20-25% of IM treated patients. The existence of second generation TK inhibitors, which are effective in patients with IM resistance, makes identification of predictors of resistance to IM an important goal in CML. In this study, we have identified a group of 19 miRNAs that may predict clinical resistance to IM in patients with newly diagnosed CML.

Haematologica, 2011

Cyclophosphamide and antithymocyte globulin is an effective conditioning regimen for patients wit... more Cyclophosphamide and antithymocyte globulin is an effective conditioning regimen for patients with severe aplastic anemia and is associated with low treatment-related mortality. Long-term complications include avascular necrosis and endocrine dysfunction.

Cancer Science, 2010

Wnt5a is a member of the Wnt family of proteins that signals through the non-canonical Wnt ⁄ Ca 2... more Wnt5a is a member of the Wnt family of proteins that signals through the non-canonical Wnt ⁄ Ca 2+ pathway to suppress cyclin D1. Deregulation of this pathway has been found in animal models suggesting that it acts as tumour suppressor in acute myeloid leukemia (AML). Although DNA methylation is the main mechanism of regulation of the canonical Wnt pathway in AML, the role of WNT5A abnormalities has never been evaluated in this clinical setting. The methylation status of WNT5A promoter-exon 1 was analyzed by methylation-specific PCR and sequencing in eleven AML-derived cell lines and 252 AML patients. We observed WNT5A hypermethylation in seven cell lines and in 43% (107 ⁄ 252) of AML patients. WNT5A methylation was associated with decreased WNT5A expression (P < 0.001) that was restored after exposure to 5-Aza-2'-deoxycytidine. Moreover, WNT5A hypermethylation correlated with upregulation of CYCLIN D1 expression (P < 0.001). Relapse (15% vs 37%, P < 0.001) and mortality (61% vs 79%, P = 0.004) rates were lower for patients in the non-methylated group. Disease-free survival and overall survival at 6 and 7 years, respectively, were 60% and 27% for unmethylated patients and 20% and 0% for hypermethylated patients (P = 0.0001 and P = 0.04, respectively). Interestingly, significant differences were also observed when the analysis was carried out according to cytogenetic risk groups. We demonstrate that WNT5A, a putative tumor suppressor gene in AML, is silenced by methylation in this disease and that this epigenetic event is associated with upregulation of CYCLIN D1 expression and confers poor prognosis in patients with AML. (Cancer Sci 2010; 101: 425-432) Materials and Methods Cell lines and patients. Eleven AML-derived cell lines (MUTZ-3, F-39P, TF-1, HL-60, NOMO-1, KG-1, MV4-II, MOLM-13, KASUMI-1, EOL-1, and HEL) were purchased from the Deutche Sammlung von Microorganismen und Zellkulturen (Braunschweig, Germany). Cells were grown at 37°C under 5% CO 2 in humidified air in RPMI medium (Gibco-BRL,

Journal of Clinical Medicine, 2020

The survival of patients with multiple myeloma (MM) has been dramatically improved in the last de... more The survival of patients with multiple myeloma (MM) has been dramatically improved in the last decade thanks to the incorporation of second-generation proteasome inhibitors (PI), immunomodulatory drugs (IMID), and, more recently, anti-CD38 monoclonal antibodies (MoAb). Nevertheless, still, a major proportion of MM patients will relapse, underscoring the need for new therapies in this disease. Moreover, survival in patients failing the current standard of care regimens (including PI, IMIDs, and anti-CD38 MoAb), which is now defined as triple-class refractory, remains dismal, and new drugs with different mechanism of action are needed. B-cell maturation antigen (BCMA)-targeted therapies and in particular chimeric antigen receptor T cell (CAR T-cell) treatment have emerged as promising platforms to overcome refractoriness to conventional drugs. In this manuscript, we review the current available data regarding CAR T-cell therapy for MM, with a special focus on target selection, clinica...