0000000000965401
AUTHOR
Bruno Paiva
showing 27 related works from this author
Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination
2020
The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r ≥ 0.94, P = 10−16), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial–mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs…
Analysis of treatment efficacy in the GEM-CESAR trial for high-risk smoldering multiple myeloma patients: Comparison between the standard and IMWG MR…
2020
8512 Background: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of sustained minimal residual disease (MRD) negativity in the bone marrow (BM) by next generation flow (NGF). The value of BM MRD assessment in MM is proven, but alternative, non-invasive methods, accurately reflecting disease burden are needed. Methods: Pts received six 4-week cycles of KRd as induction (K:36mg/m2 twice weekly, R: lenalidomide 25mg po od days 1-21 and d:dexamethasone 40mg po weekly) followed by melphalan 200mg/m2, two further cycles of KRd as consolidation and up to 2 years of Rd (R:10mg/d…
Qip-Mass Spectrometry in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Res…
2019
Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients in which the primary endpoint is the assessment of bone marrow minimal residual disease negativity by next generation flow (NGF). However, alternative methods of tumor burden evaluation in serum, like Quantitative Immunoprecipitation Mass Spectrometry (QIP-MS), a polyclonal antibody-based technology to identify intact immunoglobulins, have been also evaluated. Patients and Methods: Ninety HRsMM patients included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and ASCT and 2 further cy…
Single-Cell Characterization of the Multiple Myeloma (MM) Immune Microenvironment Identifies CD27-Negative T Cells As Potential Source of Tumor-React…
2019
Background: The broad use of immunomodulatory drugs (IMiDs) and the breakthrough of novel immunotherapies in MM, urge the optimization of immune monitoring to help tailoring treatment based on better prediction of patients' response according to their immune status. For example, current T cells immune monitoring is of limited value because the phenotype of tumor-reactive T cells is uncertain. Aims: To characterize the MM immune microenvironment at the single-cell level and to identify clinically relevant subsets for effective immune monitoring. Methods: We used a semi-automated pipeline to unveil full cellular diversity based on unbiased clustering, in a large flow cytometry dataset of 86 n…
Randomized Trial of Lenalidomide and Dexamethasone Versus Clarythromycin, Lenalidomide and Dexamethasone As First Line Treatment in Patients with Mul…
2019
Continuous treatment with lenalidomide (R) and dexamethasone (d) is a standard of care for multiple myeloma (MM) patients (pts) not candidates for autologous stem cell transplantation (ASCT). As previously reported, the addition of Clarithromycin (C) to Rd has proven to be safe and effective, and case-control analyses suggested a significant additive value with the combination. C optimizes the therapeutic effect of glucocorticoids by increasing the area under the curve, has immunomodulatory effects and may have direct antineoplastic properties. However, there are not randomized phase III trials confirming these results. GEM-Claridex in an open, randomized, phase III trial for untreated new…
Utility of CD54, CD229, and CD319 for the identification of plasma cells in patients with clonal plasma cell diseases
2015
Background Multiparameter flow cytometry (MFC) identification and characterization of plasma cells (PCs) is a useful tool to support diagnosis, prognostication, and monitoring of PC diseases (PCD). Currently, the number of MFC markers suited for the identification of PC remains limited. Moreover, antibody therapies against PC-associated markers further compromise the utility of the most widely used reagents (e.g., CD38). Despite markers other than CD38 and CD138 are recognized as potentially useful PC-identification markers, no study has comparatively evaluated their performance in combination with CD38 and CD138. Here we compared the utility of CD229, CD54, and CD319 for the identification…
Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma.
2020
[Purpose] Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG).
Biological and clinical significance of dysplastic hematopoiesis in patients with newly diagnosed multiple myeloma
2020
On behalf of the PETHEMA/GEM Cooperative Group.
Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma
2021
PETHEMA/GEM Cooperative Group.
Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma
2023
AbstractThe historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK–MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time …
Preneoplastic somatic mutations including MYD88(L265P) in lymphoplasmacytic lymphoma
2022
Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88 . We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88 L265P in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymph…
Competition between clonal plasma cells and normal cells for potentially overlapping bone marrow niches is associated with a progressively altered ce…
2011
Disappearance of normal bone marrow (BM) plasma cells (PC) predicts malignant transformation of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) into symptomatic multiple myeloma (MM). The homing, behavior and survival of normal PC, but also CD34 hematopoietic stem cells (HSC), B-cell precursors, and clonal PC largely depends on their interaction with stromal cell-derived factor-1 (SDF-1) expressing, potentially overlapping BM stromal cell niches. Here, we investigate the distribution, phenotypic characteristics and competitive migration capacity of these cell populations in patients with MGUS, SMM and MM vs healthy adults (HA) aged 60 years. Our result…
Clinical Significance and Biomarkers to Predict Unsustained Complete Remission in Transplant-Eligible Multiple Myeloma
2020
Background: Transplant-eligible MM patients are achieving unprecedented CR rates with frontline therapy. This urges the question about what other tests are informative upon a negative immunofixation (IFx-), as well as if patients with short duration CR continue having dismal survival with modern frontline plus salvage therapies and if so, how to predict risk of unsustained CR. Aim: To provide an optimal definition of unsustained CR and biomarkers to predict it in transplant-eligible MM patients treated with optimal therapy. Methods: A total of 262 patients enrolled in the PETHEMA/GEM2012MENOS65 trial and who were in CR after receiving six induction cycles of bortezomib, lenalidomide and dex…
Longitudinal Immunogenomic Profiling of Tumor and Immune Cells for Minimally-Invasive Monitoring of Smoldering Multiple Myeloma (SMM): The Immunocell…
2020
Background: Although great strides were made in the management of MM, our best chances to eradicate this malignancy may lie in preventing its progression.Most current models to predict risk of transformation in SMM are commonly established at diagnosis and not reevaluated over time, because some parameters such as tumor burden or genetic abnormalities require invasive bone marrow (BM) aspirates. It could be hypothesized that periodic monitoring of tumor biomarkers is needed to improve risk-stratification of SMM patients, and so would be new minimally-invasive methods that can replace those performed in BM samples. Such methods should also monitor immune profiles, to identify patients with s…
miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma
2020
Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity. We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis…
Heavy and Light Chain Monitoring in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and …
2019
Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of bone marrow minimal residual disease (MRD) negativity. However, other methods of disease evaluation in serum such as heavy+light chain (HLC) assessment, with a potential complementary value to the IMWG response criteria, have also been tested. Aim: To evaluate the performance of HLC assay in HRsMM pts at diagnosis and after consolidation, comparing the results with standard serological methods and Next Generation Flow (NGF) for the assessment of bone marrow MRD. Patients and Methods: Ninety HRsMM pts include…
Immunological Biomarkers of Fatal COVID-19: A Study of 868 Patients
2021
Information on the immunopathobiology of coronavirus disease 2019 (COVID-19) is rapidly increasing; however, there remains a need to identify immune features predictive of fatal outcome. This large-scale study characterized immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using multidimensional flow cytometry, with the aim of identifying high-risk immune biomarkers. Holistic and unbiased analyses of 17 immune cell-types were conducted on 1,075 peripheral blood samples obtained from 868 COVID-19 patients and on samples from 24 patients presenting with non-SARS-CoV-2 infections and 36 healthy donors. Immune profiles of COVID-19 patients were significa…
Assessment of Treatment Response By Ife, Next Generation Flow Cytometry and Mass Spectrometry Coupled with Liquid Chromatography in the GEM2012MENOS6…
2021
Abstract Introduction : In patients (pts) with multiple myeloma (MM), next generation flow cytometry (NGF) and next generation sequencing have shown an increased capacity to identify the presence of disease and to anticipate patient's prognosis as compared to serum protein immunofixation (IFE). However, both methods rely on bone marrow (BM) samples and it is important to explore alternative techniques applicable in more accessible samples such as peripheral blood. Patients and Methods: Newly diagnosed MM pts enrolled in the PETHEMA/GEM2012MENOS65 trial received six cycles of induction with bortezomib, lenalidomide and dexamethasone (VRD), intensification with high-dose therapy (melphalan or…
A machine learning model based on tumor and immune biomarkers to predict undetectable MRD and survival outcomes in multiple myeloma
2022
Abstract Purpose: Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treatment individualization based on the probability of a patient achieving undetectable MRD with a singular regimen could represent a new concept toward personalized treatment, with fast assessment of its success. This has never been investigated; therefore, we sought to define a machine learning model to predict undetectable MRD at the onset of multiple myeloma. Experimental Design: This study included 487 newly diagnosed patients with multiple myeloma. The training (n = 152) and internal validation cohorts (n = 149) consisted of 301 transplant-eligible patients…
Network meta-analysis of randomized trials in multiple myeloma: Efficacy and safety in frontline therapy for patients not eligible for transplant
2022
The treatment scenario for newly-diagnosed transplant-ineligible multiple myeloma patients (NEMM) is quickly evolving. Currently, combinations of proteasome inhibitors (PI) and/or immunomodulatory drugs (IMiD) +/- the monoclonal antibody Daratumumab are used for first-line treatment, even if head-to-head comparisons are lacking. To compare efficacy and safety of these regimens, we performed a network meta-analysis (NMA) of 27 phase 2/3 randomized trials including a total of 12935 patients and 23 different schedules. Four efficacy/outcome and one safety indicators were extracted and integrated to obtain (for each treatment) the surface under the cumulative ranking-curve (SUCRA), a metric use…
Mutational Profiling Predicts Clinical Outcomes to Azacytidine and Low Dose Cytarabine Plus Fludarabine (FLUGA) in Elderly Acute Myeloid Leukemia Pat…
2019
BACKGROUND: Older patients with acute myeloid leukaemia (AML) who are unsuitable for standard induction therapy have limited treatment options. While DNMT3A, TET2, IDH1/2 and TP53 mutations have been previously associated to better response to hypomethylating agents, there are no molecular biomarkers for low-dose cytarabine (LDAC)-based regimens. AIMS: To predict outcome in AML older patients at diagnosis based on mutation status in the context of FLUGAZA trial. FLUGAZA trial was focus on >65 years AML de novo patients comparing azacytidine vs. fludarabine and LDAC (FLUGA Scheme). METHODS: We analyzed bone marrow (BM) samples at diagnosis from 209 out of 285 AML patients treated accordin…
FlowCT for the analysis of large immunophenotypic data sets and biomarker discovery in cancer immunology
2022
Key Points FlowCT is a new computational workspace for unveiling cellular diversity and objectively identifying biomarkers in large immune monitoring studies.FlowCT identified T-cell biomarkers predictive of malignant transformation and survival in SMM and active MM data sets.
Immune biomarkers to predict SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies
2021
AbstractThere is evidence of reduced SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies. We hypothesized that tumor and treatment-related immunosuppression can be depicted in peripheral blood, and that immune profiling prior to vaccination can help predict immunogenicity. We performed a comprehensive immunological characterization of 83 hematological patients before vaccination and measured IgM, IgG, and IgA antibody response to four viral antigens at day +7 after second-dose COVID-19 vaccination using multidimensional and computational flow cytometry. Health care practitioners of similar age were the control group (n = 102). Forty-four out of 59 immune cell types …
Immunologic characterization of COVID-19 patients with hematological cancer
2020
Not available.
Pembrolizumab as Consolidation Strategy in Patients with Multiple Myeloma: Results of the GEM-Pembresid Clinical Trial
2020
PD1 expression in CD4+ and CD8+ T cells is increased after treatment in multiple myeloma patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of pembrolizumab as consolidation in patients achieving at least very good partial response but with persistent measurable disease after first- or second-line treatment. Moreover, the characteristics of the immune system were investigated to identify potential biomarkers of response to pembrolizumab. One out of the 17 evaluable patients showed a decrease in the amount of M-protein, although a potential late effect of high-dose melphalan could not be ruled out. Fourteen adverse events were considered related to pem…
The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Tri…
2021
This article belongs to the Collection The Biomarkers for the Diagnosis and Prognosis in Cancer.
Circulating tumor and immune cells for minimally invasive risk stratification of smoldering multiple myeloma
2022
Abstract Purpose: Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under- and overtreatment. We hypothesized that replacing bone marrow (BM) plasma cells (PC) for circulating tumor cells (CTC), and adding immune biomarkers in peripheral blood (PB) for the identification of patients at risk of progression due to lost immune surveillance, could improve the International Myeloma Working Group 20/2/20 model. Experimental Design: We report the outcomes of 150 patients with SMM enrolled in the iMMunocell study, in which serial assessment of tumor and immune cells in PB was performed every 6 months for a period of 3 years since enrollment. Resul…