15 results on '"Maria Luisa Martin-Ramos"'
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2. Data from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
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Bruno Paiva, Jesus F. San-Miguel, Maria-Victoria Mateos, Joan Blade, Laura Rosiñol, Juan-José Lahuerta, Joaquin Martinez-Lopez, Marta-Sonia Gonzalez-Perez, Adrian Mosquera-Orgueira, Ana Pilar Gonzalez-Rodriguez, Luis Palomera, Felipe de Arriba, Joan Bargay, Rafael Martinez-Martinez, Miguel-Teodoro Hernandez, Rafael Rios, Albert Oriol, Maria-Luisa Martin-Ramos, Norma C. Gutierrez, Maria-Jose Calasanz, Cirino Botta, Juan-José Garcés, Cristina Perez, Ibai Goicoechea, Maria-Teresa Cedena, Noemi Puig, and Camila Guerrero more...
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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 with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Español de Mieloma(GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial.Results:The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predictions of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years maintenance (GEM2014MAIN). High-confidence prediction of undetectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years.Conclusions:It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma.See related commentary by Pawlyn and Davies, p. 2482 more...
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- 2023
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3. Supplementary Data from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
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Bruno Paiva, Jesus F. San-Miguel, Maria-Victoria Mateos, Joan Blade, Laura Rosiñol, Juan-José Lahuerta, Joaquin Martinez-Lopez, Marta-Sonia Gonzalez-Perez, Adrian Mosquera-Orgueira, Ana Pilar Gonzalez-Rodriguez, Luis Palomera, Felipe de Arriba, Joan Bargay, Rafael Martinez-Martinez, Miguel-Teodoro Hernandez, Rafael Rios, Albert Oriol, Maria-Luisa Martin-Ramos, Norma C. Gutierrez, Maria-Jose Calasanz, Cirino Botta, Juan-José Garcés, Cristina Perez, Ibai Goicoechea, Maria-Teresa Cedena, Noemi Puig, and Camila Guerrero more...
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Supplementary Data from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
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- 2023
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4. Supplementary Figure from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
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Bruno Paiva, Jesus F. San-Miguel, Maria-Victoria Mateos, Joan Blade, Laura Rosiñol, Juan-José Lahuerta, Joaquin Martinez-Lopez, Marta-Sonia Gonzalez-Perez, Adrian Mosquera-Orgueira, Ana Pilar Gonzalez-Rodriguez, Luis Palomera, Felipe de Arriba, Joan Bargay, Rafael Martinez-Martinez, Miguel-Teodoro Hernandez, Rafael Rios, Albert Oriol, Maria-Luisa Martin-Ramos, Norma C. Gutierrez, Maria-Jose Calasanz, Cirino Botta, Juan-José Garcés, Cristina Perez, Ibai Goicoechea, Maria-Teresa Cedena, Noemi Puig, and Camila Guerrero more...
- Abstract
Supplementary Figure from A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable MRD and Survival Outcomes in Multiple Myeloma
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- 2023
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5. A machine learning model based on tumor and immune biomarkers to predict undetectable MRD and survival outcomes in multiple myeloma
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Camila Guerrero, Noemi Puig, Maria-Teresa Cedena, Ibai Goicoechea, Cristina Perez, Juan-José Garcés, Cirino Botta, Maria-Jose Calasanz, Norma C. Gutierrez, Maria-Luisa Martin-Ramos, Albert Oriol, Rafael Rios, Miguel-Teodoro Hernandez, Rafael Martinez-Martinez, Joan Bargay, Felipe de Arriba, Luis Palomera, Ana Pilar Gonzalez-Rodriguez, Adrian Mosquera-Orgueira, Marta-Sonia Gonzalez-Perez, Joaquin Martinez-Lopez, Juan-José Lahuerta, Laura Rosiñol, Joan Blade, Maria-Victoria Mateos, Jesus F. San-Miguel, Bruno Paiva, Guerrero, Camila, Puig, Noemi, Cedena, Maria-Teresa, Goicoechea, Ibai, Perez, Cristina, Garces, Juan-Jose, Botta, Cirino, Calasanz, Maria-Jose, Gutierrez, Norma C, Martin-Ramos, Maria-Luisa, Oriol, Albert, Rios, Rafael, Hernandez, Miguel-Teodoro, Martinez-Martinez, Rafael, Bargay, Joan, de Arriba, Felipe, Palomera, Lui, Gonzalez-Rodriguez, Ana Pilar, Mosquera-Orgueira, Adrian, Gonzalez-Perez, Marta-Sonia, Martinez-Lopez, Joaquin, Lahuerta, Juan-Jose, Rosiñol, Laura, Blade, Joan, Mateos, Maria-Victoria, San Miguel, Jesus F, and Paiva, Bruno more...
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Machine Learning ,Survival Rate ,multiple myeloma ,Cancer Research ,Neoplasm, Residual ,MRD ,Oncology ,immunomonitoring ,Humans ,Biomarkers ,Aged ,machine learning - 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 with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Español de Mieloma(GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial. Results: The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predictions of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years maintenance (GEM2014MAIN). High-confidence prediction of undetectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years. Conclusions: It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma. See related commentary by Pawlyn and Davies, p. 2482 more...
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- 2022
6. NGS-Based Molecular Karyotyping of Multiple Myeloma: Results from the GEM12 Clinical Trial
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Juan Manuel Rosa-Rosa, Isabel Cuenca, Alejandro Medina, Iria Vázquez, Andrea Sánchez-delaCruz, Natalia Buenache, Ricardo Sánchez, Cristina Jiménez, Laura Rosiñol, Norma C. Gutiérrez, Yanira Ruiz-Heredia, Santiago Barrio, Albert Oriol, Maria-Luisa Martin-Ramos, María-Jesús Blanchard, Rosa Ayala, Rafael Ríos-Tamayo, Anna Sureda, Miguel-Teodoro Hernández, Javier de la Rubia, Gorka Alkorta-Aranburu, Xabier Agirre, Joan Bladé, María-Victoria Mateos, Juan-José Lahuerta, Jesús F. San-Miguel, María-José Calasanz, Ramón Garcia-Sanz, Joaquín Martínez-Lopez, and Instituto de Salud Carlos III more...
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Cytogenetics ,Cancer Research ,Oncology ,Multiple myeloma ,Next generation sequencing ,multiple myeloma ,next generation sequencing ,cytogenetics ,high-risk ,Citogenètica ,High-risk ,Mieloma múltiple - Abstract
Next-generation sequencing (NGS) has greatly improved our ability to detect the genomic aberrations occurring in multiple myeloma (MM); however, its transfer to routine clinical labs and its validation in clinical trials remains to be established. We designed a capture-based NGS targeted panel to identify, in a single assay, known genetic alterations for the prognostic stratification of MM. The NGS panel was designed for the simultaneous study of single nucleotide and copy number variations, insertions and deletions, chromosomal translocations and V(D)J rearrangements. The panel was validated using a cohort of 149 MM patients enrolled in the GEM2012MENOS65 clinical trial. The results showed great global accuracy, with positive and negative predictive values close to 90% when compared with available data from fluorescence in situ hybridization and whole-exome sequencing. While the treatments used in the clinical trial showed high efficacy, patients defined as high-risk by the panel had shorter progression-free survival (p = 0.0015). As expected, the mutational status of TP53 was significant in predicting patient outcomes (p = 0.021). The NGS panel also efficiently detected clonal IGH rearrangements in 81% of patients. In conclusion, molecular karyotyping using a targeted NGS panel can identify relevant prognostic chromosomal abnormalities and translocations for the clinical management of MM patients., The study was supported by the Accelerator Grant: next steps: Early detection and intervention: Understanding the mechanisms of transformation and hidden resistance of incurable hematological malignancies, grants from Instituto de Salud Carlos III PI15/01484 and CRIS Foundation 2020/0063 and 2021/0088. more...
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- 2022
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7. Fragile X Syndrome Caused by Maternal Somatic Mosaicism of FMR1 Gene: Case Report and Literature Review
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Maria Jose Gómez-Rodríguez, Montserrat Morales-Conejo, Ana Arteche-López, Maria Teresa Sánchez-Calvín, Juan Francisco Quesada-Espinosa, Irene Gómez-Manjón, Carmen Palma-Milla, Jose Miguel Lezana-Rosales, Ruben Pérez de la Fuente, Maria-Luisa Martin-Ramos, Manuela Fernández-Guijarro, Marta Moreno-García, and Maria Isabel Alvarez-Mora more...
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Genetics ,Genetics (clinical) - Abstract
Fragile X syndrome (FXS) is caused by an abnormal expansion of the number of trinucleotide CGG repeats located in the 5′ UTR in the first exon of the FMR1 gene. Size and methylation mosaicisms are commonly observed in FXS patients. Both types of mosaicisms might be associated with less severe phenotypes depending on the number of cells expressing FMRP. Although this dynamic mutation is the main underlying cause of FXS, other mechanisms, including point mutations or deletions, can lead to FXS. Several reports have demonstrated that de novo deletions including the entire or a portion of the FMR1 gene end up with the absence of FMRP and, thus, can lead to the typical clinical features of FXS. However, very little is known about the clinical manifestations associated with FMR1 gene deletions in mosaicism. Here, we report an FXS case caused by an entire hemizygous deletion of the FMR1 gene caused by maternal mosaicism. This manuscript reports this case and a literature review of the clinical manifestations presented by carriers of FMR1 gene deletions in mosaicism. more...
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- 2022
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8. A Machine Learning Model Based on Tumor and Immune Biomarkers to Predict Undetectable Measurable Residual Disease (MRD) in Transplant-Eligible Multiple Myeloma (MM)
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Camila Guerrero, Noemi Puig, María Teresa Cedena, Ibai Goicoechea, Cristina Pérez Ruiz, Juan José Garcés, Cirino Botta, Maria Jose Calasanz, Norma C. Gutierrez, Maria Luisa Martin-Ramos, Albert Oriol, Rafael Rios, Miguel Hernández, Rafael Martínez, Joan Bargay, Felipe De Arriba, Luis Palomera, Ana Pilar Gonzalez, Adrián Mosquera Orgueira, Marta Sonia Gonzalez, Joaquín Martínez-López, Juan Jose Lahuerta, Laura Rosinol, Joan Bladé Creixenti, Maria-Victoria Mateos, Jesus San-Miguel, and Bruno Paiva more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
INTRODUCTION: There is expectation of using biomarkers to personalize treatment in MM. Yet, a successful treatment selection cannot be confirmed before 5 or 10 years of progression-free survival (PFS). Treatment individualization based on the probability of an individual patient to achieve undetectable MRD with a singular regimen, could represent a new model towards personalized treatment with fast assessment of its success. This idea has not been investigated previously. AIM: Develop a machine learning model to predict undetectable MRD in newly-diagnosed transplant-eligible MM patients, treated with a standard of care. METHODS: This study included a total of 278 newly-diagnosed and transplant-eligible MM patients treated with proteasome inhibitors, immunomodulatory drugs and corticosteroids. The training (n=152) and internal validation cohort (n=60) consisted of 212 active MM patients enrolled in the GEM2012MENOS65 trial. The external validation cohort was defined by 66 high-risk smoldering MM patients enrolled in the GEM-CESAR trial, which treatment differed only by the substitution of bortezomib by carfilzomib during induction and consolidation. RESULTS: We started by investigating patients' MRD status after VRD induction, HDT/ASCT and VRD consolidation according to their ISS and R-ISS, LDH levels, and cytogenetic alterations. Surprisingly, neither the ISS nor the R-ISS predicted significantly different MRD outcomes. Indeed, high LDH levels and del(17p13) were the only parameters associated with lower rates of undetectable MRD. Because these two features are relatively infrequent at diagnosis, we next aimed to evaluate other disease features and develop integrative, weighted and more effective models based on machine learning algorithms. Of 37 clinical and biological parameters evaluated, 17 were associated with MRD outcomes. These were subsequently modeled using logistic regression for machine learning classification, where the sum of the weighted coefficients multiplied by its input variable, is transformed into a probability outcome that ranges from 0 to 1 using a logit sigmoid function. The most effective model resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (plasma cell [PC] clonality in bone marrow and CTCs in blood) and immune related (myeloid precursors, mature B cells, intermediate neutrophils, eosinophils, CD27 negCD38 pos T cells and CD56 brightCD27 neg NK cells) biomarkers. Of note, immune biomarkers displayed the highest coefficient weights and were determinant to predict patients' MRD status in this model. Data obtained for an individual patient can be substituted into our formula, which results in a numerical probability of achieving undetectable (>0.5) vs persistent (0.685 or Patients predicted to achieve undetectable MRD using standard and high-confidence values showed longer PFS and overall survival (OS) than those with probability of persistent MRD. In fact, patients with >0.687 probability of achieving undetectable MRD showed 86% PFS and 94% OS at five years, whereas those in whom persistent MRD was predicted ( CONCLUSION: We demonstrated that it is possible to predict patients' MRD status with significant accuracy, using an integrative, weighted model based on machine learning algorithms. Although immune biomarkers are not commonly used, the raw data from which these can be developed is generally obtained in diagnostic laboratories using flow cytometry to screen for PC clonality. Furthermore, we made the model available to facilitate its use in clinical practice at www.MRDpredictor.com. Disclosures Puig: Celgene, Janssen, Amgen, Takeda: Research Funding; Celgene: Speakers Bureau; Amgen, Celgene, Janssen, Takeda: Consultancy; Amgen, Celgene, Janssen, Takeda and The Binding Site: Honoraria. Cedena: Janssen, Celgene and Abbvie: Honoraria. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. De Arriba: Amgen: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS-Celgene: Consultancy, Honoraria, Speakers Bureau. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Lahuerta: Celgene: Other: Travel accomodations and expenses; Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Bladé Creixenti: Janssen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Mateos: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; GSK: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. more...
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- 2021
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9. Clinical Validation of a NGS Capture Panel to Identify Mutations, Copy Number Variations and Translocations in Patients with Multiple Myeloma
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Norma C. Gutiérrez, Javier de la Rubia, Laura Rosiñol, Ricardo Sanchez, Ramón García-Sanz, Miguel T. Hernandez, Yanira Ruiz-Heredia, Albert Oriol, Alejandro Medina, Gorka Alkorta, Maria-Victoria Mateos, Manuela Fernández-Guijarro, Jesús F. San-Miguel, Rafael Valdés-Mas, Iria Vázquez, Xabier Agirre, María José Calasanz, María Jesús Blanchard, Maria Luisa Martin-Ramos, Gonzalo R. Ordóñez, Santiago Barrio, Joan Blade Creixenti, Juan José Lahuerta, Anna Sureda Balari, Isabel Cuenca, Joaquin Martinez-Lopez, and Rafael Rios more...
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Newly diagnosed ,Gene deletion ,Biochemistry ,Peripheral blood ,Paired samples ,Targeted ngs ,Family medicine ,medicine ,%22">Fish ,Oncogenic mutation ,In patient ,business - Abstract
Introduction Multiple Myeloma (MM) is a heterogeneous disease with a complex clonal and subclonal architecture with few recurrent mutations. The arrival of next-generation sequencing (NGS) has allowed us to have a deeper understanding of the disease. Due to that complexity and the low recurrence of "driver" mutations, the study of general mutational profile, copy number variation (CNV) and translocations is crucial to make an accurate diagnosis and prognosis. For that reason, a clinically validated NGS capture panel has been designed to analyze in a single assay all interesting genetic aberrations simultaneously including SNVs, indels, CNVs and chromosomal translocations. Methods In addition to genomic DNA (gDNA) from 33 healthy donors to create a robust baseline forCNV detection,we studied 161 DNA samples from 149 newly diagnosed MM patients enrolled in the GEM2012MENOS65clinical trial and treated homogeneously: gDNA from 149 BM CD138+ plasma cells and 12 paired cfDNA from peripheral blood samples obtained at diagnosis. First, starting with 100 ng of gDNA and 200ng for cfDNA samples, a custom targeted NGS panel using SureSelect capture technology (Agilent) followed by NextSeq500 (Illumina) sequencing identified SNVs, indels, CNVs and the most relevant IGH translocations within 26genes involved with MM. The average sequencing depth was 609x across samples; and 98% of the targeted regions were sequenced with >200x. Second, NGS custom panel results were compared with FISH (n=88) and whole exome sequencing (SureSelect XT V6) (n=48) results. Both NGS panel and exome raw data were analyzed by DREAMgenics applying a custom bioinformatic pipeline. Finally, 5 discordant cases were followed-up by SNP-arrays. Results We have identified 408 exonic and non-synonymous variants. At least 1 oncogenic mutation was detected in 86% (128/149) of patients. NRAS was mutated in25% of patients, followed by KRAS(23%), BRAF(12%) DIS3(11%) and TP53(9%). Other interesting pathogenic mutations were identified in FGFR3 andHIST1H1E genes in 9% and 5% of patients, respectively. In 92% (11/12) of cfDNA samples at least 1 oncogenic mutation was detected. For this 12 cases, paired samples (BM CD138+vscfDNA) were available. A total of 39 somatic mutations were identified in those cases. In cfDNA, 10 mutations were detected, and 5 were present in both samples. Furthermore, a mean decrease of 0.19VAF was observed in cfDNA (0.12; 0.01-0.48) vs plasma cells (0.31; 0.01-0.51). Regarding to CNV, 1q gain was detected in 32% of patients (28/88), and 1p and 17p deletions in 17% (15/88) and 13% (11/88), respectively. Additionally, ATR and CRBN gene amplifications were detected in 22% and 16%, respectively. When these data were compared to FISH, a 75% of sensitivity and 91% of specificity was achieved by our method, with a PPV of 68% and a NPG of 93%. Translocations were identified in 28% (25/88) of patients, including 7% (6/88)) t(11;14), 14% (12/88), t(4;14), and 1 patient t(14;16). We also detected t(6;14)(p21;q32) IGH/CCND3 in 3 patients that had also been described in MM.Translocations were detected with a 94% of sensitivity, 99% of specificity, with a predictive positive value of 94% and a predictive negative value of 99%. Importantly, NGS-based method revealed a t(10;14) in 3 patients that had not been identified by FISH, a new translocation implying the miRNA hsa-mir-4537. Finally, the impact on PFS from FISH and NGS results was analyzed separately. PFS was similar for translocations and 17p deletions. However, 1p-detected by NGS showed a higher negative prognostic impact (p=0,006 vs p=0,127 by FISH)(Fig.1). Furthermore, our panel showed that 7% of patients (6/88) had a bi-allelic TP53 inactivation. Survival analysis showed that these patients relapsed significantly earlier than the others (p=0.028). Amplifications (≥4 copies) in 1q+could not identified with this panel. Conclusions Our custom NGS-based test allows in a single assay a more comprehensive study of the genomic landscape of MM patients by (a) detecting with a high sensitivity the most important and recurrent mutations and cytogenetic alterations, (b) identifying translocations and CNVs not previously detected by FISH and (c) identifying a double-hit MM patient. Additionally, cfDNA could be analyzed with this NGS strategy identifying molecular alterations in most of the patients. Disclosures Oriol: Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau. de la Rubia:Janssen: Consultancy, Other: Expert Testimony; Celgene: Consultancy, Other: Expert Testimony; Amgen: Consultancy, Other: Expert Testimony; Ablynx/Sanofi: Consultancy, Other: Expert Testimony. Mateos:Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade Creixenti:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Garcia-Sanz:Novartis: Honoraria; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Gilead: Honoraria, Research Funding; BMS: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding. Martinez-Lopez:Novartis: Research Funding; BMS: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Vivia Biotech: Honoraria; Altum: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. more...
- Published
- 2020
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10. Randomized Trial of Lenalidomide and Dexamethasone Versus Clarythromycin, Lenalidomide and Dexamethasone As First Line Treatment in Patients with Multiple Myeloma Not Candidates for Autologous Stem Cell Transplantation: Results of the GEM-Claridex Clinical Trial
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Ricarda Belen Garcia Sanchez, Guillermo Martín Sánchez, Cristina Encinas, Morton Coleman, Maria-Victoria Mateos, Jesús F. San-Miguel, María José Casanova, Ana Isabel Teruel, Javier de la Rubia, Verónica González-Calle, Norma C. Gutiérrez, Ruben Niesvizky, Maria Luisa Martin-Ramos, Adrián Alegre Amor, Felipe de Arriba, Sebastian Garzon Lopez, Laura Rosinol Dachs, Miguel T. Hernandez, Mercedes Gironella Meda, Bruno Paiva, Jesús Martín, Maria Teresa Cedena Romero, Juan José Lahuerta, Noemi Puig, José Maria Arguiñano Pérez, Mario Arnao, Esther González Garcia, Joan Bladé, Ernesto Pérez Persona, Marta González, María del Carmen Couto Caro, Fernando Escalante, Rafael Ríos Tamayo, Albert Oriol, Ana María Vale López, Adriana C Rossi, and María José Calasanz more...
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medicine.medical_specialty ,business.industry ,Immunology ,Disease progression ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,law.invention ,Transplantation ,Clinical trial ,Autologous stem-cell transplantation ,Randomized controlled trial ,law ,Internal medicine ,medicine ,In patient ,business ,Multiple myeloma ,Lenalidomide ,medicine.drug - Abstract
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 newly diagnosed MM pts ineligible for ASCT. Enrolled pts were randomly assigned 1:1 to receive 28-day cycles of R (25mg po qd days 1-21), d (40mg po [20mg in pts >75 years], days 1, 8, 15 and 22) plus or minus C (500mg po bid) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS) and minimal residual disease (MRD) negativity rate and safety. MRD was evaluated in 99 pts using Euroflow NGF (limit of detection, 2x10-6). As expected, most pts in CR were tested for MRD whereas the majority of pts with missing MRD data achieved VGPR or less and were thus considered as MRD-positive for intent to treat analyses. Two hundred and eighty-eight pts were included (144 to C-Rd and 144 to Rd). Median age was 76 (range: 65-93), 36.8% of pts had ISS 3 and 15.6% presented with high-risk cytogenetic abnormalities. Key baseline characteristics were well balanced between the two arms. The addition of C to Rd resulted in deeper responses with a ≥ complete response (CR) rate of 20.1% in the C-Rd arm compared to 11.2% in the Rd arm (p = 0.037). Also, the ≥ very good partial response (VGPR) rate was 52.8% in the C-Rd arm as compared to the 37.1% in the Rd arm (p = 0.007). MRD analysis was performed at suspected CR and yearly afterwards. On intent-to-treat, 5/144 (3,5%) and 9/143 (6,2%) of pts achieved undetectable MRD with C-Rd and Rd, respectively (p = 0,7). With a median follow-up of 16 months (range, 1-47), no significant differences were observed in PFS: in the C-Rd arm the median was 23 months and has not been reached in the Rd arm (p = 0.09); furthermore, although disease progression and/or death rate was comparable in both arms (C-Rd: 57/144 [39.6%] vs Rd: 45/144 [31.2%]), a trend towards shorter PFS was observed in the C-Rd group (Figure 1). This effect was less evident in younger ( The most common G3-4 adverse events (AE) in the C-Rd and Rd arms were hematologic (neutropenia: 10,4% vs 16,7% [p = ns] and anemia: 2,1% vs 6,9% [p = 0,04], respectively). G3-4 infections occurred in 16% of cases in both arms and were the most frequent non-hematological AE. 7% of pts in both arms developed G3-4 GI toxicity and there were no differences between the two arms in G3-4 skin-related AEs (2,8% vs 3,5%). Only one case of invasive SPM (colon cancer) in the C-Rd arm was reported. In conclusion, the addition of C to Rd in transplant ineligible newly diagnosed MM pts significantly increases the rate and depth of responses but it is not associated with an improved PFS and OS due to a higher proportion of deaths in the C-Rd arm, mostly infectious, in pts > 75 years and being early deaths. Overexposure to steroids due to the delayed clearance induced by C in this elderly population could explain our results. Figure Disclosures Puig: The Binding Site: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Rosinol Dachs:Janssen, Celgene, Amgen and Takeda: Honoraria. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Oriol:Celgene Corporation: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau. De La Rubia:AbbVie: Consultancy; AMGEN: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Amor:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Martín Sánchez:GILEAD SCIENCES: Research Funding. Rossi:BMS: Research Funding; Janssen, Celgene, Amgen: Consultancy. Coleman:Merck: Research Funding; Pharmacyclics: Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Bladé:Jansen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Mateos:EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria. more...
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- 2019
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11. Clinical Significance and Transcriptional Profiling of Persistent Minimal Residual Disease (MRD) in Multiple Myeloma (MM) Patients with Standard-Risk (SR) and High-Risk (HR) Cytogenetics
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Javier de la Rubia, Ramón García-Sanz, David Lara-Astiaso, María-Belén Vidriales, Alberto Orfao, Josep Sarrá, Joaquin Martinez-Lopez, Luis Palomera, Jesús F. San-Miguel, Sarai Sarvide, Rafael Rios, Diego Alignani, Maria-Victoria Mateos, Bruno Paiva, Idoia Rodriguez, Laura Rosiñol, Isabel Krsnik, Joan Bargay, María Teresa Cedena, Joan Bladé, Leire Burgos, Miguel T. Hernandez, José M. Moraleda, Juan Flores-Montero, Ibai Goicoechea, Amaia Vilas-Zornoza, Jesús Martín, Maria Luisa Martin-Ramos, Noemi Puig, Lourdes Cordón, Albert Oriol, María José Calasanz, Norma C. Gutiérrez, Rafael Martínez, and Juan José Lahuerta more...
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medicine.medical_specialty ,business.industry ,Immunology ,Complete remission ,Tumor cells ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Standard Risk ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical significance ,Progression-free survival ,business ,health care economics and organizations ,Multiple myeloma ,030215 immunology - Abstract
Background: Despite significant improvements in the treatment of MM, the outcome of patients with HR cytogenetics remains poor despite similar complete remission (CR) rates as compared to SR cases. Relapses among patients in CR are attributed to the persistence of MRD, but knowledge about the impact of MRD in patients with SR and HR cytogenetics, treated with modern therapies and monitored with next-generation techniques, is limited. Similarly, there is virtually no data about in vivo mechanisms of resistance in SR and HR MM; however, since MRD represents those very few cells that are resistant to treatment, it could be hypothesized that profiling MRD cells may shed light into the mechanisms of resistance in both SR and HR patients. Aim: To determine the clinical impact of MRD in MM patients with SR vs HR cytogenetics, and to identify transcriptional mechanisms determining MRD resistance by investigating the transcriptome of MRD cells in both patient subgroups. Methods: This study was conducted in a series of 390 patients enrolled in the PETHEMA/GEM2012 trial (6 induction cycles with VRD followed by ASCT and 2 courses of consolidation with VRD). FISH was analyzed on CD138 purified PCs at diagnosis. MRD was predefined to be prospectively assessed following induction, transplant and consolidation, using next-generation flow (NGF) according to EuroFlow. In 40 patients [28 with SR and 12 with HR cytogenetics: i.e., t(4;14), t(14;16) and/or del(17p)], diagnostic and MRD tumor cells persisting after VRD-induction were isolated by FACS according to patient-specific aberrant phenotypes. Due to the small number of sorted MRD cells (median of 25,600) we used a 3' end RNAseq method optimized for generating libraries from low-input starting material (MARSeq). Differential expression analyses were performed with DESeq2 R package. Results: At the latest time-point in which MRD was assessed, MRD-positive rates progressively increased (p =.006) from SR patients (148/300, 49%) to cases with t(4;14) (24/42, 57%) and del(17p) (29/38, 76%). Furthermore, MRD levels were significantly superior in patients with del(17p) compared to SR FISH (0.02% vs 0.006%, p =.009), while MRD levels in patients with t(4;14) (0.004%) were similar to those in SR MM. Only 10 patients had a t(14;16) and 4 were MRD-positive. Among patients achieving MRD-negativity (.05). Conversely, 3-year PFS rates for MRD-positive patients decreased from those having SR FISH to those with t(4;14) and del(17p) (59%, 46% and 24%, respectively), with statistically significant differences between the first and the latest subgroups (p Since clearance of MRD notably lowered the risk of relapse and persistence of MRD significantly shortened the PFS in each cytogenetic group (p ≤.001), we investigated the unique features of MRD cells persisting after VRD-induction by comparing their transcriptome to that of patient-matched tumor cells at diagnosis (n=40). Accordingly, MRD cells showed 763 genes significantly deregulated (Padj Conclusions: This is one of the largest studies integrating patients' cytogenetics and MRD status. Our results, based on intensive treatment and MRD monitoring using NGF, unveil that achieving MRD-negativity may overcome the poor prognosis of HR cytogenetics. By contrast, persistent MRD significantly reduces PFS rates, particularly in patients with del(17p). Interestingly, MRD cells from SR and HR patients may have different transcriptional mechanisms leading to VRD resistance, and further understanding of these could provide knowledge on how to eradicate MRD in both patient subgroups. Disclosures Puig: Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Garcia-Sanz:Affimed: Research Funding. Martinez-Lopez:BMS: Research Funding; Pfizer: Research Funding; Vivia: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding. Oriol:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bladé:Janssen: Honoraria. San-Miguel:Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. more...
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- 2018
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12. Absence of Contribution to a Differential Outcome of the Stringent Complete Response IMWG Category Respect to the Conventional CR in Multiple Myeloma. a Validation Analysis Based on the Pethema/GEM2012MENOS65 Phase III Clinical Trial
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Ana Jiménez Ubieto, Jesús Martín, Javier de la Rubia, Laura Rosiñol, José Gonzalez Medina, Isabel Krsnik, Joan Bargay, Joaquin Martinez Lopez, María Teresa Cedena, Rafael Rios, María José Calasanz, Luis Palomera, Joan Bladé, Maria-Victoria Mateos, Miguel-Teodoro Hernández, Albert Oriol, Noemi Puig, Juan José Lahuerta, Jesús Blanchard, Enrique M. Ocio, José M. Moraleda, Maria Luisa Martin-Ramos, Bruno Paiva, Jesús F. San-Miguel, and Rafael Alonso Fernández more...
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medicine.medical_specialty ,business.industry ,Stringent Complete Response ,Low resolution ,Immunology ,Cell Biology ,Hematology ,Newly diagnosed ,medicine.disease ,Biochemistry ,Transplantation ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Family medicine ,Landmark analysis ,medicine ,business ,Bristol-Myers ,Multiple myeloma ,030215 immunology - Abstract
Introduction: To discriminate different outcomes among patients in CR, the International Myeloma Working Group (IMWG )introduced more stringent CR (sCR) criteria by adding to the pre-existing CR parameters the requirement of a normal free-light chain ratio (sFLCr) plus the absence of clonal plasma cells (PCs) in bone marrow (BM) by immunohistochemistry (IHC). In 2011,the low-sensitivity cytometrycriteria were included as alternative methodology to IHC to define sCR. Aim: To validate the preliminary data of our previous study (Blood 2015. 126:858-62) regarding the lack of influence of an abnormal sFLCr in the outcome of MM patients, through the analysis of a more extensiveseries of newly diagnosed multiple myeloma (NDMM) patients in CR or sCR. Patients and Methods: This study is based on 459 NDMM patients who were transplant candidates and enrolled in the GEM2012MENOS65phase 3trial;evaluable patients were enrolled in a subsequent maintenance trial (NCT02406144).CR and sCR was defined according to the IMWG criteria. Agreeing to the protocol, patients with 1.65 if the patient was κ). BM aspirates were assessed for morphological enumeration of PCs and monitoring of minimal residual disease (MRD) using next-generation flow (NGF) according toEuroFlow SOPs. The median limit of detection was of 3x10-6. We classified as sCR all patients in CR with normal sFLCr and absence of clonal PCs by NGF with a reduced threshold of sensitivity to 10-4.The median follow-up was 40 months. Results: After ASCT,392 patients were evaluable for response; 239 (61%) reached ≥CR. Data from sFLCr and MRD was available in 225 and 221 patients, respectively. In 153 out of a total of 203 (74%) patients in CR in which complete information about FLC and MRD was available were categorized as sCR. The remaining 55 patients were consider in CR because of failure to accomplish 1 of the 2 criteria: abnormal sFLCr (n=49) or MRD+veby low sensitivity flow (n=11); 5patientsshared both criteria.In a landmark from ASCT, with a follow up of 27 months, sCRdidn't show significantly differences inPFS (2 years-PFS 90% vs 83%; P=.2) neither in OS (2 years-OS 96% vs 98%; P=.6) as compared to CR patients.Interestingly, patients with abnormal (n=51) vs normal (n=174) sFLCr showed superimposable PFS (2 years-PFS 86% vs 88%; P=.6) and OS (2 years-OS 95% vs 100%; P=.2).By contrast, in the 11 patients (out of the 221, 5%) with persistent MRD (>10-4) the PFS was significantly poorer as compared with MRD-ve cases (2-yearsPFS 91% vs48%; P=.001)but the OS was similar (2 years-OS 98% vs 96%; P=.3).As validation, we reproduced the analysis in the consolidation-2 end-point (figure 1), where375patients were evaluable for response assessment,267 of them (71%) reached ≥CR. Once again, in the landmark analysis, sCR didn't show significantly differences in PFS with respect to CR patients (2 years-PFS 88% vs 84%; P=.2) neither in OS (2 years-PFS 96% vs 90%; P=.3); moreover, patients with abnormal (n=55) vs normal (n=195) sFLCr showed superimposable PFS (2 years-PFS 84% vs 87%; P=.4) and OS (2 years-OS 89% vs 96%; P=.2).In the MRD analysis, patients with persistent MRD, had significantly inferior PFS (2-years PFS 87% vs 72%; P=.04 for >10-4 MRDsensitivity). If we increase the sensitivity of the MRD to 10-6, the differences in PFS at 2 years are more evident (2 years-PFS 94% vs 67%; P10-6 sensitivity). Conclusion: These results confirm our previous findings based on GEM05menos65/ GEM10mas65 clinical trials, indicating that for MM patients stringent CR criteria does not predict a different outcome as compared to standard CR. Specifically, the sFLCr doesn't identify patients in CR at distinct risk. If this essential criterion in the definition of sCR lacks connotations for the prognosis, is it not justified to maintain a response category whose real significance depends on the combination of the traditional CR criteria with a negative MRD status based on very low (IHC) or low resolution ( Figure 1. Figure 1. Disclosures Martinez Lopez: Janssen: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Puig:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Oriol:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ocio:Pharmamar: Consultancy; AbbVie: Consultancy; Seattle Genetics: Consultancy; BMS: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. Mateos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Sanofi: Consultancy; Takeda: Consultancy; Novartis: Consultancy; MSD: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Brystol-Myers Squibb: Consultancy; Amgen: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees. Bladé:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Lahuerta:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. more...
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- 2018
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13. VTD (Bortezomib/Thalidomide/Dexamethasone) As Pretransplant Induction Therapy for Multiple Myeloma: Definitive Results of a Randomized Phase 3 Pethema/GEM Study
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M Jesús Blanchard, Maria Luisa Martin-Ramos, Miquel Granell, Norma C. Gutiérrez, Rafael Martínez-Martínez, Antonia Sampol, Jesús F. San-Miguel, Miguel T. Hernandez, Maria-Victoria Mateos, Yolanda Gonzalez-Montes, Joaquin Martinez-Lopez, Luis Palomera, Ana Isabel Teruel, María Teresa Cibeira, Adrian Alegre, Albert Oriol, Isidro Jarque, Laura Rosinol Dachs, Juan José Lahuerta, Felipe de Arriba, Enrique García Bengoechea, Ana López de la Guía, and Joan Bladé more...
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0301 basic medicine ,Melphalan ,medicine.medical_specialty ,education ,Immunology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Maintenance therapy ,Internal medicine ,Medicine ,health care economics and organizations ,Multiple myeloma ,Intention-to-treat analysis ,business.industry ,Combination chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Chemotherapy regimen ,Transplantation ,Thalidomide ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Background: The randomized PETHEMA/GEM phase III trial GEM05menos65 (www.clinicaltrials.gov NCT00461747) demonstrated that pretransplant induction therapy with VTD resulted in a significantly higher CR rate both, pretransplant and postransplant and in a significantly longer progression-free survival (PFS) when compared with thalidomide/dexamethasone (TD) and combination chemotherapy plus bortezomib (VBMCP/VBAD/B) (Rosiñol et al, Blood 2012). We report here the definitive results of the trial, ten years after the last patient was included. Methods: From April 6, 2006 to August 5, 2009, 386 patients younger than 65 years with newly diagnosed symptomatic multiple myeloma (MM) were randomized to receive three different induction regimens: six 4-week cycles of TD (thalidomide 200 mg daily; dexamethasone 40 mg on days 1-4 and 9-12) vs. six 4-week cycles of VTD (TD at identical doses plus i.v. bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11) vs. combination chemotherapy plus bortezomib (4 cycles of alternating VBMCP and VBAD chemotherapy followed by two cycles of i.v. bortezomib at the usual dose of 1.3 mg/m2 on days 1,4,8,11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. All patients were planned to undergo ASCT with high-dose melphalan at 200 mg/m2 followed by maintenance therapy with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN) for 3 years. One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics [t(4;14), t(14;16) and/or 17p deletion]. Patient characteristics at diagnosis and prognostic factors such as ISS, cytogenetics and maintenance arm were similarly distributed in the 3 arms. Results: After a median follow-up of 115 months for alive patients, VTD resulted in a significantly longer PFS when compared with TD and VBMCP/VBAD/B (52 vs 28 vs 32 months, p=0.01) (Figure 1). The median overall survival (OS) was 128 vs 99 vs 93 months, respectively, with no significant differences among the 3 arms. In the overall series, the PFS was significantly shorter in patients with high-risk cytogenetics compared with patients with standard-risk (15 vs. 42 months, p=0.001). In the TD and in the VBMCP/VBAD/B arm patients with high-risk cytogenetics had a significantly shorter PFS than patients with standard-risk (7 vs 32 months, p=0.029 in TD group; 13 vs. 38 months, p=0.027 in VBMCP/VBAD/B group). However, there was no significant difference in the VTD arm (23 vs 52 months, p=0.125). Patients with high-risk cytogenetics had a significantly shorter OS in the overall series (median 38 months vs 114, p=0.0001) and this was observed in the three treatment arms: VTD median 36 months vs not reached (p=0.0001), TD median 52 months vs 113 (p=0.017), VBMCP/VBAD/B median 29 months vs 93 (p=0.01). The achievement of a negative MRD after transplant was associated with a longer PFS and OS. Thus, on an intention to treat basis, patients who had MRD negative after transplant had a significantly longer PFS (59 vs 38 months, p=0.0001) and OS (median not reached vs 102 months, p=0.001) than those who remained MRD positive after ASCT. Of interest, there are no significant differences in PFS (41 months vs 60 months, p=0.367) or OS (114 moths vs not reached, p=0.329) between patients with high-risk or standard risk cytogenetics who achieved negative MRD after transplant. By contrast, in patients with MRD positive after transplant, the PFS ( 16 months vs 38 months, p=0.006) and OS (29 months vs 113 months, p=0.001) was significantly shorter in patients with high-risk cytogenetics compared with patients with standard-risk cytogenetics. Conclusions: Our long-term results confirm that induction with VTD results in a significantly longer PFS when compared with TD and VBMCP/VBAD/B. Patients with high-risk cytogenetics who achieved postransplant MRD negative had a similar outcome than patients with standard-risk cytogenetics, while patients with high-risk cytogenetics who remain MRD positive had a dismal prognosis. Finally, the PFS of 52 months achieved with VTD is the longest ever reported in the first line treatment of younger patients with MM elegible for ASCT and support the use of VTD as the standard of care for pretransplant induction therapy. Figure 1. Figure 1. Disclosures Rosinol Dachs: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Oriol:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Blanchard:Janssen: Honoraria. Granell:Janssen: Honoraria; Celgene: Honoraria. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Vivia: Honoraria; Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding. Alegre:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Blade:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. more...
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- 2018
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14. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study
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Javier López-Jiménez, Maria-Victoria Mateos, Joaquín Parra Martínez, Albert Oriol, Javier de la Rubia, D. Hernández, Joan Besalduch, Adrian Alegre, María Teresa Cibeira, Jesús F. San Miguel, Laura Rosiñol, Yolanda González, Miquel Granell, Norma C. Gutiérrez, Miguel T. Hernandez, Joaquín Díaz-Mediavilla, Luis Palomera, Maria Luisa Martin-Ramos, Juan José Lahuerta, Joan Bladé, Ana Isabel Teruel, Felipe de Arriba, Grupo Español de Mieloma, and Maria Asunción Etxebeste more...
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Melphalan ,Male ,medicine.medical_specialty ,Vincristine ,Immunology ,Antineoplastic Agents ,Biochemistry ,Gastroenterology ,Transplantation, Autologous ,Dexamethasone ,Disease-Free Survival ,Bortezomib ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Multiple myeloma ,Aged ,business.industry ,Stem Cells ,Hematopoietic Stem Cell Transplantation ,Induction chemotherapy ,Cell Biology ,Hematology ,Induction Chemotherapy ,Middle Aged ,medicine.disease ,Boronic Acids ,Surgery ,Thalidomide ,Transplantation ,Pyrazines ,Female ,business ,Multiple Myeloma ,medicine.drug - 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). more...
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- 2012
15. Impact of Next-Generation Flow (NGF) Minimal Residual Disease (MRD) Monitoring in Multiple Myeloma (MM): Results from the Pethema/GEM2012 Trial
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Luis Palomera, Juan Flores-Montero, María-Belén Vidriales, María José Calasanz, Josep Sarrá, Lourdes Cordón, Noemi Puig, Maria-Victoria Mateos, Maria Luisa Martin-Ramos, Jesús F. San Miguel, Laura Rosiñol, M Jesús Blanchard, Lucia Lopez-Anglada, Miguel T. Hernandez, Juan José Lahuerta, Norma C. Gutiérrez, Rafael Martínez, Jesús Martín, Joan Bladé, Albert Oriol, Javier de la Rubia, María Teresa Cedena, Ramón García-Sanz, Isabel Krsnik, J. Bargay, Bruno Paiva, Leire Burgos, José M. Moraleda, Joaquin Martinez-Lopez, Rafael Rios, and Alberto Orfao more...
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medicine.medical_specialty ,business.industry ,Immunology ,Treatment outcome ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Treatment efficacy ,Recurrence risk ,Clinical trial ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Family medicine ,medicine ,Relapse risk ,business ,Multiple myeloma ,030215 immunology - Abstract
Background: MRD is an established biomarker to evaluate treatment efficacy, define patients at risk based on persistent MRD, and eventually, act as surrogate for prolonged survival based on sensitive MRD-negative definitions. Accordingly, the IMWG has developed criteria for MRD-negativity defined by next-generation sequencing, NGF or PET/CT, and has recommended their inclusion in clinical trials. Notwithstanding, most flow cytometry results have been obtained using less sensitive methods and in fact, there is no data about the impact of NGF-based MRD assessment in clinical trials. Aim: To define the feasibility, sensitivity and clinical impact of NGF-based MRD assessment in the phase III PETHEMA/GEM2012 trial. Methods: A total of 458 patients were enrolled into the PETHEMA/GEM2012 trial. MRD was predefined to be prospectively assessed at three time-points: after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), after HDT/ASCT, and after two courses of consolidation with VRD. MRD monitoring was performed blinded for clinical outcomes in four PETHEMA/GEM laboratory cores, and data was centralized for MRD analyses. MRD assessment was performed following EuroFlow SOPs in a total of 1,134 bone marrow (BM) samples from 419 patients. The 39 cases without MRD assessment had suboptimal response to induction and were thus considered as MRD+ for intention-to-treat analyses. Noteworthy, in 14 BM samples with undetectable MRD, B-cell precursors, erythroblasts and mast cells represented Results: Overall, 225/458 (49%) patients had undetectable MRD at the latest time-point in which MRD was assessed and were thus classified as MRD-. Conversely, 233/458 (51%) cases remained MRD+: 28% with ≥10-4 MRD, 12% with 10-5 MRD, and 11% with 10-6 MRD. Detailed analyses of MRD kinetics in 320 patients with available MRD results at all three time-points, showed that the percentage of MRD- patients increased from 35% into 54% and 58% after induction, HDT/ASCT and consolidation, respectively. Furthermore, a restricted analysis among MRD+ patients showed that whereas after induction only 8% of them had MRD levels as low as 10-6, subsequent intensification with HDT/ASCT and consolidation could reduce MRD levels down to 10-6 in 32% of MRD+ cases. Progression-free survival (PFS) rates at 3-years were of 92%, 70%, 54% and 44% for patients being MRD-negative, MRD+ 10-6, 10-5 and ≥10-4, respectively (P Conclusions: This is the largest study of MRD monitoring in MM based on the total number of samples analyzed (n=1,134). Our results show that NGF-based MRD assessment is feasible in large multicenter clinical trials, is highly-sensitive, and allows the identification of hemodiluted BM samples inadequate for MRD assessment. Risk of relapse among MRD-negative patients was remarkably reduced (3%), and was particularly related to the reappearance of extramedullary plasmacytomas, which urges the need for combined cellular and imaging MRD monitoring in these patients; by contrast, even MRD levels as low as 10-5 and 10-6 conferred significantly inferior PFS. Overall, this study defines MRD-negativity as the most relevant clinical endpoint for both standard- and high-risk transplant-eligible MM patients. Figure Figure. Disclosures Paiva: Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria; Merck: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; EngMab: Research Funding. Oriol: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia; Celgene: Speakers Bureau. de la Rubia: Janssen: Other: Honoraria; Amgen: Other: Honoraria; Celgene: Other: Honoraria. Rosinol: Celgene: Honoraria; Janssen: Honoraria. Mateos: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. San Miguel: Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. more...
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