22 results on '"Davine Hofste op Bruinink"'
Search Results
2. Longitudinal minimal residual disease assessment in multiple myeloma patients in complete remission – results from the NMSG flow-MRD substudy within the EMN02/HO95 MM trial
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Alexander Schmitz, Rasmus Froberg Brøndum, Hans Erik Johnsen, Ulf-Henrik Mellqvist, Anders Waage, Peter Gimsing, Davine Hofste op Bruinink, Vincent van der Velden, Bronno van der Holt, Markus Hansson, Niels Frost Andersen, Ulf Christian Frølund, Carsten Helleberg, Fredrik H. Schjesvold, Lucia Ahlberg, Nina Gulbrandsen, Bjorn Andreasson, Birgitta Lauri, Einar Haukas, Julie Støve Bødker, Anne Stidsholt Roug, Martin Bøgsted, Marianne T. Severinsen, Henrik Gregersen, Niels Abildgaard, Pieter Sonneveld, and Karen Dybkær more...
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Multiple myeloma ,Minimal residual disease ,Flow cytometry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments. Methods Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression. Results Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with ≥3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4–2.3 months). Minimal malignant plasma cells detection limit was 4 × 10–5. Conclusions Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression. Trial registration NCT01208766 more...
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- 2022
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Catalog
3. Minimal residual disease assessment by multiparameter flow cytometry in transplant-eligible myeloma in the EMN02/HOVON 95 MM trial
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Stefania Oliva, Davine Hofste op Bruinink, Lucie Rihova, Mattia D’Agostino, Lucia Pantani, Andrea Capra, Bronno van der Holt, Rossella Troia, Maria Teresa Petrucci, Tania Villanova, Pavla Vsianska, Romana Jugooa, Claudia Brandt-Hagens, Milena Gilestro, Massimo Offidani, Rossella Ribolla, Monica Galli, Roman Hajek, Francesca Gay, Michele Cavo, Paola Omedé, Vincent H. J. van der Velden, Mario Boccadoro, and Pieter Sonneveld more...
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10−4−10−5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p more...
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- 2021
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4. Standardization of flow cytometric minimal residual disease assessment in international clinical trials. A feasibility study from the European Myeloma Network
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Davine Hofste op Bruinink, Stefania Oliva, Lucie Rihova, Alexander Schmitz, Milena Gilestro, Jeroen te Marvelde, Romana Kralova, Helle Høholt, Annemiek Broijl, Hans Erik Johnsen, Roman Hajek, Mario Boccadoro, Pieter Sonneveld, Paola Omedè, and Vincent H.J. van der Velden more...
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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5. Identification of High-Risk Multiple Myeloma With a Plasma Cell Leukemia-Like Transcriptomic Profile
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Davine Hofste op Bruinink, Rowan Kuiper, Mark van Duin, Tom Cupedo, Vincent H.J. van der Velden, Remco Hoogenboezem, Bronno van der Holt, H. Berna Beverloo, Erik T. Valent, Michael Vermeulen, Francesca Gay, Annemiek Broijl, Hervé Avet-Loiseau, Nikhil C. Munshi, Pellegrino Musto, Philippe Moreau, Sonja Zweegman, Niels W.C.J. van de Donk, Pieter Sonneveld, Hematology, CCA - Imaging and biomarkers, Anatomy and neurosciences, Immunology, and Clinical Genetics more...
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Cancer Research ,Oncology ,SDG 3 - Good Health and Well-being - Abstract
PURPOSE Primary plasma cell leukemia (pPCL) is an aggressive subtype of multiple myeloma, which is distinguished from newly diagnosed multiple myeloma (NDMM) on the basis of the presence of ≥ 20% circulating tumor cells (CTCs). A molecular marker for pPCL is currently lacking, which could help identify NDMM patients with high-risk PCL-like disease, despite not having been recognized as such clinically. METHODS A transcriptomic classifier for PCL-like disease was bioinformatically constructed and validated by leveraging information on baseline CTC levels, tumor burden, and tumor transcriptomics from 154 patients with NDMM included in the Cassiopeia or HO143 trials and 29 patients with pPCL from the EMN12/HO129 trial. Its prognostic value was assessed in an independent cohort of 2,139 patients with NDMM from the HOVON-65/GMMG-HD4, HOVON-87/NMSG-18, EMN02/HO95, MRC-IX, Total Therapy 2, Total Therapy 3, and MMRF CoMMpass studies. RESULTS High CTC levels were associated with the expression of 1,700 genes, independent of tumor burden (false discovery rate < 0.05). Of these, 54 genes were selected by leave-one-out cross-validation to construct a transcriptomic classifier representing PCL-like disease. This not only demonstrated a sensitivity of 93% to identify pPCL in the validation cohort but also classified 10% of NDMM tumors as PCL-like. PCL-like MM transcriptionally and cytogenetically resembled pPCL, but presented with significantly lower CTC levels and tumor burden. Multivariate analyses in NDMM confirmed the significant prognostic value of PCL-like status in the context of Revised International Staging System stage, age, and treatment, regarding both progression-free (hazard ratio, 1.64; 95% CI, 1.30 to 2.07) and overall survival (hazard ratio, 1.89; 95% CI, 1.42 to 2.50). CONCLUSION pPCL was identified on the basis of a specific tumor transcriptome, which was also present in patients with high-risk NDMM, despite not being clinically leukemic. Incorporating PCL-like status into current risk models in NDMM may improve prognostic accuracy. more...
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- 2022
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6. Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence
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Kristine Misund, Davine Hofste op Bruinink, Eivind Coward, Remco M. Hoogenboezem, Even Holth Rustad, Mathijs A. Sanders, Morten Rye, Anne-Marit Sponaas, Bronno van der Holt, Sonja Zweegman, Eivind Hovig, Leonardo A. Meza-Zepeda, Anders Sundan, Ola Myklebost, Pieter Sonneveld, Anders Waage, Hematology, CCA - Cancer Treatment and quality of life, and Anatomy and neurosciences more...
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Clonal Evolution ,Male ,Cancer Research ,Genome ,Oncology ,SDG 3 - Good Health and Well-being ,Humans ,Hematology ,Genomics ,Multiple Myeloma ,Transcriptome - Abstract
We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM. more...
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- 2022
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7. The multiple myeloma microenvironment is defined by an inflammatory stromal cell landscape
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Mathijs A. Sanders, Mark van Duin, Pieter Sonneveld, Cyrus Khandanpour, Sabrin Tahri, Zoltán Kellermayer, Jessica Vermeulen, Davine Hofste op Bruinink, Pieter C. van de Woestijne, P. Koen Bos, Madelon de Jong, Remco Hoogenboezem, Annemiek Broijl, Tom Cupedo, Philippe Moreau, Natalie Papazian, Hematology, Cardiothoracic Surgery, and Orthopedics and Sports Medicine more...
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Adult ,Male ,0301 basic medicine ,Stromal cell ,T cell ,Primary Cell Culture ,Immunology ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Microenvironment ,medicine ,Humans ,Immunology and Allergy ,Prospective Studies ,RNA-Seq ,Multiple myeloma ,Aged ,Tumor microenvironment ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Disease Progression ,Cancer research ,Female ,Bone marrow ,Neoplasm Recurrence, Local ,Single-Cell Analysis ,Stem cell ,Multiple Myeloma ,Memory T cell ,030215 immunology - Abstract
Progression and persistence of malignancies are influenced by the local tumor microenvironment, and future eradication of currently incurable tumors will, in part, hinge on our understanding of malignant cell biology in the context of their nourishing surroundings. Here, we generated paired single-cell transcriptomic datasets of tumor cells and the bone marrow immune and stromal microenvironment in multiple myeloma. These analyses identified myeloma-specific inflammatory mesenchymal stromal cells, which spatially colocalized with tumor cells and immune cells and transcribed genes involved in tumor survival and immune modulation. Inflammatory stromal cell signatures were driven by stimulation with proinflammatory cytokines, and analyses of immune cell subsets suggested interferon-responsive effector T cell and CD8+ stem cell memory T cell populations as potential sources of stromal cell–activating cytokines. Tracking stromal inflammation in individuals over time revealed that successful antitumor induction therapy is unable to revert bone marrow inflammation, predicting a role for mesenchymal stromal cells in disease persistence. Multiple myeloma disease progression and therapy response are influenced by the bone marrow niche in which the tumor cells reside. To characterize this supportive niche, Cupedo and colleagues use single-cell transcriptomic analysis of bone marrow stromal cell populations from individuals with multiple myeloma. They identify a myeloma-specific inflammatory mesenchymal stromal cell (iMSC) population that spatially colocalizes with tumor cells. Anti-myeloma induction therapy does not influence iMSC presence, suggesting a role for bone marrow inflammation in myeloma persistence or relapse. more...
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- 2021
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8. Combining Plasma Cell Leukemia-like Status with the Second Revision of the International Staging System Improves Risk Classification
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Davine Hofste op Bruinink, Rowan Kuiper, Mark van Duin, Tom Cupedo, Vincent H.J. van der Velden, Remco Hoogenboezem, Bronno van der Holt, Berna Beverloo, Erik T. Valent, Michael Vermeulen, Mattia D'Agostino, Francesca Gay, Annemiek Broijl, Herve Avet-Loiseau, Nikhil C Munshi, Pellegrino Musto, Philippe Moreau, Sonja Zweegman, Niels W.C.J. van de Donk, and Pieter Sonneveld more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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9. MAF Translocations Are Enriched in NDMM Patients with Elevated Levels of Circulating Tumor Cells Suggesting a Genetic Basis for Aggressive Disease Course
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Cathelijne Fokkema, Madelon M.E. de Jong, Sabrin Tahri, Davine Hofste Op Bruinink, Zoltan Kellermayer, Chelsea den Hollander, Michael Vermeulen, Natalie Papazian, Mark van Duin, Remco Hoogenboezem, Michiel J.W. Wevers, Vincent H.J. van der Velden, Mathijs A. Sanders, Annemiek Broijl, Pieter Sonneveld, and Tom Cupedo more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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10. Stability and uniqueness of clonal immunoglobulin CDR3 sequences for MRD tracking in multiple myeloma
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Elli Papaemmanuil, Venkata Yellapantula, Kasey Hutt, Sham Mailankody, Malin Hultcrantz, Eivind Coward, Theresia Akhlaghi, David J. Mayman, Minal Patel, Elsa Bernard, Ying Huang, Neha Korde, Aaron D. Viny, Christopher Famulare, Francesco Maura, Davine Hofste op Bruinink, Jeffrey E. Miller, Even H Rustad, Kaitlin M. Carroll, Maria E. Arcila, Caleb Ho, Jonathan J Keats, Dickran Kazandjian, Ola Landgren, Austin Jacobsen, Anders Waage, and Kristine Misund more...
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Neoplasm, Residual ,Gene Rearrangement, B-Lymphocyte, Heavy Chain ,Somatic hypermutation ,Bone Marrow Cells ,Computational biology ,Biology ,Immunoglobulin light chain ,Somatic evolution in cancer ,Article ,Clonal Evolution ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,Plasma Cell Myeloma ,Biomarkers, Tumor ,Gene Rearrangement, B-Lymphocyte, Light Chain ,Humans ,RNA, Messenger ,RNA, Neoplasm ,Exome sequencing ,Clinical Trials as Topic ,Genes, Immunoglobulin ,High-Throughput Nucleotide Sequencing ,Hematology ,Gene rearrangement ,Complementarity Determining Regions ,Minimal residual disease ,Clone Cells ,030220 oncology & carcinogenesis ,Immunoglobulin Light Chains ,VDJ Exons ,Somatic Hypermutation, Immunoglobulin ,Immunoglobulin Heavy Chains ,Multiple Myeloma ,Clone (B-cell biology) ,030215 immunology - Abstract
Minimal residual disease (MRD) tracking, by next generation sequencing of immunoglobulin sequences, is moving towards clinical implementation in multiple myeloma. However, there is only sparse information available to address whether clonal sequences remain stable for tracking over time, and to what extent light chain sequences are sufficiently unique for tracking. Here, we analyzed immunoglobulin repertoires from 905 plasma cell myeloma and healthy control samples, focusing on the third complementarity determining region (CDR3). Clonal heavy and/or light chain expression was identified in all patients at baseline, with one or more subclones related to the main clone in 3.2%. In 45 patients with 101 sequential samples, the dominant clonal CDR3 sequences remained identical over time, despite differential clonal evolution by whole exome sequencing in 49% of patients. The low frequency of subclonal CDR3 variants, and absence of evolution over time in active multiple myeloma, indicates that tumor cells at this stage are not under selective pressure to undergo antibody affinity maturation. Next, we establish somatic hypermutation and non-templated insertions as the most important determinants of light chain clonal uniqueness, identifying a potentially trackable sequence in the majority of patients. Taken together, we show that dominant clonal sequences identified at baseline are reliable biomarkers for long-term tracking of the malignant clone, including both IGH and the majority of light chain clones. more...
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- 2019
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11. Minimal residual disease assessment by multiparameter flow cytometry in transplant-eligible myeloma in the EMN02/HOVON 95 MM trial
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Claudia Brandt-Hagens, Stefania Oliva, Pavla Všianská, Maria Teresa Petrucci, Roman Hájek, Romana Jugooa, Monica Galli, Mattia D'Agostino, Rossella Ribolla, Davine Hofste op Bruinink, Pieter Sonneveld, Andrea Capra, Bronno van der Holt, Tania Villanova, Massimo Offidani, Michele Cavo, Lucia Pantani, Rossella Troia, Mario Boccadoro, Paola Omedè, Lucie Rihova, Milena Gilestro, Vincent H.J. van der Velden, Oliva S., Bruinink D.H., Rihova L., D'Agostino M., Pantani L., Capra A., van der Holt B., Troia R., Petrucci M.T., Villanova T., Vsianska P., Jugooa R., Brandt-Hagens C., Gilestro M., Offidani M., Ribolla R., Galli M., Hajek R., Gay F., Cavo M., Omede P., van der Velden V.H.J., Boccadoro M., Sonneveld P., Hematology, and Immunology more...
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Melphalan ,Male ,medicine.medical_specialty ,Neoplasm, Residual ,Population ,Urology ,Bone Marrow Cells ,Article ,Dexamethasone ,Disease-Free Survival ,Bortezomib ,EuroFlow ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Autograft ,Humans ,Medicine ,Autografts ,education ,Lenalidomide ,Multiple myeloma ,RC254-282 ,education.field_of_study ,Antineoplastic Combined Chemotherapy Protocol ,medicine.diagnostic_test ,business.industry ,Hematopoietic Stem Cell Transplantation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Hematology ,Translational research ,Middle Aged ,medicine.disease ,Flow Cytometry ,Minimal residual disease ,body regions ,Survival Rate ,medicine.anatomical_structure ,Risk factors ,Oncology ,Bone Marrow Cell ,Female ,Bone marrow ,business ,Multiple Myeloma ,medicine.drug ,Fluorescence in situ hybridization ,Human - Abstract
Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10−4−10−5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p p more...
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- 2021
12. Standardization of flow cytometric minimal residual disease assessment in international clinical trials - a feasibility study from the European Myeloma Network
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Paola Omedè, Stefania Oliva, Helle Høholt, Roman Hájek, Romana Králová, Lucie Rihova, Pieter Sonneveld, Jeroen G. te Marvelde, Davine Hofste op Bruinink, Vincent H.J. van der Velden, Milena Gilestro, Hans Erik Johnsen, Annemiek Broijl, Alexander Schmitz, Mario Boccadoro, Hematology, and Immunology more...
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medicine.medical_specialty ,Neoplasm, Residual ,Standardization ,business.industry ,MEDLINE ,Hematology ,Reference Standards ,Residual ,Flow Cytometry ,Minimal residual disease ,Clinical trial ,Flow (mathematics) ,Medicine ,Feasibility Studies ,Humans ,Radiology ,Multiple Myeloma/diagnosis ,business ,Multiple Myeloma ,Letters to the Editor ,Reference standards - Published
- 2021
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13. OAB-008: Identification of high-risk Multiple Myeloma with a plasma cell Leukemia-like transcriptomic profile
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Davine Hofste op Bruinink, Rowan Kuiper, Mark van Duin, Tom Cupedo, Vincent H.J. van der Velden, Remco Hoogenboezem, Bronno van der Holt, H. Berna Beverloo, Erik T. Valent, Michael Vermeulen, Francesca Gay, Annemiek Broijl, Hervé Avet-Loiseau, Nikhil C. Munshi, Pellegrino Musto, Philippe Moreau, Sonja Zweegman, Niels W.C.J. van de Donk, and Pieter Sonneveld more...
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Oncology ,Plasma cell leukemia ,Cancer Research ,medicine.medical_specialty ,Proportional hazards model ,business.industry ,Context (language use) ,Hematology ,medicine.disease ,medicine.anatomical_structure ,Circulating tumor cell ,EuroFlow ,Internal medicine ,medicine ,Bone marrow ,Stage (cooking) ,business ,Multiple myeloma - Abstract
Background Primary plasma cell leukemia (pPCL) is an aggressive subtype of multiple myeloma that is characterized by ≥20% circulating tumor cells (CTCs), whereas CTC levels in newly diagnosed multiple myeloma (NDMM) are Methods Transcriptomic data were generated of CD138-enriched bone marrow (BM) plasma cells from both NDMM patients enrolled in the Cassiopeia (NCT02541383) and HO143 (EudraCT 2016-002600-90) trials and pPCL patients from the EMN12/HO129 (EudraCT 2013-005157-75) trial. NDMM CTC levels were determined with the EuroFlow NGF protocol. HR FISH was defined as the presence of either t(4;14), t(14;16) or del17p.154 NDMM and 29 pPCL patients were divided into a discovery and validation cohort to construct and test a classifier for PCL-like disease. Subsequently, data from 8 additional NDMM cohorts were used to assess the association of PCL-like status with progression-free survival (PFS) and overall survival (OS) in Cox proportional hazards (PH) models including conventional HR markers. Results Baseline CTC levels were determined in 297 NDMM and 51 pPCL patients. CTCs could be detected in 87% of NDMM patients, with a limit of detection Conclusions (1) pPCL cannot only be identified clinically, but also molecularly. (2) PCL-like status is a novel marker for HR disease in NDMM that identifies patients with a tumor transcriptome similar to pPCL and has independent prognostic value in the context of conventional HR markers. (3) PCL-like status could help detect NDMM patients with early stage or borderline pPCL. more...
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- 2021
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14. IGF and mTOR pathway expression and in vitro effects of linsitinib and mTOR inhibitors in adrenocortical cancer
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Leo J. Hofland, Maria Cristina De Martino, Claudia Pivonello, Ronald R. de Krijger, Annamaria Colao, Richard A Feelders, Fadime Dogan, Wouter W. de Herder, Davine Hofste op Bruinink, Rosario Pivonello, Peter M. van Koetsveld, Joseph A M J L Janssen, A. Marlijn Waaijers, De Martino, M. C., van Koetsveld, P. M., Feelders, R. A., de Herder, W. W., Dogan, F., Janssen, J. A. M. J. L., Hofste op Bruinink, D., Pivonello, C., Waaijers, A. M., Colao, A., de Krijger, R. R., Pivonello, R., Hofland, L. J., Internal Medicine, and Erasmus MC other more...
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Male ,Linsitinib ,Endocrinology, Diabetes and Metabolism ,Antineoplastic Agents ,Apoptosis ,030209 endocrinology & metabolism ,Receptor, IGF Type 1 ,Adrenocortical cancer ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,SDG 3 - Good Health and Well-being ,Cell Line, Tumor ,Adrenocortical Carcinoma ,medicine ,Humans ,Adrenocortical carcinoma ,Insulin-Like Growth Factor I ,Adrenal ,IGF ,Child ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Insulin-like growth factor 1 receptor ,Everolimus ,biology ,Cell growth ,TOR Serine-Threonine Kinases ,Imidazoles ,medicine.disease ,Adrenal Cortex Neoplasms ,Diabetes and Metabolism ,Insulin receptor ,chemistry ,Child, Preschool ,Pyrazines ,030220 oncology & carcinogenesis ,Sirolimus ,Adrenal Cortex ,Cancer research ,biology.protein ,Original Article ,Female ,Signal Transduction ,medicine.drug - Abstract
Purpose: The IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC. Methods: The protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated. Results: A high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect. Conclusions: In addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone. more...
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- 2019
15. Whole-Exome and mRNA Sequencing of Multiple Myeloma Reveal Transformation to a More High-Risk and Proliferative Tumor at Relapse
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Eivind Coward, Anders Waage, Pieter Sonneveld, Eivind Hovig, Remco Hoogenboezem, Davine Hofste op Bruinink, Anders Sundan, Even H Rustad, Ola Myklebost, and Kristine Misund
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Oncology ,medicine.medical_specialty ,Proliferation index ,Immunology ,Cell Biology ,Hematology ,Cell cycle ,Biology ,medicine.disease ,Biochemistry ,Somatic evolution in cancer ,MRNA Sequencing ,Internal medicine ,medicine ,Exome ,Multiple myeloma ,Exome sequencing ,Progressive disease - Abstract
Introduction Multiple myeloma (MM) is a malignant plasma cell disorder of which the prognosis has significantly improved since the introduction of proteasome inhibitors (PIs) and immune modulatory drugs (IMiDs) in standard-of-care treatment protocols. Despite this progress, many patients still suffer from progressive disease, of which the underlying biological mechanisms are mainly unknown. To elucidate these, we have studied the genomic evolution of MM tumor samples in 29 patients before and after receiving a PI-based and/or IMiD-based treatment, using whole exome sequencing (WES) and mRNA sequencing (RNA-Seq). Methods Patient samples were selected from the Norwegian Biobank for Multiple Myeloma and the HOVON-87/NMSG-18 MM and EMN-02/HOVON-95 MM studies. Tumor DNA was isolated from CD138-positive MM cells with control DNA from peripheral blood samples. WES libraries were prepared using the SureSelectXTsample prep kit and the SureSelectXT Human All Exon V5 target 50 Mb kit (Agilent), followed by paired-end sequencing on a HiSeq2500 instrument (Illumina). Somatic, non-synonymous variants (SNSVs) were called using MuTect and Strelka. Copy number aberrations (CNAs) were estimated using Sequenza. RNA-Seq libraries were generated using the TruSeq® Stranded mRNA kit (Illumina).DESeq2 paired analysis was performed in R Studio to find differentially expressed genes. RNA-Seq expression data from diagnosis/relapse pairs from patients treated with a PI and/or IMiD were selected from the CoMMpass IA10 release database and used as validation cohort. Results We obtained 21 diagnosis/relapse pairs, as well as 8 relapse/relapse pairs, with a median time between samples of 21 months, respectively 16 months. In addition, for 3 of the patients, we had a 3rd sample included. We found a median of 54 SNSVs in our cohort, with an increase in mutational load from the first to the second sample (median 44 to 61). Three different patterns of tumor evolution were observed, confirming previous reports:stable evolution (29% of patients), where the tumor had no or minor changes;linear evolution (29% of patients), where there were acquired mutations and/or CNAs at relapse;differential clonal response (42% of patients), where there was a disappearance of certain mutations/CNAs at relapse and appearance of new ones, suggesting a shift in dominance of different clones. Of interest, of the 7 relapse-relapse tumor pairs that were included in the analysis, 5 were defined to have a differential clonal response, while the remaining 2 had linear evolution, suggesting that the tumors are more prone to genomic change later in the disease course.Tumors shifting their clonal dominance tended to select for a clone with more high-risk features later in the disease course, as illustrated by the appearance of a deletion of chromosome 17p, TP53 mutations and a gain of chromosome 1q. There was a shorter average time interval between sample 1 and 2 for those having a stable evolution pattern (average 12 months, range [5-16]), than those having a differential clonal response (19 months [5-70]), and the highest interval was in patients with linear evolution patters (29 months [15-50]). Tumors having a differential clonal response and linear evolution, showed more often a deeper treatment response (43% CR/nCR, 40% VGPR and 22% CR/nCR, 56% VGPR, respectively) compared to those with stable evolution patterns (14% VGPR), suggesting that tumors that respond well to treatment are more prone to evolve. RNA-Seq data showed a higher expression of genes involved in G2M checkpoint, E2F targets and mitotic spindle at relapse. In line with this, relapsed tumors were found to have an increased proliferation index (GEP; Zhan et al, Blood, 2006). This was confirmed in RNA-Seq data from 27 diagnosis-relapse samples from the CoMMpass dataset. Conclusion This study has performed a comprehensive genomic and transcriptomic analysis of the clonal evolution of MM tumors after treatment with PIs and IMIDs. Our data suggest that clones with high-risk factors and increased expression of genes involved in proliferation and cell cycle regulation are selected for under the pressure of these treatment regimens. The data also suggest that there is a relation between the pattern of genomic evolution and the obtained depth of response, which deserves further investigation. Disclosures Sonneveld: Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Honoraria, Research Funding. more...
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- 2018
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16. Differential Effect of Upfront Intensification Treatment in Genetically Defined Myeloma Risk Groups - a Combined Analysis of ISS, Del17p and SKY92 Scores in the EMN-02/HOVON-95 MM Trial
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Bronno van der Holt, Meral Beksac, Antonio Palumbo, Meletios A. Dimopoulos, Martin H. van Vliet, Rowan Kuiper, Pieter Sonneveld, Michele Cavo, Christoph Driessen, Hans Erik Johnsen, Roman Hájek, Mark van Duin, Davine Hofste op Bruinink, Heinz Ludwig, and Michael Vermeulen more...
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0301 basic medicine ,medicine.medical_specialty ,business.industry ,Immunology ,Salvage treatment ,Tumor cells ,Cell Biology ,Hematology ,Stage ii ,Biochemistry ,Transplantation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Risk groups ,030220 oncology & carcinogenesis ,Dna breaks ,Internal medicine ,medicine ,Risk classification ,business ,Lenalidomide ,medicine.drug - Abstract
Background The introduction of proteasome inhibitors (PIs) and immune modulatory drugs (IMiDs) to multiple myeloma (MM) treatment protocols has drastically improved the overall quality and duration of response. This rationalized challenging the role of upfront high dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) versus chemotherapy alone as intensification treatment in four recent phase III trials. Yet, these showed uniformly that upfront HDM is still superior to non-transplant intensification alternatives including PIs and/or IMiDs. However, HDM's mechanism of action involves induction of interstrand crosslinks and double-strand DNA breaks that cause collateral damage in both healthy cells (toxicity) and tumor cells, which may induce strong selection pressure on the outgrowth of resistant clones at relapse. We therefore hypothesized that certain low-risk patients could save HDM as salvage treatment and that this would improve their overall survival (OS). Methods We chose to combine three robust classification tools in MM that historically have shown a consistent performance across diverse patient cohorts: (1) International Staging System (ISS), (2) deletion of chromosome 17p (del17p) by Fluorescent in Situ Hybridization (FISH) (cutoff ≥10%) and (3) SKY92 high-risk (HR) classifier, based on gene expression profiling (GEP) of MM cells. By combining these scores, we classified ultra-low risk (uLR), intermediate-risk (IR) and HR MM as follows: uLR: ISS = 1, del17p = absent, SKY92 HR = absent. IR: ISS = 2 or 3, del17p = absent, SKY92 HR = absent. HR: ISS = 1, 2 or 3, del17p and/or SKY92 HR = present. The effect of intensification treatment on progression-free survival (PFS) and OS in these risk groups was evaluated in the phase III EMN-02/HOVON-95 MM trial (EudraCT 2009-017903-28). We focused on chemotherapy-naive MM patients aged ≤65 years, who received bortezomib, cyclophosphamide and dexamethasone (3-4xVCD) as induction therapy, followed by randomization 1 (R1) between bortezomib, melphalan and prednisone (4xVMP) and 1xHDM+ASCT, R2 between bortezomib, lenalidomide and dexamethasone (2xVRD) versus no consolidation and lenalidomide maintenance for all. At baseline, bone marrow was collected in the MM biobank at Erasmus MC Cancer Institute, the Netherlands. On this, CD138+ enrichment was performed, followed by a flowcytometric purity check, FISH analysis for del17p and GEP using HG U133 Plus 2.0 arrays (Affymetrix). PFS was defined as the time from R1 to progression or death, whichever occurred first. P-values were not adjusted for multiple testing. Results In our biobank region, 435 patients were randomized between VMP and 1xHDM, of whom ISS data were available for all, del17p status for 87%, SKY92 classification for 41% and all three risk factors for 38% of patients. Of these, 33% were ISS stage I, 47% ISS stage II, 20% ISS stage III, 10% had a del17p and 20% were SKY92 HR. A total of 43 (26%), 83 (50%) and 41 (25%) patients were classified as uLR, IR and HR, respectively. Our risk classification was both significantly associated with PFS (logrank p < 1x10-5; 4-year PFS of 64% in uLR, 49% in IR and 24% in HR) and OS (p < 1x10-4; 4-year OS of 85% in uLR, 77% in IR and 47% in HR). HR patients had a superior PFS with 1xHDM over VMP (p = 0.003), confirming previous reports. OS was related to intensification arm in both uLR and HR patients, however, in opposite direction: uLR patients treated with VMP had a better OS than those treated with 1xHDM (p = 0.047, 4-year OS of 95% with VMP versus 72% with 1xHDM); whereas OS was better after 1xHDM in HR patients (p = 0.017, 4-year OS of 68% with 1xHDM versus 22% with VMP). We found a significant interaction between intensification treatment and risk group for both PFS (likelihood ratio p = 0.03) and OS (p = 0.005). This indicates that there is indeed a differential treatment effect on survival between risk groups. Conclusions Although our findings are preliminary and need further validation, we are the first to identify a low-risk, transplant-eligible MM subgroup that - in contrast to high-risk MM patients - may benefit from receiving upfront VMP versus 1xHDM+ASCT. Moreover, this illustrates for the first time how combined molecular and clinical subclassification in MM may identify patients that benefit from alternative treatment strategies, such as prolonged bortezomib and lenalidomide. Ultimately, this may result in risk-adapted treatment approaches. Disclosures Beksac: Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: 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, Speakers Bureau; Deva: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ludwig:BMS: Speakers Bureau; Cilag-Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Kuiper:SkylineDx: Employment. van Vliet:SkylineDx: Employment. Hajek:Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Dimopoulos:Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Palumbo:Takeda Pharmaceuticals Inc.: Employment. Cavo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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; 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, Research Funding, Speakers Bureau; AbbVie: 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. Sonneveld:Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding. more...
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- 2018
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17. Minimal residual disease (MRD) monitoring by multiparameter flow cytometry (MFC) in newly diagnosed transplant eligible multiple myeloma (MM) patients: Results from the EMN02/HO95 phase 3 trial
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Pieter Sonneveld, Manuela Gambella, Mario Boccadoro, Monica Galli, Stefania Oliva, Rossella Ribolla, Lucie Říhová, Rossella Troia, Antonio Palumbo, Milena Gilestro, Roman Hájek, Massimo Offidani, Michele Cavo, Stefano Spada, Bronno van der Holt, Vincent H.J. van der Velden, Sara Grammatico, Paola Omedè, Lucia Pantani, and Davine Hofste op Bruinink more...
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Cancer Research ,medicine.medical_specialty ,business.industry ,Newly diagnosed ,medicine.disease ,Minimal residual disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Radiology ,Multiparameter flow cytometry ,business ,Multiple myeloma ,030215 immunology - Abstract
8011 Background: MRD detection is a sensitive tool to measure response in MM. We assessed MRD by MFC in newly diagnosed MM patients (pts) enrolled in the EMN02/HO95 phase 3 trial. Methods: Pts were ≤65 years old and received Bortezomib-Cyclophosphamide-Dexamethasone (VCD) induction, intensification with Bortezomib-Melphalan-Prednisone (VMP) vs High-Dose-Melphalan (HDM) followed by stem cell transplant, consolidation with Bortezomib-Lenalidomide-Dexamethasone (VRD) vs no consolidation, and Lenalidomide maintenance. MRD analysis was performed in pts achieving at least a very good partial response (VGPR) before starting maintenance (after HDM, VMP or VRD) and during maintenance every 6-12 months; samples were centralized to 3 European labs. MFC was performed on bone marrow according to Euroflow-based methods (8 colors, 2 tubes) with a sensitivity of 10-5. Quality checks were performed to compare sensitivity and to show correlation between protocols (Hofste op Bruinink D ASH 2016 abstract 2072). Results: 316 pts were evaluable before maintenance: median age was 57 years, 18% (57/316) pts had ISS III and 22% (70/316) had high risk cytogenetic (HR-C) defined as having at least one among del17, t(4;14) or t(14;16); 63% (199/316) had received HDM and 37% (117/316) VMP; thereafter 51% (160/316) had received VRD. 76% (239/316) were MRD negative (MRD-) of whom 64% (153/239) received HDM vs 36% (86/239) VMP, with a median follow-up time of 30 months from MRD enrolment. 3-year PFS was 50% in MRD positive (MRD+) vs 77% in MRD- pts (HR: 2.87, p < 0.001). Subgroup analyses were performed to evaluate the risk factors for MRD+ according to baseline characteristics and therapies: HR-C was the most important risk factor (HR 9.87, interaction-p = 0.001). Finally, 48% of MRD+ pts at pre-maintenance who had a second MRD evaluation after at least 1 year of lenalidomide became MRD-. Conclusions: MRD by MFC is a strong prognostic factor in MM pts receiving intensification with novel agents or transplant; lenalidomide maintenance further improved depth of response; HR-C is the most important prognostic factor in MRD+ pts. Clinical trial information: NCT01208766. more...
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- 2017
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18. Multiple Myeloma with a Deletion of Chromosome 17p: TP53 Mutations Are Highly Prevalent and Negatively Affect Prognosis
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Christopher P. Wardell, Pieter Sonneveld, Jie He, Mark Bailey, Claudia A.J. Erpelinck-Verschueren, François G. Kavelaars, Tariq I Mughal, Paulette van Strien, Hervé Avet-Loiseau, Cody Ashby, Davine Hofste op Bruinink, Gareth J. Morgan, Brian A Walker, Bronno van der Holt, Berna Beverloo, Mathijs A. Sanders, Anders Waage, Graham Jackson, Hoogenboezem Remco, Eric M.J. Bindels, Kristine Misund, Ivo P. Touw, and Jasper Koenders more...
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Chromosome ,Cell Biology ,Hematology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Transplantation ,Internal medicine ,Cohort ,medicine ,KRAS ,business ,Exome ,Multiple myeloma ,Exome sequencing ,Progressive disease - Abstract
Background Deletion of chromosome 17p (del17p) is detected in 10% of multiple myeloma (MM) patients at diagnosis and is associated with both a dismal prognosis and increased prevalence after treatment. Even though this suggests that it might be a driver of disease progression, relatively little is known about the genomic landscape of these tumors. With this study, we aimed to identify recurrent aberrations in a large cohort of del17p MM patients and to assess their prognostic value within this patient group. Methods The study design consisted of a discovery phase and a validation phase. For the discovery phase, 44 newly diagnosed MM (NDMM) patients were included with a del17p in at least 50% of plasma cells, as detected with fluorescent in situ hybridization (FISH). From 12 del17p patients, 2 or 3 tumor samples were available to analyze clonal evolution during disease progression. DNA was isolated from peripheral blood and CD138+ enriched bone marrow mononuclear cells, followed by a custom capture of the whole exome, Chr17p and the IgH, Igk, IgL and MYC regions (SeqCap EZ Exome Plus, Nimblegen) and paired-end sequencing. Significantly mutated genes were determined with MutSigCV and significantly deleted or amplified genomic regions with GISTIC2. Single nucleotide variants (SNVs) in TP53, FAM46C, KRAS, NRAS, DIS3 and BRAF were validated using a custom amplicon panel (TruSeq Custom Amplicon Assay v1.5, Illumina), followed by deep sequencing on a MiSeq System. Findings were validated in a cohort of 463 NDMM patients of the UK Myeloma XI trial, from which whole exome sequencing data were available for paired tumor and germline DNA (Walker et al. - J Clin Oncol 2015). All samples in both the discovery and the validation cohort were reanalyzed with one bioinformatic pipeline, from alignment to variant calling. The copy number status of TP53 was determined with Sequenza, followed by selection of del17p samples after manual inspection of the results. From a third cohort of 233 MM patients with progressive disease (PDMM) treated at the University of Arkansas for Medical Sciences (UAMS), 406 cancer-related genes were paired-end sequenced from tumor DNA with the FoundationOne Heme assay (He et al. - Blood 2016). Results In the discovery cohort, we identified a commonly deleted region (CDR) on Chr17p of 235 kb, in which one or more somatic, nonsilent aberrations (SNSA) in TP53 were detected in 25/44 (57%) patients (adj. p In the UK Myeloma XI cohort, we detected a del17p in 32/463 (7%) of patients. Of these, 15/32 (47%) had an SNSA in the remaining allele. Follow-up data were available of 73/76 del17p NDMM patients from both cohorts (n=46 transplant-eligible (TE), n=27 nontransplant-eligible (NTE)), with a median follow-up time of 17 months. TP53 mutated patients had a worse overall survival (OS) than TP53 wildtype patients (p=0.02), of which the strongest effect on OS was seen of TP53 missense mutations (p We went on to look in the FoundationOne cohort of PDMM patients and detected a del17p in 37/233 (16%) of patients and an SNSA in TP53 in 25/37 (68%) of del17p PDMM patients, which is a higher rate than in the 2 NDMM cohorts. Conclusions (1) TP53 is somatically mutated in half of del17p MM patients at diagnosis, validated in 2 independent cohorts, and this percentage is higher in del17p MM patients at progression. (2) Particularly TP53 missense mutations have a significant, negative impact on both PFS and OS in del17p MM patients. (3) The rest of the genomic landscape of del17p MM is characterized by significant mutations in FAM46C and KRAS, as well as deletions of RB1, TRAF3 and FAM46C. Disclosures Ashby: University of Arkansas for Medical Sciences: Employment. He:Foundation Medicine, Inc: Employment, Equity Ownership. Bailey:Foundation Medicine, Inc: Employment, Equity Ownership. Mughal:Foundation Medicine: Employment, Equity Ownership. Waage:Novartis, Amgen, Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Celgene: Consultancy, Honoraria. Avet-Loiseau:celgene: Consultancy; sanofi: Consultancy; janssen: Consultancy; amgen: Consultancy. Jackson:Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Morgan:Univ of AR for Medical Sciences: Employment; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Meyers: Consultancy, Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. more...
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- 2016
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19. Abstract 5023: Multiple myeloma with a clonal del17p aberration is characterized by somatic TP53 mutations, which negatively affect prognosis in this cytogenetic subgroup
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Bronno van der Holt, Jasper Koenders, Remco Hoogenboezem, Berna Beverloo, Pieter Sonneveld, Eric Bindels, Anders Waage, Mathijs A. Sanders, Ivo P. Touw, Paulina M. H. van Strien, Hervé Avet-Loiseau, Kristine Misund, Davine Hofste op Bruinink, and Claudia Erpelinck Verschueren more...
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Genetics ,Nonsynonymous substitution ,Cancer Research ,Somatic cell ,Biology ,medicine.disease ,Molecular biology ,Germline ,Frameshift mutation ,Oncology ,medicine ,Missense mutation ,Exome ,Gene ,Multiple myeloma - Abstract
Background Multiple myeloma (MM) is a malignant plasma cell disorder, in which at diagnosis circa 10% of tumors are characterized by a deletion of chromosome 17p (del17p). Previously, others and we reported that this aberration is associated with a significantly inferior prognosis, classifying it as high-risk disease. As TP53 is located on chromosome 17p (Chr17p), most research has thus far been focused on this gene. However, only in a minority of del17p MM patients a mutation could be detected (Lodé et al. - Haematologica 2010, Kortüm et al. - Br J Haematol 2015). We therefore hypothesized that other relevant mutations might be present in TP53, its surrounding genes, or disease relevant pathways. Aim With this study, we sought to identify commonly mutated genes in del17p MM, which could explain its aggressive clinical behavior. Material and Methods We obtained high molecular DNA from CD138+ purified MM cells and matched peripheral blood from patients with a del17p in ≥50% of plasma cells, as detected with fluorescent in situ hybridization (FISH). Libraries were generated using a custom capture of 111 Mb (SeqCap EZ Exome Plus, Nimblegen), comprising the whole exome, Chr17p and the IgH, Igk, IgL and MYC regions. Paired-end sequencing was performed on a HiSeq2500 platform, followed by data-analysis using an in-house bioinformatics pipeline at Erasmus MC. Results Matched tumor and germline DNA was sequenced from 54 patients, with sequential tumor samples available from 12 patients. This resulted in an average coverage of 88x and overall coverage of 94%. Of 44 del17p patients, tumor DNA was obtained before treatment start. Clinical data were collected from 40/44 patients, with a median follow-up time of 18 months. We found TP53 to be mutated most frequently. 31/54 (57%) patients had a somatic nonsynonymous mutation, insertion or deletion (71% missense, 19% stopgain/frameshift, 10% splicing). Although no hotspot mutations were detected, most TP53 mutations resided in the DNA binding domain. Of note, most TP53wt/- patients had no clonal somatic nonsynonymous mutations in other p53 pathway genes, or on Chr17p. To assess the prognostic impact of TP53 mutations in del17p MM, we focused on the 40 chemotherapy-naive patients and stratified for age ≤65 years (n = 25) and >65 years (n = 15). TP53mut/- patients had a significantly worse overall survival (OS) than TP53wt/- patients (p = 0.002). Strikingly, TP53 missense mutations showed the worst OS (p Conclusions (1) In contrast with previous reports, we find TP53 to be somatically mutated in the majority of MM patients with a clonal del17p aberration. (2) Particularly TP53 missense mutations have a significantly negative impact on both PFS and OS in del17p MM patients. This study was supported by the Plaisier Foundation, Erasmus MC Grant and the Dutch CTMM Project. Citation Format: Davine Hofste op Bruinink, Remco Hoogenboezem, Eric Bindels, Mathijs Sanders, Claudia Erpelinck - Verschueren, Paulina van Strien, Jasper Koenders, Kristine Misund, Berna Beverloo, Bronno van der Holt, Ivo Touw, Anders Waage, Hervé Avet-Loiseau, Pieter Sonneveld. Multiple myeloma with a clonal del17p aberration is characterized by somatic TP53 mutations, which negatively affect prognosis in this cytogenetic subgroup. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5023. more...
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- 2016
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20. Targeted Genomic Mutation Panel (M3 P) Results from 504 Multiple Myeloma (MM) Patients
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Joaquin Martinez-Lopez, Sanchin Pathangey, Stefan Knop, Yanira Heredia, Elias K. Mai, Inmaculada Rapado, Beatriz Sanchez-Vega, Christian Langer, Marc S. Raab, Leo Rasche, Nur Hafzan Md Hanafiah, Hartmut Goldschmidt, Laura Ann Bruins, Miriam Kull, Santiago Barrio, Mark vanDuin, Pieter Sonneveld, Lars Bullinger, Davine Hofste op Bruinink, K. Martin Kortuem, Esteban Braggio, Monika Engelhardt, Hermann Einsele, and A. Keith Stewart more...
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Genetics ,medicine.medical_specialty ,Standard of care ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Data sequences ,Genomic mutation ,Paired samples ,Family medicine ,Gene panel ,medicine ,business ,Relevant information ,Multiple myeloma ,High risk disease - Abstract
Introduction: Customized gene panel sequencing is an attractive approach to genomic tumor characterization in clinical care. Based on published MM exome data we developed a MM Mutation Panel (M3 P) that includes the most commonly mutated genes, actionable drug targets, genes targeted by current standard of care (SOC) therapies and which allows tracking of clonal evolution, copy number and sample purity. Methods and Material: M3 P (v3.0) covers 88 genes (1327 amplicons, 181kb). MM samples from 504 patients (pts) have been analyzed (corresponding germline in 81%) through collaborations between Mayo Clinic and Hospital-12-de-Octubre (Madrid, Spain), the DSMM and GMMG (Würzburg, Ulm, Freiburg and Heidelberg, Germany) and the HOVON trial groups (Rotterdam, The Netherlands). The investigated cohort includes 410 untreated pts (81%), which includes a high risk cohort of 72 pts with del17p, 25 paired samples with later follow up from the same cohort, and 94 relapsed patients, of which 50 were relapsed and refractory. Results: Overall coverage per mutation averaged >500x depth. We identified 945 variants (1.9 per pt) and in 83% of the pts a mutation was found. Clonal heterogeneity was assessed with mutations ranging from 3%-100% variant reads suggesting the presence of a significant number of subclones (e.g. 21% of mutations were in < 10% of reads). The mutation incidence was compared with and closely resembles the most recent MM comprehensive genomic data from the MMRF CoMMpass study: We compare here all pts sequenced by M3 P, untreated pts sequenced by M3 P and CoMMpass: KRAS (24%/23%/24%), NRAS (20%/20%/18%), DIS3 (13%/14%/10%), BRAF (9%/7%/6%), FAM46C (6%/6%/8%) and TRAF3 (6%/6%/7%). TP53 mutation incidence, however, was significantly increased in our cohort (14%/12%/4.2%), a difference explained by the inclusion of del17p (untreated) and relapsed refractory MM in panel sequenced pts, cohorts with elevated incidences of TP53 mutations (32% / 26% respectively). Potentially actionable targets include BRAF mutationsin 43 patients (9%), with druggable p.V600E in 19 or 5%, 8 pts (2%) with FGFR3 (p.R248C and p.G375C one patient each), p.R132 mutation in 4 out of 5 IDH1 (1%) and p.R172K IDH2 mutation in 1 of 3 (1%) pts. Mutations in the MAPK pathway (NRAS, KRAS, BRAF) were detected in 59% of pts, ranging from 36% untreated MM to 72% in refractory MM. Similarly, the CRBN/CUL4B/IKZF1/IKZF3/IRF4 pathway, important for IMiD function, harbored a significant enrichment of mutations in advanced disease (6% untreated vs 17% relapsed), including CRBN mutations (0.5% vs 7%). Nine of 17 IRF4 mutations were located at the p.K123R hotspot, with minor difference between early or late disease (1% vs 3%). Notably, in 8 of 9 pts with CRBN mutation and clinical information, all were unresponsive to IMiD therapy, supporting association of these mutations with resistance to IMiDs. Conversely, M3 P genes related to other SOC therapies, including NR3C1 (targeted by steroids) and 5 proteasome subunit genes (proteasome inhibitors), were rarely mutated across the cohorts not exceeding 1% mutation incidence for each gene. Significant differences in DIS3 and FAM46C mutation incidences were observed across cohorts: DIS3 mutations are more common in untreated pts with a 1.7 fold increased predominance (14% untreated and 8% treated). FAM46C has an expected incidence of 8% but was rarely mutated in untreated del17p high risk disease with only one of 100 patients harboring both mutations. The significance of this finding needs to be determined but implies a possible overlap in function. Finally we assessed impact on survival of the mutation variants identified in 142 untreated Mayo patients and found STAT3 mutations negatively impacting PFS (p=0.034) and OS (p=0.001). This gene is rarely mutated in MM (2% of the total cohort) thus the sample size was small and this finding needs further validation. Conclusion: We here describe 504 MM patients sequenced using the M3 P gene panel, which identified mutations in >80% of investigated patients, overlaps well with published whole exome sequence data and provides clinically relevant information. New findings were the high frequency of minor clones, the relative lack of overlap of del17 and FAM46C mutation, a higher frequency of DIS3 mutation at diagnosis compared to relapse, the prognostic significance of STAT3 mutation and the frequent presence of CRBN pathway mutation in drug resistant relapsed patients. Disclosures Sonneveld: Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Mai:Janssen-Cilag: Other: Travel Grant; Onyx: Other: Travel Grant; Mundipharma: Other: Travel Grant; Celgene: Other: Travel Grant. Goldschmidt:Takeda: 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; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Knop:Celgene Corporation: Consultancy. Kull:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez:Novartis: Honoraria, Research Funding; Bristol-Meyer Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Einsele:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau. Raab:Novartis: Research Funding. Stewart:Oncospire Inc.: Equity Ownership; Celgene: Consultancy; Novartis: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees. more...
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- 2015
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21. M3P Sequencing Panel Identifies TP53 Mutational Status As a Prognostic Factor in Chemotherapy-Naive Multiple Myeloma
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Mathijs A. Sanders, Michael Vermeulen, Sonja Zweegman, Davine Hofste op Bruinink, Mark van Duin, Jonathan Ahmann, Bronno van der Holt, Annemiek Broijl, Laura Ann Bruins, K. Martin Kortüm, A. Keith Stewart, Remco Hoogenboezem, Pieter Sonneveld, and Esteban Braggio more...
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Oncology ,Neuroblastoma RAS viral oncogene homolog ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Immunology ,Population ,Cell Biology ,Hematology ,medicine.disease_cause ,Bioinformatics ,Biochemistry ,Transplantation ,Germline mutation ,Internal medicine ,medicine ,KRAS ,Progression-free survival ,business ,education ,Exome ,V600E - Abstract
Introduction Multiple myeloma (MM) is characterized by a highly variable disease course, which can be traced to initiating and acquired genomic events. Whole exome analysis of matched tumor and germline DNA from 287 MM patients identified recurrently somatically mutated genes (RSMGs) (Lohr et al. - Cancer Cell 2014, Bolli et al. - Nat Commun 2014). Despite the fact that these RSMGs affect pathways that are biologically important in MM, the clinical relevance of many of these genes in the context of conventional prognostic markers remains to be elucidated. Aims The aims of this pilot study were: (1) To validate the prevalence of RSMGs in our newly diagnosed MM patient cohort; (2) To assess the correlation between RSMGs, clinical parameters and outcome; (3) To thereby identify the potential clinical usefulness of introducing RSMG mutational profiling in larger MM trial cohorts. Material and Methods CD138+ enriched MM cells and peripheral blood were obtained with informed consent from chemotherapy-naive patients, participating in 3 clinical trials: HOVON-65/GMMG-HD4, HOVON-87/NMSG-18 and Carthadex (EudraCT number 2004-000944-26, 2007-004007-34 and 2009-014922-40, respectively). Matched tumor and germline DNA were sequenced on an Ion Torrent sequencing platform (PGM, Life Technologies), using the M3 P Mutational Panel v3.0, comprising 1327 customized oligos (Life Technologies), targeted at the coding sequences of 88 MM-relevant genes, including the RSMGs. Somatic mutations were considered positive when present in >=10% of tumor reads and All statistical analyses were performed in SPSS version 23, using the log-rank and Mann-Whitney U-test, with the Bonferroni test to correct for multiple comparisons. Results A total of 206 DNA samples were sequenced from 103 patients (HOVON-65/GMMG-HD4 (n=16), HOVON-87/NMSG-18 (n=67), Carthadex (n=20)) with an average coverage of 574x in tumor DNA, 451x in germline DNA and an overall coverage of 98%. We collected follow-up data from 102/103 patients, with a median follow-up time of 30 months. 168 somatic mutations were detected in 44/88 genes. 82% of patients had at least 1 somatic mutation. Genes most frequently mutated were: (1) NRAS (26%), (2) KRAS (22%), (3) DIS3 (14%), (4) FAM46C (9%), (5) TP53 (7%) and (6) BRAF (6%) (Figure 1). Of note, NRAS and KRAS mutations were mutually exclusive in our cohort. Moreover, all TP53 mutations were located in its DNA binding domain. Three out of 6 BRAF mutations were predicted to cause a V600E amino acid change. We focused on these 6 RSMGs in all further analyses. Correlating mutational status with Progression Free Survival (PFS) and Overall Survival (OS) showed that TP53 mutated patients had a significantly shorter PFS compared to those with wildtype TP53 (adj. p-value=0,018; n=7 versus n=95). Comparing the mutational status of the 6 RSMGs, transplant versus non-transplant protocol, number of mutated genes in the M3 P panel, del17p and t(4;14) status, EMC92 score and ISS stage between patients with a PFS 1 year (n=23 versus n=79), only showed a significant correlation with TP53 mutational status (adj. p-value=0,012). TP53 mutational status remained the only significant prognostic factor when comparing patients with an OS 1 year (adj. p-value=0,003; n=13 versus n=89). When comparing the number of mutated genes, del17p and t(4;14) status, EMC92 score, transplant versus non-transplant protocol and ISS stage between TP53 mutated and wildtype MM, TP53 mutated patients had a significantly higher number of mutated genes in the M3 P panel (adj. p-value=0,001). Conclusions (1) With the M3 P Mutational Panel, we confirm the published prevalence of RSMGs in MM in our cohort of chemotherapy-naive patients. NRAS, KRAS, DIS3, FAM46C, TP53 and BRAF are the most frequently mutated genes. (2) TP53 mutational status is the strongest unfavorable prognostic factor in our cohort and it seems to be associated with greater mutational burden. Validation in a more extensive population is planned. (3) This warrants further investigation of the mutational status of these genes in larger clinical trial cohorts, enabling a more robust comparison with conventional prognostic markers in a multivariate analysis. Disclosures Broijl: Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Zweegman:Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Sonneveld:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees. more...
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- 2015
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22. Flowcytometric Minimal Residual Disease Assessment in the EMN-02/HOVON-95 MM Trial: Used Methods and a Comparison of Their Sensitivity
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Alexander Schmitz, Lucie Rihova, Davine Hofste op Bruinink, Pieter Sonneveld, Pavla Všianská, Milena Gilestro, Hans Erik Johnsen, Roman Hájek, Mario Boccadoro, Bronno van der Holt, Stefania Oliva, Vincent H.J. van der Velden, Helle Høholt, Jeroen G. te Marvelde, Antonio Palumbo, and Paola Omedè more...
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Melphalan ,Oncology ,medicine.medical_specialty ,Immunology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,EuroFlow ,Prednisone ,Internal medicine ,medicine ,Multiple myeloma ,030304 developmental biology ,Lenalidomide ,0303 health sciences ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Minimal residual disease ,3. Good health ,Clinical trial ,business ,Progressive disease ,030215 immunology ,medicine.drug - Abstract
Background The introduction of novel treatment strategies against multiple myeloma (MM) has resulted in a major improvement in the overall outcome, which has led to an increased need for highly sensitive methods to detect minimal residual disease (MRD) in each patient. MRD assessment by multicolor flowcytometry (MFC) has been shown to be of prognostic value in many treatment protocols over the last decade, making it an attractive method to assess response in clinical trials. However, it is currently not known (1) what the best timing is to perform MFC MRD analysis in the context of a treatment protocol including induction, intensification, consolidation and maintenance treatment, (2) which patients should be selected for this analysis, and (3) what its feasibility is in a large international trial. The ongoing EMN-02 MRD Study aims to answer these questions within the framework of the EMN-02/HOVON-95 MM trial. Here, we describe our methods and the results of our first quality assessment round to compare the sensitivity of the used protocols. Methods The EMN-02/HOVON-95 MM trial is a randomized, multicenter, phase 3 trial in which newly diagnosed MM patients 18-65 years received 4 cycles of bortezomib, cyclophosphamide and dexamethasone (VCD) as induction treatment, followed by a first randomization between either 4 cycles of bortezomib, melphalan and prednisone (VMP), or high dose melphalan (HDM) and 1 or 2 ASCT as intensification treatment. Subsequently, patients were randomized between 2 cycles of bortezomib, lenalidomide and dexamethasone (VRD) or no consolidation treatment, followed by lenalidomide maintenance treatment for all until progression or toxicity occurred. Patients undergoing a bone marrow (BM) aspiration for complete response (CR) confirmation according to the International Myeloma Working Group (IMWG) criteria (Rajkumar et al. - Blood 2011) anytime during the trial were eligible for the EMN-02 MRD Study. BM samples from patients from 13 European countries were sent to 4 central MFC MRD laboratories in the Netherlands (A), Czech Republic (B), Denmark (C) and Italy (D), either using the strict Euroflow protocol (A) (Van Dongen et al. - Leukemia 2012) or Euroflow-based methods (B, C & D). In order to check compatibility between protocols, 5 bone marrow samples from MM patients with a clinical response ranging from progressive disease (PD) to CR were each divided in equal volumes and sent to the respective laboratories on 3 different days. MFC MRD analysis was performed on a FACS Canto II (BD) (A-C) or Coulter Navios flowcytometer (D). Protocols A, B & C used the Euroflow Plasma Cell Disorder (PCD) tube 1 and 2 combination of antibodies, containing the backbone markers CD138-PO, CD38-FITC, CD45-PB and CD19-PE-Cy7, with CD56-PE, B2micro-PerCP-Cy5.5, cyIgK-APC and cyIgL-APC-C750 in tube 1, and CD28-PE, CD27-PerCP-Cy5.5, CD117-APC, CD81-APC-H7 in tube 2. Protocol D had the same backbone markers (CD138-PerCP-Cy5.5, CD38-PB, CD45-KO and CD19-PE-Cy7), together with CD27-PE, CD81-FITC and CD20-APC in tube 1 and cyIgK-FITC, cyIgL-PE, CD56-APC and CD117-APC-AF 750 in tube 2. Bulk lysis was performed in protocols A, B and D. Every laboratory acquired at least 2x10e6 leukocytes (or at least 1x10e4 plasma cells) and performed data-analysis in Infinicyt version 1.6 or higher (A, B & C) or Navios Kaluza (D), using a threshold ranging from 10-25 aberrant plasma cell events as cutoff for MFC MRD positivity. Results Acquisition of events occurred the day after BM aspiration for all samples. The total number of acquired events per sample was dependent on the level of MRD, ranging from 3x10e5 to 2x10e7 leukocytes. MFC MRD results were very comparable between labs with a 1:1 correlation between results at every level of residual disease, being 1x10e-2, 1x10e-4, 1x10-4, 1x10e-5 and 1 MRD negative sample at the level of Conclusions This is the first time that a European framework has been set up between laboratories to test MFC MRD analysis in the context of an international trial. The sensitivity of the protocols has been compared in a quality assessment round, which showed a high correlation of results. Disclosures Oliva: Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Boccadoro:CELGENE: Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbivie: Honoraria; SANOFI: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Hajek:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Palumbo:Takeda: Employment, Honoraria; Janssen Cilag: Honoraria. more...
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