Jean-Baptiste Alberge1,2, Françoise Kraeber-Bodéré1,2,3,4,5, Bastien Jamet2,3, Cyrille Touzeau1,2,5, Hélène Caillon5, Soraya Wuilleme5, Marie-Christine Béné5, Tobias Kampfenkel6, Pieter Sonneveld7, Mark van Duin7, Herve Avet-Loiseau8, Jill Corre9, Florence Magrangeas1,2,5, Thomas Carlier1,2,3, Caroline Bodet-Milin1,2,3, Michel Chérel1,2,4, Philippe Moreau1,2,5, Stéphane Minvielle10,2,5, Clément Bailly10,2,3. 1. Université de Nantes, CHU Nantes, CNRS, Inserm, CRCINA, Nantes, France. 2. Site de Recherche Intégrée sur le Cancer (SIRIC), Imaging and Longitudinal Investigations to Ameliorate Decision-Making (ILIAD), INCA-DGOS-Inserm 12558, Nantes, France. 3. Nuclear Medicine Unit, University Hospital, Nantes, France. 4. Nuclear Medicine Unit, ICO-Gauducheau, Nantes-Saint-Herblain, France. 5. Haematology Department, University Hospital, Nantes, France. 6. Janssen Research & Development, LLC, Leiden, The Netherlands. 7. Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands; and. 8. Unité de Génomique du Myélome, Institut Universitaire du Cancer de Toulouse, Institut National de la Santé, Oncopole, Toulouse, France. 9. Unité de Génomique du Myélome, Institut Universitaire du Cancer de Toulouse, Institut National de la Santé, Oncopole, Toulouse, France clement.bailly@chu-nantes.fr stephane.minvielle@univ-nantes.fr. 10. Université de Nantes, CHU Nantes, CNRS, Inserm, CRCINA, Nantes, France; clement.bailly@chu-nantes.fr stephane.minvielle@univ-nantes.fr.
Abstract
The International Myeloma Working Group recently fully incorporated 18F-FDG PET into multiple myeloma (MM) diagnosis and response evaluation. Moreover, a few studies demonstrated the prognostic value of several biomarkers extracted from this imaging at baseline. Before these 18F-FDG PET biomarkers could be fully endorsed as risk classifiers by the hematologist community, further characterization of underlying molecular aspects was necessary. Methods: Reported prognostic biomarkers (18F-FDG avidity, SUVmax, number of focal lesions, presence of paramedullary disease [PMD] or extramedullary disease) were extracted from 18F-FDG PET imaging at baseline in a group of 139 patients from CASSIOPET, a companion study of the CASSIOPEIA cohort (ClinicalTrials.gov identifier NCT02541383). Transcriptomic analyses using RNA sequencing were realized on sorted bone marrow plasma cells from the same patients. An association with a high-risk gene expression signature (IFM15), molecular classification, progression-free survival, a stringent clinical response, and minimal residual disease negativity were explored. Results: 18F-FDG PET results were positive in 79.4% of patients; 14% and 11% of them had PMD and extramedullary disease, respectively. Negative 18F-FDG PET results were associated with lower levels of expression of hexokinase 2 (HK2) (fold change, 2.1; adjusted P = 0.04) and showed enrichment for a subgroup of patients with a low level of bone disease. Positive 18F-FDG PET results displayed 2 distinct signatures: either high levels of expression of proliferation genes or high levels of expression of GLUT5 and lymphocyte antigens. PMD and IFM15 were independently associated with a lower level of progression-free survival, and the presence of both biomarkers defined a group of "double-positive" patients at very high risk of progression. PMD and IFM15 were related neither to minimal residual disease assessment nor to a stringent clinical response. Conclusion: Our study confirmed and extended the association between imaging biomarkers and transcriptomic programs in MM. The combined prognostic value of PMD and a high-risk IFM15 signature may help define MM patients with a very high risk of progression.
The International Myeloma Working Group recently fully incorporated 18F-FDG PET into multiple myeloma (MM) diagnosis and response evaluation. Moreover, a few studies demonstrated the prognostic value of several biomarkers extracted from this imaging at baseline. Before these 18F-FDG PET biomarkers could be fully endorsed as risk classifiers by the hematologist community, further characterization of underlying molecular aspects was necessary. Methods: Reported prognostic biomarkers (18F-FDG avidity, SUVmax, number of focal lesions, presence of paramedullary disease [PMD] or extramedullary disease) were extracted from 18F-FDG PET imaging at baseline in a group of 139 patients from CASSIOPET, a companion study of the CASSIOPEIA cohort (ClinicalTrials.gov identifier NCT02541383). Transcriptomic analyses using RNA sequencing were realized on sorted bone marrow plasma cells from the same patients. An association with a high-risk gene expression signature (IFM15), molecular classification, progression-free survival, a stringent clinical response, and minimal residual disease negativity were explored. Results: 18F-FDG PET results were positive in 79.4% of patients; 14% and 11% of them had PMD and extramedullary disease, respectively. Negative 18F-FDG PET results were associated with lower levels of expression of hexokinase 2 (HK2) (fold change, 2.1; adjusted P = 0.04) and showed enrichment for a subgroup of patients with a low level of bone disease. Positive 18F-FDG PET results displayed 2 distinct signatures: either high levels of expression of proliferation genes or high levels of expression of GLUT5 and lymphocyte antigens. PMD and IFM15 were independently associated with a lower level of progression-free survival, and the presence of both biomarkers defined a group of "double-positive" patients at very high risk of progression. PMD and IFM15 were related neither to minimal residual disease assessment nor to a stringent clinical response. Conclusion: Our study confirmed and extended the association between imaging biomarkers and transcriptomic programs in MM. The combined prognostic value of PMD and a high-risk IFM15 signature may help define MM patients with a very high risk of progression.
Authors: Annemiek Broyl; Dirk Hose; Henk Lokhorst; Yvonne de Knegt; Justine Peeters; Anna Jauch; Uta Bertsch; Arjan Buijs; Marian Stevens-Kroef; H Berna Beverloo; Edo Vellenga; Sonja Zweegman; Marie-Josée Kersten; Bronno van der Holt; Laila el Jarari; George Mulligan; Hartmut Goldschmidt; Mark van Duin; Pieter Sonneveld Journal: Blood Date: 2010-06-23 Impact factor: 22.113
Authors: L Rasche; S S Chavan; O W Stephens; P H Patel; R Tytarenko; C Ashby; M Bauer; C Stein; S Deshpande; C Wardell; T Buzder; G Molnar; M Zangari; F van Rhee; S Thanendrarajan; C Schinke; J Epstein; F E Davies; B A Walker; T Meissner; B Barlogie; G J Morgan; N Weinhold Journal: Nat Commun Date: 2017-08-16 Impact factor: 14.919
Authors: John D Shaughnessy; Fenghuang Zhan; Bart E Burington; Yongsheng Huang; Simona Colla; Ichiro Hanamura; James P Stewart; Bob Kordsmeier; Christopher Randolph; David R Williams; Yan Xiao; Hongwei Xu; Joshua Epstein; Elias Anaissie; Somashekar G Krishna; Michele Cottler-Fox; Klaus Hollmig; Abid Mohiuddin; Mauricio Pineda-Roman; Guido Tricot; Frits van Rhee; Jeffrey Sawyer; Yazan Alsayed; Ronald Walker; Maurizio Zangari; John Crowley; Bart Barlogie Journal: Blood Date: 2006-11-14 Impact factor: 22.113
Authors: Shaji Kumar; Bruno Paiva; Kenneth C Anderson; Brian Durie; Ola Landgren; Philippe Moreau; Nikhil Munshi; Sagar Lonial; Joan Bladé; Maria-Victoria Mateos; Meletios Dimopoulos; Efstathios Kastritis; Mario Boccadoro; Robert Orlowski; Hartmut Goldschmidt; Andrew Spencer; Jian Hou; Wee Joo Chng; Saad Z Usmani; Elena Zamagni; Kazuyuki Shimizu; Sundar Jagannath; Hans E Johnsen; Evangelos Terpos; Anthony Reiman; Robert A Kyle; Pieter Sonneveld; Paul G Richardson; Philip McCarthy; Heinz Ludwig; Wenming Chen; Michele Cavo; Jean-Luc Harousseau; Suzanne Lentzsch; Jens Hillengass; Antonio Palumbo; Alberto Orfao; S Vincent Rajkumar; Jesus San Miguel; Herve Avet-Loiseau Journal: Lancet Oncol Date: 2016-08 Impact factor: 41.316
Authors: Benjamin G Barwick; Paola Neri; Nizar J Bahlis; Ajay K Nooka; Madhav V Dhodapkar; David L Jaye; Craig C Hofmeister; Jonathan L Kaufman; Vikas A Gupta; Daniel Auclair; Jonathan J Keats; Sagar Lonial; Paula M Vertino; Lawrence H Boise Journal: Nat Commun Date: 2019-04-23 Impact factor: 14.919
Authors: Brian A Walker; Konstantinos Mavrommatis; Christopher P Wardell; T Cody Ashby; Michael Bauer; Faith Davies; Adam Rosenthal; Hongwei Wang; Pingping Qu; Antje Hoering; Mehmet Samur; Fadi Towfic; Maria Ortiz; Erin Flynt; Zhinuan Yu; Zhihong Yang; Dan Rozelle; John Obenauer; Matthew Trotter; Daniel Auclair; Jonathan Keats; Niccolo Bolli; Mariateresa Fulciniti; Raphael Szalat; Phillipe Moreau; Brian Durie; A Keith Stewart; Hartmut Goldschmidt; Marc S Raab; Hermann Einsele; Pieter Sonneveld; Jesus San Miguel; Sagar Lonial; Graham H Jackson; Kenneth C Anderson; Herve Avet-Loiseau; Nikhil Munshi; Anjan Thakurta; Gareth Morgan Journal: Leukemia Date: 2018-07-02 Impact factor: 11.528