Molecular Signature of <sup>18</sup>F-FDG PET Biomarkers in Newly Diagnosed Multiple Myeloma Patients: A Genome-Wide Transcriptome Analysis from the CASSIOPET Study
Jean-Baptiste Alberge, Françoise Kraeber‐Bodéré, Bastien Jamet, Cyrille Touzeau, Hélène Caillon, Soraya Wuillème, Marie C. Béné, Tobias Kampfenkel, Pieter Sonneveld, Mark van Duin, Hervé Avet‐Loiseau, Jill Corre, Florence Magrangeas, Thomas Carlier, Caroline Bodet‐Milin, Michel Chérel, Philippe Moreau, Stéphane Minvielle, Clément Bailly
Abstract
The International Myeloma Working Group recently fully incorporated <sup>18</sup>F-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 <sup>18</sup>F-FDG PET biomarkers could be fully endorsed as risk classifiers by the hematologist community, further characterization of underlying molecular aspects was necessary. <b>Methods:</b> Reported prognostic biomarkers (<sup>18</sup>F-FDG avidity, SUV<sub>max</sub>, number of focal lesions, presence of paramedullary disease [PMD] or extramedullary disease) were extracted from <sup>18</sup>F-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. <b>Results:</b><sup>18</sup>F-FDG PET results were positive in 79.4% of patients; 14% and 11% of them had PMD and extramedullary disease, respectively. Negative <sup>18</sup>F-FDG PET results were associated with lower levels of expression of hexokinase 2 (<i>HK2</i>) (fold change, 2.1; adjusted <i>P</i> = 0.04) and showed enrichment for a subgroup of patients with a low level of bone disease. Positive <sup>18</sup>F-FDG PET results displayed 2 distinct signatures: either high levels of expression of proliferation genes or high levels of expression of <i>GLUT5</i> 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. <b>Conclusion:</b> 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.