Molecular Signature of ¹⁸F-FDG PET Biomarkers in Newly Diagnosed Multiple Myeloma Patients: A Genome-Wide Transcriptome Analysis from the CASSIOPET Study

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, SUV_max, 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.