Molecular signature of FDG-PET biomarkers in newly diagnosed multiple myeloma patients: a genome-wide transcriptome analysis from the CASSIOPET study

Abstract

The International Myeloma Working Group has recently fully incorporated ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) into multiple myeloma (MM) diagnosis and response evaluation. Moreover, a few studies have demonstrated the prognostic value of several biomarkers extracted from this imaging at baseline. Before these FDG-PET biomarkers could be fully endorsed as risk classifiers by the haematologist community, further characterization of underlying molecular aspects is necessary. Methods: Reported prognostic biomarkers (FDG avidity, SUV_max, number of focal lesions, presence of para-medullary disease (PMD) or extra-medullary disease (EMD)) were extracted from FDG-PET imaging at baseline in a group of 139 patients from CASSIOPET, a companion study of the CASSIOPEIA cohort (ClinicalTrials.gov, NCT02541383). Transcriptomic analyses using RNA sequencing were realized on sorted bone marrow plasma cells from the same patients. Association with high-risk gene expression signature (IFM15), molecular classification, progression-free-survival (PFS), stringent clinical response (sCR) and minimal residual disease (MRD) negativity were explored. Results: FDG-PET was positive in 79.4% of patients, with 14% and 11% of them presenting PMD and EMD respectively. Negative FDG-PET scans were associated with lower expression of hexokinase-2 (HK2) (Fold Change = 2.1, padj=0.04) and enriched for the LB (low-bone disease) subgroup of patients. Positive FDG-PET profiles displayed two distinct signatures with either high expression of proliferation genes, or high expression of GLUT5 and lymphocyte antigens. PMD and IFM15 were independently associated with a lower PFS, and the presence of both biomarkers defined a group of double-positive patients at very high-risk of progression. PMD and IFM15 were neither related to MRD assessment nor to sCR. Conclusion: Our study confirmed and extended the association between imaging biomarkers and transcriptomic programs in MM. Combined prognostic value of PMD and high-risk signature with IFM15 may help define a very high-risk group of MM.