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

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.

Keywords: 18F-FDG PET; CASSIOPET study; RNA sequencing; genome-wide transcriptome; multiple myeloma.

© 2022 by the Society of Nuclear Medicine and Molecular Imaging.

Figures

Graphical abstract

FIGURE 1.

Molecular profile of 18F-FDG PET negativity in CASSIOPET trial. (A) Expression (expr.) of GLUTs and HKs on 18F-FDG PET scans with abnormal or positive (orange) vs. normal or negative (green) results in CASSIOPET cohort. (B) Expression of GLUTs and HKs in patients with standard-risk (blue) vs. high-risk (red) IFM15 gene expression signatures. (C) Distribution of normal 18F-FDG PET results across MM molecular classes as defined by UAMS. (D and E) Expression of HK2 (D) and GLUT5 (E) in MM molecular classes. Gene expression levels are given in variance stabilizing transformation–normalized counts (see Materials and Methods). n = 139 patients. *P < 0.05. **P < 0.01. ***P < 0.001. ****P < 0.0001.

FIGURE 2.

Gene expression (expr.) profiling of 18F-FDG PET scans with abnormal results. Heat map representation of standardized gene expression levels of most differentially expressed genes between 2 conditions (normal and abnormal 18F-FDG PET results), obtained with DESeq2. SLC2A3 encodes GLUT3, and SLC2A5 encodes GLUT5.

FIGURE 3.

Molecular profiles of PMD and EMD on 18F-FDG PET. (A and B) Distribution of patients with PMD at baseline for high-risk and standard-risk IFM15 expression signatures (A) and across myeloma molecular classes (B). (C and D) Distribution of patients with EMD at baseline for high-risk and standard-risk IFM15 expression signatures (C) and across myeloma molecular classes (D). n.s = not significant (P > 0.05).

FIGURE 4.

Prognostic value of imaging and gene expression profiles. (A) Multivariate Cox modeling of PFS by presence of PMD and high-risk IFM15 gene expression signature (IFM15+). (B) Kaplan–Meier curves representing PFS of MM patients separated by IFM15 and PMD status. (C) Kaplan–Meier curves depicting PFS of patients with positive 18F-FDG PET results only (n = 110/139) and according to their IFM15 risk status. (D) Multivariate Cox modeling of PFS using PET (normal or abnormal results) and IFM15 (Yes = high risk; No = standard risk) binary variables. AIC = Akaike information criterion.