High Level of Circulating Tumour DNA at Diagnosis Correlates With Disease Spreading and Defines Multiple Myeloma Patients With Poor Prognosis

Background: Multiple Myeloma (MM) is a plasma cell (PC) disorder characterized by the presence of skeletal involvement at the time of diagnosis, as detected by MRI and/or FDG PET/CT, in most of the patients. The patchy nature of the disease is probably related to the ability of fitter clones to spread into peripheral blood reaching distant sites, where favourable microenvironment conditions might promote clones’ seeding. Recently, cell-free DNA (cfDNA) has been proven to resume the heterogeneity of spatially distributed clones. However, it has to be determined to which extent cfDNA correlates with disease distribution and its possible implications with patients’ outcome. Moreover, the potential of cfDNA to track the evolutionary dynamics and the heterogeneity of MM, possibly anticipating the emergence of therapy resistant residual cells, remains to be confirmed. Aims: Aim of this study is to quantitatively and qualitatively evaluate cfDNA at diagnosis and during follow-up in correlation with imaging data to possibly define the integration of this approach with molecular bone marrow (BM) and whole-body residual disease assessment. Methods: A total of 88 newly diagnosed MM patients were screened at baseline with 18F-FDG PET/CT, and molecularly assessed by Ultra Low Pass-Whole Genome Sequencing (ULP-WGS). In a subgroup of 22 patients, cfDNA was monitored monthly, whereas PET/CT was reassessed after induction therapy to evaluate metabolic tumor response. For each pts, ULP-WGS was used to characterize both the neoplastic PC clone(s) in the BM (gDNA) and the cfDNA from peripheral blood. Data were analysed by ichorCNA and Clonality R packages. Results: At diagnosis, the cfDNA tumor fraction (TF) was significantly lower as compared to gDNA TF [median (M) TF: 4.4 vs. 59.7%, respectively]. Nevertheless, high cfDNA TF levels (> 4.4% cfDNA TF values; range: 4.4-84.3%) correlated with high gDNA TF levels (>65.7% gDNA TF values; range: 65.7-96.7%). This observation was further confirmed by a significant correlation between cfDNA TF and the percentage of BM CD138/CD38 positive plasma cells (r=0.47; p2 PET lesions, cfDNA TF was still detectable (>1% TF), thus corroborating a possible role for cfDNA in monitoring response to therapy. Summary/Conclusion: In conclusion, patients with high cfDNA TF displayed imaging data that overall suggested a higher propensity to a metastatic spread of the disease, which finally correlated with poorer prognosis. Future studies will be addressed to exploit the use of cfDNA in disease monitoring. Acknowledgements: AIRC IG2019, AIL BOLOGNA ODV