DESTINY - Describing the heterogeneity of disease distribution in multiple myeloma patients through a liquid biopsy approach

Multiple Myeloma (MM) is characterized by marked genetic and spatial heterogeneity, contributing to variable treatment responses and relapse. Although minimal residual disease (MRD) negativity is a strong predictor of survival, its evaluation through single-site bone marrow (BM) aspirates may underestimate disease complexity. This study aimed to develop a liquid biopsy–based strategy and to investigate the prognostic impact of spatial disease distribution in MM. 100 newly diagnosed MM patients were enrolled. At baseline, BM CD138+ plasma cells and peripheral blood samples were collected. Clinical, biochemical, imaging (PET/CT), and genomic data were integrated. CTCs were quantified by flow cytometry, while cfDNA and genomic DNA tumor fraction (TF) were assessed by ULP-WGS. In 59 patients, MRD was evaluated by NGS at the end of first-line therapy. CTCs and cfDNA TF significantly correlated with adverse clinical and imaging features, supporting their role as surrogates of disease burden. CTCs were associated with extensive BM involvement and renal impairment. High cfDNA TF correlated with elevated β2-microglobulin, anemia, increased plasma cell infiltration, and ISS/R-ISS stage III. Imaging confirmed higher cfDNA TF in patients with multiple focal lesions or extramedullary disease. Among 59 evaluable patients, 24/59 achieved MRD negativity and 35/59 remained MRD-positive. MRD-positive patients showed higher cfDNA TF and greater BM lesion burden. Notably, patients with sustained MRD negativity but persistent PET/CT activity displayed advanced stage, lower hemoglobin, and higher plasma cell infiltration, highlighting the impact of diffuse disease on MRD assessment. Patients who failed to achieve sustained MRD negativity had baseline high-risk profiles, including elevated cfDNA TF and advanced ISS/R-ISS stage, suggesting that cfDNA TF at diagnosis may predict MRD persistence and treatment resistance. In conclusion, liquid biopsy markers reflect diffuse disease distribution and correlate with MRD outcomes, supporting their integration into MM monitoring and risk stratification while potentially reducing reliance on invasive BM biopsies.