Multiple myeloma (MM) is a plasma cell (PC) disorder characterized by skeletal involvement at the time of diagnosis. Recently, cell-free DNA (cfDNA) has been proven to recapitulate the heterogeneity of bone marrow (BM) disease. Our aim was to evaluate the prognostic role of cfDNA at diagnosis according to disease distribution, and to investigate the role of the MM microenvironment inflammatory state in supplying the release of cfDNA. A total of 162 newly diagnosed MM patients were screened using 18F-FDG PET/CT and assessed by ultra low-pass whole genome sequencing (ULP-WGS). High cfDNA tumor fraction (ctDNA) levels were correlated with different tumor mass markers, and patients with high ctDNA levels at diagnosis were more likely to present with metabolically active paraskeletal (PS) and extramedullary (EM) lesions. Moreover, we demonstrated that microenvironment cancer-associated fibroblast (CAFs)-mediated inflammation might correlate with high ctDNA levels. Indeed, a high cfDNA TF level at diagnosis predicted a poorer prognosis, independent of R-ISS III and 1q amplification; the inclusion of >12% ctDNA in the current R-ISS risk score enables a better identification of high-risk patients. ctDNA can be a reliable and less invasive marker for disease characterization, and can refine patient risk.

多发性骨髓瘤 （MM） 是一种浆细胞 （PC） 疾病，其特征是在诊断时骨骼受累。最近，游离 DNA （cfDNA） 已被证明可以概括骨髓 （BM） 疾病的异质性。我们的目的是根据疾病分布评估 cfDNA 在诊断中的预后作用，并研究 MM 微环境炎症状态在提供 cfDNA 释放中的作用。使用 18F-FDG PET/CT 筛选了 162 例新诊断的 MM 患者，并通过超低通全基因组测序 （ULP-WGS） 进行评估。高 cfDNA 肿瘤分数 （ctDNA） 水平与不同的肿瘤质量标志物相关，诊断时 ctDNA 水平高的患者更可能出现代谢活跃的骨骼旁 （PS） 和髓外 （EM） 病变。此外，我们证明微环境癌症相关成纤维细胞 （CAFs） 介导的炎症可能与高 ctDNA 水平相关。事实上，诊断时高 cfDNA TF 水平预示着预后较差，与 R-ISS III 和 1q 扩增无关;在当前的 R-ISS 风险评分中纳入 >12% ctDNA 可以更好地识别高危患者。ctDNA 可以成为一种可靠且侵入性较小的疾病表征标志物，并且可以降低患者风险。