Simple Summary The study of malignant plasma cell DNA genomics in multiple myeloma is a hot topic, which is mainly based on one-site bone marrow aspirates. In this study, we showed that circulating tumor DNA targeted next-generation sequencing analysis revealed a more comprehensive genomic architecture than bone marrow aspirates in newly diagnosed multiple myeloma. Circulating tumor DNA mutation in the transcriptional regulation pathway and DNA repair pathway were independent predictors of progression-free survival. ctDNA alterations correlated with prognosis and therapy response in newly diagnosed multiple myeloma. Multiple myeloma (MM) is highly heterogenous and dynamic in its genomic abnormalities. Capturing a representative image of these alterations is essential in understanding the molecular pathogenesis and progression of the disease but was limited by single-site invasive bone marrow (BM) biopsy-based genomics studies. We compared the mutational landscapes of circulating tumor DNA (ctDNA) and BM in 82 patients with newly diagnosed MM. A 413-gene panel was used in the sequencing. Our results showed that more than 70% of MM patients showed one or more genes with somatic mutations and at least half of the mutated genes were shared between ctDNA and BM samples. Compared to the BM samples, ctDNA exhibited more types of driver mutations in the shared driver genes, higher numbers of uniquely mutated genes and subclonal clusters, more translocation-associated mutations, and higher frequencies of mutated genes enriched in the transcriptional regulation pathway. Multivariate Cox analysis showed that age, ctDNA mutations in the transcriptional regulation pathway and DNA repair pathway were independent predictors of progression-free survival (PFS). Our results demonstrated sequencing of ctDNA provides more thorough information on the genomic instability and is a potential representative biomarker for risk stratification and in newly diagnosed MM than bone marrow.