Multiple myeloma (MM) is a neoplastic disease of B cells characterized by the proliferation of multiple plasma cell clones, typically with intraclonal and spatial genomic heterogeneity. This makes the “single site” bone marrow aspirate, currently used for the assessment of post-treatment residual disease (MRD), not fully informative of the disease burden and genomic landscape. MRD assessment is assuming a growing importance, so tests used to monitor it should be non-invasive, reliable and able to represent the heterogeneities that characterize MM. The present study has demonstrated the possibility of using liquid biopsy, an innovative and non-invasive method, to characterize patients with active MM or with smoldering MM at high risk of evolution (HR-SMM) at onset and to determine the ‘MRD in patients that received first-line therapy, integrating the currently validated methods. In the patients enrolled in the present study it was possible to identify the tumor fraction of circulating free DNA (cfDNA-TF) in peripheral blood. It was also possible to qualitatively characterize the disease, demonstrating a high agreement of the genomic profile between circulating free DNA and bone marrow DNA (100% in patients with HR-SMM and 86% in patients with active MM). The serial execution of liquid biopsies during therapy, with a median follow-up of 24 months, permitted to evaluate the trend of cfDNA-TF, noting a rapid reduction from the early stages of therapy, with a tendency to remain below the sensitivity threshold of the method also in the subsequent phases, regardless of the possible persistence of MRD identifiable at the medullary level or by PET-CT. With a longer follow-up it will probably be possible to better evaluate the ability of this method to support or possibly replace bone marrow aspiration.