Provided herein are non-invasive methods and biomarkers that identify progression and clonal evolution of plasma cell dyscrasias. Also provided are materials and methods for the diagnosis, prognosis, staging, and monitoring of plasma cell dyscrasias based on the presence of the biomarkers in a blood biopsy, as well as methods for monitoring the progression of a plasma cell dyscrasia, determining the efficacy of a therapeutic agent, determining a targeted therapy related to a plasma cell dyscrasia, and/or treating a plasma cell dyscrasia. The methods provided herein provide several advantages over invasive biopsies.