Multiple myeloma (MM) is a complex genetic disease characterized by the heterogeneity of tumor cells. We have measured KRAS, NRAS, and BRAF gene mutations in circulating free tumor DNA (ctDNA) from plasma, bone marrow, and plasmacytoma samples as well as their correlation with various clinical and laboratory parameters. The prospective study included 113 MM patients (74 with plasmacytoma and 39 without), treated at the National Medical Research Center for Hematology (Moscow, Russia) from 2009 to 2024. FISH was performed on CD138+ bone marrow cells for 104 patients and array-CGH for two extramedullary plasmacytoma samples. Mutation analysis on CD138+ bone marrow cells was performed for 99 patients, on ctDNA for 80 patients, and, in 26 cases, samples of plasmacytoma were also investigated. Mutations in the KRAS, NRAS, and BRAF genes either in bone marrow, ctDNA, or plasmacytoma samples were found in 50% of patients. In patients with plasmacytoma, mutations in ctDNA were found in 28% of cases versus 0% in cases without plasmacytoma (p = 0.0007). Rare “noncanonical” KRAS and NRAS gene mutations were also more frequent in ctDNA compared to the bone marrow substrate (50% versus 9%, p = 0.01). Liquid biopsy in MM, particularly identification of the KRAS, NRAS, and BRAF gene mutations in ctDNA, is a valuable instrument for prognostication. Researching the intricate mechanisms underlying extramedullary involvement, and identifying novel high-risk factors associated with the disease, is worthwhile.