Objectives Progress in multiple myeloma treatment allows patients to achieve deeper responses, for which the assessment of minimal residual disease (MRD) is critical. Typically, bone marrow samples are used for this purpose; however, this approach is site-limited. Liquid biopsy represents a minimally invasive and more comprehensive technique that is not site-limited, but equally challenging. Methods While majority of current data comes from short-term studies, we present a long-term study on blood-based MRD monitoring using tumor-specific cell-free DNA detection by ASO-qPCR. One hundred and twelve patients were enrolled into the study, but long-term sampling and analysis were feasible only in 45 patients. Results We found a significant correlation of quantity of tumor-specific cell-free DNA levels with clinically meaningful events [induction therapy (P = .004); ASCT (P = .012)]. Moreover, length of cfDNA fragments is associated with better treatment response of patients. Conclusions These results support the concept of tumor-specific cell-free DNA as a prognostic marker.