We assessed the prognostic value of minimal residual disease (MRD) detection in multiple myeloma (MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) following front-line therapy. Deep sequencing was carried out in patients in which a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJH, IGH-DJH and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and ASO-PCR. The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD- by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs. 31 months; P<0.0001) and overall survival (median not reached vs. 81 months; P=0.02), compared with patients who were MRD+. When stratifying patients by different levels of MRD, the respective TTP medians were: MRD ≥10(-3) 27 months, MRD 10(-3) to 10(-5) 48 months, and MRD <10(-5) 80 months (P from 0.003 to 0.0001). 92% of VGPR patients were MRD+. In CR patients, the TTP remained significantly longer for MRD- compared to MRD+ patients (131 vs. 35 months; P=0.0009).