Recent attempts have focused on identifying fewer magnitude of minimal residual disease (MRD) rather than exploring the biological and genetic features of the residual plasma cells (PCs). Here, a cohort of 193 patients with at least one cytogenetic abnormalities (CA) at diagnosis were analyzed, and interphase fluorescence in situ hybridization (iFISH) analyses were performed in patient-paired diagnostic and posttherapy samples. Persistent CA in residual PCs were observed for the majority of patients (63%), even detectable in 28/63 (44%) patients with MRD negativity (<10-4). The absence of CA in residual PCs was associated with prolonged survival regardless of MRD status. According to the change of the clonal size of specific CA, patients were clustered into five groups, reflecting different patterns of clone selection under therapy pressure. Therapy-induced clonal selection exerted a significant impact on survival (HR = 4.0; P < 0.001). According to the longitudinal cytogenetic studies at relapse, sequential cytogenetic dynamics were observed in most patients, and cytogenetic architecture of residual PCs could to some extent predict the evolutional pattern at relapse. Collectively, the repeat cytogenetic evaluation in residual PCs could not only serves as a good complementary tool for MRD detection, but also provides a better understanding of clinical response and clonal evolution.