Knowledge about clonal diversity and selection is critical to understand multiple myeloma (MM) pathogenesis, chemoresistance and progression. If targeted therapy becomes reality, identification and monitoring of intraclonal plasma-cell (PC) heterogeneity would become increasingly demanded. Here, we investigated the kinetics of intraclonal heterogeneity among 116 MM patients using 23-marker multidimensional-flow-cytometry (MFC) and principal-component-analysis, at diagnosis and during minimal-residual-disease (MRD) monitoring. Distinct phenotypic subclones were observed in 35/116 (30%) newly-diagnosed MM patients. In 10/35 patients persistent MRD was detected after 9 induction cycles, and longitudinal comparison of patient-paired diagnostic vs. MRD samples unraveled phenotypic clonal tiding after therapy in half (5/10) of the patients. After demonstrating selection of distinct phenotypic subsets by therapeutic pressure, we investigated if distinct FACS-sorted PC subclones had different clonogenic and cytogenetic profiles. In half (5/10) of the patients analyzed, distinct phenotypic subclones showed different clonogenic potential when co-cultured with stromal cells, and in 6/11 cases distinct phenotypic subclones displayed unique cytogenetic profiles by iFISH, including selective del(17p13). Collectively, we unravel potential therapeutic selection of pre-existing diagnostic phenotypic subclones during MRD monitoring; because phenotypically distinct PCs may show different clonogenic and cytogenetic profiles, identification and follow-up of unique phenotypic-genetic myeloma PCs subclones may become relevant for tailored therapy.Leukemia accepted article preview online, 12 November 2014. doi:10.1038/leu.2014.321.