Ploidy is an MM can be divided into two groups according to the modal number of chromosomes: nonhyperdiploid (NH-MM) and hyperdiploid (H-MM), which has a more favorable outcome. The two ploidy groups represent two different oncogenetic pathways determined at the premalignant stage. The ploidy subtype also persists during the course of the disease, even during progression after the therapy, with only very rare cases of ploidy conversion. The clinical significance of ploidy conversion and its relation to drug resistance have been previously discussed. Here, we describe a female MM patient with a rare change in her ploidy status from H-MM to NH-MM, detected by cytogenetic and molecular cytogenetic examinations of consecutive bone marrow aspirates. We hypothesize that ploidy conversion (from H-MM to NH-MM) is associated with disease progression and acquired resistance to bortezomibilenalidomide therapy.