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Multiple Myeloma (MM) is a heterogeneous disease with complex genetics. Many studies have now set their focus on unraveling the genetic complexity of MM with the aim to understand treatment resistance. Despite the significant improvement in outcome for MM patients through the use of novel agents, treatment can be selective for specific clones that are present when the MM patient is first diagnosed.
Maximilian Merz from Medizinische Klinik, University Hospital of Heidelberg, Heidelberg, Germany, along with his colleagues, investigated subclonal cytogenetic aberrations (CA) with the use of interphase fluorescence in situ hybridization (iFISH), in Newly Diagnosed (ND) MM patients (pts).The prognostic significance in pts with or without bortezomib treatment and tandem ASCT was also studied, within the German part of the prospective Haemato Oncology Foundation for Adults in the Netherlands (HOVON)–65/German-Speaking Myeloma Multicenter Group (GMMG)–HD4 trial. GMMG pts were randomly assigned to either arm A: 3 cycles of vincristine, adriamycin, and dexamethasone followed by tandem ASCT and thalidomide maintenance therapy for 2 years or arm B: 3 cycles of bortezomib, adriamycin, dexamethasone (PAD), followed by tandem ASCT and bortezomib maintenance therapy for two years. The study was published in the January 2018 edition of Blood Advances.
This study demonstrated, for the first time, the association of clonal heterogeneity with a poor outcome. It also showed that clonal heterogeneity is a common phenomenon in MM. A higher frequency of gains and deletions of MYC on a subclonal level were also found, although they were only associated with adverse outcomes when present as a main clone. High-risk patients who do not display any subclones were found to benefit from continuous bortezomib treatment. However, it must be noted that without whole-genome data, the true number of subclones could be underestimated. Future studies will include investigating the subclones on a mutational level in order to elucidate mechanisms that lead to the observed.
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