A real time and viable means of assessing drug response using the patient’s own malignant cells could accelerate the design of individualized treatment strategies and improve outcome. Other targeted agents such as mTOR and HDAC inhibitors have been clinically investigated, however, these were not biomarker driven studies and thus not targeted to patients likely to respond. With the recent exception of venetoclax in BCL-2 driven t(11 14) MM, genomically guided treatments have not been successful in MM. Prior information on responses to approved myeloma and other oncology drugs remains crucial to determine the timing and sequence of treatments. clonal heterogeneity and evolution) that are still poorly understood. Patients may exhibit both de novo or acquired resistance to current therapies by mechanisms (i.e. Heterogeneity in treatment response may be influenced by several patient or disease related features such as frailty, age, comorbidity, clinical stage and the presence of one or more cytogenetic abnormalities. While some patients experience long remission, prognosis is still poor for high-risk patients. Immunomodulatory drugs and proteasome inhibitors combined with alkylating agents and steroids have improved the outcome of MM patients. Our results demonstrate that ex vivo drug testing may potentially be applied to optimize treatment selection and achieve therapeutic benefit for relapsed/refractory MM. Three patients treated based on the ex vivo results showed good response to the selected treatments. Samples positive for t(4 14) were highly sensitive to immunomodulatory drugs, proteasome inhibitors and several targeted drugs. Del(17p) positive samples were resistant to most drugs tested with the exception of histone deacetylase and BCL2 inhibitors. Patients with progressive disease and poor survival clustered in a drug response group exhibiting high sensitivity to signal transduction inhibitors. Based on their drug sensitivity profiles, MM patients were stratified into four distinct subgroups with varied survival outcomes. With the results we i) classified patients based on their ex vivo drug response profile ii) identified and matched potential drug candidates to recurrent cytogenetic alterations and iii) correlated ex vivo drug sensitivity to patient outcome.
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To identify novel therapies and aid treatment selection for MM, we assessed the ex vivo sensitivity of 50 MM patient samples to 308 approved and investigational drugs. Novel agents have increased survival of multiple myeloma (MM) patients, however high-risk and relapsed/refractory patients remain challenging to treat and their outcome is poor. Received: DecemAccepted: ApPublished: May 05, 2017 Heckman, email: multiple myeloma, functional screening, drug sensitivity and resistance testing, precision medicine, high-risk myeloma
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*These authors contributed equally to this workĬaroline A.
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Heckman 1ġInstitute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, FinlandĢDepartment of Medicine, Kuopio University Hospital, Kuopio, FinlandģDepartment of Hematology, Helsinki University Hospital, Comprehensive Cancer Center, Helsinki, FinlandĤResearch Unit on Biomedical Informatics, Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, SpainĥHematology Research Unit, University of Helsinki, Helsinki, Finland Muntasir Mamun Majumder 1, *, Raija Silvennoinen 2, 3, *, Pekka Anttila 3, David Tamborero 4, Samuli Eldfors 1, Bhagwan Yadav 1, Riikka Karjalainen 1, Heikki Kuusanmäki 1, Juha Lievonen 3, Alun Parsons 1, Minna Suvela 1, Esa Jantunen 2, Kimmo Porkka 3, 5 and Caroline A.