Identification of precision treatment strategies for relapsed/ refractory multiple myeloma by functional drug sensitivity testing
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Muntasir Mamun Majumder1,*, Raija Silvennoinen2,3,*, Pekka Anttila3, David Tamborero4, Samuli Eldfors1, Bhagwan Yadav1, Riikka Karjalainen1, Heikki Kuusanmäki1, Juha Lievonen3, Alun Parsons1, Minna Suvela1, Esa Jantunen2, Kimmo Porkka3,5 and Caroline A. Heckman1
1Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
2Department of Medicine, Kuopio University Hospital, Kuopio, Finland
3Department of Hematology, Helsinki University Hospital, Comprehensive Cancer Center, Helsinki, Finland
4Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain
5Hematology Research Unit, University of Helsinki, Helsinki, Finland
*These authors contributed equally to this work
Caroline A. Heckman, email: firstname.lastname@example.org
Keywords: multiple myeloma, functional screening, drug sensitivity and resistance testing, precision medicine, high-risk myeloma
Received: December 23, 2016 Accepted: April 20, 2017 Published: May 05, 2017
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. 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. 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. Based on their drug sensitivity profiles, MM patients were stratified into four distinct subgroups with varied survival outcomes. Patients with progressive disease and poor survival clustered in a drug response group exhibiting high sensitivity to signal transduction inhibitors. Del(17p) positive samples were resistant to most drugs tested with the exception of histone deacetylase and BCL2 inhibitors. Samples positive for t(4;14) were highly sensitive to immunomodulatory drugs, proteasome inhibitors and several targeted drugs. Three patients treated based on the ex vivo results showed good response to the selected treatments. Our results demonstrate that ex vivo drug testing may potentially be applied to optimize treatment selection and achieve therapeutic benefit for relapsed/refractory MM.
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