Abstract
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.
Highlights
Immunomodulatory drugs and proteasome inhibitors combined with alkylating agents and steroids have improved the outcome of MM patients [1]
Myeloma patients can be stratified based on distinct drug sensitivity profiles To assess drug efficacy and compare the drug response data across patient samples we used a quantitative drug sensitivity score (DSS)
In this study we showed that this variation is observed through comprehensive drug sensitivity profiling and patients could be classified into different chemosensitive groups based on their ex vivo drug response profiles
Summary
Immunomodulatory drugs and proteasome inhibitors combined with alkylating agents and steroids have improved the outcome of MM patients [1]. 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 [2]. Patients may exhibit both de novo or acquired resistance to current therapies by mechanisms (i.e. clonal heterogeneity and evolution) that are still poorly understood [3]. 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
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