Identification of precision treatment strategies for relapsed/refractory multiple myeloma by functional drug sensitivity testing

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.

The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains

“…Selected cells ( n ≥ 100) were used for interphase fluorescence in situ hybridization (FISH) following the guidelines of the European Myeloma Network 2012 [ 68 ]. The probes used for FISH were described previously [ 69 ].…”

Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types

“…The gating strategy and list of compounds are provided in Supplementary Figure S1 and S3. CellTiter-Glo® luminescent viability assay was used based on a previously described method 9, 16,17 .…”

Image-based ex-vivo drug screening for patients with aggressive haematological malignancies: interim results from a single-arm, open-label, pilot study

“…Therefore, dynamic approaches that measure drug responses in cancer cells derived from patient biopsies might complement such static genetic measurements. For example, ex-vivo chemosensitivity tests have been done in samples from patients with chronic or acute leukaemia and multiple myeloma, 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 in breast cancer-derived stable cell lines, 22 in patient-derived xenografts in mice, 23 , 24 and in gut stem-cell-derived organoids. 25 , 26 These pioneering functional assays have provided proof of concept by showing that ex-vivo responses might match clinical response; however, these studies have not been integrated into clinical routine because of practical limitations and scarce proof of clinical benefit.…”