Drug Sensitivity Screening on Multiple Myeloma for Precision Cancer Therapy

Introduction Multiple Myeloma (MM) is considered incurable and MM patients eventually relapse despite use of many promising approved drugs in standard-of-care treatment. It has been challenging to design precision medicine protocols to tailor personalized treatment for MM patients that relapse despite availability of novel drugs. In-vitro drug screening has been hampered by lack of in-vitro culture protocols that mimic tumor microenvironment and that accommodates for low cell number. Here, we report our novel MM proliferation protocol along with an in-vitro functional screening platform, that allow us to assess drug sensitivity on MM patient samples with a customized panel of 30 myeloma drugs. Using our novel drug sensitivity screening platform, we aim to identify efficient drugs for individual patients with progressive disease and select the best treatment option. Methods Previously, we have established culture settings that mimic the tumor microenvironment for MM (Wang D. et al Leukemia 2017). Here, we implemented a novel protocol that allowed primary MM cells to proliferate in a 384 well-format. Stimulated CD138+ MM cells were tested against a customized library of 30 clinically approved drugs including proteasome inhibitors (PI) and drugs that are in clinical trials. CD138+ MM cells were cultured in 384-well format in the presence of individual drugs in a concentration range over 6 logs for 72 hours (3 days). To define drugs that inhibit malignant plasma cell growth, we used the cell-based assays CellTiter-Glo® luminescent cell viability assay and CellTox™ green cytotoxicity assay as readouts by assessing drug sensitivity at day 3. We performed MM drug screening on 18 patient samples and 6 healthy B-cell (BC) control samples. We performed drug screening on myeloma cells SK-MM2 (patient derived cell line) for 527 drugs at 5 concentrations. We are currently performing drug screening on 11 MM cell lines which represents diverse cancer stage. For each patient sample, a Drug Sensitivity Score (DSS) was calculated for every drug using the IC50 value, slope and the area under the curve (AUC). Next, DSS values for the full MM patient cohort were compared to those of healthy controls to generate a selective DSS (sDSS) for each drug (sDSS = DSSpatient - average DSShealthy). Drugs which had sDSS >5 were considered clearly more effective for patient samples in the in vitro test. MM patient samples were assessed for sDSS score using our screening data and we ranked