Ex vivo drug sensitivity screening in multiple myeloma identifies drug combinations that act synergistically

• Published in: Molecular oncology Vol. 16; no. 6; pp. 1241 - 1258
• Main Authors: Giliberto, Mariaserena, Thimiri Govinda Raj, Deepak B., Cremaschi, Andrea, Skånland, Sigrid S., Gade, Alexandra, Tjønnfjord, Geir E., Schjesvold, Fredrik, Munthe, Ludvig A., Taskén, Kjetil
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2022; John Wiley and Sons Inc; Wiley
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bone marrow; Bortezomib; Bortezomib - pharmacology; Bortezomib - therapeutic use; Cell growth; Dexamethasone; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Drug Combinations; Drug Evaluation, Preclinical; Drug Resistance; Drug screening; Drug therapy, Combination; Drugs; ex vivo drug sensitivity; gain(1q21); Humans; Kinases; Medical research; Medicine, Experimental; Multiple myeloma; Multiple Myeloma - drug therapy; Patients; patient‐derived MM cells; precision medicine; synergy; United States > US; Germany; patient-derived MM cells; precision medicine; gain(1q21); synergy; ex vivo drug sensitivity; drug combinations
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13191

The management of multiple myeloma (MM) is challenging: An assortment of available drug combinations adds complexity to treatment selection, and treatment resistance frequently develops. Given the heterogeneous nature of MM, personalized testing tools are required to identify drug sensitivities. To identify drug sensitivities in MM cells, we established a drug testing pipeline to examine ex vivo drug responses. MM cells from 44 patients were screened against 30 clinically relevant single agents and 44 double‐ and triple‐drug combinations. We observed variability in responses across samples. The presence of gain(1q21) was associated with low sensitivity to venetoclax, and decreased ex vivo responses to dexamethasone reflected the drug resistance observed in patients. Less heterogeneity and higher efficacy was detected with many combinations compared to the corresponding single agents. We identified new synergistic effects of melflufen plus panobinostat using low concentrations (0.1–10 nm and 8 nm, respectively). In agreement with clinical studies, clinically approved combinations, such as triple combination of selinexor plus bortezomib plus dexamethasone, acted synergistically, and synergies required low drug concentrations (0.1 nm bortezomib, 10 nm selinexor and 4 nm dexamethasone). In summary, our drug screening provided results within a clinically actionable 5‐day time frame and identified synergistic drug efficacies in patient‐derived MM cells that may aid future therapy choices. A drug sensitivity screening method allows assessment of cell viability effects after treatment with drugs alone and in combination in cancer cells from multiple myeloma patients. Differential drug sensitivities linked to corresponding in vivo clinical responses and synergistic drug combinations were identified. This approach may enable prediction of drug efficacies and could assist clinical decisions on future therapy choices.