AACR 2021: Synergistic Selinexor-Based Combinations and Companion Biomarkers in Myeloma
Posted: Friday, April 30, 2021
Praneeth Reddy Sudalagunta, PhD, of H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, and colleagues explored ex vivo combinations of selinexor and other agents to determine companion biomarkers and synergistic combinations in primary multiple myeloma cells. They identified potential ex vivo synergy between selinexor and dexamethasone, pomalidomide, elotuzumab, and daratumumab, as well as identified mutations and expression signatures associated with each treatment. Their results were presented during the virtual edition of the American Association for Cancer Research (AACR) Annual Meeting 2021 (Abstract 1061).
The investigators analyzed 844 samples of CD138-positive cells from bone marrow aspirates of patients with multiple myeloma. All samples had whole-exome sequencing, RNA sequencing, and clinical data available prior to analysis. Cells were treated with a combination of selinexor and dexamethasone, pomalidomide, elotuzumab, and daratumumab or each agent alone.
This study determined that selinexor plus dexamethasone (P < 1 x 10-9), selinexor plus pomalidomide (P < .001), and selinexor plus elotuzumab (P < .01) were the most synergistic combinations. Selinexor plus daratumumab was successful in just 23 of 50 samples, and both phagocytosis and drug toxicity occurred with this combination.
Resistance to selinexor correlated with the expression of inflammatory cytokines, cell adhesion, and epithelial-mesenchymal transition pathways; MYC targets correlated with selinexor sensitivity. Expression of the Hedgehog signaling pathway seemed to be linked to resistance to selinexor plus elotuzumab, and sensitivity appeared to be associated with ribosomal subunit expression. Additionally, resistance to selinexor plus pomalidomide was reported to be related to cell adhesion and lysosome molecules, with sensitivity being linked to spliceosomes, ribosomes, and RNA polymerase.
Biomarkers for the selinexor plus daratumumab cohort were determined to be MYC targets, glycolysis, E2F, the G2M cell-cycle checkpoint, and MTORC1. Mutations relating to selinexor sensitivity were found in BCL7A—a chromatin remodeling protein—as well as CEP290, a gene encoding a microtubule binding protein, which correlated with resistance (P < .05).
Disclosure: For full disclosures of the study authors, visit abstractsonline.com.