IDENTIFICATION OF AN EFFECTIVE RIBONUCLEOSIDE ANALOGUE AND IMMUNOMODULATORY IMIDE DRUG COMBINATION FOR MULTIPLE MYELOMA

Abstract

Multiple myeloma (MM) is the second most common haematological malignancy and the current standard treatments mainly involve combination therapies targeting multiple pathways. Despite rapid advance in therapeutics, MM remains incurable and most patients eventually relapse. To identify effective novel drug combinations against MM, we applied our quadratic phenotypic optimisation platform (QPOP), a phenotypic-analytical hybrid multidrug interrogation platform which harnesses small experimental drug response datasets to accurately predict the optimal drug combinations, towards a panel of candidates. By applying QPOP, we identified a novel drug combination, 8-chloroadenosine and pomalidomide, that works synergistically in inhibiting MM proliferation in vitro and in vivo. Further investigation revealed that this synergistic interaction is primarily mediated through c-Myc driven glutamine metabolic dependency of MM cells. Collectively, our study offers the preclinical evidence and scientific rationale for further MYC-based biomarker-driven clinical development of nucleotide metabolism/IMiD-based drug combinations against MM.