Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bortezomib and dexamethasone

Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests a need for new molecules and combinations that may further inhibit important survival pathways for these tumour cells. In this context, zalypsis is a novel compound derived from marine organisms with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction, and has been already tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with an acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations, not only in vitro, but also ex vivo and especially in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients.