Treatment optimization for Multiple Myeloma: schedule-dependent synergistic cytotoxicity of pomalidomide and carfilzomib in an in vitro and ex-vivo model

Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), significantly enhanced the depth of response and prolonged the survival of Multiple Myeloma (MM) patients, although not all patients respond favourably to treatment. Optimization of treatment schedules and dosages of IMiDs and PIs might lead to improved treatment efficacy. In this study we aimed at exploring the optimal schedule of IMiDs and PIs in both in vitro models, including bone marrow (BM) microenvironment simulation, and an ex-vivo model using patient-derived BM samples. MM cells were exposed to IMiDs and PIs either simultaneously or sequentially. Using the median effect method of Chou Talalay, we evaluated the combination indices for simultaneous and sequential treatment schedules. We demonstrated schedule-dependent synergistic cytotoxicity for the combination of IMiDs and PIs and a maximal apoptosis was observed in IMiDs pre-exposure schedule. The superior activity of this schedule was maintained even in BM microenvironment models, and was further confirmed using patient-derived samples. Our data overall suggest that the administration of IMiDs before PIs can improve treatment efficacy. Clinical trials are needed to investigate the most effective schedule, which could be to start the administration of IMiDs before PIs to increase cells killing