A Rationally Designed Novel Polymer for Safe and Synergistic Delivery of High Dose Bortezomib, Pomalidomide/Lenalidomide, and Dexamethasone for Multiple Myeloma

Abstract Introduction. Synergistic delivery of free drugs is highly challenging due to each drug's unique pharmacokinetics and biodistribution profiles. The standard of care Bortezomib, Pomalidomide/Lenalidomide, and Dexamethasone only demonstrates synergy in a specific concentration window. This specific concentration window has been proven difficult to reach using free drugs. Whereas the Bortezomib, Pomalidomide/Lenalidomide, and Dexamethasone drug combination is the standard of care for patients, an improved method to deliver drugs more specifically to the tumor in higher concentration and at their synergistic ratios would greatly improve the clinical outcome of Multiple Myeloma patients treatments. Methods and Results. We developed a novel 10 nm biodegradable bottlebrush polymer made of various PEG macromonomers conjugated to clinically used Myeloma drugs, including Bortezomib, Pomalidomide, Lenalidomide, and Dexamethasone. By combining the different macromonomer-drug conjugates together, we defined the most synergistic drug ratio by using the Chou-Talalay method in MM.1S, and KMS11 cell lines. Before evaluating the efficacy of the combination therapy in-vivo, we determined the maximum tolerated dose (MTD) for the Bortezomib bottlebrush alone by monitoring body weight loss, performing HE BMS: Consultancy; Celgene: Consultancy; Takeda: Consultancy.