ATRA

This is a Phase IB/II trial that will investigate the safety, tolerability and efficacy of combination therapy using All-Trans Retinoic Acid (ATRA) with Carfilzomib based therapies in plasma cell myeloma also commonly referred as Multiple Myeloma (MM), in patients considered refractory to proteasome inhibitors (PIs). MM is an incurable clonal plasma cell disorder that comprises 10% of all hematologic malignancies. Over the past 30 years the global prevalence of MM has risen to 126%, with 85% of diagnoses occurring in patients \>55 years of age. In the past 15 years, survival has improved considerably, which is attributed to the development of multiple different classes of medications, including PIs. PIs are the foundation of many MM treatments in both transplant eligible and ineligible patients for the past 2 decades. While PIs have improved both progression free survival (PFS) and overall survival (OS), many patients eventually develop disease progression arising from resistance to therapies. As a result, there is an unmet need to overcome resistance and find ways to enhance MM sensitivity to PI toxicity. Carfilzomib, a modified peptide epoxyketone that selectively targets intracellular proteasome enzymes, is approved in combination with dexamethasone in patients that have received ≥1 line of therapy or in combination. There are few studies assessing ways to enhance carfilzomib-mediated MM toxicity. All-Trans Retinoic Acid (ATRA) is an oxidative metabolite of retinol (vitamin A) and plays an important role in the regulation of cellular proliferation and differentiation. In a recent pre-clinical study, ATRA was found to enhance sensitivity of carfilzomib-mediated apoptosis in vitro via an IFN-β response pathway. In the clinical setting, ATRA is a well-tolerated drug that has shown little change in the rate of adverse events in early clinical trials with MM. We hypothesize that ATRA enhances sensitivity of multiple myeloma to carfilzomib therapy.