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Multiple myeloma (MM) is a plasma-cell malignancy which remains incurable despite the recent emergence of multiple novel agents. Importantly, recent genetic and molecular analyses have revealed the complexity and heterogeneity of this disease, highlighting the need for therapeutic strategies to eliminate all clones. Moreover, the bone marrow microenvironment, including stromal cells and immune cells, plays a central role in MM pathogenesis, promoting tumor cell growth, survival, and drug resistance. New classes of agents including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors have shown remarkable efficacy; however, novel therapeutic approaches are still urgently needed to further improve patient outcomes. In this review, we discuss the recent advances and future strategies to ultimately develop MM therapies with curative potential. [ABSTRACT FROM AUTHOR]

Carfilzomib, a recently FDA-approved proteasome inhibitor, has remarkable anti-myeloma (MM) activity. However, its effectiveness is limited by associated severe side-effects, short circulation half-life, and limited solubility. Here, we report the engineering of liposomal carfilzomib nanoparticles to overcome these problems and enhance the therapeutic efficacy of carfilzomib by increasing tumoral drug accumulation while decreasing systemic toxicity. In our design, carfilzomib was loaded into the bilayer of liposomes to yield stable and reproducible liposomal nanoparticles. Liposomal carfilzomib nanoparticles were efficiently taken up by MM cells, demonstrated proteasome inhibition, induced apoptosis, and exhibited enhanced cytotoxicity against MM cells. In vivo , liposomal carfilzomib demonstrated significant tumor growth inhibition and dramatically reduced overall systemic toxicity compared to free carfilzomib. Finally, liposomal carfilzomib demonstrated enhanced synergy in combination with doxorubicin. Taken together, this study establishes the successful synthesis of liposomal carfilzomib nanoparticles that demonstrates improved therapeutic index and the potential to improve patient outcome in MM. [ABSTRACT FROM AUTHOR]