The Multiple Myeloma Drug Pipeline-2018: A Review of Small Molecules and Their Therapeutic Targets

Abstract

Treatment of multiple myeloma (MM), a neoplasm of plasma cells, formerly dependent on alkylating drugs, corticosteroids, and autologous stem cell transplantation, has changed dramatically in the past 20 years because 3 new classes of small molecule drugs (arbitrarily defined as having a molecular weight of < 900 kDa)-immunomodulators, proteasome inhibitors, and histone deacetylase blockers-have been introduced for the disease. Therapeutic options for MM expanded further in 2015 when 2 new monoclonal antibodies (daratumumab and elotuzumab) were approved by the Food and Drug Administration for MM. Although MM remains incurable, the cumulative effect of these advances has resulted in a near-doubling of the 5-year survival rate since the late 1980s. Despite these advances, therapy for MM continues to pose substantial challenges because resistance to therapy frequently develops, and relapse and recurrence are all too common. The present review focused on the pipeline for new small molecules in various stages of development and their associated cellular targets. In addition to newer versions of alkylators, immunomodulators, proteasome inhibitors, and histone deacetylase inhibitors, the present review considered the prospects for adding new classes of small molecules to the MM armamentarium, which offer the potential for oral efficacy, relative simplicity of preparation, and prospects for improvement in the cost-to-benefit ratio. Included are agents that affect myeloma epigenetics and the ubiquitination-proteasome system and the unfolded protein response, apoptotic mechanisms, chromosomal abnormalities, nuclear protein transport, and various kinases involved in cellular signaling pathways.

Keywords: Bcl-2 inhibitors; Epigenetics; Immunomodulators; Nuclear export inhibitors; Ubiquitination–proteasome system.