Recent Advances in the Applications of Small Molecules in the Treatment of Multiple Myeloma

Abstract

Therapy for multiple myeloma (MM), a hematologic neoplasm of plasma cells, has undergone remarkable changes over the past 25 years. Small molecules (molecular weight of less than one kDa), together with newer immunotherapies that include monoclonal antibodies, antibody-drug conjugates, and most recently, chimeric antigen receptor (CAR) T-cells, have combined to double the disease's five-year survival rate to over 50% during the past few decades. Despite these advances, the disease is still considered incurable, and its treatment continues to pose substantial challenges, since therapeutic refractoriness and patient relapse are exceedingly common. This review focuses on the current pipeline, along with the contemporary roles and future prospects for small molecules in MM therapy. While small molecules offer prospective benefits in terms of oral bioavailability, cellular penetration, simplicity of preparation, and improved cost-benefit considerations, they also pose problems of toxicity due to off-target effects. Highlighted in the discussion are recent developments in the applications of alkylating agents, immunomodulators, proteasome inhibitors, apoptosis inducers, kinesin spindle protein inhibitors, blockers of nuclear transport, and drugs that affect various kinases involved in intracellular signaling pathways. Molecular and cellular targets are described for each class of agents in relation to their roles as drivers of MM.

Keywords: cereblon E3 ligase modulators; melflufen; myeloma; selinexor; venetoclax.

Figure 1

Structures of Alkylating Agents with Activity Against Multiple Myeloma.

Figure 2

Structures of Immunomodulators (Cereblon E3 Ligase Modulators) With Activity Against MM.

Figure 3

Structures of Proteasome Inhibitors Active Against MM.

Figure 4

Structures of Histone Deacetylase Inhibitors Active Against MM.

Figure 5

Chemical Structures of Apoptosis Inducers Active Against Myeloma.

Figure 6

Structural Formulas of Additional Small Molecules with Activity Against MM.

Figure 7

Bruton’s tyrosine kinase inhibitors with anti-myeloma activity.