The course of
multiple myeloma (MM) from initial diagnosis to a relapsed/refractory state is characterized by acquisition of drug resistance as well as progressive immunologic dysfunction. Despite this, however, a number of novel
therapies that work in part or solely via immune stimulation are in development for MM, with promising early clinical results. Several new whole-cell or multiepitope
vaccine approaches are demonstrating immunologic efficacy in smoldering MM or as posttherapy consolidation, with trials ongoing to see whether this translates into delayed progression or elimination of
minimal residual disease. Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibition in combination with
immunomodulatory drugs demonstrated excessive toxicity in randomized trials; however,
antibodies targeting PD-1/PD-L1 and other checkpoint molecules continue to be explored in combination with
tumor-targeted
antibodies and other T cell-directed
therapies.
B-cell maturation antigen (
BCMA) has emerged as the next big
antigen target, with multiple
BCMA-specific
antibody-drug conjugates (ADCs) and T cell-directed
bispecific antibodies/bispecific therapeutic engagers (
BiTEs) entering the clinic. In initial trials, the ADC
GSK2857916 and the
BiTE AMG 420 have demonstrated high response rates in relapsed/refractory patients, with depth and durability of responses that may end up rivaling
chimeric antigen receptor T-cell
therapies. These agents have unique toxicities that require close monitoring, but they are moving forward in larger registration studies and in combination with standard MM agents. Additional ADCs and
bispecific antibodies targeting
BCMA and other
surface antigens (eg, CD38, CD46, CD48, FcRH5, and
G protein-coupled receptor, class C group 5 member D) are moving forward in phase 1 trials and may provide even more options for MM patients.