Promises and pitfalls in the use of PD-1/PD-L1 inhibitors in multiple myeloma

In the biology of multiple myeloma (MM), immune dysregulation has emerged as a critical component for novel therapeutic strategies. This dysfunction is due to a reduced antigen presentation, a reduced effector cell ability and a loss of reactive T cells against myeloma, together with a bone marrow microenvironment that favors immune escape. The Programmed Death-1 (PD-1) pathway is associated with the regulation of T cell activation and with the apoptotic pathways of effector memory T cells. Specifically, the binding with PD-1 ligand (PD-L1) on the surface of tumor plasma cells down-regulates T cell-proliferation, thus contributing to the immune escape of tumor cells. In relapsed and/or refractory MM (RRMM) patients, PD-1/PD-L1 blockade was analyzed by using nivolumab, pembrolizumab, and durvalumab. Outcomes with single agents were unsatisfactory, whereas combination strategies with backbone immunomodulatory drugs (IMiDs) suggested a synergistic action in such a complex immunological landscape, even in patients previously refractory to these drugs. Nevertheless, these combinations were also associated with an increased incidence of adverse events. This review aims to analyze the available preclinical and clinical data on the role of PD-1/PD-L1 inhibitors in MM therapy, focusing on available preliminary efficacy and safety data and offering insights for future investigation.