Update on PD-1/PD-L1 Inhibitors in Multiple Myeloma
Tomas Jelinek, Bruno Paiva, Roman Hajek
The treatment of cancer, especially of various types of solid tumors, has been revolutionized by the blockade of the PD-1/PD-L1 pathway by immune checkpoint inhibitors. Their success amongst hematologic malignancies, however, has been limited so far to the treatment of classic Hodgkin's lymphoma, which portrays a typical overexpression of PD-1 ligands (PD-L1, PD-L2) as a consequence of changes in chromosome 9p24.1.
Their current application in multiple myeloma (MM) is rather uncertain, as discordant results have been reported by distinct research groups concerning especially the expression of PD-1/PD-L1 molecules on malignant plasma cells or on the responsible immune effector cell populations, respectively. In MM it seems that an approach based on combination treatment might be appropriate as unsatisfactory results have been yielded by monotherapy with PD-1/PD-L1 inhibitors.
Immunomodulatory drugs, which are the current cornerstone of MM treatment, are the most logical partners as they possess many possibly synergistic effects. Nevertheless, the initially optimistic results have become disappointing due to the excessive and unpredictable toxicity of the combination of pembrolizumab with lenalidomide or pomalidomide. The FDA has suspended or put on hold several phase 3 trials in relapsed as well as in newly diagnosed myeloma patients.
There are also other potentially synergistic and promising combinations, such as the anti-CD38 monoclonal antibody daratumumab, irradiation, etc. Not only the effective partner but also the correct timing of the initiation of the PD-1/PD-L1 inhibitors treatment seems to be of utmost importance. These strategies are currently being examined in various stages of myeloma such as during consolidation post autologous stem cell transplantation, targeting minimal residual disease or even in high risk smoldering myeloma.