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.

• Keywords
• PD-1, PD-L1, durvalumab, multiple myeloma, nivolumab, pembrolizumab, safety, toxicity,
• MeSH
• Programmed Cell Death 1 Receptor antagonists & inhibitors   MeSH
• Molecular Targeted Therapy MeSH
• Immunomodulation drug effects   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Multiple Myeloma drug therapy   immunology   metabolism   pathology   MeSH
• Drug Evaluation, Preclinical MeSH
• Antineoplastic Agents, Immunological pharmacology   therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Signal Transduction drug effects   MeSH
• T-Lymphocytes drug effects   immunology   metabolism   MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Programmed Cell Death 1 Receptor MeSH
• PDCD1 protein, human MeSH Browser
• Antineoplastic Agents, Immunological MeSH

The introduction of PD-1/PD-L1 pathway inhibitors has marked a significant milestone in the treatment of various types of solid tumors. The current situation in multiple myeloma (MM) is rather unclear, as distinct research groups have reported discordant results. This discrepancy dominantly concerns the expression of PD-1/PD-L1 molecules as well as the identification of the responsible immune effector cell population. The results of monotherapy with PD-1/PD-L1 inhibitors have been unsatisfactory in MM, suggesting that a combination approach is needed. The most logical partners are immunomodulatory agents as they possess many synergistic effects. We are also proposing other rational and promising combinations (e.g., daratumumab, ibrutinib, anti-CD137) that warrant further investigation.

• Keywords
• Daratumumab, PD-1, PD-L1, durvalumab, ibrutinib, irradiation, multiple myeloma, nivolumab, pembrolizumab, pidilizumab,
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH