Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression

© 2021 by the authors.Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterations in the expression of surface molecules are also responsible for immunosuppression. In this scenario, immunotherapy, as is the case of immunotherapeutic monoclonal antibodies (mAbs), aims to boost the immune system against tumor cells. In fact, mAbs exert part of their cytotoxic effects through different cellular and soluble immune components and, therefore, patients’ immunosuppressive status could reduce their efficacy. Here, we will expose the alterations observed in symptomatic MM, as compared to its precursor stages and healthy subjects, in the main immune populations, especially the inhibition of effector cells and the activation of immunosuppressive populations. Additionally, we will revise the mechanisms responsible for all these alterations, including the interplay between MM cells and immune cells and the interactions among immune cells themselves. We will also summarize the main mechanisms of action of the four mAbs approved so far for the treatment of MM. Finally, we will discuss the potential immune-stimulating effects of non-immunotherapeutic drugs, which could enhance the efficacy of immunotherapeutic treatments.A.D.-T was supported by a fellowship from the Regional Education Council of Castilla y Léon co-financed by the European Social Fund; T.P. is supported by a grant from Asociación Española Contra el Cáncer (AECC) (INVES18043PAÍN). This study was funded by the Instituto de Salud Carlos III and co-financed by FEDER (PI18/01600 and PI19/01384); by the AECC (Proyectos Estratégicos: PROYE20047GUTI); by Fundación Ramón Areces (FRA16/003); and by the Gerencia Regional de Salud, Junta de Castilla y León grants (GRS 2066/A/19)