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

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Diaz-Tejedor, A; Lorenzo-Mohamed, M; Puig, N; Garcia-Sanz, R; Mateos, MV; Garayoa, M; Paino, T
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Simple Summary A common characteristic of multiple myeloma (MM) is the dysfunction of patients' immune system, a condition termed immunosuppression. This state is mainly due to alterations in the number and functionality of the principal immune populations. In this setting, immunotherapy has acquired high relevance in the last years and the investigation of agents that boost the immune system represent a field of interest.

In the present review, we will summarize the main cellular and molecular alterations observed in MM patients' immune system. Furthermore, we will describe the mechanisms of action of the four immunotherapeutic drugs approved so far for the treatment of MM, which are part of the group of monoclonal antibodies (mAbs).

Finally, the immune-stimulating effects of several therapeutic agents are described due to their potential role in reversing immunosuppression and, therefore, in favoring the efficacy of immunotherapy drugs, such as mAbs, as part of future pharmacological combinations. 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.