Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and suppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations.

Multiple myeloma (MM) is a challenging, progressive, and highly heterogeneous hematological malignancy. MM is characterized by multifocal proliferation of neoplastic plasma cells in the bone marrow (BM) and sometimes in extramedullary organs. Despite the availability of novel drugs and the longer median overall survival, some patients survive more than 10 years while others die rapidly. This heterogeneity is mainly driven by biological characteristics of MM cells, including genetic abnormalities. Disease progressions are mainly due to the inability of drugs to overcome refractory disease and inevitable drug-resistant relapse. In clinical practice, a bone marrow biopsy, mostly performed in one site, is still used to access the genetics of MM. However, BM biopsy use is limited by its invasive nature and by often not accurately reflecting the mutational profile of MM. Recent insights into the genetic landscape of MM provide a valuable opportunity to implement precision medicine approaches aiming to enable better patient profiling and selection of targeted therapies. In this review, we explore the use of the emerging field of liquid biopsies in myeloma patients considering current unmet medical needs, such as assessing the dynamic mutational landscape of myeloma, early predictors of treatment response, and a less invasive response monitoring.

Despite the improvement of patient’s outcome obtained by the current use of immunomodulatory drugs, proteasome inhibitors or anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. More recently, the testing in clinical trials of novel drugs such as anti-BCMA CAR-T cells, antibody–drug conjugates or bispecific antibodies broadened the possibility of improving patients’ survival. However, thus far, these treatment strategies have not been able to steadily eliminate all malignant cells, and the aim has been to induce a long-term complete response with minimal residual disease (MRD)-negative status. In this sense, approaches that target not only myeloma cells but also the surrounding microenvironment are promising strategies to achieve a sustained MRD negativity with prolonged survival. This review provides an overview of current and future strategies used for immunomodulation of MM focusing on the impact on bone marrow (BM) immunome.