The Route of the Malignant Plasma Cell in Its Survival Niche: Exploring {\textquotedblleft}Multiple Myelomas{\textquotedblright}

Simple Summary Multiple Myeloma is a hematological neoplasia originating from malignant plasma cells in the bone marrow. Despite improved therapies, this cancer is still considered incurable due to the occurrence of relapse and the development of drug resistance over time. Apart from cell-intrinsic oncogenic features such as genetic alterations and clonal evolution that promote tumor growth and survival, increasing evidence demonstrates that the bone marrow microenvironment plays a pivotal role in disease relapse and immune evasion by providing protected bone marrow niches in which dormant myeloma cells are able to reside and survive. This review summarizes the ways of the bone marrow micromilieu to nurture and interact with the malignant plasma cells, and provides insights into the vicious cycles arising from the interplay between myeloma cells and their surrounding tumoral stroma. Knowledge about these mechanisms and how to disrupt them may provide novel approaches to targeting and tackling multiple myeloma. Growing evidence points to multiple myeloma (MM) and its stromal microenvironment using several mechanisms to subvert effective immune and anti-tumor responses. Recent advances have uncovered the tumor-stromal cell influence in regulating the immune-microenvironment and have envisioned targeting these suppressive pathways to improve therapeutic outcomes. Nevertheless, some subgroups of patients include those with particularly unfavorable prognoses. Biological stratification can be used to categorize patient-, disease- or therapy-related factors, or alternatively, these biological determinants can be included in a dynamic model that customizes a given treatment to a specific patient. Genetic heterogeneity and current knowledge enforce a systematic and comprehensive bench-to-bedside approach. Given the increasing role of cancer stem cells (CSCs) in better characterizing the pathogenesis of solid and hematological malignancies, disease relapse, and drug resistance, identifying and describing CSCs is of paramount importance in the management of MM. Even though the function of CSCs is well-known in other cancer types, their role in MM remains elusive. With this review, we aim to provide an update on MM homing and resilience in the bone marrow micro milieu. These data are particularly interesting for clinicians facing unmet medical needs while designing novel treatment approaches for MM.