Monoclonal Gammopathies and the Bone Marrow Microenvironment: From Bench to Bedside and Then Back Again

Abstract

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called "smoldering" MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients' survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities.

Keywords: bone marrow microenvironment; monoclonal gammopathy of undetermined significance; multiple myeloma; smoldering myeloma; tumor associated immune cells.

Figure 1

Genetic alterations involved in the pathogenesis of monoclonal gammopathies. Longitudinal evolution of cPCs according to current knowledge [13]. For the malignant transformation of a post-GC B cell to an MM cell, a genetic event is necessary, initiating the transition to the phase of MGUS. Malignant plasma cell accumulates new genetic mutations over time, acquiring growth advantage in a subclone and leading to further expansion of some clones (orange/red) and to the extinction of others (white, yellow). Abbreviations: cPCs, clonal plasma cells; post-GC, post-germinal center; MM, multiple myeloma; MGUS, monoclonal gammopathy of undetermined significance.

Figure 2

The immune and non-immune compartment of the Bone Marrow Niche in the progression from MGUS and SMM to active MM [25]. Representation of the main actors of the BM niche and the modification they undergo during disease evolution [26]. MM is characterized by quantitative and functional abnormalities related to immune cells such as inverted the CD4⁺/CD8⁺ T cell and T cells/neutrophils ratio. TAMs more dramatically increase in patients with advanced MM than in those with MGUS, supporting tumor cell proliferation and drug resistance. Moreover, as MM progresses, Th1 and ILC1 decrease, while Th17 increase. Due to the inhibition of T and NK cell activation and effector functions, as well as the promotion of Treg development or their differentiation into osteoclasts, MDSCs play a role in the progression of MM by obstructing the anti-tumor immune response and causing osteolytic lesions. Dysfunctional effector functions of cytotoxic T cells (e.g., CD8⁺ T cells and γδ T cells) contribute to impaired anti-tumor immune response. Among non-immune cells, BMSCs play a critical role in MM pathogenesis by cell contact, secretion of cytokines, growth factors, and extracellular vesicles. Osteoclast precursors differentiate into bone-resorbing osteoclasts due to the interaction between RANKL, expressed by BMSCs and upregulated during MM progression, and its receptor RANK on osteoclasts. BMSCs secrete cytokines, such as IL-6, that promote the expression of survival proteins, inducing the growth and survival of MM cells. These alterations, associated with exhaustion/senescence, and the increased expression of inhibitory receptors, cooperate to tumor growth, drug resistance, and immune escape in the context of MM. Abbreviations: MM, multiple myeloma; MGUS, monoclonal gammopathy of undetermined significance; TAMs, tumor-associated macrophages; MDSC, myeloid-derived suppressor cells; Th1, T helper 1; ILC1, innate lymphoid cells 1; Th17, T helper 17; Treg, T regulatory cells; BMSCs, bone marrow stromal cells; RANK, receptor activator of nuclear factor-κB.