In this issue of Blood Advances, in the article entitled “Stromal alterations in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma and multiple myeloma (MM),” Bogun et al1 performed functional and molecular analyses on bone marrow-derived mesenchymal stem cells (MSCs) isolated from healthy individuals and patients with plasma cell neoplasms at various stages of disease, including MGUS, smoldering multiple myeloma (SMM), and MM. They found that MGUS MSCs already had a high proportion of senescent cells and reduced capacity for osteogenic differentiation and hematopoietic support, which became more pronounced with disease progression. This raises the interesting question of whether (and how much) MSCs drive disease initiation.
Ongoing research is dedicated to unraveling the mechanisms underlying the evolution of the asymptomatic or premalignant stages of MM. Despite substantial progress, we are still lacking effective biomarkers that can predict the likelihood of progression. Although the focus is often on tumor cells, it is important to recognize that MM is intrinsically associated with the surrounding microenvironment. The bone marrow (BM) niche is a highly complex and dynamic microenvironment formed by a stromal compartment with numerous immune and nonimmune cell types and hematopoietic cells. MSCs represent an integral component of the BM microenvironment and are multipotent in nature, with the ability to differentiate into osteoblasts, adipocytes, and chondrocytes in response to diverse signaling cues.2 The maintenance of BM homeostasis relies on bidirectional crosstalk between hematopoietic and stromal compartments, which are hijacked by tumor cells to favor tumor cell growth, immune evasion, and drug resistance.2
In MM, MSCs have an impaired osteogenic differentiation capacity and hematopoietic support.3 Similarly, MM-specific inflammatory MSCs promote tumor survival and immune modulation.4 The dynamic interplay between MSCs and MM cells in the BM milieu induces some anomalies observed in MSCs that exert both stimulatory and protective effects on MM cells.5 These observations underscore that MSCs are not mere bystanders within the BM microenvironment but rather active players in the pathophysiology of the disease, with far-reaching implications for therapeutic strategies.
Several studies have shown that BM niche lesions can initiate hematologic malignancies, especially myeloid malignancies.6 Therefore, an intriguing and unanswered question in MM is whether a perturbed BM niche, such as altered MSCs, can predispose someone to malignant transformation and the initiation of MM or whether these changes result from remodeling by transformed plasma cells and merely contribute to the manifestation and/or progression of the disease. This study offers insights to address this question.
Through comparative transcriptomic analyses of MSC RNA-sequencing data from age-matched healthy individuals and patients with MGUS, SMM, and MM, Bogun et al found a close relationship between MGUS and SMM MSCs. However, all 3 groups shared a common genetic signature of 296 differentially expressed genes. This signature includes components of the bone morphogenic protein (BMP)/transforming growth factor (TGF)-signaling pathway. BMP/TGF-β signaling determines MSCs’ osteolineage commitment and tissue identity by regulating downstream Suppressor of Mothers against Decapentaplegic signaling and osteogenic gene expression.7 Bogun et al reported that this pathway was indeed observed in MGUS and increased with progression to SMM and MM. Overall, this signature suggests that stromal alterations are already imprinted in the MGUS stage and implies that a dysfunctional niche can initiate myeloma.
Furthermore, these transcriptomic changes are also associated with functional perturbations. They found that MSCs had a decreased ability to form fibroblast colonies and diminished osteogenic-chondrogenic differentiation capacity, along with increased cellular senescence, compared with healthy MSCs. Soluble factors released in asymptomatic and symptomatic patients with MM appear to be responsible for the functional changes observed in MSCs. Blocking TGFB1 signaling using the selective inhibitor SD208 was indeed able to reverse the aberrant phenotype restoring osteogenic differentiation capacity. This suggests a prominent role for the BMP/TGF-signaling pathway in the dysfunction of MSCs and in disease progression.
The imbalance between osteoblasts and osteoclasts contributes to defective bone remodeling, which is implicated in the early disease stages and significantly fuels tumor growth.8 The contribution of BMP/TGF signaling in this scenario is still controversial and not well defined. Therefore, targeting this pathway requires careful evaluation of both its efficacy and potential adverse effects.
In addition, MSCs exert immunomodulatory effects on both the innate and adaptive immune responses through various molecular mechanisms. The induction of an immunosuppressive microenvironment by MSCs4 may contribute to the transition from MGUS to MM. Therefore, a comprehensive assessment of the immunological dysfunction exhibited by MSCs in the context of myeloma is needed and is likely to yield valuable insights with significant clinical implications.
In conclusion, although the results presented by Bogun et al are limited by the small patient sample size, they provide valuable insights for future investigations and could serve as a guide for the use of MSCs as predictive markers for disease progression or persistence after anti-MM therapy or as potential targets for early therapeutic interventions to hinder progression to MM.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
