Defining the significance of MGUS: the bone marrow microenvironment is compromised from an early stage in MM

Multiple myeloma (MM) remains an incurable disease despite the ability to readily detect its precursor states: monoclonal gammopathy of unknown significance (MGUS), and smoldering MM (SMM). Although early intervention is an attractive approach to treatment, premalignancy does not always lead to progression. Therefore, comprehensive molecular characterization of the tumor microenvironment and the host immune response is required to understand disease progression further.¹

In a recent study, Oksana Zavidij from the Dana-Farber Cancer Institute and colleagues aimed to elucidate the transcriptomic alterations within the immune microenvironment in disease progression, by performing single-cell RNA-seq (scRNA-seq) on patient samples across all stages of MM. This study was published in Nature Cancer.¹

Methods

• scRNA-seq was performed on bone marrow (BM) samples that were collected at the Dana-Farber Cancer Institute from patients with MGUS (n = 5 patients), low-risk SMM (n = 3), high-risk SMM (n = 8), or newly diagnosed MM (n = 7), as well as healthy donors (n = 9)
  • CD138⁻ or CD45⁺ cell fractions were isolated using magnetic-activated cell sorting and in silico cell filtering based on gene expression
  • Approximately 19,000 CD45⁺/CD138⁻ cells from the microenvironment were sequenced
  • 21 subpopulations of cells were isolated by clustering cells based on the gene expression profile
  • Using the expression of known marker genes and finding the top differentially expressed genes for each cluster, cells were classified into ten broad types, ranging from hematopoietic progenitor cells and pre-B cells to mature populations engaged in the immune response
• Sequencing data was validated by performing mass cytometry by time-of-flight (CyTOF) on BM aspirates of patients with MGUS, SMM and MM (n = 13), and healthy BM controls (n = 4)

Results¹

The tumor microenvironment changes considerably during myeloma progression, starting at the MGUS stage with increased populations of natural killer (NK) cells, T cells, and nonclassical monocytes (Figure 1). At the SMM stage, there is an early accumulation of regulatory and gamma-delta T cells, followed by loss of CD8⁺ memory populations, and an increase in interferon (IFN) signaling. At the MM stage, CD14⁺ monocytes show a loss of antigen presentation through dysregulation of major histocompatibility complex (MHC) type II genes, which leads to T cell suppression. Find a more detailed list of key findings in Table 1.

Figure 1. Adapted representation of immune cell composition changes between healthy and multiple myeloma bone marrow samples¹

Table 1. Summary of key findings from scRNA-seq and CyTOF analysis in the microenvironment of bone marrow samples from patients with MGUS, SMM, and MM¹

Conclusions and further discussion

During the 6th World Congress on Controversies in Multiple Myeloma (COMy) Meeting, Irene Ghobrial from the Dana-Farber Cancer Institute, and one of the corresponding authors of this study presented the results right before their publication.² Figure 2 represents a visual summary of the alterations observed in the immune microenvironment during progression to MM. These results are heterogeneous across patients and, despite the small sample size, could help develop future strategies on immune-based biomarkers for patient stratification and therapeutic targets to prevent progression to active disease.¹

In her talk, she highlighted the importance of developing a comprehensive analysis of MM evolution, combining the genetic and epigenetic events in the plasma cell with tumor microenvironment regulation of the disease activation through immune and non-immune cells. With that aim, her group is working on what they call “Precision Prevention”: identifying signatures of expression that include both, plasma cells and microenvironment, and could potentially lead to personalized early treatment decision.^2,3

 Figure 2. Immune microenvironment dysregulation model from healthy BM to MM; adapted from Zavidij et al.¹

It is essential to read these data in the context of an aging population with an increased cellular senescence burden. During the last COMy 2020, Gordon Cook, University of Leeds, gave us an overview of the immune status in MM and how the cellular senescence also affects the immune system.⁴

The so-called immunosenescence is a gradual deterioration of immune function brought on by the natural aging process. Changes in the number and function of hematopoietic stem cells have been described, entailing a decreased diversity of functional T cells, increasing pro-inflammatory cytokines, and leading to a chronic inflammatory state with advancing age. This state is one of the multiple reasons why in the elderly population there is an increased incidence of metabolic diseases, infections, frailty, and ultimately, cancer.⁴

Crucial advances on the evolution of MM will be achieved with the future results from the PROMISE study (NCT03689595): the first US cancer screening study for MM where investigators want to analyze samples from 50,000 high-risk individuals, defined as African American > 45 years, or people with a first-degree relative with MM. They estimate to be able to identify at least 3,000 positive cases to study thoroughly, and potentially prevent MM precursor progression to active disease.²   

In conclusion, it is possible now to confirm a multilayered immune modulation that can be present at the early stages of MM. The prognostic power of this signature needs to be further elucidated within the heterogeneity of patients with MGUS, SMM, and MM.