Role of the Bone Marrow Milieu in Multiple Myeloma Progression and Therapeutic Resistance

Ho, Matthew; Goh, Chia Yin; Patel, Ashish; Staunton, Susannah; O'Connor, Ronan; Godeau, Marc; Bianchi, Giada

doi:10.1016/j.clml.2020.05.026

Cited by 32 publications

(30 citation statements)

References 250 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To better understand the basic mechanisms of myeloma progression in patients with SMM, most of the genetic studies have focused on investigating CD138 + PC characteristics such as chromosomal aberrations (14), gene expression profiling (15), whole-exome sequencing of clonal PC (16)(17)(18). However, PC extrinsic factors in the BM microenvironment may also play a crucial role in myeloma progression (8). In this regard, several studies have reported impairment of immune cell functions in symptomatic MM compared to MGUS (19,20).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease

et al. 2021

View full text Add to dashboard Cite

BackgroundWe previously reported algorithms based on clinical parameters and plasma cell characteristics to identify patients with smoldering multiple myeloma (SMM) with higher risk of progressing who could benefit from early treatment. In this work, we analyzed differences in the immune bone marrow (BM) microenvironment in SMM to better understand the role of immune surveillance in disease progression and to identify immune biomarkers associated to higher risk of progression.MethodsGene expression analysis of BM cells from 28 patients with SMM, 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and 22 patients with symptomatic MM was performed by using Nanostring Technology.ResultsBM cells in SMM compared to both MGUS and symptomatic MM showed upregulation of genes encoding for key molecules in cytotoxicity. However, some of these cytotoxic molecules positively correlated with inhibitory immune checkpoints, which may impair the effector function of BM cytotoxic cells. Analysis of 28 patients with SMM revealed 4 distinct clusters based on immune composition and activation markers. Patients in cluster 2 showed a significant increase in expression of cytotoxic molecules but also inhibitory immune checkpoints compared to cluster 3, suggesting the presence of cytotoxic cells with an exhausted phenotype. Accordingly, patients in cluster 3 had a significantly longer progression free survival. Finally, individual gene expression analysis showed that higher expression of TNF superfamily members (TNF, TNFAIP3, TNFRSF14) was associated with shorter progression free survival.ConclusionsOur results suggest that exhausted cytotoxic cells are associated to high-risk patients with SMM. Biomarkers overexpressed in patients with this immune gene profile in combination with clinical parameters and PC characterization may be useful to identify SMM patients with higher risk of progression.

show abstract

Section: Discussionmentioning

confidence: 99%

Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Hence, the role of B cells in modulating the immune response in the setting of both solid tumors and lymphoid malignancies including MM is less well understood. Over the past decade however, emerging evidence demonstrates that Bregs are crucial in the maintenance of immune tolerance and the suppression of inflammation within BM milieu [14,[35][36][37]. However, the role that CD19+CD24hiCD38hi Bregs play in MM is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Real-world data combined with studies on Regulatory B Cells for newly diagnosed Multiple Myeloma from a tertiary referral Hospital in South-Western China

et al. 2021

Self Cite

View full text Add to dashboard Cite

Multiple myeloma (MM) is a heterogeneous disease that remains incurable with significant interpatient variability in outcomes. Regulatory B cells (Bregs) were observed to be involved into specific defects in MM. Here, we provide our risk-adapted approach to newly diagnosed MM (NDMM), combining with the fundamental dysfunction of Bregs. We reported one hundred consecutive patients with NDMM from SouthWestern China, primarily treated with bortezomib plus dexamethasone with or without a 3 rd agent, were enrolled from 2017. Bone marrow aspirates were obtained and flow cytometry (FCM) was used to quantify the percentage of Bregs from the bone marrow. The correlation between Bregs and clinical characters were further analyzed. This study found using bortezomib plus dexamethasone as backbone showed promising efficacy with acceptable tolerability in NDMM. The relatively compromised progression free survival (PFS) points to the essential synergy of bortezomib and lenalidomide here. This study also found that altered proportions of Bregs were closely correlated with treatment efficacy and prognosis in MM. Further understanding of Bregs biology might provide new opportunities to develop immunotherapy, which could prove beneficial in treating MM.

show abstract

“…However, a state of dormancy next occurs in which a functional immune system maintains the survival of tumor cells under constant immune pressure (equilibrium). In this phase, resistant tumor cells acquire genetic and epigenetic alterations that eventually lead to escape the immune recognition, allowing for uncontrolled proliferation and clinical progression (escape) ( 19 – 21 ). A potential application of this model in MM identifies in the MGUS/SMM precursor stages a phase of immune equilibrium ( 22 ).…”

Section: Immune Dysfunction and Tumor Immune Evasion Mechanismsmentioning

confidence: 99%

“…Its mechanisms of actions include CDC, ADCC, ADCP, and direct cytotoxicity without crosslinking of the Fc receptors of the antibody ( 48 , 49 ). Moreover, both Daratumumab and Isatuximab may induce the depletion of CD38+ immune suppressor cells such as Tregs and Bregs ( 21 , 50 , 51 ). In the phase III ICARIA-MM study, isatuximab combined with PomDex showed superiority in terms of ORR (60.4 vs 35.3%) and median PFS (11.5 months vs 6.5 months) ( 52 ).…”

Section: Immunotherapy In MMmentioning

confidence: 99%

Harnessing the Immune System Against Multiple Myeloma: Challenges and Opportunities

et al. 2021

View full text Add to dashboard Cite

Multiple myeloma (MM) is an incurable malignancy of plasma cells that grow within a permissive bone marrow microenvironment (BMM). The bone marrow milieu supports the malignant transformation both by promoting uncontrolled proliferation and resistance to cell death in MM cells, and by hampering the immune response against the tumor clone. Hence, it is expected that restoring host anti-MM immunity may provide therapeutic benefit for MM patients. Already several immunotherapeutic approaches have shown promising results in the clinical setting. In this review, we outline recent findings demonstrating the potential advantages of targeting the immunosuppressive bone marrow niche to restore effective anti-MM immunity. We discuss different approaches aiming to boost the effector function of T cells and/or exploit innate or adaptive immunity, and highlight novel therapeutic opportunities to increase the immunogenicity of the MM clone. We also discuss the main challenges that hamper the efficacy of immune-based approaches, including intrinsic resistance of MM cells to activated immune-effectors, as well as the protective role of the immune-suppressive and inflammatory bone marrow milieu. Targeting mechanisms to convert the immunologically “cold” to “hot” MM BMM may induce durable immune responses, which in turn may result in long-lasting clinical benefit, even in patient subgroups with high-risk features and poor survival.

show abstract

Role of the Bone Marrow Milieu in Multiple Myeloma Progression and Therapeutic Resistance

Cited by 32 publications

References 250 publications

Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease

Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease

Real-world data combined with studies on Regulatory B Cells for newly diagnosed Multiple Myeloma from a tertiary referral Hospital in South-Western China

Harnessing the Immune System Against Multiple Myeloma: Challenges and Opportunities

Contact Info

Product

Resources

About