Association of Immune Marker Changes With Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Landgren, Ola; Hofmann, Jonathan N.; McShane, Charlene M.; Santo, Loredana; Hultcrantz, Malin; Korde, Neha; Mailankody, Sham; Kazandjian, Dickran; Kazunori, Murata; Thoren, Katie L.; Ramanathan, Lakshmi; Doğan, Ahmet; Rustad, Even H; Lu, Sydney X.; Akhlaghi, Theresia; Kristinsson, Sigurður Y.; Björkholm, Magnus; Devlin, Sean M.; Purdue, Mark P.; Pfeiffer, Ruth M.; Turesson, Ingemar

doi:10.1001/jamaoncol.2019.1568

Cited by 63 publications

(70 citation statements)

References 23 publications

(80 reference statements)

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“…This is supported by a recent study that investigated serum immune markers in MGUS patients over time [14]. Authors found for the first time a conversion from low-to high-risk MGUS based on changes in monoclonal proteins in up to 70% of patients with high-risk disease before progression [14]. These findings and our current study support repeated risk assessments in patients with asymptomatic plasma cell diseases.…”

Section: To the Editorsupporting

confidence: 90%

“…However, risk of progression is not constant but might actually change during the course of the disease due to clonal evolution. This is supported by a recent study that investigated serum immune markers in MGUS patients over time [14]. Authors found for the first time a conversion from low-to high-risk MGUS based on changes in monoclonal proteins in up to 70% of patients with high-risk disease before progression [14].…”

Section: To the Editormentioning

confidence: 64%

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Cytogenetic subclone formation and evolution in progressive smoldering multiple myeloma

et al. 2019

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Section: To the Editorsupporting

confidence: 90%

Section: To the Editormentioning

confidence: 64%

Cytogenetic subclone formation and evolution in progressive smoldering multiple myeloma

et al. 2019

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“…Multiple myeloma (MM) is always preceded by an asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM) 10,11,12 . Historically, translocations between the IGH locus and recurrent oncogenes and trisomies of odd chromosomes (i.e., hyperdiploidy) have been considered as initiating events 13,14 .…”

mentioning

confidence: 99%

Timing the initiation of multiple myeloma

et al. 2020

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The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2 nd -3 rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the premalignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.

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“…Immunoparesis with suppression of uninvolved immunoglobulins is a well-recognized feature of multiple myeloma (MM) and has been associated with an inferior prognosis. For example, studies have linked immunoparesis with an increased risk of progression to MM from precursor states (1)(2)(3)(4)(5)(6). Similarly, several studies suggest immunoparesis in newly diagnosed patients is connected with a worse progression-free and overall survival (7,8), while immunoglobulin recovery after high-dose therapy confers a good prognosis (9,10).…”

Section: Introductionmentioning

confidence: 99%

Intravenous Immunoglobulin G Suppresses Heat Shock Protein (HSP)-70 Expression and Enhances the Activity of HSP90 and Proteasome Inhibitors

et al. 2020

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Intravenous immunoglobulin G (IVIgG) is approved for primary immunodeficiency syndromes but may induce anti-cancer effects, and while this has been attributed to its anti-inflammatory properties, IgG against specific tumor targets may play a role. We evaluated IVIgG alone, and with a Heat shock protein (HSP)-90 or proteasome inhibitor, using multiple myeloma and mantle cell lymphoma (MCL) cells in vitro, and with the proteasome inhibitor bortezomib in vivo. IVIgG inhibited the growth of all cell lines tested, induced G 1 cell cycle arrest, and suppressed pro-tumor cytokines including Interleukin (IL)-6, IL-8, and IL-10. Genomic and proteomic studies showed that IVIgG reduced tumor cell HSP70-1 levels by suppressing the ability of extracellular HSP70-1 to stimulate endogenous HSP70-1 promoter activity, and reduced extracellular vesicle uptake. Preparations of IVIgG were found to contain high titers of anti-HSP70-1 IgG, and recombinant HSP70-1 reduced the efficacy of IVIgG to suppress HSP70-1 levels. Combining IVIgG with the HSP90 inhibitor AUY922 produced superior cell growth inhibition and correlated with HSP70-1 suppression. Also, IVIgG with bortezomib or carfilzomib was superior to each single agent, and enhanced bortezomib's activity in bortezomib-resistant myeloma cells. Moreover, IVIgG reduced transfer of extracellular vesicles (EVs) to cells, and blocked transfer of bortezomib resistance through EVs. Finally, IVIgG with bortezomib were superior to the single agents in an in vivo myeloma model. These studies support the possibility that anti-HSP70-1 IgG contained in IVIgG can inhibit myeloma and MCL growth by interfering with a novel mechanism involving uptake of exogenous HSP70-1 which then induces its own promoter.

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Association of Immune Marker Changes With Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Cited by 63 publications

References 23 publications

Cytogenetic subclone formation and evolution in progressive smoldering multiple myeloma

Cytogenetic subclone formation and evolution in progressive smoldering multiple myeloma

Timing the initiation of multiple myeloma

Intravenous Immunoglobulin G Suppresses Heat Shock Protein (HSP)-70 Expression and Enhances the Activity of HSP90 and Proteasome Inhibitors

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