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The Asymptomatic Version of Myeloma: MGUS and Smoldering Myeloma
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The Asymptomatic Version of Myeloma: MGUS and Smoldering Myeloma

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 47513

Special Issue Editor

Prof. Dr. María Victoria Mateos

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Guest Editor
Instituto de Investigación Biomédica de Salamanca (IBSAL), Cancer Research Center-IBMCC (USAL-CSIC), CIBERONC, University Hospital of Salamanca, 37007 Salamanca, Spain
Interests: myeloma; asymptomatic myeloma; minimal residual disease; early treatment; novel drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

All cases of multiple myeloma (MM) are preceded by precursor states termed monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). MGUS is present in approximately 3%­–4% of the general population over the age of 50, and it is associated with a risk of progression to MM or related disorder at a rate of 1% per year. SMM accounts for approximately 10% of all MMs, and the risk or progression to MM is not uniform, ranging from 1% to 10% per year. Both plasma cell disorders are asymptomatic with absence of myeloma-related events, and the cutoff of serum M spike is 3 g/dl or bone marrow plasma cell infiltration of 10% for distinguishing both entities. These criteria are useful in clinical practice, and in the SMM field, some models have emerged to identify different risk subgroups of patients that lead to the proposal of clinical trials in SMM patients at high risk of progression to MM with the attempt of delaying the MM development. Positive results have so far been reported which resulted, in 2014, in the update of the diagnostic criteria for MM, including some SMM patients with an imminent risk of progression to MM identified through the presence of some biomarkers. However, in spite of these major advances, our understanding of the pathogenesis of MGUS and SMM and how they can evolve to MM remains incomplete, and emerging insights in the biology of these preneoplastic lesions and their transition to clinical malignancy are crucial to understand the biology of the disease that can potentially contribute to make clinical decisions about the optimal approach for the management of these premalignant diseases.

This Special Issue aims to deepen the mechanisms involved in the transition from MGUS and SMM to MM and how they can be incorporated to the clinical models and how this approach might impact on the management of MGUS and SMM and which patients would be candidates to preventive versus curative approaches.

Dr. María Victoria Mateos
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Monoclonal gammopathy
  • Smoldering myeloma
  • Prognostic features
  • Genetic abnormalities
  • Microenvironment
  • Immune system

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Published Papers (7 papers)

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Research

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12 pages, 7219 KiB  
Article
Application of Next-Generation Sequencing for the Genomic Characterization of Patients with Smoldering Myeloma
by Martina Manzoni, Valentina Marchica, Paola Storti, Bachisio Ziccheddu, Gabriella Sammarelli, Giannalisa Todaro, Francesca Pelizzoni, Simone Salerio, Laura Notarfranchi, Alessandra Pompa, Luca Baldini, Niccolò Bolli, Antonino Neri, Nicola Giuliani and Marta Lionetti
Cancers 2020, 12(5), 1332; https://doi.org/10.3390/cancers12051332 - 23 May 2020
Cited by 8 | Viewed by 3125
Abstract
Genomic analysis could contribute to a better understanding of the biological determinants of the evolution of multiple myeloma (MM) precursor disease and an improved definition of high-risk patients. To assess the feasibility and value of next-generation sequencing approaches in an asymptomatic setting, we [...] Read more.
Genomic analysis could contribute to a better understanding of the biological determinants of the evolution of multiple myeloma (MM) precursor disease and an improved definition of high-risk patients. To assess the feasibility and value of next-generation sequencing approaches in an asymptomatic setting, we performed a targeted gene mutation analysis and a genome-wide assessment of copy number alterations (CNAs) by ultra-low-pass whole genome sequencing (ULP-WGS) in six patients with monoclonal gammopathy of undetermined significance and 25 patients with smoldering MM (SMM). Our comprehensive genomic characterization highlighted heterogeneous but substantial values of the tumor fraction, especially in SMM; a rather high degree of genomic complexity, in terms of both mutations and CNAs, and inter-patient variability; a higher incidence of gene mutations and CNAs in SMM, confirming ongoing evolution; intraclonal heterogeneity; and instances of convergent evolution. ULP-WGS of these patients proved effective in revealing the marked genome-wide level of their CNAs, most of which are not routinely investigated. Finally, the analysis of our small SMM cohort suggested that chr(8p) deletions, the DNA tumor fraction, and the number of alterations may have clinical relevance in the progression to overt MM. Although validation in larger series is mandatory, these findings highlight the promising impact of genomic approaches in the clinical management of SMM. Full article
(This article belongs to the Special Issue The Asymptomatic Version of Myeloma: MGUS and Smoldering Myeloma)
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18 pages, 4452 KiB  
Article
Characteristics of MGUS and Multiple Myeloma According to the Target of Monoclonal Immunoglobulins, Glucosylsphingosine, or Epstein-Barr Virus EBNA-1
by Adrien Bosseboeuf, Nicolas Mennesson, Sophie Allain-Maillet, Anne Tallet, Eric Piver, Olivier Decaux, Caroline Moreau, Philippe Moreau, Philippe Lehours, Francis Mégraud, Valéry Salle, Edith Bigot-Corbel, Jean Harb and Sylvie Hermouet
Cancers 2020, 12(5), 1254; https://doi.org/10.3390/cancers12051254 - 15 May 2020
Cited by 12 | Viewed by 3801
Abstract
Chronic stimulation by infectious or self-antigens initiates subsets of monoclonal gammopathies of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM). Recently, glucosylsphingosine (GlcSph) was reported to be the target of one third of monoclonal immunoglobulins (Igs). In this study of [...] Read more.
Chronic stimulation by infectious or self-antigens initiates subsets of monoclonal gammopathies of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM). Recently, glucosylsphingosine (GlcSph) was reported to be the target of one third of monoclonal immunoglobulins (Igs). In this study of 233 patients (137 MGUS, 6 SMM, 90 MM), we analyzed the GlcSph-reactivity of monoclonal Igs and non-clonal Igs. The presence of GlcSph-reactive Igs in serum was unexpectedly frequent, detected for 103/233 (44.2%) patients. However, GlcSph was targeted by the patient’s monoclonal Ig for only 37 patients (15.9%); for other patients (44 MGUS, 22 MM), the GlcSph-reactive Igs were non-clonal. Then, the characteristics of patients were examined: compared to MM with an Epstein-Barr virus EBNA-1-reactive monoclonal Ig, MM patients with a GlcSph-reactive monoclonal Ig had a mild presentation. The inflammation profiles of patients were similar except for moderately elevated levels of 4 cytokines for patients with GlcSph-reactive Igs. In summary, our study highlights the importance of analyzing clonal Igs separately from non-clonal Igs and shows that, if autoimmune responses to GlcSph are frequent in MGUS/SMM and MM, GlcSph presumably represents the initial pathogenic event for ~16% cases. Importantly, GlcSph-initiated MM appears to be a mild form of MM disease. Full article
(This article belongs to the Special Issue The Asymptomatic Version of Myeloma: MGUS and Smoldering Myeloma)
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Review

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21 pages, 1762 KiB  
Review
Immunoglobulin M Paraproteinaemias
by Louis-Pierre Girard, Cinnie Yentia Soekojo, Melissa Ooi, Li Mei Poon, Wee-Joo Chng and Sanjay de Mel
Cancers 2020, 12(6), 1688; https://doi.org/10.3390/cancers12061688 - 25 Jun 2020
Cited by 16 | Viewed by 8580
Abstract
Monoclonal paraproteinaemia is an increasingly common reason for referral to haematology services. Paraproteinaemias may be associated with life-threatening haematologic malignancies but can also be an incidental finding requiring only observation. Immunoglobulin M (IgM) paraproteinaemias comprise 15–20% of monoclonal proteins but pose unique clinical [...] Read more.
Monoclonal paraproteinaemia is an increasingly common reason for referral to haematology services. Paraproteinaemias may be associated with life-threatening haematologic malignancies but can also be an incidental finding requiring only observation. Immunoglobulin M (IgM) paraproteinaemias comprise 15–20% of monoclonal proteins but pose unique clinical challenges. IgM paraproteins are more commonly associated with lymphoplasmacytic lymphoma than multiple myeloma and can occur in a variety of other mature B-cell neoplasms. The large molecular weight of the IgM multimer leads to a spectrum of clinical manifestations more commonly seen with IgM paraproteins than others. The differential diagnosis of B-cell and plasma cell dyscrasias associated with IgM gammopathies can be challenging. Although the discovery of MYD88 L265P and other mutations has shed light on the molecular biology of IgM paraproteinaemias, clinical and histopathologic findings still play a vital role in the diagnostic process. IgM secreting clones are also associated with a number of “monoclonal gammopathy of clinical significance” entities. These disorders pose a novel challenge from both a diagnostic and therapeutic perspective. In this review we provide a clinical overview of IgM paraproteinaemias while discussing the key advances which may affect how we manage these patients in the future. Full article
(This article belongs to the Special Issue The Asymptomatic Version of Myeloma: MGUS and Smoldering Myeloma)
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16 pages, 476 KiB  
Review
Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All
by Oliver C. Lomas, Tarek H. Mouhieddine, Sabrin Tahri and Irene M. Ghobrial
Cancers 2020, 12(6), 1554; https://doi.org/10.3390/cancers12061554 - 12 Jun 2020
Cited by 25 | Viewed by 15489
Abstract
Monoclonal Gammopathy of Undetermined Significance (MGUS) is considered to be a benign precursor condition that may progress to a lymphoproliferative disease or multiple myeloma. Most patients do not progress to an overt condition, but nevertheless, MGUS is associated with a shortened life expectancy [...] Read more.
Monoclonal Gammopathy of Undetermined Significance (MGUS) is considered to be a benign precursor condition that may progress to a lymphoproliferative disease or multiple myeloma. Most patients do not progress to an overt condition, but nevertheless, MGUS is associated with a shortened life expectancy and, in a minority of cases, a number of co-morbid conditions that include an increased fracture risk, renal impairment, peripheral neuropathy, secondary immunodeficiency, and cardiovascular disease. This review aims to consolidate current evidence for the significance of these co-morbidities before considering how best to approach these symptoms and signs, which are often encountered in primary care or within a number of specialties in secondary care. Full article
(This article belongs to the Special Issue The Asymptomatic Version of Myeloma: MGUS and Smoldering Myeloma)
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17 pages, 296 KiB  
Review
Treatment of Smoldering Multiple Myeloma: Ready for Prime Time?
by E. Bridget Kim, Andrew J. Yee and Noopur Raje
Cancers 2020, 12(5), 1223; https://doi.org/10.3390/cancers12051223 - 13 May 2020
Cited by 11 | Viewed by 3532
Abstract
The current standard of care for smoldering multiple myeloma (SMM) is observation until there is end-organ involvement. With newer and more effective treatments available, a question that is increasingly asked is whether early intervention in patients with SMM will alter the natural history [...] Read more.
The current standard of care for smoldering multiple myeloma (SMM) is observation until there is end-organ involvement. With newer and more effective treatments available, a question that is increasingly asked is whether early intervention in patients with SMM will alter the natural history of their disease. Herein, we review the evolving definition of SMM and risk stratification models. We discuss evidence supporting early intervention for SMM—both as a preventative strategy to delay progression and as an intensive treatment strategy with a goal of potential cure. We highlight ongoing trials and focus on better defining who may require early intervention. Full article
(This article belongs to the Special Issue The Asymptomatic Version of Myeloma: MGUS and Smoldering Myeloma)
14 pages, 580 KiB  
Review
PD-L1–PD-1 Pathway in the Pathophysiology of Multiple Myeloma
by Hideto Tamura, Mariko Ishibashi, Mika Sunakawa-Kii and Koiti Inokuchi
Cancers 2020, 12(4), 924; https://doi.org/10.3390/cancers12040924 - 10 Apr 2020
Cited by 49 | Viewed by 7580
Abstract
PD-L1 expressed on tumor cells contributes to disease progression with evasion from tumor immunity. Plasma cells from multiple myeloma (MM) patients expressed higher levels of PD-L1 compared with healthy volunteers and monoclonal gammopathy of undetermined significance (MGUS) patients, and its expression is significantly [...] Read more.
PD-L1 expressed on tumor cells contributes to disease progression with evasion from tumor immunity. Plasma cells from multiple myeloma (MM) patients expressed higher levels of PD-L1 compared with healthy volunteers and monoclonal gammopathy of undetermined significance (MGUS) patients, and its expression is significantly upregulated in relapsed/refractory patients. Furthermore, high PD-L1 expression is induced by the myeloma microenvironment and PD-L1+ patients with MGUS and asymptomatic MM tend to show disease progression. PD-L1 expression on myeloma cells was associated with more proliferative potential and resistance to antimyeloma agents because of activation of the Akt pathway through PD-1-bound PD-L1 in MM cells. Those data suggest that PD-L1 plays a crucial role in the disease progression of MM. Full article
(This article belongs to the Special Issue The Asymptomatic Version of Myeloma: MGUS and Smoldering Myeloma)
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9 pages, 5061 KiB  
Review
Imaging of Monoclonal Gammapathy of Undetermined Significance and Smoldering Multiple Myeloma
by Bastien Jamet, Clément Bailly, Thomas Carlier, Cyrille Touzeau, Anne-Victoire Michaud, Mickael Bourgeois, Philippe Moreau, Caroline Bodet-Milin and Françoise Kraeber-Bodere
Cancers 2020, 12(2), 486; https://doi.org/10.3390/cancers12020486 - 19 Feb 2020
Cited by 10 | Viewed by 4055
Abstract
Multiple myeloma (MM) is always preceded by an initial monoclonal gammopathy of undetermined significance (MGUS) that then develops into asymptomatic or smoldering multiple myeloma (SMM), which constitutes an intermediate clinical stage between MGUS and MM. According to a recent study, risk factors for [...] Read more.
Multiple myeloma (MM) is always preceded by an initial monoclonal gammopathy of undetermined significance (MGUS) that then develops into asymptomatic or smoldering multiple myeloma (SMM), which constitutes an intermediate clinical stage between MGUS and MM. According to a recent study, risk factors for faster MGUS to MM progression include an M protein of 1.5 g/dL or more and an abnormal free light chain ratio in patients with non-IgM MGUS. Therefore, the International Myeloma Working Group (IMWG) decided to recommend whole-body computed tomography (WBCT) for patients with high-risk MGUS in order to exclude early bone destruction. Studies evaluating magnetic resonance imaging (MRI) in SMM found an optimal cutoff of two or more focal lesions to be of prognostic significance for fast progression into symptomatic disease and considered this biomarker as a myeloma-defining event (MDE) needing to start therapy with the aim to avoid progression to harmful bone lesions. Moreover, studies assessing positron emission tomography (PET) with computed tomography (CT) using 18F-deoxyglucose (FDG) (FDG-PET/CT) in SMM showed that presence of focal bone lesion without underlying osteolysis is associated with a rapid progression to symptomatic MM. Latest IMWG guidelines recommended to perform WBCT (either CT alone or as part of an FDG-PET/CT protocol) as the first imaging technique at suspected SMM and, if these images are negative or inconclusive, to perform whole-body MRI. The goal of this paper is to clarify the role of different imaging modalities in MGUS and SMM workups. Full article
(This article belongs to the Special Issue The Asymptomatic Version of Myeloma: MGUS and Smoldering Myeloma)
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