Cytogenetic profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: a study in highly purified aberrant plasma cells

Abstract We investigated whether interleukin-1β (IL-1β) is differentially expressed in plasma cells from monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patients because IL-1β appears to play a major role in the development of lytic bone lesions, the major clinical feature distinguishing MGUS from myeloma. In situ hybridization (ISH) for IL-1β was performed using bone marrow aspirates from 51 MM, 7 smoldering MM, 21 MGUS, and 5 normal control samples. Using the ISH technique IL-1β mRNA was detectable in the plasma cells from 49 of 51 patients with active myeloma and 7 of 7 patients with smoldering myeloma. In contrast, 5 of 21 patients with MGUS and 0 of 5 normal controls had detectable IL-1β message. Bone lesions were present in 40 of the 51 MM patients analyzed, and all 40 patients had IL-1β mRNA by ISH. These results show that greater than 95% of MM patients but less than 25% of MGUS patients are positive for IL-1β production. In the future, continued follow-up of IL-1β positive and negative MGUS patients should determine whether aberrant expression of plasma cell IL-1β is predictive of those MGUS patients that will eventually progress to active myeloma.

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Obesity is Associated with a 2-Fold Elevated Risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) Among African-American and Caucasian Women.

Blood ◽

10.1182/blood.v114.22.4876.4876 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4876-4876

Author(s):

Ola Landgren ◽

Vincent Rajkumar ◽

Ruth Pfeiffer ◽

Robert Kyle ◽

Jerry Katzmann ◽

...

Keyword(s):

Multiple Myeloma ◽

African American ◽

African Americans ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Pearson Correlation ◽

Elevated Risk ◽

Caucasian Women ◽

Undetermined Significance

Abstract Abstract 4876 Background Recent studies have found obesity to be associated with a 1.5- to 2-fold elevated risk of developing multiple myeloma. This is of particular interest given that elevated levels of the pro-inflammatory cytokine interleukin (IL)-6 have been found in obese persons, and, at the same time, IL-6 has well-known proliferative and anti-apoptotic effects on monoclonal plasma-cells. Also insulin-like growth factors (IGFs) have been proposed to play a role since obesity often causes insulin resistance, which in turn modulates the bioavailability of IGF-1 Similar to IL-6, prior studies have found IGF-1 to have both growth and survival effects on monoclonal plasma-cells. Based on these facts, we have speculated that obesity might increase the risk of the multiple myeloma precursor monoclonal gammopathy of undetermined significance (MGUS), or, alternatively, that obesity may increase the risk for transformation from MGUS to multiple myeloma. We conducted the first large screening study designed to assess the association between obesity and MGUS among almost 2,000 African-American and Caucasian women. Methods We included 1000 African-American and 996 Caucasian women (age 40-79, median 48 years) from the Southern Community Cohort Study to assess MGUS risk in relation to obesity. Per our sampling strategy, about 50% of the participants were obese. Medical record-abstracted weight and height (measured on the day of study enrollment) and self-reported values had very high concordance (Pearson correlation >0.95). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Using logistic regression models, we estimated odds ratios (ORs) as measures of risk. Results Among all study participants, 39 (3.9%) African-Americans and 21 (2.1%) Caucasians were found to have MGUS, yielding a 1.9-fold (95%CI 1.1-2.3; p=0.021) higher risk of MGUS among African-Americans (vs. Caucasians). On multivariate analysis, we found obesity (OR=1.8, 95%CI 1.03-3.1; p=0.039), African-American race (OR=1.8, 95%CI 1.04-3.1; p=0.037), and increasing age (quartiles: ≥55 vs. <43 years) (OR=2.5, 95%CI 1.1-5.7; p=0.028) to be independently associated with an excess risk of MGUS. Another interesting finding was that the distribution of the monoclonal immunoglobulin isotype usage among African-American and Caucasian women was significantly different (p=0.007). Their respective rates were: IgG in 79.5% and 71.3 %; IgA in 7.7% and 0%; IgM in 7.7% and 19%; biclonal in 5.1% and 4.7%; and triclonal in 0% and 4.7%. The distribution of serum light-chain types between the two races was also significantly different (P=0.003, chi-square test): kappa in 53.8% and 47.6%; lambda in 43.6% and 42.8%; biclonal 2.6% and 4.7%; and triclonal in 0% and 4.7%. Conclusions Our finding that MGUS is twice as common among obese (vs. non-obese) women, and independent of race, supports the hypothesis that obesity is etiologically linked to myelomagenesis and may have public health impact. The observed 2-fold excess of MGUS among African-Americans (vs. Caucasians) of similar socio-economic status, coupled with other recent studies supports a role for susceptibility genes as the cause for racial disparity in the prevalence of MGUS. Disclosures No relevant conflicts of interest to declare.

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Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma

Blood ◽

10.1182/blood.v88.1.289.bloodjournal881289 ◽

1996 ◽

Vol 88 (1) ◽

pp. 289-296 ◽

Cited By ~ 2

Author(s):

D Billadeau ◽

B Van Ness ◽

T Kimlinger ◽

RA Kyle ◽

TM Therneau ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Gammopathy ◽

Mononuclear Cells ◽

Plasma Cells ◽

Median Percentage ◽

Color Flow ◽

Circulating Cells ◽

Allele Specific ◽

Polymerase Chain ◽

Undetermined Significance

The blood of most patients with active multiple myeloma (MM) contains cells related to the bone marrow tumor. However, identifying clonal cells in the blood of patients with monoclonal gammopathy of undetermined significance (MGUS) has been difficult. In this study, we analyzed blood mononuclear cells (BMNCs) from 16 patients with MGUS, 2 with amyloidosis, 8 with smoldering MM (SMM), 2 with indolent MM (IMM), and 15 with active MM using three different methods to detect and quantitate clonal cells, ie, immunofluorescence microscopy (IM) for monoclonal plasma cells, three-color flow cytometry (FC) for CD38(+)CD45- CD45(dim) cells, and the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). Using ASO-PCR, we were able to detect clonal cells in the blood in 13 of 16 patients with MGUS, 2 of 2 with amyloid, 6 of 8 with SMM, 2 of 2 with IMM, and 13 of 15 with MM. In 9 of the 13 patients with MGUS with blood involvement, the number of clonal cells was very small ( < 0.04% of the BMNCs). The median percentage of clonal cells as determined by ASO-PCR was 0.02 for MGUS, 0.02 for SMM, and 0.24 for MM. Clonal plasma cells or CD38+CD45- CD45(dim) cells were identified by IM or FC in 6 of 16 MGUS patients, 4 of 8 with SMM, and 11 of 15 with MM. In all cases in which IM or FC detected clonal cells, the ASO-PCR was positive. This study shows that, by using ASO-PCR, clonal cells can be found at very low levels in the blood in most patients with MGUS. However, the number of clonal cells in the blood of MGUS patients is less than those with overt MM (P = .006). In contrast to MGUS, patients with active MM are more likely to have identifiable clonal circulating plasma cells (P = .05).

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The role of bone marrow microenvironment in the progression of multiple myeloma from monoclonal gammopathy of undetermined significance

Oncohematology ◽

10.17650/1818-8346-2021-16-3-26-32 ◽

2021 ◽

Vol 16 (3) ◽

pp. 26-32

Author(s):

A. S. Khudovekova ◽

Ya. A. Rudenko ◽

A. E. Dorosevich

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Bone Marrow Microenvironment ◽

Genetic Mutations ◽

Microbiome Composition ◽

The Impact ◽

Undetermined Significance

Multiple myeloma is a tumor of plasma cells, one of the most common malignant blood diseases. It is preceded by a stage called monoclonal gammopathy of undetermined significance, from which true multiple myeloma develops in only a small percentage of cases. It was assumed that this process is associated with the accumulation of genetic mutations, but in recent years there is increasing evidence that the bone marrow microenvironment plays a key role in progression and that it can become a target for therapy that prevents the myeloma development. The review considers the role of mesenchymal stem cells, immune system cells, endotheliocytes, fibroblasts, adipocytes, osteoclasts and osteoblasts in multiple myeloma progression, as well as the impact of the sympathetic nervous system and microbiome composition.

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Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma

Blood ◽

10.1182/blood.v88.1.289.289 ◽

1996 ◽

Vol 88 (1) ◽

pp. 289-296 ◽

Cited By ~ 81

Author(s):

D Billadeau ◽

B Van Ness ◽

T Kimlinger ◽

RA Kyle ◽

TM Therneau ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Gammopathy ◽

Mononuclear Cells ◽

Plasma Cells ◽

Median Percentage ◽

Color Flow ◽

Circulating Cells ◽

Allele Specific ◽

Polymerase Chain ◽

Undetermined Significance

Abstract The blood of most patients with active multiple myeloma (MM) contains cells related to the bone marrow tumor. However, identifying clonal cells in the blood of patients with monoclonal gammopathy of undetermined significance (MGUS) has been difficult. In this study, we analyzed blood mononuclear cells (BMNCs) from 16 patients with MGUS, 2 with amyloidosis, 8 with smoldering MM (SMM), 2 with indolent MM (IMM), and 15 with active MM using three different methods to detect and quantitate clonal cells, ie, immunofluorescence microscopy (IM) for monoclonal plasma cells, three-color flow cytometry (FC) for CD38(+)CD45- CD45(dim) cells, and the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). Using ASO-PCR, we were able to detect clonal cells in the blood in 13 of 16 patients with MGUS, 2 of 2 with amyloid, 6 of 8 with SMM, 2 of 2 with IMM, and 13 of 15 with MM. In 9 of the 13 patients with MGUS with blood involvement, the number of clonal cells was very small ( < 0.04% of the BMNCs). The median percentage of clonal cells as determined by ASO-PCR was 0.02 for MGUS, 0.02 for SMM, and 0.24 for MM. Clonal plasma cells or CD38+CD45- CD45(dim) cells were identified by IM or FC in 6 of 16 MGUS patients, 4 of 8 with SMM, and 11 of 15 with MM. In all cases in which IM or FC detected clonal cells, the ASO-PCR was positive. This study shows that, by using ASO-PCR, clonal cells can be found at very low levels in the blood in most patients with MGUS. However, the number of clonal cells in the blood of MGUS patients is less than those with overt MM (P = .006). In contrast to MGUS, patients with active MM are more likely to have identifiable clonal circulating plasma cells (P = .05).

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Phenotype of plasma cells in multiple myeloma and monoclonal gammopathy of undetermined significance

Neoplasma ◽

10.4149/neo_2009_06_526 ◽

2009 ◽

Vol 56 (6) ◽

pp. 526-532 ◽

Cited By ~ 11

Author(s):

L. KOVAROVA ◽

I. BURESOVA ◽

T. BUCHLER ◽

R. SUSKA ◽

L. POUR ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Undetermined Significance

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A Comprehensive Review of the Genomics of Multiple Myeloma: Evolutionary Trajectories, Gene Expression Profiling, and Emerging Therapeutics

Cells ◽

10.3390/cells10081961 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1961

Author(s):

Hassan Awada ◽

Bicky Thapa ◽

Hussein Awada ◽

Jing Dong ◽

Carmelo Gurnari ◽

...

Keyword(s):

Multiple Myeloma ◽

Expression Profiling ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Plasma Cell Dyscrasia ◽

Genomic Evolution ◽

Cytogenetic Aberrations ◽

Evolutionary Trajectories ◽

Prognostic Implications ◽

Undetermined Significance

Multiple myeloma (MM) is a blood cancer characterized by the accumulation of malignant monoclonal plasma cells in the bone marrow. It develops through a series of premalignant plasma cell dyscrasia stages, most notable of which is the Monoclonal Gammopathy of Undetermined Significance (MGUS). Significant advances have been achieved in uncovering the genomic aberrancies underlying the pathogenesis of MGUS-MM. In this review, we discuss in-depth the genomic evolution of MM and focus on the prognostic implications of the accompanied molecular and cytogenetic aberrations. We also dive into the latest investigatory techniques used for the diagnoses and risk stratification of MM patients.

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MicroRNAs as a Potential New Preventive Approach in the Transition from Asymptomatic to Symptomatic Multiple Myeloma Disease

Cancers ◽

10.3390/cancers13153650 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3650

Author(s):

Vanessa Desantis ◽

Antonio Giovanni Solimando ◽

Ilaria Saltarella ◽

Antonio Sacco ◽

Viviana Giustini ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Hematological Malignancy ◽

Bone Lesions ◽

Step Process ◽

Asymptomatic Phase ◽

Undetermined Significance ◽

Premalignant Conditions

Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bone marrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact on MM tumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions.

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Characterization of Monoclonal Gammopathy of Undetermined Significance Progression to Multiple Myeloma through Meta-Analysis of GEO Data

Blood ◽

10.1182/blood-2019-129699 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4395-4395

Author(s):

Jihad Aljabban ◽

David Chen ◽

Francesca Cottini ◽

Saad Syed ◽

Nabeal Aljabban ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Signaling Pathways ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

De Novo ◽

Conflicts Of Interest ◽

Meta Analysis ◽

Upstream Regulators ◽

Undetermined Significance

Background: Monoclonal gammopathy of undetermined significance (MGUS) is characterized by plasma cell production of abnormal monoclonal protein, or M protein. While MGUS itself is asymptomatic, it generally carries a 1% per year risk to progression to multiple myeloma (MM). The etiology of MGUS, as well as why it progresses to MM in some cases, remains unclear. Moreover, it is not known why some MGUS patients, such as African Americans, have higher risk to progression to MM. Contrasting MGUS and MM can potentially highlight genes that differentiate benign gammopathies from malignant ones and may be involved in disease progression from MGUS to MM. Methods: We employed our STARGEO platform to tag samples from the NCBI Gene Expression Omnibus and performed two separate meta-analysis to compare MGUS and MM transcriptomes. For the first meta-analysis, we tagged MGUS plasma cells recovered from the bone marrow of 101 patients and tagged plasma cells from 64 healthy subjects as a control. For the second analysis. We tagged CD138+ cells from the bone marrow of 383 MM patients and used the MGUS tagged samples as a control. We then analyzed the signature in Ingenuity Pathway Analysis (IPA). Results: From our first meta-analysis of MGUS, we identified EIF2 signaling, regulation of EIF4 and p70S6K signaling, and JAK/STAT signaling as top canonical pathways. Top upstream regulators included TP53, TGFB1, and the proto-oncogene MYCN and MYC (with predicted activation). The most upregulated genes included pro-oncogenes such as KIT and MLLT3, which is well-studied in acute leukemia but not yet described in MGUS. Another top upregulated gene was NRG3, a myeloma growth factor. Additionally, our analysis highlighted key genes involved in transcription and epigenetic regulation. For example, there was upregulation of RBFOX2, which is involved in alternative splicing during oncogenesis and tumor progression, and of PARP15, a transcriptional repressor with poly(ADP-ribose) polymerase activity and candidate gene for drug targeting. Also, there was upregulation of the DNA damage-inducible gene GADD45A, found to promote global DNA methylation. Lastly, we found upregulation of COMMD3, a gene with a recently identified role in humoral activity and B cell migration. From our second meta-analysis comparing MM and MGUS directly, we identified mitochondrial dysfunction, oxidative phosphorylation, purine nucleotides de novo biosynthesis, and sirtuin signaling as top upstream regulators. Like our first analysis, TP53 (with predicted inhibition), TGFB1, and MYC (with predicted activation) were top upstream regulators. The most upregulated gene was NUP62, a nucleoporin and novel regulator of cell proliferation and inducer of MYC activity. Our analysis also illustrated pro-oncogenic signaling pathways such as the Wnt pathway through upregulation of the ubiquitin ligase RNF14 and serine/threonine kinase through upregulation of SRPK2. Moreover, we found upregulation of the super-enhancer DUSP4, a phosphatase whose over-activity may drive MM severity. Lastly, we found upregulation of lysosomal associated membrane protein LAMP5. LAMP5 was recently identified in single-cell RNA sequencing of MM patients and may play a significant role in disease. Conclusions: Our study illustrates signaling pathways in MGUS that are present in MM such as EIF2, JAK/STAT, and MYC signaling. We also illustrate gene activity in MGUS that may predispose to MM progression such as NRG3, RBFOX2, and PARP15. GADD45RA and COMMD3 may play novel roles in MGUS. Our second analysis highlighted disease activity that persist from MGUS to MM, such as MYC signaling. It is possible that the genes from this analysis that aims to distinguish MM from MGUS may be responsible for tipping the scales from benignity to malignancy. Genes such as DUSP4, RN14, LAMP5, and others could serve as novel biomarkers or targets to MM and risk of progression of MGUS to MM. Disclosures No relevant conflicts of interest to declare.

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