Monoclonal Gammopathy Of Undetermined Significance Stage Research Articles

DCE-MRI to distinguish all monoclonal plasma cell disease stages and correlation with diffusion-weighted MRI/PET-based biomarkers in a hybrid simultaneous whole body-2-[18F]FDG-PET/MRI imaging approach

BackgroundDynamic contrast-enhanced-MRI (DCE-MRI) is able to study bone marrow angiogenesis in patients with multiple myeloma (MM) and asymptomatic precursor diseases but its role in the management of MM has not yet been established. The aims of this prospective study was to compare DCE-MRI-based parameters between all monoclonal plasma cell disease stages in order to find out discriminatory parameters and to seek correlations with other diffusion-weighted MRI and positron emission tomography (PET)-based biomarkers in a hybrid simultaneous whole-body-2-[18F]fluorodeoxyglucose (FDG)-PET/MRI (WB-2-[18F]FDG-PET/MRI) imaging approach.MethodsPatients with newly diagnosed Monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or symptomatic MM according to international myeloma working group and underwent WB-2-[18F]FDG-PET/MRI imaging including bone marrow DCE sequences at the Nantes University Hospital were prospectively enrolled in this study before receiving treatment.ResultsOne hundred and sixty-seven patients (N = 167, mean age: 64 years ± 11 [Standard deviation], 66 males) were considered for the analysis. DCE-MRI-based Peak Enhancement Intensity (PEI), Time to PEI (TPEI) and their maximum intensity time ratio (MITR: PEI/TPEI) values were significantly different between the different monoclonal plasma cell disease stages, PEI values increasing and TPEI values decreasing progressively along the spectrum of plasma cell disorders, from MGUS stage to symptomatic multiple myeloma. PEI values were significantly higher in patients with diffuse bone marrow involvement (either in PET or in MRI images) than in those without diffuse bone marrow involvement, unlike TPEI values. PEI and TPEI values were not significantly different between patients with or without focal bone lesions.ConclusionDifferent DCE-MRI-based parameters (PEI, TPEI, MITR) could significantly differentiate all monoclonal plasma cell disease stages and complemented conventional MRI and PET-based biomarkers.

Single-Cell RNA-Sequencing of 370 Bone Marrow and Peripheral Blood Immune Cell Samples from Patients with MGUS and Smoldering Multiple Myeloma Reveal Significant Immune Dysregulation at the MGUS Stage, and Novel Interactions between Tumor and Immune Cells

Introduction A patient's risk of progression from Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) to full-blown Multiple Myeloma (MM) is the result of complex interactions between the tumor burden, alterations of tumor -omics, and tumor-extrinsic factors such as immune dysregulation. Prior studies have suggested that immune dysregulation can be observed as early as at the MGUS stage, but immune alterations in patients with MGUS have not been comprehensively studied at scale. Furthermore, it is unclear which of the immune cell populations that are altered in disease may directly interact with the tumor, as opposed to responding to general changes in the milieu. Methods Here, we present results from the largest single-cell RNA-sequencing cohort (n=370) of bone marrow CD138-negative (n=243) and peripheral blood mononuclear cell samples (n=127) from patients with MGUS and SMM. Specifically, we profiled 51 samples from patients with MGUS, 226 samples from patients with SMM, 28 samples from patients with MM, and 61 samples from healthy donors. Bone marrow samples were subjected to magnetic bead enrichment for CD138 (Miltenyi Biotec) prior to library preparation. Libraries were prepared with the Chromium Single-cell 5' kit by 10X Genomics and sequenced on NovaSeq S4 flow cells at the Genomics Platform of the Broad Institute of MIT and Harvard (Cambridge, MA). CellRanger v.6.0.1. was used to extract FASTQ files and produce count matrices. Droplets with more than 15% mitochondrial gene expression or fewer than 200 genes per cell were filtered out, doublets were identified using Scrublet, SCDS, and scDblFinder, and samples were integrated using Harmony. Excluding plasma cells, immune cells isolated from both the CD138-positive and CD138-negative fractions were included in this analysis. Results Overall, we profiled 2,327,008 immune cells, including T-cells, NK cells, B-cells, Monocytes, Dendritic cells, megakaryocytes, and progenitor cells. To identify immune cell populations that are more likely to interact with tumor cells, we compared the abundance of populations between matched bone marrow CD138-positive and CD138-negative fractions in patients and healthy donors. In healthy donors, we observed a significant enrichment of CD14+ monocyte subpopulations and CD168+ macrophages expressing complement factor C1q in the CD138-positive fractions, which is in line with their role in promoting and maintaining plasma cell differentiation. In patients, where decreased abundance of CD14+ monocytes is observed, this interaction was no longer significant, although macrophages were still enriched in the CD138-positive fraction. Consistent with prior publications, megakaryocytes were enriched in the CD138-positive fraction of patients, an interaction that has been shown to promote myeloma progression in vitro and in vivo. Of note, pro-B-cells, pre-B-cells, and memory B-cells were enriched in the CD138-positive fraction of patients, raising questions about their potential involvement in the clonal population. Lastly, Granzyme K-expressing CD8+ T-cells were significantly enriched in the CD138-positive fraction of patients, suggesting an interaction between this population and tumor cells. Remarkably, despite their early stage, patients with MGUS had on average fewer pDCs, progenitor cells, and CD14+ Monocytes, and more CD4+ T-cells (including Tregs), Granzyme B-expressing CD8+ T-cells and CD56dim NK cells, compared to healthy donors. These results suggest that bone marrow immune cell composition can be significantly altered at the MGUS stage. Discussion In the largest to date single-cell RNA-sequencing study of bone marrow and peripheral blood immune cells from patients with MGUS and SMM, we have comprehensively mapped alterations in bone marrow immune cell composition in patients with MGUS, and identified immune cell populations that are more likely to interact directly with tumor cells in the bone marrow microenvironment.

How to Recognize and Treat MGRS

AbstractMonoclonal gammopathy of renal significance (MGRS) represents a group of B-cell or plasma cell proliferative disorders that causes kidney injury via a monoclonal immunoglobulin they produce. The need for this new category of hematologic disorders came from a lack of renal definition in the current diagnostic criteria for plasma cell disorders, Waldenstrom macroglobulinemia and chronic lymphocytic leukemia (CLL). By definition, the hematologic conditions considered to be MGRS do not meet standard consensus criteria for malignancy or treatment, but they cannot be diagnosed as monoclonal gammopathy of undetermined significance (MGUS) because of the end-organ damage. Although generally not life threatening except in the cases of immunoglobulin (AIg) amyloidosis and monoclonal immunoglobulin deposition disease (MIDD) with extrarenal manifestations, the kidney diseases secondary to MGRS are progressive and are associated with significant morbidity. The MGUS designation is also problematic because treatment is not recommended for the MGUS stage of these hematologic disorders. The clone directed therapy required for preservation of kidney function would not be available when these conditions were classified as MGUS, IgM MGUS or low-grade CLL. MGRS clearly separates these conditions from MGUS and allows for the use of clone directed therapy without contradicting current diagnostic criteria and guidelines.

Health Care Burden of Monogammopathy of Renal Significance

Health Care Burden of Monogammopathy of Renal Significance

Maternal cigarette smoking and expression of selected micro-RNAS in the plasma collected after spontaneous vaginal delivery

Several studies have shown a gradual increase in the extent of bone marrow angiogenesis in various stages of proliferative plasma cell disorders, from monoclonal gammopathy of undetermined significance (MGUS) to active multiple myeloma (MM). The main aim of this study was to evaluate tumor angiogenesis parameters in detail and to correlate them with the expression of osteopontin (OPN) and vascular endothelial growth factor (VEGF) in the bone marrow of patients with MGUS and MM. In addition, we wanted to determine their prognostic significance in active MM.Ninety-five patients were enrolled in the study: 14 diagnosed with MGUS, 13 with asymptomatic myeloma (AMM) and 68 with active MM. Computer assisted image analysis was used to determine the angiogenesis parameters, the quantity of microvessels per 1 mm2 (MVD), the area occupied by microvessels per 1 mm2 and the percentage of microvessel area in total section area (TVA). Double immunohistochemical methods CD138 + VEGF and CD138 + OPN were used to evaluate expression of these proteins in plasma cells, and OPN was also analyzed for its interstitial expression (iOPN).A significant positive correlation was determined between VEGF and iOPN with angiogenic parameters in the MGUS stage of the disease. In advanced stages of the disease, a significant negative correlation was recorded between OPN and iOPN with parameters of angiogenesis. Overall survival was significantly shorter for patients with negative iOPN (p = 0.002) and higher angiogenic parameters, MVD (p = 0.009), TVA (p = 0.008) and area of microvessels per 1 mm2 (p = 0.02). Positive VEGF expression in our model predicted a better three-year survival of patients with active MM (OR: 5.25, p = 0.03; HR: 0.44, p = 0.04).The results of our study suggested a possible key role of VEGF and OPN in the induction of angiogenesis in early-stage disease.

Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma

AbstractAnalysis of intraclonal heterogeneity has yielded insights into the clonal evolution of hematologic malignancies. We compared the clonal and subclonal compositions of the underlying plasma cell dyscrasia in 544 systemic light chain amyloidosis (PC-AL) patients with 519 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or symptomatic MM; ie, PC–non-AL patients). Using interphase fluorescence in situ hybridization, subclones were stringently defined as clone size below two thirds of the largest clone and an absolute difference of ≥30%. Subclones were found less frequently in the PC-AL group, at 199 (36.6%) of 544 as compared with 267 (51.4%) of 519 in the PC–non-AL group (P < .001), and were not associated with the stage of plasma cell dyscrasia in either entity. In both groups, translocation t(11;14), other immunoglobulin heavy chain translocations, and hyperdiploidy were typically found as main clones, whereas gain of 1q21 and deletions of 8p21, 13q14, and 17p13 were frequently found as subclones. There were no shifts in the subclone/main clone ratio depending on the MGUS, SMM, or MM stage of plasma cell dyscrasia. In multivariate analysis, t(11;14) was associated with lower rates of subclone formation and hyperdiploidy with higher rates. PC-AL itself lost statistical significance, demonstrating that the lower subclone frequency in AL is a reflection of its exceptionally high t(11;14) frequency. In summary, the subclone patterns in PC-AL and PC–non-AL are closely related, implying that subclone formation depends on the main cytogenetic categories and is independent of disease entity and stage.

The expression of osteopontin and vascular endothelial growth factor in correlation with angiogenesis in monoclonal gammopathy of undetermined significance and multiple myeloma

Several studies have shown a gradual increase in the extent of bone marrow angiogenesis in various stages of proliferative plasma cell disorders, from monoclonal gammopathy of undetermined significance (MGUS) to active multiple myeloma (MM). The main aim of this study was to evaluate tumor angiogenesis parameters in detail and to correlate them with the expression of osteopontin (OPN) and vascular endothelial growth factor (VEGF) in the bone marrow of patients with MGUS and MM. In addition, we wanted to determine their prognostic significance in active MM.Ninety-five patients were enrolled in the study: 14 diagnosed with MGUS, 13 with asymptomatic myeloma (AMM) and 68 with active MM. Computer assisted image analysis was used to determine the angiogenesis parameters, the quantity of microvessels per 1mm2 (MVD), the area occupied by microvessels per 1mm2 and the percentage of microvessel area in total section area (TVA). Double immunohistochemical methods CD138+VEGF and CD138+OPN were used to evaluate expression of these proteins in plasma cells, and OPN was also analyzed for its interstitial expression (iOPN).A significant positive correlation was determined between VEGF and iOPN with angiogenic parameters in the MGUS stage of the disease. In advanced stages of the disease, a significant negative correlation was recorded between OPN and iOPN with parameters of angiogenesis. Overall survival was significantly shorter for patients with negative iOPN (p=0.002) and higher angiogenic parameters, MVD (p=0.009), TVA (p=0.008) and area of microvessels per 1mm2 (p=0.02). Positive VEGF expression in our model predicted a better three-year survival of patients with active MM (OR: 5.25, p=0.03; HR: 0.44, p=0.04).The results of our study suggested a possible key role of VEGF and OPN in the induction of angiogenesis in early-stage disease.

Abstract IA25: Targeting genetic heterogeneity in multiple myeloma through immune activation.

Abstract IA25: Targeting genetic heterogeneity in multiple myeloma through immune activation.

Molecular pathogenesis of multiple myeloma.

Multiple myeloma (MM), one of the most intractable malignancies, is characterized by the infiltration and growth of plasma cells, the most differentiated cells in the B-cell lineage, in the bone marrow. Despite the introduction of novel therapeutic agents, including proteasome inhibitors and immunomodulatory drugs, the prognosis of patients with MM is still worse than that of most hematological malignancies. A better understanding of the molecular pathogenesis of the disease is essential to achieve any improvement of treatment outcome of MM patients. All MM cases pass through the phase of asymptomatic expansion of clonal plasma cells, referred to as monoclonal gammopathy of undetermined significance (MGUS). It has long been believed that MM evolves linearly from MGUS to terminal phases, such as extramedullary tumors and plasma cell leukemia via the accumulation of novel mutations. However, recent studies using next-generation sequencing have disclosed the complex genomic architecture of the disease. At each step of progression, the acquisition of novel mutations is accompanied by subclonal evolution from reservoir clones with branching patterns. Each subclone may carry novel mutations and distinct phenotypes, including drug sensitivity. In addition, minor clones already exist at the MGUS stage, which could expand later in the clinical course, resulting in relapse and/or leukemic conversion. The ultimate goal of treatment is to eradicate all clones, including subclonal populations with distinct biological characteristics. This goal could be achieved by further improving treatment strategies that reflect the genomic landscape of the disease.

Chronic Infection, a Neglected Cause Of Development Of Monoclonal Gammopathy Of Undetermined Significance (MGUS) and Myeloma

IntroductionChronic infection can lead to B-cell malignancy via the direct transformation of infected B-lymphocytes or indirectly via cell transformation consecutive to chronic antigen-driven stimulation; the two mechanisms may occur simultaneously (Seifert et al. Methods Mol Biol 2013; 971:1; Hermouet et al. New Engl J Med 2003; 348:178; de Martel et al. Lancet Oncol 2012). Numerous studies have established that viruses (Epstein-Barr virus (EBV), human herpes virus 8, hepatitis C virus (HCV)) or bacteria (H. pylori) can induce lymphoma and chronic lymphocytic leukemia (CLL). In contrast, the role of chronic infection in the pathogenesis of myeloma is rarely investigated. Yet monoclonal immunoglobulins (mc Ig) that arise in HCV-positive myeloma patients typically target the virus (Bigot-Corbel et al. Blood 2008). Thus HCV infection may lead to monoclonal gammopathy of undetermined significance (MGUS) and eventually, myeloma. The present study shows that mc Ig also frequently target EBV, and less frequently, H. pylori. MethodsIn order to study the specificity of mc Ig, we designed a new assay based on a multiplexed infectious protein (MIP) microarray that combines representative panels of epitopes of a panel of germs that included HCV, EBV, H. pylori and 5 other germs, spotted in triplicate on nitrocellulose-coated slides (Feron et al. Anal Biochem 2013; 433:202). Slides were first incubated with either serum or purified mc Ig, then with an infrared dyed (IRD)-labeled secondary antibody, and fluorescence signals were detected and quantified. ResultsThe specificity of purified mc Ig from 101 patients diagnosed with MGUS (n=34) or myeloma (n=67) was analysed using the 8-germ MIP microarray assay. We found that 20.6% of MGUS and 24.2% of myeloma patients (p=0.810) presented with a mc Ig that was specific for an antigen from HCV, EBV, or H. pylori. Indeed for 23/101 patients (22.7%), the purified mc Ig recognized HCV (n=10), EBV (n=11) or H. pylori (n=2). In contrast, none of the 101 mc Ig studied targeted CMV, a virus against which a majority of individuals possess antibodies.Interestingly, HCV- and EBV-specific mc Ig all targeted a single antigen. For 10/11 (91%) of the HCV-positive patients, the mc Ig was directed against HCV core protein. Regarding EBV-positive patients, the mc Ig specifically recognized EBV in 23% cases (11/59 tested), and in all cases the mc Ig targeted Epstein Barr nuclear antigen (EBNA). For 8% (2/25 tested) of H. pylori-positive patients, the mc Ig targeted different antigens of H. Pylori. The specificity of each mc Ig was confirmed by Western Blot analysis. ConclusionAltogether, 22.7% of the 101 MGUS and myeloma patients examined presented a mc Ig specific for HCV, EBV or H. pylori. Thus beside lymphoma and CLL, chronic infection by these 3 germs can also induce MGUS and eventually, trigger the pathogenic processes that lead to myeloma. Efforts should be made to identify the subsets of patients with mc Ig specific for HCV, EBV and H. pylori, preferably at the MGUS stage, as anti-infection treatment is expected to cure MGUS and prevent progression toward myeloma. Disclosures:No relevant conflicts of interest to declare.

V. Molecular classification and risk stratification of myeloma

Multiple myeloma (MM) cells are the malignant counterpart of post-germinal centre (GC) long-lived plasma cells (PCs), characterized by strong bone marrow (BM) dependence, somatic hypermutation of immunoglobulin (Ig) genes and isotype class-switch resulting in absence of IgM expression in all but 1% of tumours. However, MM cells differ from healthy PCs because they retain the potential for a low rate of proliferation (1–3% of cycling cells). Virtually every case of MM is preceded by a premalignant PC tumour called monoclonal gammopathy of undetermined significance (MGUS) that, like MM, produces a typical M-spike (almost always non-IgM) by serum protein electrophoresis (SPEP) or free light chain in the urine [1].

Disparities in the prevalence, pathogenesis and progression of monoclonal gammopathy of undetermined significance and multiple myeloma between blacks and whites

There is marked racial disparity in the incidence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma, with a two to threefold increased risk in blacks compared with whites. The increased risk has been seen both in Africans and African Americans. Similarly, an increased risk of monoclonal gammopathies in blacks compared with whites has been noted after adjusting for socioeconomic and other risk factors, suggesting a genetic predisposition. The higher risk of multiple myeloma in blacks is likely a result of the higher prevalence of the premalignant MGUS stage; there are no data to suggest that blacks have a higher progression rate of MGUS to myeloma. Studies are emerging that suggest the baseline cytogenetic characteristics, and progression may differ by race. In contrast, to the increased risk noted in blacks, studies suggest that the risk may be lower in certain racial and ethnic groups, notably persons from Japan and Mexico. We review the literature on racial disparity in the prevalence, pathogenesis and progression of MGUS and multiple myeloma between blacks and whites. We also discuss future directions for research that could inform management of these conditions and positively influence patient outcomes.

Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis

Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common premalignant disorders in Western countries. Recent studies show that almost every multiple myeloma (MM) case is preceded by an MGUS stage. Interestingly, prevalence and incidence patterns for MGUS and MM show striking disparity patterns across ethnic/racial groups, most notably the two- to threefold increase in both these disorders in African Americans compared with Caucasians. In contrast, studies on Asian patients show lower prevalence/incidence for MGUS/MM compared with Caucasians. Familial aggregation for both MGUS and MM has been observed; the risk for MGUS or MM in family members with these disorders is increased about two- to three fold compared with the general population. Although underlying mechanisms remain unclear, there is evidence of heterogeneity among MGUS patients from different ethnic/racial groups. For example, compared with Caucasians, African-American and African MGUS patients have reportedly lower rates of immunoglobulin M (IgM) MGUS (versus IgG/IgA MGUS) and higher rates of unquantifiable immunoglobulins (Igs). This review focuses on racial disparity and familial aggregation patterns for MGUS and MM and discusses how these observations provide novel clues with regard to pathogenesis.

Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma (MM). It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. Among 77,469 healthy adults enrolled in the nationwide population-based prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 71 subjects who developed MM during the course of the study in whom serially collected (up to 6) prediagnostic serum samples obtained 2 to 9.8 years prior to MM diagnosis were available. Using assays for monoclonal (M)-proteins (electrophoresis/immunofixation) and kappa-lambda free light chains (FLCs), we determined longitudinally the prevalence of MGUS and characterized patterns of monoclonal immunoglobulin abnormalities prior to MM diagnosis. MGUS was present in 100.0% (87.2%-100.0%), 98.3% (90.8%-100.0%), 97.9% (88.9%-100.0%), 94.6% (81.8%-99.3%), 100.0% (86.3%-100.0%), 93.3% (68.1%-99.8%), and 82.4% (56.6%-96.2%) at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis, respectively. In approximately half the study population, the M-protein concentration and involved FLC-ratio levels showed a yearly increase prior to MM diagnosis. In the present study, an asymptomatic MGUS stage consistently preceded MM. Novel molecular markers are needed to better predict progression to MM in patients with MGUS.

Hyperdiploidy Is a Common Finding in Monoclonal Gammopathy of Undetermined Significance and Monosomy 13 Is Restricted to These Hyperdiploid Patients

Two pathways, hyperdiploid and nonhyperdiploid, are proposed for progression to plasma cell neoplasia. Implication of monosomy 13 (Delta13) is unclear in monoclonal gammopathy of undetermined significance (MGUS), and data on DNA content of plasma cells [DNA index (DI)] are rare. We ascertained DI in 169 multiple myeloma (MM) and 96 MGUS patients. Interphase fluorescence in situ hybridization (FISH) coupled to cytoplasmic staining of specific Ig (cIg-FISH) was done to look for trisomies and to ascertain Delta13. Hyperdiploidy and hypodiploidy were found in 54% and 11.5% of MGUS patients and in 59.5% and 25% of MM patients, respectively. In MGUS patients tested using probes for odd chromosomes, cIg-FISH showed association between trisomies for chromosomes 3, 7, 9, 11, or 15 and hyperdiploidy. Delta13 was found in 45.3% and 24.6% of MM and MGUS patients, respectively. Most Delta13 cases observed in MGUS were found within hyperdiploid clones, 38% versus 11% in hypodiploid cases, in sharp contrast with the occurrence of Delta13 in MM patients, 31.9% and 76.3%, respectively. That peculiar distribution of Delta13 according to DI persisted with other thresholds used to ascertain hyperdiploidy, such as DI >or= 1.05. A strong relationship between IgA peak and hypodiploidy (P = 0.007) was only observed in MM, whereas lambda light chain was significantly associated with hypodiploidy in MGUS (P = 0.001) and MM (P = 0.05). Hyperdiploidy shows similar pattern in MGUS and MM. This fits well a hyperdiploid pathway leading to MM after a preceding MGUS stage. Yet-to-be-determined secondary event(s) needs to occur for the transition to MM, unrelated to changes in chromosome number or to loss of chromosome 13. In contrast, the "nonhyperdiploid" pathway needs to be clarified further because hypodiploidy is less common in MGUS than in MM and Delta13 is rare in hypodiploid MGUS patients compared with hypodiploid MM patients.

Both IGH translocations and chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma.

Molecular and genetic events associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are still poorly characterized. We investigated serial bone marrow specimens from 11 patients with MGUS who eventually progressed to MM (MM post-MGUS) by interphase fluorescence in situ hybridization for immunoglobulin heavy-chain gene (IgH) translocations and chromosome 13q deletions (del(13q)). In nine patients, IgH translocations were present both in MGUS and MM post-MGUS plasma cells, including three t(11;14)(q13;q32) and one t(4;14)(p16;q32), which was observed already 92 months prior to MM. Similarly, all five MM patients with del(13q) had this aberration already at the MGUS stage. Two patients without IgH translocation and del(13q) had chromosomal gains suggesting hyperdiploidy, but IgH translocations and/or del(13q) did not emerge at MM post-MGUS. IgH translocations and del(13q) are early genetic events in monoclonal gammopathies, suggesting that additional events are required for the transition from stable MGUS to progressive MM.

Origins of the malignant clone in typical Waldenstrom's macroglobulinemia

Histopathology and phenotypic considerations in IgM-secreting B-cell tumors allow distinction between different diseases, but insight into pathogenesis is restricted. Here, variable region (V) gene analysis can complement classification but, more importantly, can also reveal disease origins and clonal history. We used V H gene analysis to probe origins in Waldenstrom's macroglobulinemia (WM), and contrasted these with the less malignant counterpart, IgM-secreting monoclonal gammopathy of undetermined significance (MGUS). Limited data on WM sequences had previously shown evidence for somatic mutation, but with conflicting analysis of intraclonal variation in tumor sequences. To further the investigation, we analyzed seven cases of WM and compared these with three cases of IgM MGUS. In both diseases, V H genes were somatically mutated with no evidence of intraclonal variation, even at the MGUS stage. A sensitive V H gene-probe assay revealed no evidence for isotype switch transcripts in any of the WM and IgM MGUS cases. These findings reveal an origin of WM and IgM MGUS from a IgM cell, which transforms after cessation of somatic mutation but without initiating switch events. In contrast, IgM-secreting multiple myeloma arises at a later stage in differentiation, when isotype switch mechanisms have been engaged. Semin Oncol 30:136-141. © 2003 Elsevier Inc. All rights reserved.

Low plasma cell 3(H) thymidine incorporation in monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma and remission phase myeloma: a reliable indicator of patients not requiring therapy.

The kinetics of bone marrow plasma cells were evaluated by means of in vitro 3(H)thymidine incorporation in 143 patients with monoclonal gammopathies. Fifty-three patients had symptomatic multiple myeloma (MM) at diagnosis, nine were in stable remission, six in unstable remission, and 16 in the relapse phase. Thirty-seven patients were classified has having monoclonal gammopathy of undetermined significance (MGUS) and 22 as smouldering myeloma (SM). A thymidine labelling index (LI%) of greater than 3 at initial diagnosis predicted a very short survival. High LI% values (median 2.8 +/- 1.1) were also seen at relapse. However, the major new finding was that the LI% could be used to discriminate precisely between the SM-MGUS group and the MM patients including stage I disease (P less than 0.0001). Only one patient developed MM during follow up, that being 8 months after the initial diagnosis of SM. During the unmaintained stable remission (plateau) phase a low proliferative activity was also observed (LI% = 0.6 +/- 0.2). Thus the LI% was extremely useful in identification of both poor risk groups with a LI% greater than 3 and stable patients requiring no immediate therapy with a LI% less than 1. The ability to discriminate between MGUS and SM and stage I MM should prove particularly useful clinically.