Expression of shared idiotypes by paraproteins from patients with monoclonal gammopathy of undetermined significance

We have previously demonstrated the expression of shared idiotypes by the paraproteins from approximately one-quarter of patients with multiple myeloma (MM). We have now investigated whether similar cross-reactivity is expressed in the paraproteins of patients with monoclonal gammopathy of undetermined significance (MGUS), using a panel of 32 monoclonal antibodies (MAB) generated against follicular B cell lymphomas. The paraproteins from 76/409 (19%) patients with MGUS reacted with at least one of 23 different anti-idiotypic antibodies used in this study. 18 MABs demonstrated reactivity with more than one patient's paraprotein. Moreover, 10 MABs reacted frequently (with 5–22 paraproteins). Over half (41/76) of the reactive patients' paraproteins reacted with more than one MAB from this panel. This frequency of anti-idiotypic reactivity was similar to that of previously studied patients with myeloma, chronic lymphocytic leukaemia (CLL), and follicular B-cell lymphomas. There was no correlation between specific anti-idiotypic reactivity and the propensity to develop serious disease (MM, macroglobulinaemia, amyloidosis, or other lymphoproliferative disorders) in patients with MGUS. These results suggest that MGUS is derived from cells producing antibodies that are similar to those of other B-cell malignancies and that the pattern of idiotype expression is irrelevant to malignant potential.     

Interleukin-6 is expressed by plasma cells from patients with multiple myeloma and monoclonal gammopathy of undetermined significance

Interleukin-6 (IL-6) is an important growth factor for human myeloma cells in vitro and in vivo . However, the identity of the cells producing IL-6 in vivo in patients with multiple myeloma (MM) remains the subject of debate. We have developed a sensitive dual-colour fluorescence in situ hybridization (FISH) technique to investigate the expression of IL-6 mRNA by individual bone marrow plasma cells from patients with multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS) and healthy subjects. IL-6 mRNA could be identified in all immunoglobulin light chain (IgLC) expressing cells from all patients with MM and MGUS. The IL-6 protein could also be detected by direct immunofluorescence in all plasma cells (cytoplasmic light chain positive) from all patients with MM and MGUS. Furthermore, it was also possible to demonstrate cytoplasmic IL-6 staining of plasma cells from patients with MM by flow cytometric analysis. In contrast, neither the IL-6 mRNA or protein could be detected in normal plasma cells from healthy bone marrow donors. These data demonstrate that plasma cells from patients with MM and MGUS express the IL-6 mRNA and synthesize the IL-6 protein and support the hypothesis that autocrine synthesis of IL-6 is of importance in patients with MM.     

Pathogenesis of monoclonal gammopathy of undetermined significance and progression to multiple myeloma

Monoclonal gammopathy of undetermined significance (MGUS), including immunoglobulin light chain only MGUS, is an age-dependent premalignant tumor that is present in about 4% of Caucasian individuals over the age of 50 years. It is comprised of two different kinds of tumors: about 15% lymphoid or lymphoplasmacytoid MGUS and the remainder plasma cell MGUS. Plasma cell MGUS is stable but can sporadically progress to multiple myeloma (MM) at an average rate of about 1% per year. Most, if not all, MM tumors are preceded by plasma cell MGUS, which shares four partially overlapping oncogenic features with MM. It presently is not possible to unequivocally distinguish an MGUS tumor cell from an MM tumor cell. However, two models based on clinical laboratory tests indicate that it is possible to stratify MGUS tumors into groups that have average rates of progression as low as 0.26% per year and as high as 12% per year.     

Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma

Patients with multiple myeloma (MM) have an increased risk of deep venous thrombosis (DVT), particularly when treated with immunomodulatory drugs. Recently, 2 small hospital-based studies observed persons with the MM precursor condition, monoclonal gammopathy of undetermined significance (MGUS), to be at increased risk of developing DVT. Among 4 196 197 veterans hospitalized at least once at US Veterans Affairs hospitals, we identified a total of 2374 cases of MGUS, and 39 272 persons were diagnosed with DVT (crude incidence 0.9 per 1000 person-years). A total of 31 and 151 DVTs occurred among MGUS and MM patients, respectively (crude incidence 3.1 and 8.7 per 1000 person-years, respectively; P < .01). Compared with the entire study population, the relative risk (RR) of DVT after a diagnosis of MGUS and MM was 3.3 (95% confidence interval [CI], 2.3-4.7) and 9.2 (95% CI, 7.9-10.8), respectively. The most prominent excess risk of DVT was found during the first year after diagnosis of MGUS (RR = 8.4; 95% CI, 5.7-12.2) and MM (RR = 11.6; 95% CI, 9.2-14.5). Among 229 MGUS cases (9.5%) that progressed to MM, only one person had a DVT diagnosis before transformation. Our findings suggest the operation of shared underlying mechanisms causing coagulation abnormalities among patients with MGUS and MM.     

Peripheral blood lymphocyte subsets in multiple myeloma and monoclonal gammopathy of undetermined significance

Summary. Peripheral blood lymphocyte subsets were analysed by flow cytometry and compared among 43 patients with untreated multiple myeloma (MM), 16 patients with monoclonal gammopathy of undetermined significance (MGUS) and 26 controls. The age and sex distributions of the patients and controls were comparable, which is important, since in the controls there was a significant effect of age and/or sex on the number of CD3⁺, CD57⁺, CD8⁺57⁺, CD16⁺ and CD3^-56⁺ lymphocyte subsets, and on the CD4⁺/CD8⁺ and CD4⁺Leu–8⁺/CD4⁺ ratios. In MM, the number of CD8⁺ and CD57⁺ cells and the CD4⁺/CD8⁺ ratio were related to the clinical stage. The number of CD20⁺, CD3⁺, CD4⁺, CD16⁺ and CD3^-56⁺ cells and the CD3⁺/CD20⁺ ratio were significantly different in MM patients compared to age- and sex-matched controls as was the number of CD3¹ and CD4¹ cells of MGUS patients compared to controls. Further, there were significant differences in the CD3^-/CD20⁺ ratio between MM and MGUS patients and between stage I MM and MGUS. The role of peripheral blood lymphocyte subsets in differentiating monoclonal gammopathies merits further study.     

Circulating clonotypic B cells in multiple myeloma and monoclonal gammopathy of undetermined significance

The B-cell compartment in which multiple myeloma stem cells reside remains unclear. We investigated the potential presence of mature, surface-membrane immunoglobulin-positive B lymphocytes clonally related to the tumor bone marrow plasma cells among different subsets of peripheral blood B cells from ten patients (7 with multiple myeloma and 3 with monoclonal gammopathies of undetermined significance). The presence of clonotypic immunoglobulin heavy chain gene rearrangements was determined in multiple highly-purified fractions of peripheral blood B-lymphocytes including surface-membrane IgM⁺ CD27⁻ naïve B-lymphocytes, plus surface-membrane IgG⁺, IgA⁺ and IgM⁺ memory CD27⁺ B cells, and normal circulating plasma cells, in addition to (mono)clonal plasma cells, by a highly-specific and sensitive allele-specific oligonucleotide polymerase chain reaction directed to the CDR3 sequence of the rearranged IGH gene of tumor plasma cells from individual patients. Our results showed systematic absence of clonotypic rearrangements in all the different B-cell subsets analyzed, including M-component isotype-matched memory B-lymphocytes, at frequencies <0.03 cells/μL (range: 0.0003–0.08 cells/μL); the only exception were the myeloma plasma cells detected and purified from the peripheral blood of four of the seven myeloma patients. These results indicate that circulating B cells from patients with multiple myeloma and monoclonal gammopathies of undetermined significance are usually devoid of clonotypic B cells while the presence of immunophenotypically aberrant myeloma plasma cells in peripheral blood of myeloma patients is a relatively frequent finding.     

The relationship between proliferation and apoptosis in patients with monoclonal gammopathy of undetermined significance or multiple myeloma

Multiple myeloma (MM) is a clonal neoplastic lymphoproliferative disease affecting terminally differentiated B cells i.e. plasma cells characterized by slow proliferation activity and different resistance to apoptosis with latent accumulation of myeloma cells in the bone marrow. This process is induced by failure of normal tissue homeostatic mechanisms. We compared plasma cell proliferation and apoptic indices in various phases of MM and in monoclonal gammophaty of untetermined significance.     

Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic disorders characterized by monoclonal plasma cell proliferation in the bone marrow in the absence of end-organ damage. Updated diagnostic criteria for these disorders, risk-stratification models to determine prognosis, and the current management of these two entities are discussed in this review.     

Familial occurrence of multiple myeloma and monoclonal gammopathy of undetermined significance in 5 siblings

The etiology of monoclonal gammopathies remains unclear but familial occurrence of immunopathies seems to favor a possible hereditary background. In support of this view we report on a family in which five siblings had a monoclonal gammopathy. When MGUS was diagnosed in two of them, a family study was carried out: one sister died from multiple myeloma and four out of the seven living siblings were discovered to have a MGUS. The immunogenetic study (HLA) showed no direct correlation between haplotypes and the presence of the monoclonal protein. Nevertheless possible environmental exposure to viruses, chemicals and radiation was apparently excluded. This new report on familial involvement, the second ever reported for number of affected subjects, strongly supports the theory of genetic predisposition in the development of plasma cell dyscrasias.     

Hypercoagulability in multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance

Patients with multiple myeloma are at an increased risk of venous thromboembolism (VTE), especially when treated with the immunomodulatory drugs, thalidomide and lenalidomide, in combination with dexamethasone and/or chemotherapy. Several studies have shown that patients with multiple myeloma precursor disease (monoclonal gammopathy of undetermined significance [MGUS]) also have a higher risk of thrombosis compared to the general population. The underlying mechanisms for the hypercoagulable state are not completely understood. In this review, we discuss risk factors for thrombosis in multiple myeloma, as well as prophylactic strategies, the evidence for thrombosis among patients with MGUS, and proposed mechanisms for the hypercoagulability.     

Parental longevity and survival among patients with multiple myeloma and monoclonal gammopathy of undetermined significance: a population-based study

Parental longevity is associated with an increased life expectancy; results with regard to specific diseases are conflicting. There are limited data focusing on host characteristics and their effect on survival among multiple myeloma (MM) patients and individuals with monoclonal gammopathy of undetermined significance (MGUS). Therefore, our aim was to evaluate the impact of parental longevity on survival of patients with MM and MGUS. A total of 4675 patients with MM, 6812 MGUS patients and 13 398 population-based controls for MM as well as 19 110 controls for MGUS, from 1988 to 2013, were included in the study. Longevity was defined as >90 years of age. Among MM patients, parental longevity was associated with a decreased risk of death [hazard ratio (HR) = 0·92, 95% confidence interval (CI) 0·84–0·99] and the same was true for MGUS patients (HR = 0·87, 95% CI 0·78–0·96). Having one long lived parent significantly decreased the risk of death in both groups, but was not statistically significant when both parents exceeded 90 years of age. In conclusion, parental longevity decreases the risk of death for patients with MM and MGUS which may reflect the importance of the host's genetic and environmental factors in relation to survival.     

Secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation in multiple myeloma

In the course of multiple myeloma, patients may develop a M-protein band different from the original: secondary monoclonal gammopathy of undetermined significance. In this retrospective single center analysis, we describe the occurrence and clinical relevance of secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation (post-transplant monoclonal gammopathy of undetermined significance). A total of 138 patients who had undergone 139 allogeneic stem cell transplantations (39.6% in the upfront setting and 60.4% for relapsed multiple myeloma) were included in the study. Sixty-seven (48.2%) patients developed secondary monoclonal gammopathy of undetermined significance, after a median latency of 6.9 months. Secondary monoclonal gammopathy of undetermined significance occurred more often in patients who achieved at least very good partial response after allogeneic stem cell transplantation, compared to partial response or less (54.8% vs. 26.5%; P=0.005). The incidence was also higher in the upfront setting as compared to relapsed disease, or with a sibling donor compared to matched unrelated donor, but less often after T-cell depletion. Importantly, development of post-transplant monoclonal gammopathy of undetermined significance as a time-dependent variable independently predicted for superior progression-free and overall survival (median progression-free survival 37.5 vs. 6.3 months, P<0.001; median overall survival 115.3 vs. 31.0 months, P=0.004). Clinicians should be aware of the benign nature of this phenomenon, and secondary monoclonal gammopathy of undetermined significance should not be confused with relapse or progression of disease. (Trial registered with trialregister.nl; HOVON 108: NTR 2958.)     

Multicolor fluorescence in situ hybridization studies in multiple myeloma and monoclonal gammopathy of undetermined significance

The aim of the study was to test the multicolor fluorescence in situ hybridization technique (M-FISH) in seven multiple myeloma (MM) and eight monoclonal gammopathy (MGUS) patients. None of the eight MGUS patients had chromosomal abnormalities by conventional cytogenetics. In two of these patients structural abnormalities of chromosomes 2, 11 and 19 were found by M-FISH. However, these findings were not confirmed by conventional in situ hybridization. M-FISH only showed numerical chromosomal abnormalities in one out of the three MM cases with a normal karyotype. In the two MM cases with complex karyotype, M-FISH demonstrated the origin of the marker chromosomes. M-FISH is a useful technique to identify the origin of the marker chromosomes in MM. In contrast, MM or MGUS patients with normal karyotypes by conventional cytogenetics did not show structural abnormalities by M-FISH.     

Cancer risk in patients with monoclonal gammopathy of undetermined significance

Argentine hemorrhagic fever (AHF) is a viral disease caused by Junin virus and characterized by hematologic and neurological involvement. The main hematologic features are leukopenia, thrombocytopenia, and bone marrow hypoplasia. Hematopoietic growth factors serum levels were measured by ELISA technique in forty-eight patients with confirmed diagnosis of AHF. Patients were classified according to the clinical picture in 15 severe (SCF), 17 moderate (MoCF), and 16 mild (MiCF) cases. Erythropoietin levels were decreased in 28 of 45 patients and raised in 4 SCF patients. Twenty-four of 38 patients had high G-CSF levels at admittance in accordance with clinical picture severity, while IL-3, GM-CSF, and TGF-beta were normal in most cases. A direct correlation was found between G-CSF and TNF-alpha levels. Thrombopoietin levels were found to be raised in 19 of 21 patients. In conclusion, the low levels of Epo may contribute to the severe bone marrow erythroblastopenia described in AHF patients, while G-CSF seems to be a marker of illness severity.     

Increase in the suppressor-inducer T cell subset in multiple myeloma and monoclonal gammopathy of undetermined significance

The expression of CD4 (helper-inducer), CD8 (suppressor-cytotoxic) and CD4 subpopulations (2H4 and 4B4) were studied in patients with multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS) and in healthy controls. The percentages of CD4+ cells and CD8+ cells among total T cells were not different between the three groups studied. However the percentage of CD4+ cells of the suppressor-inducer type (CD4 + 2H4 +) was 53 +/- 9% in patients with MGUS, and 51 +/- 9% in those with MM, compared to 46 +/- 5 in the controls (P = 0.033 and P = 0.07 respectively). A significant negative correlation between serum polyclonal IgM and the percentage of CD4 + 2H4 + cells was found in patients with MM but not in those with MGUS. No difference was found in the percentage of CD4 + 4B4 + (helper CD4+ cells) between the various groups. These findings suggest that the elevation of the suppressor-inducer subset occurs prior to clinical manifestations of MM, perhaps as an immune response to the malignant clone. The existence of elevated proportions of CD4 suppressor-inducer cells was associated with the hypogammaglobulinaemia observed in patients with MM. Since no hypogammaglobulinaemia was present in those with MGUS, additional factors are needed to explain the influence of the CD4 + 2H4 + cells on the production of immunoglobulins.     

Bone disease from monoclonal gammopathy of undetermined significance to multiple myeloma: pathogenesis, interventions, and future opportunities

Manifestations of bone disease-osteopenia, osteolytic lesions, and fractures-are the hallmark of multiple myeloma (MM) and occur clinically in the vast majority of patients. These abnormalities can have devastating clinical effects by increasing both the morbidity and mortality of patients. Bone disease is usually found when patients are diagnosed with active MM; however, recent data suggest that it is present in early myelomagenesis, including patients with myeloma precursor disease, monoclonal gammopathy of undetermined significance (MGUS). The primary mechanisms of abnormal bone remodeling are increased osteoclastic activity, which occurs in close proximity to active myeloma cells, and decreased activity of the surrounding osteoblasts. Better understanding of the pathogenesis of bone disease in MM will allow us to enhance our current therapeutic options in the treatment of bone disease. In patients with active MM and at least one lytic lesion, intravenous bisphosphonates have been shown to decrease skeletal-related events and pain, improve performance status, and maintain quality of life. Emerging evidence suggests that intervention at earlier stages of disease may prevent skeletal-related events at time of progression, but there is no evidence that bisphosphonates in this setting change the natural history of the disease.