Detection of monoclonal B lymphocytes in multiple myeloma by immunofluorescence tests of surface immunoglobulins.

Peripheral blood lymphocytes of 16 patients with secretory type of multiple myeloma and 5 with nonmyelomatous monoclonal gammopathy were investigated for the surface immunoglobulins on the cell by immunofluorescence. A low pH shock of cells before staining was applied to dissociate the passively absorbed immunoglobulins present on the cell surface. Increases of B lymphocytes bearing surface immunoglobulins which have the same light chains as those of monoclonal immunoglobulins produced by the plasma cells were found in 5 of 11 common secretory myeloma patients and in all of 6 Bence-Jones myeloma patients. Ratios of cells bearing light chains of kappa- and lambda-types (kappa/lambda) appeared abnormal in almost all with an exception of only 3 cases of myeloma patients, even in the cases where the number of Ig bearing cells did not increase. Increases of possible monoclonal B cells bearing IgG, in addition to IgA cells, were observed in some patients with IgA myeloma. Increases of B cells bearing certain heavy chains were also observed in all 5 patients with Bence-Jones myeloma during the course of disease. No abnormalities of B cells bearing surface immunoglobulin were found in nonmyelomatous monoclonal gammopathy. These results suggest that proliferation of monoclonal B lymphocytes, which may be progenitors to the malignant plasma cells, occurs in a majority of myeloma patients, but not in nonmyelomatous monoclonal gammopathy.     

CD5 B lymphocyte antigen in monoclonal gammopathy.

Because B lymphocytes bearing the CD5 antigen have been involved in many B-cell malignancies, we have investigated the presence of the CD5 B-cell antigen on B and plasma cells in monoclonal gammopathy. Quantification of CD5 B cells was made in the peripheral blood of seven individuals with monoclonal gammopathy of undetermined significance (MGUS) and in that of 21 patients with multiple myeloma (MM). The bone marrow of ten patients with MM was also studied. Patients with progressive MM presented a significant reduction in both B and CD5 B lymphocytes (i.e., percentages and absolute numbers), when compared with individuals with MGUS and patients with stable MM. These latter individuals and patients did not differ from healthy donors. No CD5 B cells were found in the bone marrow of patients with MM. Moreover, no CD5 antigen could be detected on eight freshly established human myeloma cells lines including six totally dependent on interleukin-6. However, it was weakly expressed on two standard myeloma cell lines not requiring exogenous interleukin-6 (i.e., RPMI 8226 and U 266). In conclusion, our data show mainly an overall reduction of the polyclonal CD5 B lymphocytes similar to what is observed for the other polyclonal B lymphocytes in patients with active MM. Finally, the expression of the CD5 antigen human myeloma cell lines is not constant.     

Clonally related IgA- and IgE-secreting plasma cells in a myeloma patient

OBJECTIVES: The purpose of this work was to study the clonal relationship between the cells that secrete monoclonal proteins in an IgA/ IgE double multiple myeloma patient. Double monoclonal gammopathy is a rare condition in which two types of monoclonal proteins can be found in the serum and/or urine of patients with multiple myeloma or gammopathy of undetermined significance. The study of the relationship between the cells expressing the different monoclonal proteins may provide insight in the pathogenesis of these disorders. METHODS: The clonal relationship of the two tumoral plasma cell populations was examined by immunophenotyping and sequence analysis of the variable regions of the immunoglobulin heavy chain genes. Both immunoglobulin sequences were isolated from the bone marrow using a polymerase chain reaction (PCR)-based cloning strategy. Rare isotype-switch variants were detected by a myeloma-specific PCR in combination with different isotype-specific primers. An in vitro culture system, based on the activation of the CD40 molecule on the B cell, was used in order to isolate and expand myeloma-related B cells from peripheral blood that could possibly be regarded as myeloma precursor cells. RESULTS: The variable parts of the immunoglobulin heavy chains linked to either Calpha or Cepsilon were exactly the same, including the same somatic mutations. From the in vitro CD40 cultures B cells could be isolated that either expressed IgA or IgE with exactly the same variable immunoglobulin part as the myeloma clone. No pre-switched IgM myeloma-related B cells could be found. CONCLUSION: Both cell populations in this IgA/IgE myeloma patient shared a common clonal origin. No evidence for a pre-switched IgM precursor myeloma cell was found in this patient.     

CD117 expression in gammopathies is associated with an altered maturation of the myeloid and lymphoid hematopoietic cell compartments and favorable disease features

Aberrant CD117 expression is associated with a favorable outcome in multiple myeloma. We analyzed 106 patients with symptomatic multiple myeloma (n=50), smoldering multiple myeloma (n=38) and monoclonal gammopathy of undetermined significance (n=18) to elucidate biological features of CD117⁺ versus CD117⁻ monoclonal gammopathies. CD117⁺ (mono)clonal plasma cells were detected in 30% symptomatic multiple myeloma, 45% smoldering multiple myeloma and 72% monoclonal gammopathy of undetermined significance patients. CD117 expression was associated with higher percentages of normal bone marrow plasma cells, CD117⁺ myeloid precursors and CD38⁺ B lymphocytes in all monoclonal gammopathies. Conversely, the number of bone marrow CD34⁺ myeloid cells and peripheral blood neutrophils was reduced among CD117⁺ multiple myeloma but not monoclonal gammopathy of undetermined significance patients.CD117 expression by (mono)clonal plasma cells is associated with uniquely altered patterns of production of hematopoietic bone marrow cells with decreased peripheral blood neutrophil counts and persistence of normal residual bone marrow plasma cells.     

B and T cell markers of bone marrow and peripheral blood lymphoid cells in patients with paraproteinaemia.

Studies have been carried out on B and T cells in bone marrow and peripheral blood from patients with paraproteinaemia. The peripheral blood of patients with multiple myeloma showed a significant increase of B cells, mainly lymphoid cells bearing immunoglobulins corresponding to the paraproteins, while in patients with benign monoclonal gammopathy only a slight increase of B cells and a moderate decrease of T cells have been found. As to the bone marrow, the B cell population was significantly raised in patients with multiple myeloma, but it remained unchanged in patients with benign monoclonal gammopathy. Our findings may offer a new possibility to distinguish between these two diseases and provide further data to their pathogenesis.     

Pre-B cells in peripheral blood of multiple myeloma patients

Although multiple myeloma is a disease of plasma cells, abnormalities have been detected in both B and T lymphocytes in peripheral blood. Although multiple myeloma patients are deficient in surface Ig (sIg)- positive B lymphocytes, analysis of lymphocytes present in blood indicates an abnormally large pool of circulating pre-B cells. These pre-B cells express BA-1, do not bear sIg, and contain cytoplasmic mu chains. High numbers of pre-B cells occur in 88% of individuals with frank myeloma and in 44% of individuals with monoclonal gammopathy of undetermined significance. Pre-B cells bearing BA-1 differ between patients in their expression of HLA-DR and receptors for peanut agglutinin (PNA). Those pre-B cells in myeloma patients are either BA- 1+ PNA- HLA-DR+ (54% of patients) or BA-1+ PNA+ HLA-DR- (30% of patients), or have a mixture of phenotypes (14% of patients). Pre-B cells of the PNA- phenotype are almost always HLA-DR+, and PNA+ pre-B cells are HLA-DR-. Within the same patient, the pre-B cell population varies by both quantitative and qualitative definitions. The number of pre-B cells may increase 460-fold and temporal shifts of surface phenotype from BA-1+ PNA- to BA-1+ PNA+ or vice versa have been detected. These observations indicate an abnormality in the B lymphocyte differentiation pathway leading to pre-B cells in the periphery that vary in number and cell surface phenotype, and that are unable to express sIg.     

Monoclonal gammopathy‐associated pure red cell aplasia

Pure red cell aplasia (PRCA) is a rare disorder characterized by inhibition of erythroid precursors in the bone marrow and normochromic, normocytic anaemia with reticulocytopenia. Among 51 PRCA patients, we identified 12 (24%) patients having monoclonal gammopathy, monoclonal gammopathy of undetermined significance or smouldering multiple myeloma, with presence of monoclonal protein or abnormal serum free light chains and atypical bone marrow features of clonal plasmacytosis, hypercellularity and fibrosis. Thus far, three patients treated with anti‐myeloma based therapeutics have responded with reticulocyte recovery and clinical transfusion independence, suggesting plasma cells play a key role in the pathogenesis of this specific monoclonal gammopathy‐associated PRCA.     

The clinical aspects of biclonal gammopathies. Review of 57 cases

Between 1966 and 1979, biclonal gammopathy was recognized in 57 patients. Clinical and laboratory features differentiated three groups: biclonal gammopathy of undetermined significance, 37 cases (65 percent); multiple myeloma, nine cases (16 percent); and lymphoproliferative disease--including lymphoma, macroglobulinemia, chronic lymphocytic leukemia and unclassified lymphoproliferative disorders--11 cases (19 percent). With biclonal gammopathy of undetermined significance, symptomatic multiple myeloma developed after two years in one patient; the others remained stable. One patient with multiple myeloma had osteosclerotic myeloma and a severe sensorimotor peripheral neuropathy, and another presented with plasma cell leukemia. In the remainder response to therapy and survival were much the same as in patients with multiple myeloma with a monoclonal protein. Patients with lymphoproliferative disease responded to chemotherapy like that for monoclonal gammopathy. Of the 57 patients, 30 (53 percent) had IgG and IgA components, 15 (26 percent) had IgG and IgM, six had two IgG components, three had IgA and IgM, one had IgA proteins, one had IgA and IgE and 1 had triclonal gammopathy. Of the 115 light chains, 70 percent were kappa; the chains were both kappa and lambda in 63 percent of biclonal pairs. In many cases, serum electrophoresis produced only a single band on the acetate strip, and the biclonal gammopathy was not recognized until immunoelectrophoresis was done. Although the clinical features of biclonal gammopathy and its response to therapy are similar to those of monoclonal gammopathy, this subject is of importance because of the lack of clinical data in the literature.     

Immunophenotypic aberrations, DNA content, and cell cycle analysis of plasma cells in patients with myeloma and monoclonal gammopathies

We describe the immunophenotypic and gross DNA defects in 55 patients with myeloma and 50 patients with monoclonal gammopathy and review the literature on this subject (MedLine, 1994-2000). Our data confirmed previous reports indicating that in myeloma nearly all marrow plasma cells are abnormal (98.7 +/- 8.1%). In monoclonal gammopathy the fraction of abnormal plasma cells was 35.0 +/- 32.8%. In both myeloma and monoclonal gammopathy, the most frequent aberrant phenotypic features consisted of absence of expression of CD19, strong expression of CD56, and decreased intensity of expression of CD38; aberrant expression of CD10, CD20, CD22, or CD28 was observed in less than one-third of myeloma cases. The vast majority of cases had two or more phenotypic aberrations. In the DNA studies, 7% of myeloma cases were biclonal and 93% of cases were monoclonal. In those studies with only one plasma cell mitotic cycle, 37% had normal DNA content and 63% were aneuploid (hyperploid, 61%; hypoploid, 2%). The mean percentages of plasma cells in S- and G2M phases were 4.9 +/- 8.5 and 4.4 +/- 6.9%, respectively. Thirty-eight percent of cases had more than 3% of plasma cells in S phase. In monoclonal gammopathy, the DNA index of abnormal plasma cells ranged from 0.89 to 1.30 and the percentage of diploid (31%) and aneuploid (69%) cases was not different from the results found in myeloma. The differences in percentage of abnormal plasma cells in S- (7.4 +/- 8.6%) and G2M-phases (2.4 +/- 1.7%) in patients with monoclonal gammopathy were not statistically significant.     

Lymphocyte Subpopulations in Benign Monoclonal Gammopathy

Peripheral blood samples from normal individuals and from patients with benign monoclonal gammopathy or multiple myeloma were separated and assayed by immunofluorescence and rosette formation for T, B, T^G and T^M subpopulations. When compared with normal individuals and multiple myeloma patients, the benign monoclonal gammopathy patients could be divided into 2 groups. The 1st group demonstrated a T/B ratio similar to normal individuals, whereas in the 2nd group the ratio resembled that of the myeloma patients, with a decrease in the fraction of T lymphocytes, accompanied by an increased number of B lymphocytes. An analysis of the monoclonal Ig fraction levels indicated that the 2 groups differ in this respect as well. In the 1st group, the level of the monoclonal immunoglobulin was stable, with small fluctuations. The 2nd group demonstrated a general increasing M-component, especially in the 4–6 months preceding the study. The 2 benign monoclonal gammopathy groups exhibited a trend to a lower T^M/T^G ratio compared to normals; this change is more prominent in the 2nd group. Analysis of the T lymphocyte subpopulations indicated an overall decrease in the fraction of T^M multiple myeloma. The above-mentioned parameters might thus aid in discriminating among BMG patients with regard to their tendency towards a malignant transformation.     

Immunoglobulin class switch from IgG to IgA in a patient with smoldering multiple myeloma

Serum of a 67-year-old male patient with smoldering multiple myeloma was shown to contain two monoclonal immunoglobulins, IgG and IgA. For the initial seven months, monoclonal IgG was predominantly elevated. During the next one year and eight months, however, serum concentration of the monoclonal IgA increased, with a concomitant decrease of IgG. N-terminal amino acid sequences of heavy and light chains separated from monoclonal IgG and IgA were analyzed. Both light chains were lambda-type and showed identical amino acid sequences of variable regions. The heavy chains also had the same N-terminal amino acid sequence between IgG and IgA. These results strongly suggest that two monoclonal proteins, IgG and IgA, in this patient were produced by B lymphocytes within a clone and that class switch from IgG to IgA in immunoglobulin production during B cell differentiation has taken place in the clinical course of this case.     

Nephrotic syndrome in a patient with IgM myeloma with associated neutrophilia

An unusual case having IgM monoclonal gammopathy with clinical and pathologic features of multiple myeloma (MM) in association with neutrophilia and nephrotic syndrome is reported. The patient showed lytic bone lesions, decreased IgG and IgA levels, Bence-Jones proteinuria, nephrotic proteinuria with edema, and histological plasma cell infiltration typical of MM. Moreover, mature neutrophilic leukocytosis, hepatomegaly, high leukocyte alkaline phosphatase score (LAP), absence of Philadelphia (Ph) chromosome and bcr gene rearrangement were also evidenced, all these features representing findings typical of the recently described plasma cell dyscrasia-associated neutrophilia. After the diagnosis, the patient was treated with melphalan and prednisone, with an excellent response to the treatment. Different from the 30 cases so far reported, this is the first case of plasma-cell dyscrasia with associated neutrophilia due to IgM-producing monoclonal gammopathy. At the same time, this is the first reported case of nephrotic syndrome secondary to IgM myeloma.     

Monoclonal Blood Lymphocytes in Benign Monoclonal Gammopathy and Multiple Myeloma in Relation to Clinical Stage

20 patients with benign monoclonal gammopathy (BMG) have been studied for blood lymphocyte and subpopulations. 4 patients had slightly decreased T-lymphocyte values. Total B-lymphocytes were within the normal range. In 3 BMG patients an abnormal ratio between χ- and Λ-bearing lymphocytes was detected indicating circulating monoclonal cells. 41 patients with untreated multiple myeloma have also been analysed for blood monoclonal lymphoid cells using the χ:Λ-ratio. 54% of the patients had monoclonal blood cells at diagnosis. The incidence and numbers of such cells increased with advanced clinical stage. Thus, it seems as if tumor volume is the main factor responsible for the appearance of monoclonal blood cells in multiple myeloma.     

Quantitation of the monoclonal plasma cell component in bone marrow from patients with serum paraproteinemia and nondiagnostic marrow morphology

Twenty-one patients with serum monoclonal gammopathy but lacking acceptable morphological evidence of myelomatosis were studied with reference to the degree, if any, of monoclonal plasma cell expansion in aspirated marrow samples, enriched for plasma cells and analysed with respect to light chain distribution. Four of these patients had a biopsy-proven plasmacytoma of bone. Bone marrow aspirated from sites distant to the tumor showed clear evidence of infiltration by monoclonal plasma cells in two of the cases studied; the other two patients had normal results. Of the 17 other cases, 14 showed evidence of a monoclonal plasma cell component qualitatively concordant with the serum paraprotein as one would expect. These cases could be subdivided into those with myeloma (six cases) and those with monoclonal gammopathy of undetermined significance (eight cases) on the basis of conventional biochemical and radiological criteria. Three of the 17 patients, however, did not show evidence of monoclonal plasma cell infiltration, despite the presence of lytic lesions. It is important to recognize this minority group that simulates myeloma but that may well reflect alternative pathology that has not been identified.     

Eosinophilic fibrohistiocytic lesion of bone marrow associated with monoclonal gammopathy and osteolytic lesions

We describe a 63-year-old male patient with severe osteoporosis, multiple lytic bone lesions, and monoclonal gammopathy (IgG lambda). Whereas the tentative diagnosis in this case was multiple myeloma, bone marrow trephine biopsies of the iliac crest and from an osteolytic lesion of the tibia both showed a peculiar infiltrate consisting of numerous elongated mast cells, eosinophils, and some plasma cells and lymphocytes. The bone marrow lesions fit the diagnosis of eosinophilic fibrohistiocytic lesion of bone marrow (EFHBM). The patient had no abnormality that could be related to a known allergic disease, and no relationship to drug hypersensitivity could be established. The features of the bone marrow infiltrate and its association with monoclonal gammopathy may suggest a linkage between EFHBM and the monoclonal gammopathy.     

Establishment and characterization of an amylase-producing human myeloma cell line

Two stable lines of IgA lambda-producing plasma cells (KHM-1A and KHM- 1B) that were free of the Epstein-Barr virus were established from a patient with multiple myeloma complicated by hyperamylasemia. Surface marker studies of the two cell lines showed that the cells had no surface immunoglobulins but were positive for cytoplasmic immunoglobulins (IgA lambda) and for HLA-DR and PCA-1. Secretion of IgA monoclonal immunoglobulin by the two lines was detected by a plaque- forming cell assay and by an enzyme-linked immunosorbent assay of culture media. KHM-1B cells also secreted alpha-amylase, but no such activity was detected in the culture-conditioned supernatant fluid of KHM-1A.     

Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry

Multiple myeloma remains largely incurable. However, a few patients experience more than 10 years of relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with a complete response, since some patients revert to having a profile of monoclonal gammopathy of undetermined significance. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of multiple myeloma patients with long-term disease control (n=28), patients with newly diagnosed monoclonal gammopathy of undetermined significance (n=23), patients with symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Similarly to the patients with monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8⁺ T cells and natural killer cells. However, the numbers of bone marrow T-regulatory cells were lower in patients with long-term disease control than in those with symptomatic multiple myeloma. It is noteworthy that B cells were depleted in patients with monoclonal gammopathy of undetermined significance and in those with symptomatic multiple myeloma, but recovered in both the bone marrow and peripheral blood of patients with long-term disease control, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B cells. The number of bone marrow dendritic cells and tissue macrophages differed significantly between patients with long-term disease control and those with symptomatic multiple myeloma, with a trend to cell count recovering in the former group of patients towards levels similar to those found in healthy adults. In summary, our results indicate that multiple myeloma patients with long-term disease control have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting improved immune surveillance.     

Monoclonal gammopathy of undetermined significance. Natural history in 241 cases

Two hundred forty-one patients with a monoclonal protein in the serum but initially no evidence of multiple myeloma, macroglobulinemia, amyloidosis or lymphoma were followed up for more than five years. At the conclusion of the studies the patients were classified as follows: Group 1, patients without significant increase in monoclonal protein, 57 per cent; group 2, patients with more than 50 per cent increase in monoclonal serum protein or development of monoclonal urine protein, 9 per cent; group 3, patients who died without five-year serum studies, 23 per cent; and group 4, patients in whom myeloma, macroglobulinemia or amyloidosis developed, 11 per cent. Initially, the hemoglobin level, size of serum monoclonal protein peak, number of plasma cells in the bone marrow and levels of normal immunoglobulins were not significantly different among the four groups. The median interval from recognition of the monoclonal protein to diagnosis of multiple myeloma was 64 months, of macroglobulinemia 103 months and of amyloidosis 92 months. A significant increase of the monoclonal protein or development of myeloma, macroglobulinemia or amyloidosis occurred in 18 per cent of the patients with monoclonal immunoglobulin G(IgG), in 28 per cent with immunoglobulin A (IgA) and in 25 per cent with immunoglobulin M (IgM). Retrospective analysis of age, sex, presence of organomegaly, hemoglobin level, size and type of serum monoclonal protein peak, presence of small amounts monoclonal light chain in the urine, serum albumin level, levels of uninvolved immunoglobulins, IgG subclass and level of plasma cells in the bone marrow did not show how to distinguish initially between stable benign disease and progressive disease. Therefore, periodic reexamination of patients with monoclonal gammopathy is essential.     

Monoclonal gammopathy and spurious hypophosphatemia

BACKGROUND: Spuriously low levels of plasma phosphate have been reported previously in patients with multiple myeloma and polyclonal gammopathy. We report 2 cases of spurious hypophosphatemia in patients with elevated concentrations of serum monoclonal immunoglobulins, 1 of whom had monoclonal gammopathy of undetermined significance and the other multiple myeloma. METHODS: Plasma phosphate concentrations were measured using nondeproteinized and deproteinized plasma samples from patients with monoclonal gammopathies. RESULTS: In 2 patients with monoclonal gammopathy, the levels of plasma inorganic phosphate were reported as <1.0 mg/dL when the phosphate concentration was determined using an analyzer that employs nondeproteinized plasma. When the samples were reanalyzed using a laboratory method that removes serum proteins, normal or elevated concentrations of phosphate were found. Plasma levels of phosphate in 4 other patients with monoclonal gammopathy were normal by both methods. CONCLUSIONS: These data confirm previous reports that spurious hypophosphatemia occurs in some patients with increased levels of serum monoclonal immunoglobulins when laboratory methods using nondeproteinized samples are employed. The occurrence of unusually low plasma phosphate concentrations in patients without symptoms or clinically apparent causes of hypophosphatemia should alert physicians to search for monoclonal gammopathy.     

Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy

The presenting clinico-hematologic features of 386 patients with nonmyelomatous monoclonal gammopathy (MG) were correlated with the frequency of malignant transformation to evaluate the most important variables conditioning its evolution into multiple myeloma (MM) or Waldenstrom macroglobulinemia (WM). Most of the patients (335) had monoclonal gammopathy of undetermined significance (MGUS: 39 IgA, 242 IgG, 54 IgM): the remaining 51 patients (12 IgA, 39 IgG) fulfilled all of the MGUS diagnostic criteria (according to Durie) except that bone marrow plasma cell (BMPC) content was 10% to 30%, and so they were defined as having monoclonal gammopathy of borderline significance (MGBS). There were no significant differences between the MGUS and MGBS groups in terms of age, sex, or median follow-up. After a median follow- up of 70 and 53 months, respectively, 23 of 335 MGUS and 19 of 51 MGBS patients had undergone a malignant evolution. Univariate analysis of the IgA and IgG patients showed that the cumulative probability of the disease evolving into MM correlated with diagnostic definition (MGBS v MGUS), BMPC content (> or = 10% v < 5% and < or = 5% v > 5%) and reduced serum polyclonal Ig. In the IgG cases, there was also a significant correlation with detectable Bence Jones proteinuria, serum monoclonal component (MC) levels and age at diagnosis (> 70 v < = or 55 years). In the IgG cases as a whole, the same variables remained in the Cox model where the BMPC percentage was considered after natural logarithmic transformation and the monoclonal component as g/dL value. The relative risks of developing MM are the following: 2.4 for each 1 g/dL increase of IgG, serum MC, 3.5 for detectable light chain proteinuria, 4.4 for the increase of 1 unit in log. BMPC percentage, 6.1 for age > 70, 3.6 and 13.1 for a reduction in one or two polyclonal Ig. In conclusion, our study allows the identification of a particular subset of MGUS patients (MC < = or 1.5 g/dL, BMPC < 5%, no reduction in polyclonal Ig and no detectable light chain proteinuria) at very low- risk of evolution, who can be considered as having benign monoclonal gammopathies. We also describe a previously undefined group of MG patients (with monoclonal gammopathy of borderline significance) who are at high-risk of malignant evolution. These findings could have a considerable impact on the cost/benefit ratio of monitoring programs in these patients.