Neuropathies and paraproteins.

PURPOSE OF REVIEW: There is an increasingly recognized association between haematological and neurological disease. This is especially true in the peripheral nervous system in which, to an extent, proof of a link is easier to achieve. The most sensitive low level paraprotein detection methods should always be employed in which a paraprotein is suspected. Peripheral nerves can be damaged not only by the immunological targeting of the myelin by the paraprotein, but by deposition (light chain amyloid and cryoglobulins) or direct infiltration (neurolymphomatosis). This has resulted in other defined paraprotein-related disease pathogeneses. RECENT FINDINGS: Our opportunities for treating these patients are greater not only through better recognition of disease but also treatments introduced from haematological research. Beyond rituximab, combination therapies, proteasome inhibition and novel biological treatments are being described in haematological practice with early efficacy in neurology. Important developments here should be exploited in neurology to improve outcomes. SUMMARY: This review of the current literature focuses not only on the long-term outcome studies in anti-myelin-associated glycoprotein neuropathy, but developments in the diagnosis and treatment of monoclonal gammopathy of undetermined significance and Waldenström's Macroglobulinaemia.

A clone-directed approach may improve diagnosis and treatment of proliferative glomerulonephritis with monoclonal immunoglobulin deposits.

The optimal treatment for the monoclonal gammopathies of renal significance is not known, but there is consensus among experts that treatment should be specific for the underlying clone. The majority of patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) do not have an identifiable clone, and prior studies have found poor renal outcomes for patients with PGNMID treated with a variety of regimens. Here we present a retrospective case series of 19 patients with PGNMID with a more uniform, clone-directed approach. A circulating paraprotein was detected in 37% of patients, and the overall clone detection rate was 32%. Treatment was directed at the underlying clone or, for patients without a detectable clone, empirically prescribed to target the hypothesized underlying clone. Of the 16 patients who underwent treatment, the overall renal response rate was 88%, and 38% of patients experienced complete renal response (proteinuria reduction to under 0.5 gm/24 hours) with initial treatment. All patients were End Stage Renal Disease-free at last follow-up (median 693 days after diagnosis), and treatment was well tolerated. Thus, a clone-directed approach may lead to novel, targeted treatment strategies that could significantly improve outcomes for patients with PGNMID.

Monoclonal immunoglobulin-associated proliferative glomerulonephritis characterized by organized deposits of striated ultra-substructures: A case report.

We herein report the case of a 64-year-old male who presented with progressive glomerulonephritis notable for organized and striated ultra-substructures. The patient was diagnosed with hypertension and proteinuria 3 years prior to admission and subsequently developed nephrotic syndrome and impairment of renal function. Laboratory tests did not reveal any evidence of infections or autoimmune diseases. Monoclonal gammopathy was not detected in serum or urine, although a small population of abnormal plasma cell clones was detected by flow cytometry. A renal biopsy showed mesangial and endocapillary proliferative glomerulonephritis with lobular accentuation, accompanied with focal and segmental double-contour formation. Additionally, moderate tubulointerstitial scarring and arteriosclerosis were noted. Immunofluorescence staining revealed positive staining for IgG, IgM, C3, C1q, and fibrinogen. IgG subclass and light chain staining showed restricted positivity for IgG1κ. Electron microscopy demonstrated massive amounts of subendothelial deposits with a fibrillary and branching profile. At higher magnification, a periodic striated pattern was observed within the microfilament-like structures. Immunohistochemical staining was negative for myoglobin, laminin, and collagens (type III and IV). Steroid and antihypertensive therapy did not show improvement in renal function. The second biopsy performed 2 years later revealed a similar lobular proliferative glomerulonephritis pattern with more extensive tubulointerstitial damage, indicating poor response to immunosuppressive therapy. The patient progressed to end-stage renal disease and required hemodialysis. We discuss the possible origins of the deposits with unusual substructures observed in this case.

Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies.

BACKGROUND: Serum monoclonal anti-myelin-associated glycoprotein (anti-MAG) antibodies may be pathogenic in some people with immunoglobulin M (IgM) paraprotein and demyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be beneficial. This is an update of a review first published in 2003 and previously updated in 2006 and 2012. OBJECTIVES: To assess the effects of immunotherapy for IgM anti-MAG paraprotein-associated demyelinating peripheral neuropathy. SEARCH METHODS: On 1 February 2016 we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials (RCTs). We also checked trials registers and bibliographies, and contacted authors and experts in the field. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs involving participants of any age treated with any type of immunotherapy for anti-MAG antibody-associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance and of any severity.Our primary outcome measures were numbers of participants improved in disability assessed with either or both of the Neuropathy Impairment Scale (NIS) or the modified Rankin Scale (mRS) at six months after randomisation. Secondary outcome measures were: mean improvement in disability, assessed with either the NIS or the mRS, 12 months after randomisation; change in impairment as measured by improvement in the 10-metre walk time, change in a validated linear disability measure such as the Rasch-built Overall Disability Scale (R-ODS) at six and 12 months after randomisation, change in subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; change in serum IgM paraprotein concentration or anti-MAG antibody titre at six months after randomisation; and adverse effects of treatments. DATA COLLECTION AND ANALYSIS: We followed standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified eight eligible trials (236 participants), which tested intravenous immunoglobulin (IVIg), interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Two trials of IVIg (22 and 11 participants, including 20 with antibodies against MAG), had comparable interventions and outcomes, but both were short-term trials. We also included two trials of rituximab with comparable interventions and outcomes.There were very few clinical or statistically significant benefits of the treatments used on the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial and more responsive outcomes are being developed. A well-performed trial of IVIg, which was at low risk of bias, showed a statistical benefit in terms of improvement in mRS at two weeks and 10-metre walk time at four weeks, but these short-term outcomes are of questionable clinical significance. Cyclophosphamide failed to show any benefit in the single trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified.Two trials of rituximab (80 participants) have been published, one of which (26 participants) was at high risk of bias. In the meta-analysis, although the data are of low quality, rituximab is beneficial in improving disability scales (Inflammatory Neuropathy Cause and Treatment (INCAT) improved at eight to 12 months (risk ratio (RR) 3.51, 95% confidence interval (CI) 1.30 to 9.45; 73 participants)) and significantly more participants improve in the global impression of change score (RR 1.86, 95% CI 1.27 to 2.71; 70 participants). Other measures did not improve significantly, but wide CIs do not preclude some effect. Reported adverse effects of rituximab were few, and mostly minor.There were few serious adverse events in the other trials. AUTHORS' CONCLUSIONS: There is inadequate reliable evidence from trials of immunotherapies in anti-MAG paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. IVIg has a statistically but probably not clinically significant benefit in the short term. The meta-analysis of two trials of rituximab provides, however, low-quality evidence of a benefit from this agent. The conclusions of this meta-analysis await confirmation, as one of the two included studies is of very low quality. We require large well-designed randomised trials of at least 12 months' duration to assess existing or novel therapies, preferably employing unified, consistent, well-designed, responsive, and valid outcome measures.

Inactivation of protein-phosphatase 2A causing hyperphosphorylation of autoantigenic paraprotein targets in MGUS/MM is due to an exchange of its regulatory subunits.

Hyperphosphorylated paratarg-7 (pP-7) carrier state is the strongest molecularly defined risk factor for monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM). pP-7 is inherited as autosomal-dominant trait and depending on the ethnic background is found in over one-third of MGUS/MM patients. P-7, which is the antigenic paraprotein target in these patients, is hyperphosphorylated at serine17. P-7 hyperphosphorylation can be induced in wild-type P-7 (wtP-7) carriers by PKCζ and reverted by protein-phosphatase 2A (PP2A). Here we show that dephosphorylation of pP-7 is defective in pP-7 carriers due to inactivation of the PP2A by substitution of the regulatory B55δ subunit with B56γ3. In lymphoblastoid cell lines from pP-7 carriers, transfection of recombinant B55δ or treatment with ceramide led to a partial reconstitution of PP2A activity and dephosphorylation of pP-7 to wtP7. Similar results were observed with other previously reported autoantigenic paraproteins targets. In conclusion, the mechanisms responsible for the defective dephosphorylation and maintaining the hyperphosphorylated state of P-7 and other autoantigenic paraprotein targets have been elucidated, facilitating the identification of the genetic basis underlying this phenomenon which is obviously common in the pathogenesis of MGUS/MM/WM and not restricted to pP-7 cases.

Pathogenic mechanisms in inflammatory and paraproteinaemic peripheral neuropathies.

PURPOSE OF REVIEW: This review summarizes the major recent developments in understanding of pathogenic mechanisms in inflammatory and paraproteinaemic neuropathies. RECENT FINDINGS: In the inflammatory neuropathies, there has been a particular focus on antibody-mediated disease affecting the nodal/paranodal regions. Disruption of electrical integrity at these sites on the axonal membrane can cause conduction block without other electrophysiological features of demyelination, which has led to calls for a revision in the classification of axonal versus demyelinating neuropathies to include the new category of 'nodo-paranodopathies'. There has likewise been an expansion in knowledge regarding the diverse disease mechanisms of the paraproteinaemic neuropathies. These also include disease mediated by antibodies binding to peripheral nerve antigens, but additionally encompass immune complex deposition, cellular infiltration, and cytokine production. SUMMARY: An increasing range of laboratory tests for antibodies, growth factors, and cytokines are proposed as useful in the management of inflammatory and paraproteinaemic neuropathies. Furthermore, the traditional electrodiagnostic classification into axonal and demyelinating neuropathy may not always accurately reflect the underlying disease process. Understanding how these paraclinical tests aid in identifying the underlying disease has relevance to the practising clinician both in terms of diagnosis and for the selection of rational treatments.

Cryofibrinogenemia triggered by a monoclonal paraprotein successfully treated with cyclophosphamide.

Cryofibrinogenemia is a rare clinical finding with a yet unknown physiopathogenic mechanism. We describe the case of a woman with cold-induced extensive necrotic lesions that responded poorly to initial corticosteroid and anticoagulant therapies. Serum cryoglobulin determinations were persistently negative. After several years of evolution, she developed severe cold-related skin lesions that required left-leg amputation. Further analysis disclosed the presence of cryofibrinogen and an apparently insignificant serum monoclonal immunoglobulin Gκ peak. We additionally demonstrate that the cold precipitation of fibrinogen was directly related to the monoclonal paraprotein presence. The lesions responded dramatically to a B cell-targeted therapy with intravenous cyclophosphamide and dexamethasone.

Autoantibodies in immune-mediated neuropathies.

PURPOSE OF REVIEW: Over the past 25 years, many autoantibodies directed against peripheral nerve glycan and protein antigens have been described. Principally through this area of research, significant advances have been achieved in the understanding of the pathophysiology of inflammatory neuropathies. More evidence constantly continues to emerge supporting the role of antibodies in pathogenesis. This review reports the recent studies highlighting the complex association between autoantibodies directed against various peripheral nerve antigens and immune polyneuropathies. RECENT FINDINGS: The discovery of serum antibodies directed against ganglioside and glycolipid complexes has generated huge interest in this area of research. The expectation that nodal proteins are important targets continues to be pursued in line with the improvements in detection methodology. Basic studies continue to support a direct role for autoantibodies in neuropathy pathogenesis. SUMMARY: Discovery of new target epitopes has not only raised hopes for further improvement in our understanding of pathophysiology and availability of new diagnostic markers, but also for future targeted therapies. Further studies are required to elucidate the precise pathological and clinical significance of these new antibodies.

Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies.

BACKGROUND: Serum monoclonal anti-myelin-associated glycoprotein antibodies may be pathogenic in some people with immunoglobulin M (IgM) paraprotein and demyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be beneficial. This is an update of a review first published in 2003 and previously updated in 2006. OBJECTIVES: To assess the effects of immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated demyelinating peripheral neuropathy. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register 6 June 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to May 2011) and EMBASE (January 1980 to May 2011) for controlled trials. We also checked bibliographies and contacted authors and experts in the field. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials involving participants of any age treated with any type of immunotherapy for anti-myelin-associated glycoprotein antibody-associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance and of any severity.Our primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin Scale at six months after randomisation. Secondary outcome measures were: Neuropathy Impairment Scale or the Modified Rankin Score at 12 months after randomisation; 10-metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; IgM paraprotein levels and anti-myelin-associated glycoprotein antibody titres at six months after randomisation; and adverse effects of treatments. DATA COLLECTION AND ANALYSIS: The two authors independently selected studies. Two authors independently assessed the risk of bias in included studies. MAIN RESULTS: We identified seven eligible trials (182 participants), which tested intravenous immunoglobulin, alfa interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Only two trials, of intravenous immunoglobulin (with 33 participants, including 20 with antibodies against myelin-associated glycoprotein), had comparable interventions and outcomes, but both were short-term trials.There were no clinical or statistically significant benefits of the treatments used on the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial. Intravenous immunoglobulin showed a statistical benefit in terms of improvement in Modified Rankin Scale at two weeks and 10-metre walk time at four weeks. Cyclophosphamide failed to show any benefit in the trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified. A trial of rituximab was of poor methodological quality with a high risk of bias and a further larger study is awaited. Serious adverse events were few in the other trials. AUTHORS' CONCLUSIONS: There is inadequate reliable evidence from trials of immunotherapies in anti-myelin-associated glycoprotein paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. There is very low quality evidence of benefit from rituximab. Large well designed randomised trials of at least six to 12 months duration are required to assess existing or novel therapies, preferably employing unified, consistent, well designed, responsive and valid outcome measures.

Familial monoclonal gammopathy: hyper-responsive B cells in unaffected family members.

BACKGROUND: In Iceland, eight families have been identified with multiple cases of monoclonal gammopathies (MG) and other lymphoproliferative diseases. In one of these families with several cases of monoclonal gammopathy of undetermined significance (MGUS) and Waldenströms macroglobulinemia, in vitro stimulation with poke-weed mitogen revealed hyper-responsive B cells showing increased immunoglobulin production in one-third of disease-free family members. DESIGN AND METHODS: In this study, the families were further traced and the list of names produced was compared with The Icelandic Cancer Registry (ICR) to find all recent cases of lymphoproliferative diseases. First-degree relatives and descendants older than 20yrs of age (n=350) were selected for screening for paraprotein. Selected family members were tested for B-cell hyper-responsiveness and the lymphocyte phenotype was analysed by flow cytometry. RESULTS: Comparison of the total list of 4370 family members with the ICR revealed 22 new cases and screening for serum paraprotein identified nine new cases of MG, eight being first-degree relatives of known probands. Sixty cases of lymphoproliferative diseases are currently known within the eight families, five of them containing both IgG/A and IgM disorders. Twelve hyper-responders (HR) were identified in four families, eight from one family, of whom four were known already. Stimulated B cells from HR had a significantly higher proportion of CD27(+) memory/plasma cells than controls. CONCLUSION: Identification of new affected family members by screening confirms a hereditary predisposition to B-cell proliferative diseases. Contrary to most studies, IgG/A and IgM disorders occurred together in five families. In four families, enhanced B-cell responsiveness was found in healthy subjects clustered around cases.

Anti-MAG neuropathy: From biology to clinical management.

The acquired chronic demyelinating neuropathies include a growing number of disease entities that have characteristic, often overlapping, clinical presentations, mediated by distinct immune mechanisms, and responding to different therapies. After the discovery in the early 1980s, that the myelin associated glycoprotein (MAG) is a target antigen in an autoimmune demyelinating neuropathy, assays to measure the presence of anti-MAG antibodies were used as the basis to diagnose the anti-MAG neuropathy. The route was open for describing the clinical characteristics of this new entity as a chronic distal large fiber sensorimotor neuropathy, for studying its pathogenesis and devising specific treatment strategies. The initial use of chemotherapeutic agents was replaced by the introduction in the late 1990s of rituximab, a monoclonal antibody against CD20+ B-cells. Since then, other anti-B cells agents have been introduced. Recently a novel antigen-specific immunotherapy neutralizing the anti-MAG antibodies with a carbohydrate-based ligand mimicking the natural HNK-1 glycoepitope has been described.

Clinicopathologic Assessment of Monoclonal Immunoglobulin-associated Renal Disease in the Kidney Allograft: A Retrospective Study and Review of the Literature.

BACKGROUND: Monoclonal immunoglobulin (MIg)-associated renal disease (MIgARD) comprises a group of disorders caused by direct deposition of paraproteins in the kidney. Allograft MIgARD is infrequently encountered and poorly characterized. METHODS: First, we assessed our allograft biopsies diagnosed with MIgARD between 2007 and 2018. The cohort included the following 26 patients: proliferative glomerulonephritis with MIg deposits (PGNMID) (n = 13), AL amyloidosis (n = 5), light chain deposition disease (n = 5), light chain proximal tubulopathy (n = 2), and light chain cast nephropathy (n = 1). Second, we conducted a literature review to evaluate the rare non-PGNMID entities. We identified 20 studies describing 29 patients that were added to our cohort (total n = 42). RESULTS: Part 1: Patients' median age was 55 years; 31% were women, and 19% were blacks. Twelve patients (46%) lost their grafts at a median of 8 months after diagnosis. Compared to non-PGNMID, PGNMID patients had lower frequency of detectable paraproteins (31% versus 92%, P = 0.004) and hematologic neoplasms (23% versus 77%, P = 0.02). Within PGNMID group, 6 patients changed their apparent immunofluorescence phenotype between monotypic and polytypic, while all 3 patients with hematologic neoplasms had substructure on electron microscopy. Part 2: Whereas light chain cast nephropathy occurred the earliest and had the worst graft survival, AL amyloidosis occurred the latest and had the best graft survival. CONCLUSIONS: MIgARD in the kidney allograft is associated with poor prognosis. While posttransplant PGNMID can change its apparent clonality by immunofluorescence supporting oligoclonal immune responses, the presence of deposit substructure is an important indicator of underlying hematologic neoplasm. Non-PGNMID are often associated with hematologic neoplasms and varied prognosis.

A frequent target of paraproteins in the sera of patients with multiple myeloma and MGUS.

Antigenic targets of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) paraproteins might play a role in the pathogenesis of these neoplasms. We screened a human fetal brain-derived macroarray with the IgA or IgG containing sera of 192 consecutive MGUS and MM patients. Twenty-nine of 192 (15.1%) paraproteins reacted with paratarg-7, a protein of unknown function which is expressed in all human tissues. Paratarg-7 reactivity was similarly frequent among IgA and IgG paraproteins, but all paratarg-7 reactive IgG paraproteins belonged to the IgG3 subtype with 24/57 IgG3 (42.1%) paraproteins displaying this specificity. Sequence analysis of paratarg-7 derived from patients having a paraprotein with specificity for paratarg-7 revealed no differences to paratarg-7 derived from patients with paraproteins of other specificities or healthy controls, excluding mutations or polymorphisms as a reason for its autoimmunogenicity. Similarly, Western-blot analysis showed identical bands for paratarg-7 derived from patients and controls. The above-random frequency of paratarg-7 as a paraprotein target suggests that paratarg-7 might be involved in the development of the respective clonal proliferations. The identification of paratarg-7 as an antigenic target enables the more detailed analysis of tumor-host interactions in these patients and their role in the pathogenesis of MM and MGUS.

Antigenic determinants in IgM paraprotein-related neuropathies.

The association of neuropathy with IgM paraprotein has been known for several years, but only recently the pathogenetic relevance of this association has been clarified. Reactivity of the paraprotein with several neural antigens has been reported even if their pathogenetic relevance is not always clear. IgM binding to the Myelin-associated glycoprotein (MAG) is associated with a homogeneous demyelinating neuropathy, deposits of the paraprotein and complement on nerve myelin, and improvement concomitantly to anti-MAG IgM reduction. In particular, treatment with rituximab durably improved the neuropathy in two thirds of the patients, particularly those with moderately increased anti-MAG titres, which might be more easily reduced by this treatment. Several other IgM reactivities with nerve antigens have been reported in these patients, including several gangliosides and sulfatide even if, with the only exceptions of anti-sulfatide and anti-GQ1b ganglioside reactivities, their possible pathogenetic relevance remains to be established.

[A case of multifocal motor neuropathy with IgM lambda anti-GM1 antibody and IgM kappa paraprotein reacting exclusively with GM2].

A 57-year-old previously healthy woman visited our clinic complaining of frequent muscle cramps and progressive weakness in the hands and fingers for 3 years. On examination, cranial nerves were unremarkable. There were moderate weakness and mild muscle wasting with fasciculation in the left thumb flexor and interossei on both sides. Tendon reflexes were hypoactive. There were no pathologic reflexes or sensory deficit. The cerebrospinal fluid was unremarkable. Nerve conduction studies demonstrated conduction block in the right ulnar nerve. Compound muscle action potential in the left median nerve was low-normal. Distal motor latencies, motor and sensory nerve conduction velocities were normal in all nerves tested. A diagnosis of multifocal motor neuropathy was made. Two courses of intravenous immunoglobulin infusion gave no beneficial effects. The patient had IgM kappa monoclonal gammopathy of undetermined significance. Her serum IgM reacted with GM2, GM1, and GA1 but not with GD1a, GD1b, GD3, GalNAc-GD1a, GT1b, GQ1b, galactocerebroside, or sulfated glucuronyl paragloboside. IgM kappa paraprotein reacted exclusively with GM2. Only IgM lambda bound to GM1 and GA1, suggesting the possibility that another paraprotein, though undetectable by immunoelectrohoresis, had a reactivity with GM1 and GA1. This case showed previously unreported antigenic specificity of paraproteins in cases of MMN.

[Renal monoclonal immunoglobuline deposition disease as a rare variant of renal damage in multiple myeloma].

A case of the immunoglobuline deposit disease diagnosis in MM patient having the symptoms of intensive proteinuria, macrohematuria and terminal renal failure is reported. The disease was diagnosed by the evidence from electron microscopy of the kidney and liver biopsies.

Anti-GM2 gangliosides IgM paraprotein induces neuromuscular block without neuromuscular damage.

We analyzed the effect on the mouse neuromuscular synapses of a human monoclonal IgM, which binds specifically to gangliosides with the common epitope [GalNAc beta 1-4Gal(3-2 alpha NeuAc)beta 1-]. We focused on the role of the complement. Evoked neurotransmission was partially blocked by IgM both acutely (1 h) and chronically (10 days). Transmission electron microscopy shows important nerve terminal growth and retraction remodelling though axonal injury can be ruled out. Synapses did not show mouse C5b-9 immunofluorescence and were only immunolabelled when human complement was added. Therefore, the IgM-induced synaptic changes occur without complement-mediated membrane attack.

Glycosylation of IgG B cell receptor (IgG BCR) in multiple myeloma: relationship between sialylation and the signal activity of IgG BCR.

Little is known about the glycosylation of the isotype switched B cell receptor (BCR) in multiple myeloma, and the way it might affect receptor function. In this work IgG BCRs isolated from the individual lysates of peripheral blood lymphocytes (PBL) of 32 patients with IgG multiple myeloma and healthy controls were investigated for the expression of sialic acid (SA), galactose (Gal) and N-acetylglucosamine (GlcNAc), the sugars known to specify the glycoforms of human serum IgG. The degree of glycosylation and signaling status of all 32 isolated myeloma IgG BCRs were correlated and compared with the glycosylation of the IgG paraproteins isolated from sera of the same patients. It was shown that BCR IgG in myeloma is more heavily sialylated when compared with normal controls, that the increased sialylation of IgG BCR is associated with higher levels of tyrosine phosphorylation (signaling activity) of the IgG BCR supramolecular complex and that BCR IgG and serum IgG paraprotein from the same patient differed in all cases in the levels of terminal sugar expression. The results suggest that the development of the malignant clone in MM from post-switch B cells expressing IgG BCR at their surfaces to plasma cells secreting IgG paraprotein may be followed by permanent glycosylation changes in the IgG molecules.