Immunoglobulin M Monoclonal Gammopathy Research Articles

Multiomics analysis in IgM monoclonal gammopathies reveals epigenetic influence on oncogenesis via DNA methylation

AbstractCurrently, the role of DNA methylation in the immunoglobulin M (IgM)–monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multiomics prospective analysis was conducted integrating DNA methylation, RNA sequencing (RNA-seq), and whole-exome sequencing data in 34 subjects (23 with Waldenstrom macroglobulinemia [WM], 6 with IgM monoclonal gammopathy of undetermined significance [MGUS], and 5 normal controls). Analysis was focused on defining differences between IgM gammopathies (WM/IgM-MGUS) compared with controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions that were annotated according to genomic region. Next, integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. We found that pathways involved in cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of the CXCR4 signaling pathway along with several interleukin (interleukin 6 [IL-6], IL-8, and IL-15) signaling pathways in WM compared with IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. Overall, this report defines how aberrant DNA methylation in IgM gammopathies may play a critical role in the epigenetic control of oncogenesis and key cellular functions.

Lymphoplasmacytic Lymphoma: An Atypical Presentation with IgG Monoclonal Gammopathy

Introduction Lymphocytic lymphoma (LPL) is a rare type of low-grade mature B-cell non-Hodgkin lymphoma, characterized by a monoclonal population of B lymphocytes, lymphoplasmacytic cells, and plasma cells. In around 95% of LPL cases, the serum immunoglobulin M (IgM) paraprotein is increased, which is correlated to Waldenstrom's Macroglobulinemia (WM), a clinicopathological disease. Only around 5% of LPL cases are associated with the serum paraproteins immunoglobulin G (IgG) or immunoglobulin A (IgA), or light chains alone, or are not linked to a paraprotein. Non-IgM LPLs have a wide range of clinical and pathological features, and MYD88 L265P mutations can occur, though at a lower frequency than WM. Hence, MYD88 testing is advised for prospective therapeutic purposes. Case Presentation A 69-year-old male was referred to a hematologist for uncontrolled epistaxis and periorbital edema. On initial workup, he had high total protein, elevated globulin, hypoalbuminemia, anemia, and proteinuria. Further investigation revealed a high IgG level with low IgM, IgA, and complement levels. Serum Protein Electrophoresis (SPEP): Increased total protein, decreased alpha two and beta globulins with a large monoclonal protein peak migrating in the gamma region, which accounts for 4.77 g/dl of the total 5.38g/dl gamma. Elevated Kappa Quantitative Free Light Chains of 355.39 (3.30 - 19.40mg/L), Decreased Lambda Quantitative Free Light Chains of 1.51 (5.71 - 26.30mg/L), Elevated Kappa Lambda Free Light Chains Ratio of 235.36 (0.26 - 1.65). Serum ImmunoFixation Electrophoresis demonstrated IgG-type kappa monoclonal protein with an additional faint band in IgG kappa. X-Ray skeletal survey showed a possible small lytic area in the inferior aspect of the C2 vertebral body, prompting him to have a cervical spine MRI which revealed no lytic lesions but an 18 mm vertebral body hemangioma inside T2. Molecular testing was positive for MYD88 Mutation c.794T>C (p. L265P) and negative for CXCR4 mutation. Plasma cell myeloma prognostic panel and chromosome analysis were normal. Flow cytometry of bone marrow aspirate showed a kappa light chain restricted plasma cell population (1.6% of total cells) with the following immunophenotype: positive for CD138, CD38, CD45, and negative for CD19, CD20, CD56, CD 117, and lambda light chains. The B-cell population showed kappa light chain restriction with the following immunophenotype: positive for CD19, CD20, and kappa light chains and negative for CD5, CD10, CD11c, CD23, and lambda light chains (Image 2). PET-CT of the whole body was negative for the extension of the disease. Transfusion with the two least incompatible PRBCs had little effect. However, plasmapheresis significantly improved his hemoglobin level by less than 7g/dl. A bone marrow biopsy revealed he had LPL with IgG Monoclonal Gammopathy (Image 1). He received one cycle of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone), followed by seven cycles of KCD (Carfilzomib, Cyclophosphamide, Dexamethasone) and Rituximab. The patient was diagnosed with low-grade B cell lymphoma with plasmocytic differentiation/lymphoplasmacytic lymphoma, with MYD88 mutation c.794T>C (p. L265P) positivity and CXCR4 mutation negativity. After plasmapheresis, the IgG level dropped to 1958. Follow-up SPEP revealed decreased alpha2 and beta globulins, decreased free lambda light chains, and increased K/L ratio. The patient was treated with Acalabrutinib, and his anemia, epistaxis, and coagulopathy resolved. Repeat PET-CT scan revealed no evidence of illness progression. Discussion LPL is not always linked with IgM monoclonal gammopathy; it can also be associated with IgG or IgA monoclonal gammopathy, light chains alone, or no monoclonal paraprotein. Non-IgM LPL has a high prevalence of extramedullary involvement, a lower rate of MYD88 mutation, and few hyper viscosity symptoms. The MYD88 mutation does not allow WM and Non-IgM LPL to be distinguished from other lymphoproliferative disorders with similar clinical and immunophenotypic features. The case described is unique as the patient has high levels of IgG (11,200) at presentation. In contrast to our patient, who has LPL with IgG Monoclonal gammopathy, approximately 95 percent of LPL patients have IgM Monoclonal gammopathy, which corresponds with WM. As a result, clinicians should be on the lookout for LPL that lacks an IgM Monoclonal Paraprotein.

Mutational Landscape of Bone Marrow CD19 and CD138 Cells in Waldenström Macroglobulinemia (WM) and IgM Monoclonal Gammopathy of Undetermined Significance (IgM MGUS)

Background Waldenström's Macroglobulinemia (WM) is an incurable B-cell neoplasm characterized by serum monoclonal immunoglobulin M (IgM) and clonal lymphoplasmacytic cells infiltrating the bone marrow (BM). Smoldering WM (sWM) is the asymptomatic/indolent form with a high risk of progressing to symptomatic WM requiring treatment whereas IgM monoclonal gammopathy of undetermined significance (IgM MGUS) is an early precursor stage of WM. Despite recurrent and activating mutations, including MYD88, CXCR4, ARID1A, KMT2D, and CD79B have been identified, the genetic basis for WM and the risk of progression of IgM MGUS to WM remain to be fully elucidated. Methods Based on the mutational profiling of WM and our previous wide transcriptome analyses on BM CD19+ and CD138+ cells of patients with WM and IgM MGUS, we decided to investigate the mutation status of these patients as follows: WM (n=10), sWM (n=7), and IgM MGUS (n=5), by performing high throughput targeted AmpliSeq next generation sequencing on 117 target genes potentially involved in B-cell lymphomagenesis and in the risk of progression of IgM MGUS to WM (Trojani A. et al. Cancers, 2021). Results We identified genetic aberrations in multiple genes, including previously described classic mutations in MYD88 (L260P alias L265P) found in 82.3% (14/17) of WM/sWM patients and in 60% (3/5) of IgM MGUS subjects. The CXCR4 mutation (S338Ter) was detected in 23.5% of CD19+ cells of WM patients, whereas it was absent in IgM MGUS subjects. Interestingly, we also identified new mutated genes, including WNK2 somatic mutations affecting 47% of WM patients, for which a recurrent allelic variant (V1635Ter) was observed, and BCL9 with a recurrent frameshift variant (P516Lfs) identified in 29.4% of WM patients exclusively in the CD19 cell fraction. The BCL9 (P516Lfs) variant was also detected in the B cells of one IgM MGUS patient. Moreover, sequencing evaluation revealed recurrently frameshift or missense mutations involving NFKB2 (L473Afs), PTPN13 (P1546Tfs), CARD11 (S622del), KMT2C (I823T), and ATM in WM and IgM MGUS patients (Figure 1). Of interest, KMT2C (also known as MLL3) exhibited a somatic hypermutated phenotype in both CD19+ and CD138+ cells of WM and IgM MGUS samples. The KMT2C mutations were not mutually exclusive with those involving KMT2D in our cohort of patients. Conclusion The present genomic analysis revealed new insights into the mutational landscape of Waldenström Macroglobulinemia, providing evidence of the recurrence of some variants in subjects with IgM MGUS as well. Notably, we uncovered new genetic mutations with somatic variants recurrently observed (n≥3) in KMT2C, WNK2, BCL9, PTPN13, CARD11 and NFKB2 genes. These recurring somatic events provide a genomic basis for future research and a better understanding of the WM pathogenesis as well as the risk of transformation of IgM MGUS to WM.

Electrophysiological features and prognosis of peripheral neuropathy associated with IgM monoclonal gammopathy: a single-center analysis in South Korea

Background: Clinical spectrum of immunoglobulin M (IgM) monoclonal gammopathy varies from IgM monoclonal gammopathy of unknown significance (IgM-MGUS) to hematological malignancies. We evaluated the clinical features, electrophysiological characteristics, and prognosis of patients with peripheral neuropathy associated with IgM monoclonal gammopathy (PN-IgM MG).Methods: We retrospectively evaluated 25 patients with PN-IgM MG. Peripheral neuropathy was classified as axonal, demyelinating, or undetermined, based on electrophysiological studies. We classified the enrolled patients into the IgM-MGUS and malignancy groups, and compared the clinical and electrophysiological features between the groups.Results: Fifteen patients had IgM-MGUS and 10 had hematologic malignancies (Waldenström’s macroglobulinemia: two and B-cell non-Hodgkin’s lymphoma: eight). In the electrophysiological evaluation, the nerve conduction study (NCS) criteria for demyelination were met in 86.7% of the IgM-MGUS group and 10.0% of the malignancy group. In particular, the distal latencies of the motor NCS in the IgM-MGUS group were significantly prolonged compared to those in the malignancy group (median, 9.1 ± 5.1 [IgM-MGUS], 4.2 ± 1.3 [malignancy], <i>p</i> = 0.003; ulnar, 5.4 ± 1.9 [IgM-MGUS], 2.9 ± 0.9 [malignancy], <i>p</i> = 0.001; fibular, 9.3 ± 5.1 [IgM-MGUS], 3.8 ± 0.3 [malignancy], <i>p</i> = 0.01; P-posterior tibial, 8.3 ± 5.4 [IgM-MGUS], 4.4 ± 1.0 [malignancy], <i>p</i> = 0.04). Overall treatment responses were significantly worse in the malignancy group than in the IgM-MGUS group (<i>p</i> = 0.004), and the modified Rankin Scale score at the last visit was higher in the malignancy group than in the IgM-MGUS group (2.0 ± 1.1 [IgM-MGUS], 4.2 ± 1.7 [malignancy], <i>p</i> = 0.001), although there was no significant difference at the initial assessment. Conclusions: The risk of hematological malignancy should be carefully assessed in patients with PN-IgM MG without electrophysiological demyelination features.

IgM monoclonal gammopathy of undetermined significance: clinicopathologic features with and without IgM-related disorders.

A subset of patients with immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) develop IgM-related disorders (IgM-RD) including peripheral neuropathy, cryoglobulinemia and/or cold agglutinin disease (CAD). We examined the clinical and bone marrow pathologic findings in 191 IgM MGUS patients (2016 World Health Oragnization criteria). Clonal plasma cells were identified in 41 of 171 (24%) cases by immunohistochemistry (IHC) and clonal B cells in 43 of 157 (27%). IgM-RD was identified in 82 (43%) cases, including peripheral neuropathy (n=67, 35%), cryoglobulinemia (n=21, 11%), and CAD (n=10, 5%). Cases of CAD showed distinctive features including lack of MYD88 mutations (P=0.048), supporting the concept of primary CAD as a distinct clinicopathologic disorder. Following exclusion of CAD, comparison of the remaining cases with (n=72) or without (n=109) IgM-RD showed IgM-RD to be more frequent in men than women (P=0.02) and to be more highly associated with MYD88 L265P (P=0.011). Cases with and without IgM-RD otherwise showed similar features including serum IgM concentrations, presence of lymphoid aggregates, clonal B cells by flow cytometry or clonal plasma cells by IHC. No differences were observed in overall survival between cases with and without IgM-RD. No cases in this series met criteria for plasma cell type IgM MGUS as defined in the 2022 International Consensus Classification of lymphoid neoplasms. These results show IgM-RD to be common in patients with IgM MGUS. While CAD shows distinctive features, the remaining cases of IgM-RD largely show pathologic findings similar to IgM MGUS without IgM-RD.

Serum Neurofilament Light Chain and Contactin-1 Levels Are Not Potential Serum Biomarkers in Anti-MAG IgM Paraprotein Related Peripheral Neuropathy

IntroductionPeripheral neuropathies (PN) caused by immunoglobulin M (IgM) paraproteinemia are rare disorders that require close collaboration between hematologists and neurologists for adequate diagnosis and management. The IgM paraproteinemia is caused by an underlying B-cell clone that can often be classified as IgM monoclonal gammopathy (IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenström macroglobulinaemia (WM)). Anti-myelin-associated glycoprotein (MAG) IgM paraprotein related PN (anti-MAG PNP) is the most frequent variety and accounts for approximately 50% of cases. Treatment targeted at the B-cell clone i.e. rituximab +/- chemotherapy, is only indicated in severe and/or progressive cases. However, establishing disease severity and tracking progression over time is difficult since the most prominent symptoms, i.e. imbalance, gait ataxia, sensory disturbances and tremor, are difficult to capture reliably. Anti-MAG titers and paraprotein levels do not correlate well with disease activity and are thus not suitable as biomarkers for disease severity, activity and/or response. The lack of reliable biomarkers also impacts successful execution of clinical trials and therefore hampers introduction of novel targeted non-cytotoxic therapies such as BTK inhibition in this patient population. Therefore, biomarkers for disease severity, activity and response to treatment represent a great unmet need in anti-MAG PN.Nerve damage proteins are increasingly used as disease-overarching response biomarkers in neuropathies, and have been introduced not only in the research setting but also in routine clinical care. Neurofilament light chain (NfL) is used as response biomarker by detecting axonal damage regardless of the underlying disorder, and, recently, contactin-1 (CNTN-1) has been identified as a potential biomarker for damage to the paranode (a nerve region in between the node of Ranvier and compact myelin) where the MAG protein is also present. We therefore aimed to assess whether serum NfL, and CNTN-1 levels may function as nerve damage biomarkers in anti-MAG PN.MethodsWe included treatment-naïve patients with anti-MAG PN (PN) who fulfilled the following criteria: IgM paraproteinemia in the serum, presence of an IgM MAG-antibody in the serum, a clinical diagnosis of anti-MAG PN by a neurologist with expertise in peripheral nerve disorders confirmed by nerve conduction studies. As controls, treatment-naïve patients with IgM MGUS or WM without signs of neuropathy were included (non-PN). NfL levels were measured in serum using a Simoa assay. Abnormal sNfL levels were defined as at or above the 95th percentile of age-specific cut-off values in healthy controls (HCs). CNTN-1 levels were measured using the Human Magnetic Luminex Assay. Abnormal sCNTN1 levels were defined as below the 5th percentile of values in HCs. Differences between PN and non-PN groups were assessed with the Mann-Whitney U test.ResultsA total of 24 PN and 10 non-PN patients were included (Table 1). In the PN cohort, all patients had anti-MAG antibodies, with a titer of >10.000 in 22 (92%) patients. Data from 222 HCs (mean age 46 years; SD 14; range 19-98 years) were used to establish reference values. Median sNfL levels were similar between PN and non-PN patients (Table 2). Abnormal sNfL levels were present in 4 (17%) PN patients (range sNfL: 29.7-42.8 pg/mL) and in 1 (10%; 59.2pg/mL) non-PN patient (Figure 1A). Median sCNTN1 levels were also similar between PN and non-PN patients (Table 2). One (4%) patient in the PN cohort and 1 (10%) patient in the non-PN cohort had abnormal CNTN-1 levels (Figure 1B).ConclusionOur results do not support further studies on NfL and/or CNTN-1 in serum as potential biomarkers in anti-MAG PN, since the majority of anti-MAG PN and non-PN patients had normal levels of sNfL and sCNTN-1. In case sNfL was abnormal, levels were only modestly increased above cutoff and substantially lower compared to the high levels seen in other neuropathies. [Display omitted] DisclosuresMinnema: Alnylam: Consultancy; Celgene: Other: Travel expenses; BMS: Consultancy; Cilag: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy. Kersten: Celgene: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding. Vos: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel reimbursement.

Characterization of B-Cell and Plasma Cell Compartment By Eight-Color Multiparameter Flow Cytometry in Patients with Waldenstrom Macroglobulinemia Prospectively Enrolled in the Fondazione Italiana Linfomi (FIL) BIO-WM Trial

Characterization of B-Cell and Plasma Cell Compartment By Eight-Color Multiparameter Flow Cytometry in Patients with Waldenstrom Macroglobulinemia Prospectively Enrolled in the Fondazione Italiana Linfomi (FIL) BIO-WM Trial

Rapidly progressive immunoglobulin M monoclonal gammopathy presenting with nephrotic syndrome and hepatic failure

We report a 73-year-old male with no relevant past medical history who presented with nephrotic syndrome and jaundice. Subsequent studies revealed immunoglobulinM (IgM) monoclonal gammopathy. Kidney biopsy revealed monoclonal Ig deposition disease and amyloidosis. Bone marrow biopsy demonstrated <10% infiltration by lymphoplasmacytic cells. However, rapidly progressive hypergammaglobulinemia of IgM and hyperbilirubinemia were noted. Despite aggressive treatment, the patient developed acute kidney injury and complications of hepatic failure. He eventually died of pneumonia, just two months after diagnosis.

Waldenström macroglobulinemia: 2019 update on diagnosis, risk stratification, and management.

Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in >90% of patients and is found in the majority of IgM monoclonal gammopathy of undetermined significance patients. Age, hemoglobin level, platelet count, β2 microglobulin, and monoclonal IgM concentrations are characteristics that are predictive of outcomes. Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogs are active but usage is declining for less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. Potential for stem cell transplantation should be considered in selected younger patients. Bortezomib, fludarabine, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.

Unraveling the heterogeneity of IgM monoclonal gammopathies: a gene mutational and gene expression study.

Immunoglobulin M (IgM) monoclonal gammopathies show considerable variability, involving three different stages of presentation: IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), asymptomatic Waldenström's macroglobulinemia (AWM), and symptomatic WM (SWM). Despite recent findings about the genomic and transcriptomic characteristics of such disorders, we know little about the causes of this clinical heterogeneity or the mechanisms involved in the progression from indolent to symptomatic forms. To clarify these matters, we have performed a gene expression and mutational study in a well-characterized cohort of 69 patients, distinguishing between the three disease presentations in an attempt to establish the relationship with the clinical and biological features of the patients. Results showed that the frequency of genetic alterations progressively increased from IgM-MGUS to AWM and SWM. This means that, in contrast to MYD88 p.L265P and CXCR4 WHIM mutations, present from the beginning of the pathogenesis, most of them would be acquired during the course of the disease. Moreover, the expression study revealed a higher level of expression of genes belonging to the Toll-like receptor (TLR) signaling pathway in symptomatic versus indolent forms, which was also reflected in the disease presentation and prognosis. In conclusion, our findings showed that IgM monoclonal gammopathies present higher mutational burden as the disease progresses, in parallel to the upregulation of relevant pathogenic pathways. This study provides a translational view of the genomic basis of WM pathogenesis.

Advances in the understanding of IgM monoclonal gammopathy of undetermined significance.

Among monoclonal gammopathies of undetermined significance (MGUSs), the immunoglobulin M (IgM) MGUS subtype stands as a unique entity and plays a pivotal role as a pre-malignant condition for multiple B-cell non-Hodgkin lymphomas, most notably Waldenström macroglobulinemia (WM). A relationship between IgM MGUS and WM has been proposed for decades. However, insight regarding the pathobiology of these two conditions improved significantly in recent years, strengthening the hypothesis that WM and IgM MGUS are different stages of the same disease. Therefore, the understanding of IgM MGUS and that of WM are interconnected and advances in one will likely impact the other. Furthermore, IgM MGUS has been more commonly recognized as the underlying etiology of IgM-related disorders. In this review, we explore recent advances in the understanding of the pathobiology of IgM MGUS and WM and the treatment of common IgM-related disorders.

Diagnostic Tools of Waldenströms Macroglobulinemia - Best Possibilities for Non-invasive and Long-term Disease Monitoring.

Waldenströms macroglobulinemia (WM) is a B-cell malignancy characterized by high level of monoclonal immunoglobulin M (IgM) paraprotein in blood serum and associated with the bone marrow infiltration by malignant cells with lymphoplasmacytic differentiation. WM remains incurable advances in therapy. Most of WM cases are associated with a somatic point mutation L265P in MYD88. Significantly higher risk of progression from the IgM monoclonal gammopathy of undetermined significance (IgM MGUS) to WM for patients with mutated MYD88 gene suggests that this mutation is an early oncogenic event and plays a central role in development of malignant clones. The second, most prevalent mutation in WM is found in the CXCR4 gene and is often associated with drug resistance and aggressive disease presentation. Therefore, detection of these mutations (MYD88L265P and CXCR4S338X) could be useful diagnostic and prognostic tool for the patients with WM. While detection of these mutations in bone marrow sample is common, the aim of our study was to compare sensitivity of detection of mutation from different cell fraction from peripheral blood and bone marrow. The results show possibility to describe MYD88 and CXCR4 mutation status even from peripheral blood sample (sensitivity for MYD88L265P was 100%, for CXCR4S338X 91%), which significantly facilitate material collection. Moreover, comparable detection sensitivity of these mutations in bone marrow and peripheral blood samples examined before and during the therapy offers a promising tool for more routine diagnostic and monitoring of disease progression.Key words: Waldenström macroglobulinemia - hematology - neoplasms - lymphoma - mutation - MYD88 - CXCR4.

Anti-sulfatide/galactocerebroside antibodies in immunoglobulin M paraproteinemic neuropathies.

Anti-sulfatide antibodies have been observed in heterogeneous neuropathies and their clinical relevance is still controversial. Whether the combination of sulfatide with galactocerebroside would increase sensitivity or specificity of enzyme-linked immunosorbent assay testing compared to sulfatide alone was assessed. Immunoglobulin M (IgM) antibodies to sulfatides, galactocerebroside and combined sulfatide and galactocerebroside (Sulf/GalC) were measured in 229 neuropathy patients, including 73 with IgM paraproteinemic neuropathy [62 with anti-myelin-associated glycoprotein (anti-MAG) antibody] and 156 with other neuropathies. Results from 27 patients with IgM monoclonal gammopathy without neuropathy and 28 healthy subjects served as control. Thirty-three patients showed increased titers of anti-sulfatide antibodies, 28 of whom had an IgM paraproteinemic neuropathy (P < 0.0001). When evaluating the reactivity for the combination Sulf/GalC, 57/229 patients were found to be positive, including 36/73 (49%) with IgM paraproteinemic neuropathy (P < 0.0001). Patients with known anti-sulfatide antibodies also showed anti-Sulf/GalC reactivity, with increased titers in 48.5% of the cases. Testing for anti-Sulf/GalC antibodies allowed 24 additional patients to be detected (eight with IgM paraproteinemic neuropathies), who had no reactivity to the individual glycolipids. Amongst the 11 subjects with IgM paraproteinemic neuropathy who were negative for anti-MAG antibodies, only two were reactive to sulfatide, whilst six (55%) were found to be positive when tested against the combination of sulfatide and galactocerebroside. Testing for both sulfatide and galactocerebroside in IgM paraproteinemic neuropathies seems to increase the sensitivity compared to anti-sulfatide antibodies alone (49% and 39%, respectively, with a slightly reduced specificity, from 97% to 87%), helping the characterization of otherwise undefined neuropathy that could benefit from immunomodulatory therapy.

Clinical Presentation and Gene Expression Profiling of Immunoglobulin M Multiple Myeloma Compared With Other Myeloma Subtypes and Waldenström Macroglobulinemia.

PurposeMultiple myeloma (MM) is a clonal bone marrow disease characterized by the neoplastic transformation of differentiated postgerminal B cells. It is a heterogeneous disease both at the genetic level and in terms of clinical outcome. Immunoglobulin M (IgM) MM is a rare subtype of myeloma. Similar to Waldenström macroglobulinemia (WM), patients with MM experience IgM monoclonal gammopathy; however, both diseases are distinct in terms of treatment and clinical behavior.Materials and MethodsTo shed light on the presentation of IgM MM, its prognosis, and its gene expression profiling, we identified and characterized 21 patients with IgM MM from our database.ResultsOne of these patients presented with a rare IgM monoclonal gammopathy of undetermined significance that progressed to smoldering myeloma. The median survival of the 21 patients was 4.9 years, which was comparable to a matched group of patients with non-IgM MM with similar myeloma prognostic factors (age, gender, albumin, creatinine, anemia, lactate dehydrogenase, β2-microglobulin, cytogenetics abnormalities), but much less than the median survival reported for patients with WM (9 years). We identified a cluster of genes that differ in their expression profile between MM and WM and found that the patients with IgM MM displayed a gene expression profile most similar to patients with non-IgM MM, confirming that IgM MM is a subtype of MM that should be differentiated from WM.ConclusionBecause the prognosis of IgM MM and WM differ significantly, an accurate diagnosis is essential. Our gene expression model can assist with the differential diagnosis in controversial cases.

Characteristics and Prognosis of Patients with Immunoglobulin M Monoclonal Gammopathy.

Many patients with immunoglobulin M (IgM) monoclonal gammopathy remain asymptomatic and, consequently, untreated; however, few studies have evaluated the clinical course and prognosis of these patients. Using the screening procedures at our hospital, 74 patients with IgM monoclonal gammopathy were selected. We excluded 11 patients in whom the treatment for lymphoid neoplasms had been initiated at the time of IgM monoclonal protein detection. The remaining 63 patients were considered to be the patient population with IgM MGUS and asymptomatic WM, and were analyzed. In these patients, the median overall survival was longer than 14 years. More than half of these patients died from causes other than lymphoid neoplasm. The cumulative incidence of lymphoid neoplasm requiring treatment was 17.5%. In five of eight patients requiring treatment for lymphoid neoplasms, the causes of death were related with these lymphoid neoplasms. Our study suggests that not all patients with IgM monoclonal gammopathy require uniform treatment for prolonged survival; however, most lymphoid neoplasms requiring treatment are refractory diseases. Our findings may help manage patients with macroglobulinemia.

Kidney Diseases Associated With Monoclonal Immunoglobulin M–Secreting B-Cell Lymphoproliferative Disorders: A Case Series of 35 Patients

Kidney diseases associated with immunoglobulin M (IgM) monoclonal gammopathy are poorly described, with few data for patient outcomes and renal response. Case series. 35 patients from 8 French departments of nephrology were retrospectively studied. Inclusion criteria were: (1) detectable serum monoclonal IgM, (2) estimated glomerular filtration rate (eGFR)< 60mL/min/1.73m(2) and/or proteinuria with protein excretion > 0.5g/d and/or microscopic hematuria, and (3) kidney biopsy showing monoclonal immunoglobulin deposits and/or lymphomatous B-cell renal infiltration. All patients received chemotherapy, including rituximab-based regimens in 8 cases. Patients were classified into 3 groups according to renal pathology: glomerular AL amyloidosis (group 1; n=11), nonamyloid glomerulopathies (group 2; n=15, including 9 patients with membranoproliferative glomerulonephritis), and tubulointerstitial nephropathies (group 3; n=9, including cast nephropathy in 5, light-chain Fanconi syndrome in 3, and isolated tumor infiltration in 1). Posttreatment hematologic response (≥50% reduction in serum monoclonal IgM and/or free light chain level) and renal response (≥50% reduction in 24-hour proteinuria or eGFR≥30mL/min/1.73m(2) in patients with glomerular and tubulointerstitial disorders, respectively). Nephrotic syndrome was observed in 11 and 6 patients in groups 1 and 2, respectively. Patients in group 3 presented with acute kidney injury (n=7) and/or proximal tubular dysfunction (n=3). Waldenström macroglobulinemia was present in 26 patients (8, 12, and 6 in groups 1, 2, and 3, respectively). Significant lymphomatous interstitial infiltration was observed in 18 patients (4, 9, and 5 patients, respectively). Only 9 of 29 evaluable patients had systemic signs of symptomatic hematologic disease (2, 5, and 2, respectively). In groups 1, 2, and 3, respectively, hematologic response was achieved after first-line treatment in 3 of 9, 9 of 10, and 5 of 6 evaluable patients, while renal response occurred in 5 of 10, 9 of 15, and 5 of 8 evaluable patients. Retrospective study; insufficient population to establish the impact of chemotherapy. IgM monoclonal gammopathy is associated with a wide spectrum of renal manifestations, with an under-recognized frequency of tubulointerstitial disorders.

Anti-sulfatide IgM antibodies in peripheral neuropathy: to test or not to test?

Anti-sulfatide immunoglobulin M (IgM) antibodies have been associated with different forms of neuropathies but their diagnostic role in neuropathy remains unclear. The clinical association of increased titers of anti-sulfatide IgM antibodies in 570 patients with neuropathy and related disorders examined in our laboratory since 2004 was reviewed. Sera were tested by enzyme-linked immunosorbent assay at the initial serum dilution of 1:32,000 and titrated by serial two-fold dilution. In all positive patients IgM antibodies to myelin-associated glycoprotein (MAG) were also measured by western blot. High titers of anti-sulfatide antibodies were found in 39 patients including 33 (85%) who also had anti-MAG IgM. Six patients did not have anti-MAG IgM including five in whom moderately increased anti-sulfatide titers were associated with different forms of neuropathy. One patient with a demyelinating neuropathy and IgM monoclonal gammopathy had markedly increased anti-sulfatide titers (1:256,000). Increased titers of anti-sulfatide IgM antibodies are not infrequent in patients with neuropathy where they are often associated with a concomitant reactivity to MAG. A selective reactivity to sulfatide, however, is rarely found and is associated with different forms of neuropathy limiting its usefulness in the diagnosis of neuropathy.

Improved accuracy of discrimination between IgM Multiple Myeloma and Waldenström Macroglobulinaemia by testing for MYD88 L265P mutations

Improved accuracy of discrimination between IgM Multiple Myeloma and Waldenström Macroglobulinaemia by testing for <i><scp>MYD</scp>88</i> L265P mutations

Lymphoplasmacytic Lymphoma and Waldenström Macroglobulinemia

Lymphoplasmacytic lymphoma (LPL) is a low-grade, B-cell neoplasm composed of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that typically involve the bone marrow, and it is associated with an immunoglobulin M (IgM) gammopathy. The definition of Waldenström macroglobulinemia (WM) and its relationship to LPL has been confusing in the past. In addition, the diagnosis of LPL itself can be challenging because LPL lacks disease-specific morphologic, immunophenotypic, and genetic features to differentiate it from other mature B-cell neoplasms. Accurate diagnosis of LPL/WM rests on recognition of the differential diagnostic features between LPL and other diagnostic possibilities and the use of the recently refined definition of WM and its relationship with LPL: The presence of an IgM monoclonal gammopathy of any level in the setting of bone marrow involvement by LPL. This review summarizes the clinical, laboratory, and histologic features of LPL/WM, with particular emphasis on unique aspects of LPL/WM that may aid in accurate diagnosis.

Detection of anti-MAG antibodies in polyneuropathy associated with IgM monoclonal gammopathy

Detection of serum antibodies to myelin-associated glycoprotein (MAG) by Western blot (WB) is a valuable assay to diagnose a distinct type of demyelinating polyneuropathy with immunoglobulin M (IgM) monoclonal gammopathy. In this study, the diagnostic accuracy of a new and more practical ELISA to detect these antibodies was validated. Routine WBs from 2 independent laboratories and ELISA were used to detect anti-MAG IgM in serum from 207 patients with neuropathy and controls. The sensitivity and specificity of these assays were compared and related to the patient clinical and electrophysiologic characteristics. In ELISA, anti-MAG antibodies were found in serum from 49 (72%) of 68 patients with demyelinating polyneuropathy and IgM monoclonal gammopathy. However, in this subgroup of patients, only 30 (44%) and 37 (54%) were positive in the 2 WBs. All of the patients positive in the 2 WBs were also positive in ELISA. A high correlation was found for IgM activity in ELISA to MAG and sulfate-3-glucuronyl paragloboside (SGPG) (Spearman rho = 0.72, p < 0.0001), supporting the notion that the shared sulfated glucuronic acid moiety of MAG and SGPG is preserved. Most patients positive in anti-MAG ELISA had a slowly progressive sensory-motor demyelinating polyneuropathy, even if the WB was negative. In control groups, however, 4 WB-negative patients with a nondemyelinating monoclonal gammopathy-related polyneuropathy were positive in anti-MAG ELISA. The remaining samples were negative in ELISA. ELISA is more sensitive than Western blot to diagnose anti-myelin-associated glycoprotein related polyneuropathy, although a positive serology may be found in other forms of polyneuropathy as well.