Diagnosis of patients with IgM monoclonal gammopathy due to analytical interference.

Avon Haematology Unit, Bristol Haematology and Oncology Centre, Bristol, Department of Haematology, St Helier Hospital, Carshalton, Surrey, UK, Department of Haematology, Sahlgrenska University Hospital, Gothenburg, Sweden, Department of Medicine, Malmo University Hospital, Malmo, Sweden, Division of Immunity and Infection, University of Birmingham, Birmingham, Department of Clinical Biochemistry, Frenchay Hospital, Bristol, Department Haematology, University College, London, Glasgow Western Infirmary, Glasgow, UK, Department of Haematology, NTNU/St Olavs Hospital, Trondheim, Department of Haematology, Ulleval University Hospital, Oslo, Norway, Department of Haematology Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark, and Myeloma UK.

Detection of MYD88 L265P and Whim-like CXCR4 Mutation in Patients with IgM Monoclonal Gammopathy

A broad spectrum of diseases are associated with IgM monoclonal gammopathy, including Waldenstrom macroglobulinemia (WM), various types of B cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), primary amyloidosis (AL), and monoclonal gammopathy of undetermined significance (MGUS); these are called IgM monoclonal gammopathy related diseases (IgM-RD). We investigated MYD88 L265P and WHIM-like CXCR4 mutations in various IgM-RD. Patients with serum immunofixation electrophoresis confirmed IgM monoclonal gammopathy who had enough material for DNA extraction and presented between January 2008 and October 2016 at Peking Union Medical College Hospital were enrolled in this cohort. We performed real-time allele-specific-polymerase chain reaction and Sanger sequencing to explore the presence of MYD88 L265P and WHIM-like CXCR4 mutations. One hundred and twelve patients (64 male and 48 female patients) were included in this retrospective study. The median age at diagnosis was 62years (range, 30-84years). In total, 64 patients (57.1%) carried the MYD88 L265P mutation and 14 patients (12.5%) carried the CXCR4 WHIM-like mutation. We identified the MYD88 L265P somatic variant in cases with WM (39/42), MGUS (8/18), NHL (14/41, including 4/13 diffuse large B cell lymphoma (DLBCL), 1/8 mucosa-associated lymphoid tissue, 3/6 splenic marginal zone lymphoma (SMZL), 1/4 chronic lymphocytic leukemia, 2/3 nodal marginal zone lymphoma (NMZL), 1/2 mantle cell lymphoma, 1 Burkitt lymphoma, and 1 B cell NHL that could not be classified), primary AL (2/2), and IgM-PN (1/1). The mutation was absent in five patients with Cryoglobulinemia, two with primary cold agglutinin disease and one with MM. The CXCR4 WHIM-like mutation was present in 10/42 patients with WM, 3/41 with NHL (1 DLBCL, 1 SMZL, and 1 NMZL), and 1/18 patients with IgM MGUS. Among the patients with NHL, those with the mutated MYD88 L265P genotype were younger and had lower level of IgG and IgA than the patients with the wild-type genotype. Patients with the mutated MYD88 L265P genotype with WM and MZL were compared. More male patients, higher levels of IgM and lower levels of LDH were found in the WM group. There was no significant difference in overall survival between the two groups. We present a study of the prevalence of the MYD88 L265P mutation and CXCR4 WHIM-like mutation in IgM RD. The MYD88 L265P mutation may play a key role in the pathogenesis of IgM monoclonal gammopathies. It would be interesting in the future to use MYD88 mutation status to differentiate among diseases.

Monoclonal antibodies are found in approximately 10% of patients with peripheral neuropathy (PN) of unknown etiology. Several autoantibodies, including anti-MAG (myelin-associated glycoprotein) antibodies, have been reported to induce neuropathy. It has been suggested that over 50% of patients with PN and IgM monoclonal gammopathy (MG) have anti-MAG IgM antibodies in their sera. This work aimed at studying the frequency and characteristics of PN in a group of Egyptian patients with MGs and to estimate the serum level of anti-MAG antibodies and its relationship to peripheral nerve dysfunction. Forty patients with MGs were enrolled in the study. Their mean age was 56.65±8.55years. There were 17 males and 23 females. Patients were subjected to complete general and neurological examination, laboratory investigations including serum LDH, β2 microglobulin, serum protein electrophoresis, urinary Bence-Jones protein, bone marrow aspiration and/or trephine biopsy, quantitative estimation of serum IgM and IgG by nephelometry, detection of anti-MAG antibodies by indirect immunofluorescence, radiological assessment and nerve conduction study of both upper and lower limbs. Clinical and electrophysiological evidences of PN were found in 32 (80%) out of the 40 patients with MG. Twenty-five patients (62.5%) had distal symmetrical polyneuropathy and seven (17.5%) had mononeuritis or mononeuritis multiplex. The majority of patients (65%) had sensory or predominantly sensorimotor polyneuropathy. The neuropathy was mainly demyelinating in 22 patients (55%) and axonal in the other 10 (25%) patients. Anti-MAG antibodies were positive in nine patients (22.5%) and six of them (66.6%) had PN. The latter was predominantly demyelinating motor neuropathy in 4 and axonal in the remaining 2. However, the relationship between the presence of anti-MAG antibodies and the development and type of PN was not statistically significant. Anti-MAG showed significant association with IgM level (P=0.003**) and the MG subtypes: Waldenström's macroglobulinemia (WM) and monoclonal gammopathy of undetermined significance (MGUS) (P=0.004**). The present study showed high frequency (>60%) of distal symmetrical polyneuropathy in Egyptian patients with MG. The neuropathy was predominantly sensory and demyelinating. Anti-MAG antibodies were detected only in 22.5% of the patients, especially those with WM and MGUS and were associated with more motor and demyelinating neuropathy. We recommend that patients with chronic polyneuropathies should be evaluated for underlying plasma cell dyscrasia.

Platelet RNA Splicing Profiles Can Distinguish IgM MGUS Patients from Healthy Individuals

The occurrence of a peripheral neuropathy (PN) in association with a monoclonal gammopathy is quite common and suggests that monoclonal proteins may play a pathogenetic role in peripheral nervous system damage. In fact, paraproteinemic PN constitute an heterogeneous group of disorders related to various pathogenetic factors, and the histopathologic features in peripheral nerve biopsies differ from one condition to another. In several well defined disorders, the responsibility of the monoclonal component in the development of the PN has been evidenced. This is the case for most of the PN associated with an IgM monoclonal gammopathy, either a monoclonal gammopathy of undetermined significance (MGUS) or Waldenstrom's macroglobulinemia. The responsibility of the monoclonal protein in the occurrence of amyloid neuropathy related to multiple myeloma is also recognized. However, most IgG or IgA MGUS, as well as the monoclonal component in POEMS syndrome, have an uncertain causal relationship with the neuropathy. PN associated with monoclonal cryoglobulin (type 1) are occasional and differ from those associated with mixed cryoglobulins (types 2 or 3).

The occurrence of a peripheral neuropathy (PN) in association with a monoclonal gammopathy is quite common and suggests that monoclonal proteins may play a pathogenetic role in peripheral nervous system damage. In fact, paraproteinemic PN constitute an heterogeneous group of disorders related to various pathogenetic factors, and the histopathologic features in peripheral nerve biopsies differ from one condition to another. In several well defined disorders, the responsibility of the monoclonal component in the development of the PN has been evidenced. This is the case for most of the PN associated with an IgM monoclonal gammopathy, either a monoclonal gammopathy of undetermined significance (MGUS) or Waldenstrom's macroglobulinemia. The responsibility of the monoclonal protein in the occurrence of amyloid neuropathy related to multiple myeloma is also recognized. However, most IgG or IgA MGUS, as well as the monoclonal component in POEMS syndrome, have an uncertain causal relationship with the neuropathy. PN associated with monoclonal cryoglobulin (type 1) are occasional and differ from those associated with mixed cryoglobulins (types 2 or 3).

Clinicopathological definition of Waldenstrom's macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia

Prevalence of MGCS Among Patients With Monoclonal Gammopathies.

Lymphoplasmacytic non-Hodgkin lymphoma/Waldenström's macroglobulinemia with CD5+, CD23+, and CD10-

Lenalidomide: A double-edged sword for concomitant multiple myeloma and post-essential thrombocythemia myelofibrosis.

The term monoclonal gammopathy pertains to the expansion of a single clone of B lymphocytes that produce an excess of a homogeneous immunoglobulin. Monoclonal gammopathy of undetermined significance (MGUS) is diagnosed in a patient who presents with a monoclonal gammopathy in the absence of histologic evidence, signs, or symptoms of a malignant lymphoproliferative or plasmacytic disorder. MGUS is among the most common premalignant conditions in Western populations, having a prevalence of about 4 % in white adults older than age 50. The immunoglobulin type M (IgM) subtype of MGUS (IgM-MGUS) exhibits unique features that distinguish it from non-IgM MGUS, including a distinctive racial prevalence pattern and spectrum of malignant outcomes. Putative risk factors predisposing to development of IgM-MGUS have been identified, but most await confirmation. The MYD88 L265P mutation that is characteristic of Waldenstrom macroglobulinemia (WM) is found in about half of IgM-MGUS patients. The most common malignant outcome is WM, but patients can develop other lymphoproliferative B-cell diseases. Patients progress to WM at a rate of 1.5 % per year, and they continue to be at risk of progression more than 20 years following diagnosis. Size of the monoclonal component at diagnosis has been the most consistent predictor of prognosis. IgM MGUS is also associated with other nonmalignant comorbidities, and patients diagnosed with it have inferior survival compared to the general population. Thus, there is growing consensus that IgM monoclonal gammopathy may indeed have clinical significance. Further, while routine screening for IgM-MGUS is not widely advocated, it is recommended that, when discovered, IgM-MGUS patients should be followed for life.

Immunoglobulin Heavy Chain (IGH) Gene Rearrangement In Waldenström Macroglobulinemia and Other Monoclonal IgM Disorders

Waldenstrom macroglobulinemia (WM) is an uncommon B-cell malignancy arising from B cells that are arrested after somatic hypermutation in the germinal center and before terminal differentiation to plasma cells [1]. It is characterized by IgM monoclonal gammopathy and bone marrow involvement by a lymphoplasmacytic lymphoma clone. WM accounts for approximately 5% of non-Hodgkin’s lymphomas, although recent data suggest its incidence is declining [2,3]. WM, considered an incurable disease in most cases, is an indolent lymphoma with a median age at diagnosis of 65 years and median survival of 5–10 years [4]. While once thought to closely resemble multiple myeloma, genomic studies of WM have found that this condition genetically clusters with other indolent lymphomas [5]. Morphologically, bone marrow in WM reveals plasmacytoid lymphocytes, small lymphocytes and plasma cells [6]. Characteristic features include the presence of Dutcher bodies (intranuclear pseudo-inclusions of IgM) and Russell bodies (prominent cytoplasmic globules). Cells stain positive for pan-B-cell markers, including CD19, CD20, CD25 and, in most cases, CD79a. Unlike chronic lymphocytic leukemia and follicular lymphoma, cells are usually negative for CD5, CD10 and CD23. One of the unique features of WM is its genetics. Recent studies revealed that deletion of 6q21 occurs in 42–63% of WM cases and over 70% demonstrate MYD88 mutations, which may convey a more aggressive phenotype [7]. In addition, the mutation of CXCR4 is present in 29% of cases and appears to play a critical role in WM biology [8]. WM is associated with a spectrum of disease severity. The presence of IgM monoclonal gammopathy of unknown significance (serum M spike <3 g/dl and <10% clonal marrow involvement) commonly precedes development of WM. Cytopenias, adenopathy, organomegaly or hyperviscosity syndrome is often absent at diagnosis and approximately a third of patients with WM remain asymptomatic. Patients with asymptomatic disease are considered to have smoldering disease and a watch-and-wait approach is appropriate.

Plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), Waldenström macroglobulinemia (WM) and light chain AL amyloidosis, are characterized by clonal expansion of plasma cells which produce a vast amount of an immunoglobulin-derived M-protein. We noted that MGUS diagnosis often coincided with diagnoses of senile cataract and glaucoma and tested the associations of MGUS, MM, WM and AL amyloidosis with subsequent eye diseases identified from the Swedish patient registers between 1997 and 2012. Standardized incidence ratios (SIRs) for senile cataract was significantly increased to 1.80 after MGUS, 1.70 after MM, 1.85 after WM and 2.31 after AL amyloidosis. The SIR for glaucoma was 1.60 after MGUS, 1.76 after WM and 2.18 after AL amyloidosis. All SIRs decreased systematically from age below 60 years to over 79 years, but most risks were also significant in age group over 79 years. The M-protein and the related increase in blood viscosity could be a novel etiologic discovery for these common eye diseases. As MGUS prevalence is around 3% at 60 years and close to 10% at age over 80 years, its contribution to the eye disease burden is expected to be remarkably high.