Early detection of multiple myeloma: A first step towards a screening programme.

Novel therapies for multiple myeloma have substantially improved the prognosis, but before patients are able to benefit from treatment, a diagnosis must have been made. The Myeloma UK laboratory working group has developed a three-part tool box to help primary care physicians to suspect myeloma despite mostly vague symptoms, to do the right tests and to derive the proper conclusions from the results. Commentary on: Drayson et al. Laboratory practice is central to earlier myeloma diagnosis; utilising a primary care diagnostic tool and laboratory guidelines integrated into haematology services. Br J Haematol 2024;204:476-486.

Kidney and urinary tract involvement in systemic mastocytosis.

Systemic mastocytosis (SM) is a disorder of excessive mast cell accumulation in tissues due to a somatic gain-of-function mutation, commonly in the KIT gene, which prevents apoptosis of mast cells. Whereas bone marrow, skin, lymph nodes, spleen and gastrointestinal tract are commonly involved, kidneys are rarely involved directly by SM. However, there are increasing reports of indirect kidney involvement in patients with SM. Novel anti-neoplastic agents to treat advanced forms of SM include non-specific tyrosine kinase inhibitors, which are reported to be associated with kidney dysfunction in some patients. SM is also associated with immune-mediated glomerulonephritis (GN) such as mesangioproliferative GN, membranous nephropathy and diffuse proliferative GN. Kidney injury, in the form of monoclonal deposition disease and primary light chain amyloidosis, is reported in SM associated with plasma cell dyscrasia. In this narrative review we discuss the various ways kidneys (and the urinary tract) are involved in patients with SM.

Paraprotein associated heparin resistance during cardiopulmonary bypass.

INTRODUCTION: Heparin resistance during cardiopulmonary bypass poses a significant intraoperative dilemma. Antithrombin deficiency related heparin resistance is well described, but less common causes are still poorly understood and inadequately managed. CASE REPORT: We present a case of heparin resistance during cardiopulmonary bypass in a gentleman with no previous haematological history or thrombotic risk factors. The patient required three times the regular dose of unfractionated heparin to achieve acceptable conditions to initiate and maintain bypass. The patient was found to have elevated serum immunoglobulin M (IgM) kappa paraprotein on post-operative investigation. DISCUSSION: Paraproteins may exhibit non-specific binding to long polymeric chains of unfractionated heparin and inhibits the interaction between heparin and antithrombin. As a result, excessive doses of heparin are required to overcome this, which increases the risk of perioperative bleeding and other complications. CONCLUSION: Elevated serum paraprotein levels should be recognised as a cause of heparin resistance during cardiopulmonary bypass.

Prognostic significance of serum immunoglobulin paraprotein in mucosa-associated lymphoid tissue (MALT) lymphoma.

To assess the prognostic significance of immunoglobulin (Ig) paraproteinaemia in mucosa-associated lymphoid tissue (MALT) lymphoma, 218 patients diagnosed with MALT lymphoma were enrolled in this study. Serum Ig paraprotein was detected in 42 of 218 patients (19.3%), mostly IgM-K (15, 35.7%), followed by IgM-L and IgG-L. Advanced age (p = 0.025), poor Eastern Cooperative Oncology Group performance status (p = 0.014), bone marrow involvement (p = 0.019), B symptoms (p = 0.039), advanced disease stage (III-IV) (p < 0.0001), elevated serum ß2-microglobulin level (p < 0.0001), multiple extranodal sites of involvement (p < 0.0001), nodal involvement (p < 0.0001), systemic therapy (p < 0.0001) and higher MALT-lymphoma International Prognostic Index (MALT-IPI) scores (p = 0.001) were significantly associated with the presence of serum Ig paraprotein. Multivariate Cox regression analysis showed that Ig paraproteinaemia was an independent prognostic predictor for inferior progression-free survival (PFS) and overall survival. A new prognostic index based on MALT-IPI and Ig paraproteinaemia, as assessed using receiver operating characteristic curves and the area under the curve statistics, showed better discriminative ability than MALT-IPI in predicting PFS. In conclusion, Ig paraproteinaemia was a promising prognostic predictor for MALT lymphoma. Ig paraproteinaemia together with MALT-IPI might contribute to optimising therapeutic management in clinical practice.

[Detection of paraprotein in plasma cell tumors].

Paraprotein is a laboratory biomarker of plasma cell tumors and other lymphoproliferative diseases. Its determination is necessary for diagnosing, monitoring and assessment of therapy effectiveness. The lecture presents the main methods of qualitative and quantative analysis of monoclonal proteins: gel electrophoresis, capillary electrophoresis, immunofixation and nephelometry features, possibilities and limitations are reviewed. The main sources of errors and artifacts during these studies are considered. Also the difficulties in the diagnosis and interpretation of the results of serum and urine tests are highlighted.

Biochemical profile of Bence-Jones type multiple myeloma.

Multiple myeloma (MM) is a malignant tumor occurring from plasma cells that produce an abnormal monoclonal immunoglobulin - a paraprotein. A distinctive feature of Bence-Jones myeloma is the excretion of monoclonal free light chains of immunoglobulins with 24h urine, and the absence of monoclonal intact immunoglobulins secretion. Comprehensive analysis of biochemical parameters in blood serum and 24h urine in patients with Bence-Jones multiple myeloma using electrophoretic and immunoturbidimetric methods to assess their sensitivity as biomarkers. 50 patients with a morphologically confirmed diagnosis of MM of the Bence-Jones immunochemical type were examined. 28 people without oncological diseases were examinedas a control. Detection of monoclonal secretion in blood serum and daily urine was performed by immunofixation electrophoresis on the Hydrasys 2 electrophoretic system (Sebia). The determination of free light chains of immunoglobulins (FLC) was performed by the immunoturbidimetric method (Binding Site) on an Advia 1800 analyzer (Siemens). Analysis of IgG, IgA, IgM, ß2-microglobulin and C-reactive protein was performed on Cobas 6000 analyzer (Roche). The median excretion of Bence-Jones protein in 24h urine of MM patients was 0.49 g/24h (0.06-2.45 g/24h). In the blood serum, in 86% of cases, the presence of paraproteinemia, represented by κ and λ type light chains of immunogloublins was detected. At the same time, the frequency of detection of monoclonal secretion in blood serum in Bence-Jones type λ myeloma was 95.7%, which was statistically significantly higher than the frequency of detection of monoclonal secretion of type κ - 77.8%. In patients with identified paraproteinemia, Bence-Jones protein excretion in daily urine (median 0.82 g/day) was statistically significantly higher than in patients without a monoclonal component detected in blood serum (median 0.04 g/24h). The levels of FLC in blood serum obtained by immunoturbidimetry in Bence-Jones myeloma of the corresponding type were higher than the reference levels in 100% of cases. The median level of κ-FLC reached 4358 mg/l, λ-FLC - 2225 mg/l, which was statistically significantly higher than the control levels. The median concentrations of IgG, IgA and IgM in patients with Bence-Jones myeloma were statistically significantly lower than in the control group, while the medians of ß2-microglobulin and C-reactive protein were significantly higher than in the control. Our investigation showed high diagnostic efficiency of electrophoretic and immunoturbidimetric analysis of monoclonal secretion in patients with Bence-Jones MM, while FLC analysis demonstrated maximum sensitivity. Bence-Jones MM revealed biochemical signs of secondary immunodeficiency and general inflammatory syndrome.

The Association between Metabolic Syndrome and Multiple Myeloma.

Multiple myeloma (MM) is a haematological malignancy arising from monoclonal proliferation of plasma cells in the bone marrow, resulting in the presence of paraproteins or M-protein in serum. The involvement of paraproteins produced by malignant plasma cells in the development of hyperlipidaemia and low-HDL cholesterol has been described, as has an association with MM and obesity, hypertension, and type 2 diabetes mellitus, and insulin resistance, that is, features of the metabolic syndrome (MS). There is an association between MS components, inflammatory cytokines, and the development of MM, and some drugs used in the treatment of MS such as statins and metformin may improve outcomes in MM.

Paraproteinemia and neuropathy.

Paraproteinemia is associated with different peripheral neuropathies. The major causes of neuropathy correlated with paraproteinemia are the deposition of immunoglobulin in the myelin, represented by anti-myelin-associated glycoprotein (MAG) neuropathy; deposition of immunoglobulin or its fragment in the interstitium, represented by immunoglobulin light chain amyloidosis (AL amyloidosis); and paraneoplastic mechanisms that cannot be solely attributed to the deposition of immunoglobulin or its fragment, represented by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS) syndrome. Patients with anti-MAG neuropathy and POEMS syndrome present with slowing of nerve conduction parameters. This characteristic fulfills the electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) defined by the European Academy of Neurology and Peripheral Nerve Society (EAN/PNS). Although direct damage caused by the deposition of amyloid can induce axonal damage in AL amyloidosis, some patients with this condition have features fulfilling the EAN/PNS electrodiagnostic criteria for CIDP. Conventional immunotherapies for CIDP, such as steroids, intravenous immunoglobulin, and plasma exchange, offer no or only minimal-to-modest benefit. Although rituximab can reduce the level of circulating autoantibodies, it may only be effective in some patients with anti-MAG neuropathy. Drugs including melphalan, thalidomide, lenalidomide, and bortezomib for POEMS syndrome and those including melphalan, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, and daratumumab for AL amyloidosis are considered. Since there will be more therapeutic options in the future, thereby enabling appropriate treatments for individual neuropathies, there is an increasing need for early diagnosis.

An upsurge of the serum free light chains as a possible missing link in tumour lysis syndrome in multiple myeloma.

Multiple myeloma (MM) is a slow-growing malignancy characterized by a low proliferation rate of plasma cells and a relatively rare incidence of tumour lysis syndrome (TLS). Three myeloma patients developed TLS following cytotoxic therapy (two after radiation treatment) that was associated with an abrupt increase of serum free light chains (FLC). All three patients demonstrated extramedullary plasmacytomas that exhibited aggressive features compared to the original myeloma. The findings suggested that an abrupt liberation (rather than slow secretion) of FLC from myeloma cells may trigger a fulminant cast nephropathy and present an unrecognized risk factor and potentially aggravating component of TLS.

Paraprotein implicated in hardware failures in nucleic acid testing of blood donors.

BACKGROUND AND OBJECTIVES: Analyser blockage due to gel formation by paraproteins leading to invalid results is a rare problem in viral nucleic acid testing (NAT) at New Zealand Blood Service (NZBS) despite many blood samples tested without problems from individuals with known paraproteins. This study aimed to identify common factors in samples causing blockages. METHOD: Retrospective data were gathered on blood samples known to have blocked analysers at NZBS testing sites. Patients with plasma cell dyscrasia undergoing haematopoietic stem cell (HSC) harvest formed the comparator arm. These patients were identified from registry data of individuals undergoing autologous stem cell transplantation at Auckland City Hospital between 2013 and 2017. RESULTS: Four individuals were identified as having blocked analysers between 2010 and 2018. A total of 184 HSC transplant patients were identified, with contemporaneous paraprotein levels available for 177 (96%). Patients with intact immunoglobulin subtypes (134, 73%) were further analysed. Of these, 119 patients (65%) also had total protein and globulin levels available. Mean paraprotein (37.5 g/l), total protein (95.3 g/l), globulin levels (51.5 g/l) and proportion of lambda subtype (75%) were higher in the blocker group compared with non-blocking comparators (4.7 g/l, 66.8 g/l, 27.7 g/l, 36.6% respectively) (P = 0·03, 0·02, 0·007, 0·12). The highest paraprotein and total protein levels from the non-blocking cohort overlapped with the lowest of the blocker group. DISCUSSION: High protein levels (paraprotein >20 g/l, total protein >75 g/l) and a trend towards lambda subtype were associated with NAT analyser blockage. The overlap with non-blocking donor samples suggests factors in addition to protein quantity that are also important.

Types of paraproteinemia in patients with multiple myeloma: A cross-sectional study.

OBJECTIVE: To determine the types of paraproteins in patients with multiple myeloma in a tertiary care setting. METHODS: The cross-sectional study was conducted at the Liaquat National Hospital, Karachi, from November 2015 to May 2016, and comprised patients with multiple myeloma selected using consecutive, non-probability sampling technique. Detailed history was taken and immunofixation assay was conducted to assess the type of paraproteins in the patients. Data was recorded on a proforma and analysed using SPSS 22. RESULTS: Of the 87 patients, 62(71.3%) were males and 25(28.7%) were females. The overall mean age was 57.41±10.53 years. Of the total, 52(71.3%), patients had Immunoglobulin G kappa and 61(70%) had Immunoglobulin A kappa paraprotein. CONCLUSIONS: The most common types of paraprotein was found to be Immunoglobulin G kappa followed by Immunoglobulin A kappa.

[POEMS-syndrome: diagnostic difficulties].

POEMS syndrome is a rare paraneoplastic syndrome whose name is an acronym formed from the initial letters of the names of the symptoms originally used to determine it: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes. Due to the rarity of the disease and the small number of cases described in the literature, its diagnosis is difficult. The average time from onset of symptoms to diagnosis is 18 months. Moreover, the prognosis of the disease depends on the early onset of specific treatment. The article describes a clinical case of POEMS-syndrome in a 53-year-old man, which illustrates the difficulties associated with the timely recognition of this unusual disease.

[Monoclonal gammopathy of renal significance: consensus of hematologists and nephrologists of Russia on the establishment of nosology, diagnostic approach and rationale for clone specific treatment].

Monoclonal gammopathy of renal significance (MGRS) is a new nosology in modern nephrology and oncohematology. MGRS is defined as kidney injury due to nephrotoxic monoclonal immunoglobulin produced by the B-cell line clone which does not reach the hematological criteria for specific treatment initiation. Monoclonal proteins pathological effects on kidney parenchyma result in irreversible decline of kidney function till the end stage renal disease that in line with the position of International Consensus of hematologists and nephrologists determinates critical necessity for clone specific treatment in patients with MGRS despite the absence of hematological indications for treatment initiation. Main challenge of MGRS in Russian Federation is an inaccessibility of an in-time diagnostic and appropriate treatment for the great majority of patients due to the following reasons: 1) limited knowledge about the MGRS among hematologists and nephrologists; 2) lack of necessary diagnostic resources in most health-care facilities; 3) lack of approved clinical recommendations and medical economic standards for treatment of this pathological entity. Consensus document comprises the opinion of experts leading nephrologists and hematologists of Russian Federation on the problem of MGRS including the incoherence in nosology classification, diagnostics approach and rationale for clone specific treatment. Consensus document is based on conclusions and agreements reached during the conference of leading nephrologists and hematologists of Russia which was held in the framework of symposia Plasma cell dyscrasias and lymphoproliferative diseases: modern approaches to therapy, 1516 of March 2019, Pavlov First Saint Petersburg State Medical University. The present Consensus is intended to define the principal practical steps to resolve the problem of MGRS in Russian Federation that are summarized as final clauses.

Saposin C is a frequent target of paraproteins in Gaucher disease-associated MGUS/multiple myeloma.

Patients with Gaucher disease (GD) have an increased risk of monoclonal gammopathies for which antigenic targets might play a role in their pathogenesis. Here we report the identification of saposin C (sapC) as high-titre (1:1 000 000) target structure of 7/16 GD-associated paraproteins. Anti-sapC immunoglobulin (Ig) showed identity with the paraprotein Ig type and subclass in each patient that showed anti-sapC immunoreactivity. Absorption and depletion studies completely removed the paraprotein from the sera of GD patients. No immunoreactivity against sapC was detected in healthy donors and in other plasma cell dyscrasias, demonstrating that anti-sapC reactivity is highly restricted to GD. Several uncharacterized forms of post-translational modified sapC were detected but their role in the pathogenesis is not clear. We confirm the frequent presence of low-titre (1:250) anti-lysolipid reactivities in the sera of GD patients but we could show that this immunoreactivity is not mediated by the paraprotein and is not restricted to GD patients.

Obinutuzumab, a new anti-CD20 antibody, and chlorambucil are active and effective in anti-myelin-associated glycoprotein antibody polyneuropathy.

BACKGROUND AND PURPOSE: Rituximab, a chimeric anti-CD20 monoclonal antibody, has been used in polyneuropathy associated with anti-myelin-associated glycoprotein (anti-MAG) antibody polyneuropathy with controversial results. Herein, two patients with anti-MAG antibody neuropathy and concurrent chronic lymphocytic leukemia (CLL) are reported, who dramatically responded to obinutuzumab, a novel glycoengineered humanized anti-CD20 monoclonal antibody. METHODS: Patient 1 was an 82-year-old man with severe demyelinating sensory-motor neuropathy. He was wheelchair-bound, with loss of sensation up to the knees. He had a CLL, immunoglobulin M (IgM) lambda monoclonal gammopathy, with anti-MAG antibodies >70 000 Bühlmann titer units (BTU). Patient 2 was an 84-year-old woman with demyelinating neuropathy, paresthesias and gait instability. She had CLL and IgM kappa paraprotein with anti-MAG antibodies >70 000 BTU. Both patients were treated with obinutuzumab intravenously at 100 mg on day +1, 900 mg +2, then at 1000 mg on days 8 and 15 of cycle 1 and day 1 of cycles 2-6; chlorambucil was given orally at 0.5 mg/kg on days 1 and 15 of cycles 1-6. RESULTS: Patient 1 at cycle 6 was able to stand, gait was possible with monolateral support, hypoesthesia and strength improved. M-protein and IgM level decreased. In patient 2, already after three cycles, the monoclonal component disappeared and there was dramatic improvement of symptoms and gait normalization. At the end of therapy anti-MAG antibody titer decreased to 5462 BTU. Neurophysiology also improved. CONCLUSIONS: In our patients, obinutuzumab was effective as a first-line treatment of anti-MAG antibody polyneuropathy. CLL might have had a role in the response to therapy, but the associations might be considered in future trials.

Collapsing Glomerulopathy in Lambda Light Chain Amyloidosis: A Report of 2 Cases.

Amyloid nephropathy is an uncommon disease that frequently presents with reduced kidney function and proteinuria and, in developed nations, is most often associated with underlying paraproteinemia. The histologic appearance of glomerular amyloid deposition includes mesangial and capillary wall infiltration by an amorphous eosinophilic material, and features of endo- or extracapillary proliferation are not typically seen. Rare cases of crescentic injury have been reported in a subset of patients with amyloid nephropathy, particularly those with amyloid derived from serum amyloid A protein. Collapsing glomerulopathy, which like crescentic injury is associated with an extracapillary proliferation, has not to our knowledge been reported in the setting of amyloid nephropathy. We report 2 patients presenting with acute kidney injury and nephrotic syndrome found to have amyloid nephropathy with prominent epithelial cell hyperplasia and glomerular collapse on biopsy. This injury is likely multifactorial and related to direct podocyte injury and vascular compromise and expands further the spectrum of paraprotein-associated renal injury.

[Successful diagnosis of lymphoplasmacytic lymphoma with IgG paraprotein using MYD88 L265P mutation analysis].

A 76-year-old woman presented to our hospital with leukocytosis and abnormal lymphocytes. M protein of the immunoglobulin G (IgG) type was detected using immunoelectrophoresis. A bone marrow biopsy revealed infiltration of small mature lymphocytes, lymphoplasmacytoid cells with Dutcher bodies, grape cells, and Russell bodies. The MYD88 L265P mutation was detected in the abnormal peripheral lymphocytes, and a diagnosis of lymphoplasmacytoid lymphoma was established. MYD88 L265P mutation analysis is useful for making a diagnosis of non-IgM lymphoplasmacytoid lymphoma because it enables the differentiation from other low-grade B-cell malignancies.

IgMk paraprotein from gammopathy patient can bind to cardiolipin and interfere with coagulation assay: a case report.

BACKGROUND: The monoclonal gammopathies are a group of plasma-cell proliferative disorders characterized by the secretion of monoclonal immunoglobulin (M protein or paraprotein). Some rare cases have revealed the specific affinity of paraprotein as autoantibody. Here we report a patient with monoclonal gammopathy of undetermined significance (MGUS) accompanied by a remarkable increase of anticardiolipin antibody (aCL) and an extensively decreased coagulation factor activity, however, without any clinical signs of antiphospholipid syndrome (APS) and bleeding. RESULTS: Our further investigation indicated that IgMκ paraprotein of this patient possessed an antibody activity against phospholipids so as to bind to cardiolipin and interfere with coagulation assay in vitro. CONCLUSIONS: This case might be indicative that an abnormality of coagulation tests, disturbed by IgMκ paraprotein, does not predict a risk of bleeding in this patient.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM): a practical guide to management.

Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma are precursor conditions of symptomatic multiple myeloma (MM). Diagnostic principles are aimed at excluding MM requiring therapy, other conditions associated with paraproteins that may require different management, and risk stratifying patients for the purposes of tailored follow-up and investigation. The International Myeloma Working Group have recently published a revised definition of MM, which singles out a small group of patients with smoldering multiple myeloma who are at very high risk of progression and organ damage; such patients are now included under the definition of MM and recommended to start anti-myeloma treatment. Furthermore, the recently published National Institute of Health and Care Excellence guideline recommends cross-sectional imaging techniques in place of skeletal survey. These recent recommendations are discussed, and practical guidance for investigation and management are presented.