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      Prevalence of corneal findings and their interrelation with hematological findings in monoclonal gammopathy

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          Abstract

          Purpose

          To determine prevalence of paraproteinemic keratopathy (PPK) among patients with monoclonal gammopathy (MG). To evaluate interrelation between corneal and hematological parameters in patients with PPK.

          Methods

          Fifty-one patients with monoclonal gammopathy of undetermined significance (n = 19), smoldering multiple myeloma (n = 5) or multiple myeloma (n = 27) were prospectively included in this study. Best-corrected visual acuity, slit-lamp biomicroscopy, Scheimpflug tomography, in-vivo confocal laser scanning microscopy, optical coherence tomography and complete hematological workup were assessed.

          Results

          We identified n = 19 patients with bilateral corneal opacities compatible with PPK. PPK was newly diagnosed in 13 (29%) of 45 patients with a primary hematological diagnosis and in n = 6 patients without previous hematological diagnosis. The most common form was a discreet stromal flake-like PPK (n = 14 of 19). The median level of M-protein (p = 0.59), IgA (p = 0.53), IgG (p = 0.79) and IgM (p = 0.59) did not differ significantly between the patients with and without PPK. The median level of the FLC κ in serum of patients with kappa-restricted plasma cell dyscrasia was 209 mg/l in patients with PPK compared to 38.1 mg/l in patients without PPK (p = 0.18). Median level of FLC lambda in serum of patients with lambda-restricted plasma cell dyscrasia was lower in patients with PPK compared to patients without PPK (p = 0.02).

          Conclusion

          The PPK was mostly discreet, but its prevalence (29%) was higher than expected. Median level of the monoclonal paraprotein was not significantly higher in patients with PPK compared to patients without PPK. Our results suggest a lack of correlation between morphology and severity of the ocular findings and severity of the monoclonal gammopathy.

          Trial registration

          German Clinical Trial Register: DRKS00023893.

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          Most cited references58

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          Multiple myeloma

          Multiple myeloma is a malignancy of terminally differentiated plasma cells, and patients typically present with bone marrow infiltration of clonal plasma cells and monoclonal protein in the serum and/or urine. The diagnosis of multiple myeloma is made when clear end-organ damage attributable to the plasma cell proliferative disorder or when findings that suggest a high likelihood of their development are present. Distinguishing symptomatic multiple myeloma that requires treatment from the precursor stages of monoclonal gammopathy of undetermined significance and smouldering multiple myeloma is important, as observation is the standard for those conditions. Much progress has been made over the past decade in the understanding of disease biology and individualized treatment approaches. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have joined the traditional armamentarium (corticosteroids, alkylating agents and anthracyclines) and, along with high-dose therapy and autologous haemopoietic stem cell transplantation, have led to deeper and durable clinical responses. Indeed, an increasing proportion of patients are achieving lasting remissions, raising the possibility of cure for this disease. Success will probably depend on using combinations of effective agents and treating patients in the early stages of disease, such as patients with smouldering multiple myeloma.
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            Dangerous small B-cell clones.

            The detection of a monoclonal immunoglobulin in serum or urine usually raises concerns about the size of the underlying B-cell-derived clone and possible systemic effects caused by its expansion. However, a small clone can synthesize a very toxic protein, producing devastating systemic damage and protean clinical presentations. The resulting "monoclonal component-related diseases," although difficult to diagnose, may be progressive and even fatal. The monoclonal protein can aggregate and deposit systemically as occurs in light-chain amyloidosis, monoclonal immunoglobulin deposition disease, crystal-storing histiocytosis, and monoclonal cryoglobulinemia. Alternatively, some monoclonal proteins possess antibody activity toward autogenous antigens and cause chronic cold agglutinin disease, mixed cryoglobulinemia, and peripheral neuropathies. Other humoral mediators may contribute to neuropathy in variant disorders such as the POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome. The clone synthesizing the noxious monoclonal proteins is often small, and sensitive techniques may be required to detect these immunoglobulins. A delay in diagnosis can allow irreversible organ damage and dramatically shorten survival. Prompt recognition of suggestive signs and symptoms should trigger a thorough diagnostic approach to reach the correct diagnosis quickly, because this is the key to effective therapy. Although the treatment of these conditions is not optimal, significant advances have been made, improving the duration and quality of life.
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              Detection and prevalence of monoclonal gammopathy of undetermined significance: a study utilizing mass spectrometry-based monoclonal immunoglobulin rapid accurate mass measurement

              High-sensitivity mass spectrometry assays are available to detect monoclonal immunoglobulins. To better assess the prevalence of monoclonal gammopathy of undetermined significance (MGUS), we identified 300 patients diagnosed with MGUS or related gammopathy who had a prior negative work-up for monoclonal proteins as part of the Olmsted County MGUS screening study. Two mass spectrometry-based detection methods (matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) and monoclonal immunoglobulin rapid accurate mass measurements (miRAMM) along with traditional immunofixation were performed on the Olmsted baseline and MGUS diagnostics serum samples. Among the 226 patients considered negative for MGUS based on protein electrophoresis and serum-free light-chain assay, a monoclonal protein could be detected at baseline in 24 patients (10.6%) by immunofixation, 113 patients (50%) by MADLI-TOF mass spectrometry, and 149 patients (65.9%) by miRAMM mass spectrometry. In addition, using miRAMM, some patients demonstrated an oligoclonal to monoclonal transition giving insight into the origin of MGUS. Using the sensitive miRAMM, MGUS is present in 887 of 17,367 persons from the Olmsted County cohort, translating into a prevalence of 5.1% among persons 50 years of age and older. This represents the most accurate prevalence estimate of MGUS thus far.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Role: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                31 October 2022
                2022
                : 17
                : 10
                : e0276048
                Affiliations
                [1 ] Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
                [2 ] Department of Hematology, Oncology, and Pneumology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
                [3 ] Department of Gastroenterology, Hepatology, Diabetology, Endocrinology and Oncology, Klinikum Worms, Worms, Germany
                [4 ] Institute for Pathology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
                Cedars Sinai Medical Center, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-8644-6390
                https://orcid.org/0000-0002-7025-8280
                Article
                PONE-D-21-09281
                10.1371/journal.pone.0276048
                9621422
                36315502
                e9b56eab-ac7e-4289-88c5-37d04f364f88
                © 2022 Al Hariri et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 March 2021
                : 27 September 2022
                Page count
                Figures: 3, Tables: 4, Pages: 16
                Funding
                The author(s) received no specific funding for this work.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Cornea
                Medicine and Health Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Cornea
                Medicine and Health Sciences
                Hematology
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Hematologic Cancers and Related Disorders
                Myelomas and Lymphoproliferative Diseases
                Myeloma
                Multiple Myeloma
                Medicine and Health Sciences
                Hematology
                Hematologic Cancers and Related Disorders
                Myelomas and Lymphoproliferative Diseases
                Myeloma
                Multiple Myeloma
                Medicine and Health Sciences
                Hematology
                Plasma Cell Disorders
                Multiple Myeloma
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Plasma Cells
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Plasma Cells
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Plasma Cells
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Plasma Cells
                Physical Sciences
                Materials Science
                Material Properties
                Optical Properties
                Opacity
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Serology
                Medicine and Health Sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Tomography
                Research and Analysis Methods
                Imaging Techniques
                Diagnostic Radiology
                Tomography
                Medicine and Health Sciences
                Radiology and Imaging
                Diagnostic Radiology
                Tomography
                Medicine and Health Sciences
                Ophthalmology
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                All relevant data are within the manuscript and its Supporting Information files.

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