Molecular alterations of IL-6R, lck and c-myc genes in transforming monoclonal gammopathies of undetermined significance

Chronic stimulation by infectious or self-antigens initiates subsets of monoclonal gammopathies of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM). Recently, glucosylsphingosine (GlcSph) was reported to be the target of one third of monoclonal immunoglobulins (Igs). In this study of 233 patients (137 MGUS, 6 SMM, 90 MM), we analyzed the GlcSph-reactivity of monoclonal Igs and non-clonal Igs. The presence of GlcSph-reactive Igs in serum was unexpectedly frequent, detected for 103/233 (44.2%) patients. However, GlcSph was targeted by the patient’s monoclonal Ig for only 37 patients (15.9%); for other patients (44 MGUS, 22 MM), the GlcSph-reactive Igs were non-clonal. Then, the characteristics of patients were examined: compared to MM with an Epstein-Barr virus EBNA-1-reactive monoclonal Ig, MM patients with a GlcSph-reactive monoclonal Ig had a mild presentation. The inflammation profiles of patients were similar except for moderately elevated levels of 4 cytokines for patients with GlcSph-reactive Igs. In summary, our study highlights the importance of analyzing clonal Igs separately from non-clonal Igs and shows that, if autoimmune responses to GlcSph are frequent in MGUS/SMM and MM, GlcSph presumably represents the initial pathogenic event for ~16% cases. Importantly, GlcSph-initiated MM appears to be a mild form of MM disease.

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Monoclonal gammopathies of clinical significance

Hematology ◽

10.1182/hematology.2020000122 ◽

2020 ◽

Vol 2020 (1) ◽

pp. 380-388

Author(s):

Angela Dispenzieri

Keyword(s):

Differential Diagnosis ◽

Clinical Significance ◽

Monoclonal Gammopathy ◽

Monoclonal Gammopathies ◽

Skin Biopsies ◽

Unexplained Symptoms ◽

Symptoms And Signs ◽

Important Disease ◽

Iv Immunoglobulin ◽

Undetermined Significance

Abstract “Monoclonal gammopathy of clinical significance” (MGCS) is the term used to describe nonmalignant monoclonal gammopathies causing important disease. MGCS is the differential diagnosis for any patient presenting with what appears to be a monoclonal gammopathy of undetermined significance but is also experiencing other unexplained symptoms. Broadly, these conditions can be separated into symptoms and signs referable to the nerves, the kidneys, and the skin. The first step in making these diagnoses is to consider them. With a particular condition in mind, the next step is to order those tests that can help confirm or dismiss a particular diagnosis. Nearly all of the renal and dermatologic conditions are diagnosed by renal and skin biopsies, respectively. The importance of a highly competent renal pathologist and dermatopathologist cannot be underestimated. Biopsy is less specific for the neuropathic conditions. Because several of the MGCSs are syndromes, recognizing other manifestations is also key. Treatment recommendations for many of these conditions are anecdotal because of their rarity, but for several of the conditions, IV immunoglobulin, rituximab, and plasma cell–directed therapy are the best options.

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IgG and IgA Monoclonal Gammopathies of Undetermined Significance (MGUS) at Low Risk of Evolution: Proposal and Validation of a Prognostic Scoring System

Blood ◽

10.1182/blood.v112.11.5136.5136 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5136-5136

Author(s):

Francesca Gaia Rossi ◽

Luigi Marcheselli ◽

Maria Teresa Petrucci ◽

Davide Rossi ◽

Vincenzo Callea ◽

...

Keyword(s):

Multivariate Analysis ◽

Scoring System ◽

Test Group ◽

Test Sample ◽

Neoplastic Progression ◽

Prognostic Role ◽

Monoclonal Gammopathies ◽

Monoclonal Component ◽

Undetermined Significance

Abstract PURPOSE: The presenting clinico-hematologic features of 1283 patients with IgG and IgA class monoclonal gammopathies of undetermined significance (MGUS) were correlated with the frequency of malignant transformation to evaluate the most important variables prognostically associated with its evolution into multiple myeloma (MM). PATIENTS AND METHODS: Two IgG MGUS patient populations were evaluated: a study sample (553 pts) and a test sample (378 pts). The IgA MGUS population included 352 cases. RESULTS: Considering IgG cases the median follow-up was 6.7 yrs in the study group vs 3.6 yrs in test group; in the first 47/553 pts developed MM vs 22/378 in the latter. At multivariate analysis serum monoclonal component (MC) £1.5 g/dl, absence of BJ proteinuria, normal serum polyclonal Ig levels and age less than 70 defined a prognostically favourable subset of patients. On the basis of these four variables, pts could be stratified into 3 different 10 yrs-evolution risk groups (HR 1.0, 4.28, 11.6; P<0.001). This scoring system was validated in the test sample. Considering IgA cases, thirty out of 352 patients developed MM after a median follow-up of 4.8 yrs. At multivariate analysis, Hb < 12.5 g/dl and serum polyclonal Ig reduction resulted related with neoplastic progression. CONCLUSIONS: using simple variables, whose prognostic role we have previously described, we could validate a prognostic model useful to identify situations with different evolution risk in IgG MGUS. Considering IgA cases a possible prognostic role of Hb level emerged, while the negative one of monoclonal component class or serum levels was not confirmed.

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Recommendations for use of Tumor Markers in Monoclonal Gammopathies

Journal of Medical Biochemistry ◽

10.2478/v10011-007-0020-x ◽

2007 ◽

Vol 26 (2) ◽

pp. 165-172

Author(s):

Marijana Dajak

Keyword(s):

Tumor Markers ◽

Monoclonal Gammopathy ◽

Clinical Biochemistry ◽

M Protein ◽

Monoclonal Gammopathies ◽

Undetermined Significance

Preporuke za Primenu Tumorskih Markera Kod Monoklonskih GamapatijaMonoklonske gamapatije čine grupu poremećaja koji se karakterišu klonskom proliferacijom plazma ćelija. M protein je tumorski marker specifičan za monoklonske gamapatije jer odražava klonsku produkciju imunoglobulina. Monoklonske gamapatije uključuju: multipli mijelom,Waldenström-ovu makroglobulinemiju (WM), nesekretorni mijelom, prikriveni (smoldering) multipli mijelom, monoklonsku gamapatiju od neodređenog značaja (MGUS,Monoclonal gammopathy of undetermined significance), primarnu sistemsku amiloidozu i bolest teških lanaca. Dijagnoza multiplog mijeloma je zasnovana na detekciji M proteina u serumu i/ili urinu, infiltraciji plazma ćelija u koštanoj srži i litičkim koštanim lezijama na radiografiji skeleta. Prema NACB (National Academy of Clinical Biochemistry) preporukama, tumorski markeri za dijagnozu,screening, identifikaciju klonaliteta, praćenje bolesti i prognostičku evaluaciju kod monoklonskih gamapatija su: elektroforeza proteina u serumu i/ili urinu, imunofiksacija u serumu i/ili urinu, slobodni laki lanci (SLL) u serumu i/ili urinu, viskoznost seruma i β2-mikroglobulin. Imunofiksacija se koristi za identifikaciju klonaliteta (tipa) M proteina primećenog na elektroforezi i kada postoji sumnja bez obzira na normalan proteinski elektroforetogram. Posebno je korisna za prepoznavanje i razlikovanje biklonskih ili triklonskih gamapatija. Viskoznost seruma trebalo bi određivati ako pacijent ima znake i simptome sindroma hiperviskoznosti. WM je najčeŠći uzrok hiperviskoznosti, ali se takođe može pojaviti i kod pacijenata sa velikim nivoima monoklonskog IgA ili IgG. Automatizovana imunoodređivanja SLL u serumu su osetljivija od tradicionalne elektroforetske metode i imunofiksacije za detekciju mijeloma monoklonskih lakih lanaca, nesekretornog mijeloma i AL amiloidoze. Osim toga, odnos SLL u serumu je nezavisan faktor rizika za nastanak maligne progresije kod pacijenata sa MGUS. Određivanje SLL u serumu i elektroforeze proteina seruma kao testova prve linije za razmatranje prisustva mogućih poremećaja B ćelija daje dodatnu dijagnostičku informaciju.

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