General MM

What is monoclonal gammopathy of clinical significance?

Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition, characterized by elevated levels of a monoclonal immunoglobulin (M-Ig) in the serum (< 30 g/L) but without any end-organ damage. Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to describe several severe conditions that, similar to MGUS, emerge from the abnormal secretion of an M-Ig; unlike MGUS though, MGRS has a detrimental effect on renal function.

The primary cause of both MGUS and MGRS is the existence of a defective B-cell clone, which results in abnormal M-Ig secretion. Jean Paul Fermand from the Saint-Louis Hospital in Paris, France, and colleagues introduced a new term, monoclonal gammopathy of clinical significance (MGCS), to describe a set of pathologies derived from abnormally-functioning B-cell clones, and which lead to severe organ damage. The study was published in the journal Blood in July 2018. 

Key Data:
  • MGCS mechanisms of tissue injury: Deposition of M-Ig; auto-antibody activity (auto-AbA); formation of immune complexes; complement activation; absorption of biologically active molecules; induction of cytokine secretion
  • MGCS due to M-Ig deposition: Organized or non-organized deposits
  • MGCS with organized M-Ig deposits:
    • AL amyloidosis: fibrillary deposits; systemic, mainly involved organs or tissues (MIO) = heart and kidney
    • Acquired Fanconi syndrome: precipitation of light chains (LC) into crystals; MIO = kidney
    • Crystal storing histiocytosis (CSH): M-Ig crystals within the lysosomes of macrophages; systemic
    • Crystalline keratopathy: M-Ig derived crystals in the cornea; MIO = cornea
    • Type I cryoglobulinemia: Microtubular or crystalline deposits; systemic
    • Immunotactoid glomerulopathy: Microtubular IgG deposits; MIO = kidney
  • MGCS with non-organized deposits:
    • Monoclonal immunoglobulin deposition disease (MIDD): linear granular deposits along basal membranes; systemic, MIO = kidney
    • Proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID): M-Ig deposited in the glomerular capillary walls and mesangium; limited to kidney
    • Macroglobulinosis: amorphous intra-dermis M-Ig deposits; limited to the skin (dermis)
  • MGCS due to auto-AbA of M-Ig: activity against various antigens can cause organ lesions; antigens include: collagen IV, collagen VII, phospholipase A2 receptor; myelin-associated glycoprotein (MAG)
  • Conditions due to Auto-AbA:
    • Bullous skin diseases: Auto-AbA against collagen VII; MIO = skin
    • IgM-associated peripheral neuropathy: Auto-AbA against MAG or less frequently gangliosides; MIO = peripheral nerve
    • Acquired C1 inhibitor deficiency: Auto-AbA of M-Ig resulting in angioedema
    • Von Willebrand disease: Auto-AbA of M-Ig resulting in bleeding
    • Cold agglutinin disease (CAD): Auto-AbA of M-IgM resulting in cold-induced skin manifestations and intra-vascular hemolysis
    • Type II mixed cryoglobulinemia: M-IgM with rheumatoid activity; MIO = skin, kidney, peripheral nerve
    • Xanthomatosis: Auto-AbA against various lipoproteins; MIO = skin, and tendons
  • MGCS secondary to complement alternative pathway (CAP) activation
    • C3 glomerulopathy (C3G): Associated with an indolent M-IgG; MIO = kidney only
    • Atypical hemolytic uremic syndrome: Auto-AbA against CAP regulator protein, factor H; systemic
  • MGCS due to cytokine secretion
    • POEMS: Marked elevation of serum VEGF levels which correlates with disease activity; MIO = Peripheral nerve
  • MGCS of unknown mechanism
    • Scleromyxedema: MIO = skin
    • Scleredema: MIO = skin only
    • Acquired cutis laxa: MIO = mainly skin and other, such as lung and digestive tract
    • Schnitzler’s syndrome: MIO = mainly skin but also bone lesions and systemic symptoms
    • Systemic capillary leak syndrome: MIO = systemic
    • TEMPI syndrome: MIO = systemic
    • Sporadic late onset nemaline myopathy (SLONM): MIO = muscles only (skeletal and possibly cardiac)
  • MGCS diagnosis:
    • For MGCS due to M-Ig deposition: It is important to show that the deposition is associated with pathological features; recommended laboratory techniques include immunohistology and electron microscopy
    • For MGCS due to auto-AbA of M-Ig: It is crucial to detect a higher titer of auto-AbA; recommended techniques include sensitive immuno-blotting or ELISA
    • For an MGCS secondary to CAP activation: It is recommended to measure the levels of the serum complement; low levels of protein components suggest activation of the complement classical pathway by immune-complexes
    • For MGCS of unknown mechanism: Epidemiological and immunological data may suggest a relationship between the symptoms and the condition
  • MGCS treatment relies on limiting the activity of the small, abnormal B-cell clone. Effective treatments include monoclonal antibodies and local irradiation. Anti-CD38 monoclonal antibodies are currently being examined for the treatment of AL amyloidosis, and are likely to be used in the treatment of various MGCS. High-dose intravenous immunoglobulins (IVIG) are sometimes proposed as an alternative, but their efficacy is usually temporary.
Conclusions

The term MGCS can be used to encompass a series of monoclonal gammopathies that share as common feature abnormal levels of an M-Ig and whose origin lies on a defective B-cell clone. Uncontrolled proliferation of this clone may lead to deleterious defects and severe organ damage; thus, identifying and treating these conditions early, can help limit their pathogenic consequences.

References

Fermand J.P. et al. Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications. Blood. 2018 Jul 16. pii: blood-2018-04-839480. DOI: 10.1182/blood-2018-04-839480. [Epub ahead of print]

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