Monoclonal gammopathy of undetermined significance (MGUS) (bsh 2023)

Intro

MGUS Definition – presence of a monoclonal protein in the serum or urine of an individual with no evidence of myeloma, AL amyloidosis, Waldenstrom’s or other related disorders.

MGCS - Monoclonal gammopathy of clinical significance. MGRS - renal significance

M-protein Definition – monoclonal immunoglobulin secreted by an abnormally expanded clone of plasma cells in an amount greater than seen in normal polyclonal antibody responses.

Detectable in 1% of population overall. 4.5% of >40 yo’s, 9% of >85 yo’s

 

Causes for M-proteins / elevated free light chains

DDx – MGUS, Myeloma, SBP/SEP, AL Amyloidosis, Waldenstroms, MGCS, MGRS

  • (note: MGUS is 100x more common than myeloma)

Abnormal serum free light chain (SFLC) ratio can occur with any immune dysregulation – e.g. SLE, HIV, HSCT

Light chain levels likely to be elevated above normal range in renal impairment

 

Diagnostic Criteria

MGUS.png

investigations

Identifying the monoclonal gammopathy

  • Complete Immunoglobulin

    • Immunoglobulin profile, ie serum total IgG, IgA and IgM levels

    • Serum protein electrophoresis (SPE) to detect presence of monoclonal band

    • Immunofixation (IFE) to confirm subtype of monoclonal protein (IgG, IgA, IgM, IgD, IgE etc)

    • Densitromety of monoclonal peak to quantify the paraprotein (g/l)

  • Light chains

    • Serum free light chains (SFLC) to quantify Kappa and Lambda chains and calculate ratio

    • Urine IFE to quantify urinary Bence Jones Protein (BJP). Less sensitive than SFLC

Excluding Myeloma/LPD etc

  • FBC, U&E, eGFR

  • ?Skeletal imaging (see below)

  • ?Bone marrow biopsy (see below)

interpreting / acting on results

Myeloma is highly unlikely if both paraprotein <10g/l and SFLC ratio 0.1-7

Laboratories should provide interpretive text with paraprotein (pp) and SFLC results to aid appropriate assessment of results and timely referrals to haematology where indicated.

Local practice is likely to vary. Myeloma UK GP Myeloma Diagnostic Tool advises:

  • Urgent referral to haematology if:

    • Any pp / abnormal SFLC ratio with urgent clinical symptoms (e.g. AKI, cord compression)

  • 2WW referral to haematology if:

    • IgG pp >15

    • IgM or IgA pp >10

    • IgE or IgD pp of any quantity

    • SFLC ratio <0.1 or >7

  • Recheck levels in primary care in 3 months if:

    • IgG pp <15 / IgM or IgA pp <10 without relevant symptoms

    • SFLC ratio abnormal but in the range of 0.1-7

risk stratification / prognosis

Principles

Roughly, progression of MGUS to Myeloma is 1% per year.

The risk of progression remains constant, ie after 20 yrs f/up, the risk for the same individual is still 1% per year

Factors affecting risk for an individual

  • Type of paraprotein (e.g. IgG lowest risk)

  • Presence of abnormal SFLC ratio in addition to paraprotein increases the risk of progression

  • In contrast, Light chain MGUS (no paraprotein) has low risk of progression

  • Rate of change in paraprotein / SFLC

  • (BM factors: % abnormal plasma cells by flow, clonal heterogeneity, abnormal cytogenetics)

  • Others: Family history, Male sex, Advanced age

2005 Mayo Clinic Risk Stratification (many others available)

One point for each:

  • Paraprotein >15g/l

  • Non-IgG sub-type

  • Abnormal SFLC ratio

Absolute risk of progression at 20 years:

  • 0 = 2% (low)

  • 1 = 10% (low-intermediate)

  • 2 = 18% (high-intermediate)

  • 3 = 27% (high)

management

Practice varies nationally - how much is done in primary vs secondary care, how far to investigate asymptomatic patients, how and where to follow-up patients.

Make sure you know your local practice and rationale for it.

At first detection, BSH recommends:

All patients:

  • History and examination

  • FBC, Creatinine, eGFR and corrected calcium

  • Urine dipstick + urine ACR if proteinuria present

  • Immunoglobulin profile, paraprotein and SFLC

  • Urinary BJP

In addition, all Mayo clinic high-intermediate and high risk (2 or 3 points) patients:

  • LDH, Beta-2-microglobulin, Pro-BNP

  • Skeletal imaging (low dose whole body CT, whole body MRI, PET-CT) or staging CT if IgM

  • BM biopsy including immunophenotpying, FISH and trephine

Follow-up, BSH recommends:

  • Bloods at 6 months and then annually (FBC, U&E, Bone profile, PP, SFLC)

  • Whichever clinical model is used, it requires adequate resource

  • Where possible provision of psychological support is highly valuable

  • Educate and inform patients to ensure critical symptoms are reported in between f/up appointments

Rationale for BSH approach:

  • Only <5% of people with paraprotein <15g/l will have >10% BM plasma cells

  • Plausible that earlier detection of myeloma will lead to better outcomes (evidence for this lacking)

  • Of note, pattern of disease progression is highly variable. If the purpose of monitoring is to detect rising pp, need to consider that this only succeeds in 50% of pts that progress. To be weighed against psychological and health economic impact of monitoring.

  • See guideline for more details

Screening for MGUS

Should we screen the population for MGUS? No (as of 2023)

Plausible that earlier detection of myeloma will lead to better outcomes but evidence for this is currently lacking

Largest project underway is iStopMM (screening of 120,000 Icelandic adults)

monoclonal gammopathy of clinical significance (MGCS)

MGUS is asymptomatic.

But increasing recognition of clinical syndromes - renal, skin, nerves and cardiac in particular - that are plausibly driven by monoclonal B-cell clones —> termed MGCS

Systemic chemotherapy to control the clone in these conditions may be beneficial.

Examples:

  • Scleromyxoedema

  • Acquired cutis laxa

  • IgM peripheral neuropathies (anti-MAG antibodies)

  • Cold agglutinin disease

  • Sporadic late onset nemaline myopathy

  • Type 2 cryoglobulinaemia

  • POEMS syndrome

  • Systemic capillary leak

  • Schnitzler syndrome

monoclonal gammopathy of renal significance (MGrS)

BSH guideline coming imminentaly (2023)

Light chain cast nephropathy

Light-chain deposition disease