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
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
Systemic capillary leak
Schnitzler syndrome
monoclonal gammopathy of renal significance (MGrS)
BSH guideline coming imminentaly (2023)
Light chain cast nephropathy
Light-chain deposition disease