Am I a mug not understanding MGUS?

Barbara turned 80 a couple of months back, and is in to see you about some blood test results. ‘The last doctor I saw was worried I might have bone cancer - have I?’. Quick review of the results.…IgG paraprotein detected 10.3 g/L, serum FLC ratio 0.75, lab comment = IgG MGUS. ‘Well Barbara, good news, it isn’t cancer…’ Whilst thinking what on earth do I do with MGUS? Is this an opportune moment to send Barbara for a strategic urine sample to do some rapid googling……

One of the consequences of the updated NICE cancer guideline to widen use of serum electrophoresis and serum free light chains (sFLC) for suspected myeloma will be a higher number of incidental MGUS findings, and as the British Society of Haematology recognise in their BSH 2023 MGUS guidance ‘The primary care physician faces the challenge of unfamiliarity with the laboratory tests and the fact that MM (multiple myeloma) is a relatively uncommon cancer. Compounding this is that these tests also reveal the 100 times more common condition of MGUS’.

What is MGUS?

MGUS = monoclonal gammopathy of undetermined significance. It is an asymptomatic condition characterised by a proliferation of plasma cells from the bone marrow which produce a monoclonal protein (AKA M-protein or paraprotein) either as a complete immunoglobulin/Ig (IgG, IgA, IgD, IgE, IgM) and/or free light chains/FLC (kappa, lambda), without features of myeloma. It is common, and the incidence rises with age, affecting 3.2% aged >50 years but 8.9% of those aged >85 years. Overall the incidence of progression to myeloma is low at ~1%/year.

What’s the big deal?

So if the risk of progression to myeloma is so low at ~1%/year why are we worried? Whilst the overall risk of myeloma progression is low, the risk varies with Ig type and concentration and sFLC ratio. So our job in Primary Care is to risk assess, identify those at higher risk of progression to myeloma who need referral or monitoring, whilst avoiding unnecessary testing and harm in those unlikely to do so.

How do I assess someone with MGUS?

Local guidance should be followed if available, but if not National Guidance from BSH 2023, Myeloma UK and a recent NEJM review is very helpful:

1. Check baseline investigations - serum electrophoresis and sFLC and/or urine Bence Jones Protein (BJP) if sFLC not available, FBC, ESR, U&E, corrected calcium, and dip urine for protein and do ACR if +ve. 
2. Check for features suggestive of myeloma - think CRAB criteria (Calcium raised, Renal failure, Anaemia, Bony lesions).
3. Look at the paraprotein type and concentration, and the sFLC ratio (or presence of BJP)
4. Urgent referral for suspected cancer to haematology if any of:
   • Features suggestive of myeloma 
   • IgD or IgE paraprotein at any concentration
   • IgA or IgM paraprotein concentrations >10g/L
   • IgG paraprotein concentration >15g/L
   • Significant abnormal sFLC ratio (<0.1 or >7.0) or presence of BJP in urine.

What about monitoring?

How often, or if, to monitor people with MGUS is an area of uncertainty, and will certainly be guided by the patients life expectancy and personal preferences, but some useful rules of thumb from the guidance above:

1. Repeat the investigations above at 6 months (potentially 2-3 months if near the referral thresholds above), as the highest risk of progression is in the first year of MGUS diagnosis.
2. Then review clinically for features that suggest progression, notably progressive back or generalised pain, anaemia, deterioration renal function, rising ESR, hypercalcaemia or new fracture.
3. Refer urgently to haematology if any clinical features of progression, or they meet any of the thresholds for referral above, or the paraprotein concentration increases by >5g/L and 25%.

Annual monitoring is recommended by the BSH, although if low risk the NEJM suggest monitoring every 2-3 years, and it’s worth noting the risk model from Myeloma UK (see table 6) which also helps guide progression risk. However given the BSH guidance states that ‘risk-stratified follow-up should be initiated, with an emphasis on not following up those patients who are unlikely to progress within their lifetimes’ it would be entirely appropriate for us to have the discussion with older or frailer patients with limited life expectancy if they want monitoring at all.

Barbara has no clinical features of myeloma (her back pain which triggered the tests is easing with a new armchair) and the rest of her bloods are stable, and with an IgG paraprotein <15g/L and a normal sFLC ratio she has a low risk of progression (~5% in 20 years based on the risk table). You agree to repeat the tests in 6 months, but if they’re stable Barbara is quite clear that’s enough - ‘No offence, but I’m over 80 and had enough of repeated blood tests, so after that I’ll take my chances’. Seems sensible to me.