Paraprotein

South Tees Hospitals NHS Foundation Trust

Definition/Description

A paraprotein is a monoclonal band of immunoglobulin found in the serum or urine. In the urine it is uncommon to find intact immunoglobulin, as this is a large unfiltered protein, however immunoglobulin light chains can be identified if present above the renal threshold for reabsorption (Bence-Jones protein). Free light chains can also be detected in the serum (SFLC) and this is now a more sensitive test than BJP.

Monoclonal immunoglobulin is produced by a clonal B-lymphocyte population which can be benign (e.g. monoclonal gammopathy of undetermined significance [MGUS]) or malignant (e.g. multiple myeloma or B-cell lymphoma). An IgM paraprotein is extremely rare in myeloma but can be seen as a MGUS or B-cell lymphomas.

Testing for a paraprotein is normally performed when there is a concern over underlying multiple myeloma (e.g. unexplained bone pain, pathological fracture, anaemia, renal impairment, hypercalcaemia, increased total protein or decreased immunoglobulins) or to investigate an unexplained raised plasma viscosity or ESR. Testing is performed by serum protein electrophoresis and free light chain analysis (SFLC), present in ~99% cases myeloma. Non-directed screening is not recommended.

Red Flag Symptoms

None provided

Guidelines on Management

Differential Diagnosis:

MGUS - benign condition found in 3% of the population over the age of 50 years or 5% of those over 70 years. Risk of progression ~ 1-2% per year.
Multiple myeloma - 25% have no serum paraprotein (abnormal SFLC ratio only). <1% have no serum paraprotein or abnormal SLFC ratio.
Solitary plasmacytoma - solitary area of plasma cell infiltration which can be present in the bone or as an extramedullary mass.
Amyloidosis - rare disorder but poor outlook as often diagnosed late due to non-specific symptoms. Amyloid protein deposition in various organs including heart, liver, kidneys, gastrointestinal tract, peripheral nerves and spleen. Features can include proteinuria (can be nephrotic), non-dilated cardiomyopathy, hepatomegaly and autonomic or peripheral neuropathy. Requires specialist investigation if suspected.
B-cell lymphoproliferative disorder - usually presents with features such as lymphadenopathy, splenomegaly or systemic symptoms such as weight loss or drenching night sweats.
Rare disorders such as osteosclerotic myeloma (POEMS syndrome) or heavy chain disease.

Examination:

Examine for lymphadenopathy and splenomegaly.

Baseline investigations:

FBC, U+E, calcium, serum immunoglobulins, serum electrophoresis and serum free light chains (SFLC).
Serum free light chains measurement is looking for a discrepant kappa / lambda light chain ratio. If both light chains are raised, but the ratio remains normal, then this is usually reactive or due to renal impairment.
If patients do have renal impairment then the normal ratio will be altered (renal reference range 0.37 3.1) due to differing excretion of kappa and lambda light chains (guidance is given in footer of the published results).
Borderline SFLC ratios of 0.2 5.0 are often also benign, consider referral only if clinical concern of haematological malignancy.
As immunoglobulins and light chains will be increased in acute illness, repeat mildly abnormal results after resolution of illness (unless levels meet referral criteria below).
Symptoms of bone pain should be investigated by plain radiography with consideration of more detailed imaging if felt appropriate (eg. MRI).

Distinguishing MGUS from symptomatic multiple myeloma can largely be done with simple tests available in the community. This involves looking for signs of myeloma related organ damage such as anaemia, hypercalcaemia, renal impairment, bone lesions, symptomatic hyperviscosity or recurrent bacterial infections.

Referral Criteria/Information

Referral:

Please refer patients on a 2WW pathway with a paraprotein or clonal light chain abnormality who have:

Total PP 15 g/L (If IgG)
Total PP 10 g/L (If IgA or IgM)
Any level of IgD or IgE PP
Clonal light chain > 500 mg/L
SFLC ratio 7.0
OR
A detectable paraprotein with symptoms or signs suggestive of a serious paraprotein-related disorder e.g.:
- Unexplained bone pains or lytic lesions on imaging
- Hypercalcaemia (but <3.0 mmol/L)
- Unexplained anaemia (<100 g/L), neutropenia (<1.0 x 10 thrombocytopenia (<100 x 10 9 /L) or 9 /L)
- B-symptoms
- Lymphadenopathy or splenomegaly
- Unexplained neuropathy
- Features of amyloidosis (nephrotic syndrome, cardiac failure, neuropathy etc.)
- Any patient with a newly discovered paraprotein, regardless of the absolute value, if there is clinical concern (routine referral).

URGENT REFERRAL if acute kidney injury, symptomatic hypercalcaemia (Ca >3.0mmol/L), hyperviscosity or suspicion of spinal cord compression.

Patients without any of the above are highly likely to have MGUS with a risk of progression <1% per year and are therefore suitable to be monitored in primary care.

Follow-up of MGUS:

Over time, MGUS may progress or the underlying condition may reveal itself, so long-term follow up is required. Progression is not just to multiple myeloma, but also to other paraprotein disorders (e.g. B-cell lymphoma, amyloidosis). The approximate yearly risk of disease progression is about a tenth of the paraprotein value in grams per litre (e.g. 10 g/l = about 1% per year) a useful risk assessment tool can be found at QMed Rx - MGUG Prognosis Calculator. The vast majority of patients will therefore never develop a problem related to the MGUS.

If patients are being monitored in the community, recommendations are for blood testing (FBC, U+E, calcium, immunoglobulins, serum electrophoresis and serum free light chains) initially at 3 months, followed by 6-12 monthly intervals unless there is a >25% rise in paraprotein or affected light chain, or the patient develops any of the above criteria that suggest they require referral.