MGUS, myeloma, and other paraprotein-related problems

Globulins: Proteins produced by plasma cells in the bone marrow. Serum globulin level is the difference between total protein level and albumin level.

Polyclonal increase in plasma cells: increase in globulin (which may show up as increased total protein with normal albumin) with no paraprotein on immunoelectrophoresis. Side-effect of processes such as inflammation, infection, liver disease, cancer.

Paraprotein: due to a monoclonal increase in plasma cells. Causes include:

  • MGUS
  • Myeloma
  • Amyloidosis
  • Waldenstein’s macroglobulinaemia
  • Related disorders, whatever that means

Paraproteins are detected by serum protein electrophoresis and characterised by immunofixation. Any level of paraprotein is abnormal.

Myeloma: a malignancy of the plasma cells. Part of a spectrum known as the plasma cell dyscrasias, ranging from MGUS to plasma cell leukaemia. The malignant clone of plasma cells remains in the bone marrow, releasing immunoglobulins which cause a paraprotein (usually IgG or IgA – IgM suggests an alternative diagnosis such as Waldstein’s macroglobulinaemia, and IgD/IgE are rare).

Amyloidosis: may be secondary to myeloma or develop separately

MGUS criteria:

  • Paraprotein <30
  • Bone marrow clonal plasma cells <10%, low level of infiltration on trephine biopsy if done
  • No myeloma-related organ or tissue impairment (see below)
  • No evidence of other beta-cell lymphoproliferative disorder, light-chain amyloidosis, or other light chain/heavy chain/immunoglobulin-associated tissue damage

MGUS is present in the blood of 3% of >50s. Progression to myeloma is 1%/yr with IgG or IgA, 1.5%/yr with IgM. Note that BJP may be present at low levels in MGUS.

Asymptomatic (smouldering) myeloma criteria:

  • Serum paraprotein >30 g/l or bone marrow clonal plasma cells >10% on biopsy
  • No myeloma-related organ or tissue impairment.

Symptomatic myeloma criteria (one list that I found – seems they vary slightly):

  • Serum or urinary paraprotein (any level)
  • Bone marrow clonal plasma cells
  • Myeloma-related organ or tissue impairment

(Note that symptomatic myelomas may not literally be symptomatic: asymptomatic organ/tissue impairment also qualifies.)

Secretory myeloma (small proportion): No detectable paraprotein, but myeloma-related organ or tissue impairment and bone marrow clonal plasma cells.

Myeloma-related organ/tissue impairment: think CRAB

  • Calcium raised (>2.75 mmol/l, or >0.25 over ULN)
  • Renal impairment attributable to myeloma
  • Anaemia (<100g/l, or more than 2g below LLN)
  • Bone lesions (lytic lesions or osteoporosis with compression fractures)
  • Other – Symptomatic hyperviscosity, amyloidosis, or >2 episodes bacterial infection 12 months.

Symptoms/signs of lymphoma

  • Night sweats/fever/weight loss
  • Lymphadenopathy/hepatosplenomegaly
  • Symptoms/signs of hyperviscosity – headache, retinal vein engorgement
  • Pancytopaenia

Symptoms/signs of light chain amyloidosis

  • Carpal tunnel syndrome
  • Peripheral neuropathy
  • Macroglossia
  • Unexplained heart failure
  • Nephrotic syndrome

Note that myeloma is more typically associated with IgG or IgA paraproteins, and lymphoproliferative disorders (such as lymphoma or Waldenstrom’s macroglobulinaemia) with IgM paraproteins.

The reason for measuring serum immunoglobulins is that immunoparesis (low serum immunoglobulins) together with recurrent bacterial infections are a minor possible sign of myeloma.

Initial investigation for patients with a paraprotein

  • FBC
  • PV
  • U&Es
  • Calcium
  • Serum immunoglobulin levels
  • Serum protein electrophoresis – for quantification
  • Immunofixation – for identification of paraprotein type.
  • Urine for Bence-Jones
  • Urinary protein levels (?nephrotic syndrome)
  • X-ray of any areas of bone pain

(NB – Bone scanning is not helpful in myeloma investigation, as osteoblastic activity is not a feature in the lesions and these show up as cold spots.)

Criteria for haematology referral

  • Symptoms or signs of myeloma or lymphoproliferative disorder
  • Hypercalcaemia, renal failure or anaemia, as above, or X-ray abnormalities suggestive of bony involvement from myeloma
  • IgG paraprotein >15g/L
  • IgA or IgM paraprotein >10g/L
  • IgD or IgE paraprotein at all

Re-testing should be 3-monthly initially. BMJ says gradually increase to 6 – 12 months – emedicine is more specific & states that if all well at 3 months the patient should then be tested at 6 months. Do note that evolution of MGUS to MM can be abrupt – therefore, reassess a patient who deteriorates even if recent bloods were fine.

MGUS is associated with an increased risk of DVT & of fractures.

There is no treatment for MGUS, but peripheral neuropathy 2ry to MGUS/amyloidosis may possibly be treatable – one very small trial showed results with rituximab, and cyclophosphamide/prednisolone may also be of help. Treatment is also not indicated for smouldering myeloma on current evidence as it makes no difference to the risk of progression, but research is ongoing into whether treating individuals with smouldering myeloma that are at higher risk of progression makes a difference. (However, smouldering myeloma should be under the care of a haematologist while low-risk myeloma can be followed up in primary care.)

Treatment of MM is not curative, but can prolong life & help with symptoms. 5-year survival for MM is 35%. Treatment is with chemotherapy, plus bisphosphonates for prophylaxis against skeletal-related events (hypercalcaemia, fracture, spinal cord compression) and erythropoetin as needed for anaemia. Radiotherapy can be useful for spinal disease, as can vertebral augmentation, a treatment in which something-or-other with a long name is injected into vertebral fractures. Symptomatic hyperviscosity can be treated with plasma exchange. Early and aggressive treatment of patients presenting in renal failure is necessary to preserve renal function (bortezomib + high dose prednisolone is recommended there). In suspected cord compression, dexamethasone should be started immediately pending urgent spinal imaging (MRI if possible, CT as second choice).

Note that hypercalcaemia, renal failure, and spinal cord compression are emergencies – should be discussed with a haematologist urgently.


Investigating an incidental finding of a paraprotein – BMJ

Monoclonal Gammopathies of Uncertain Origin –

Multiple Myeloma –

Multiple Myeloma – BMJ


About Dr Sarah

I'm a GP with a husband and two young children.
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