Case 91 – summary

Thank you for all your contributions this week!

This week we had a look at MGUS (monoclonal gammopathy of undetermined significance).

Our patient was diagnosed with IgA lambda MGUS, which was monitored 6 monthly for 4 years. This then progresses to myeloma.

MGUS is a clonal disorder of plasma cells that can be associated with a variety of conditions. There is an excellent table of conditions which should prompt testing for monoclonal paraprotein in the ‘How I manage monoclonal gammopathy of undetermined significance’ article, a link is at the end of the summary.

The incidence of MGUS increases with age, and around 3% of the >50year old population may have it.

Risk factors for developing MGUS include being male, increasing age, family history of myeloma or MGUS and there is also a increase risk in people of African American or black African heritage.

MGUS can progress to a malignant plasma cell disorder eg myeloma, amyloid. IgM MGUS is typically associated with lymphocytes/lymphoplasmacytoid cells and can progress to lymphoplasmocytic lymphoma. Very rarely it can progress to IgM myeloma.

There are several characteristics which may influence likelihood of progression.

The overall risk of progression to myeloma is around 1% year.

Of the none IgM MGUS 69% have IgG pp, 11% IgA, 3% have both IgG and IgA pp and there are occasional patients with IgE and IgD MGUS.

17% of all patient’s with MGUS from the Mayo clinic data had IgM MGUS


Diagnostic criteria IMWG 2010 guidelines:


  • Serum monoclonal protein <30g/L
  • Clonal bone marrow plasma cells <10%
  • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder


  • Serum IgM monoclonal protein <30g/L
  • No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage that can be attributed to the plasma cell proliferative disorder

Light chain MGUS

  • Abnormal FLC ratio (<0.26 or >1.65)
  • Increased level of the appropriate free light chain (increased FLC in patients with ratio >1.65 and increased FLC in patients with ratio <0.26)
  • No immunoglobulin heavy chain expression on immunofixation


  • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
  • Clonal bone marrow plasma cells <10%
  • Urinary monoclonal protein <500mg/24h


Smouldering multiple myeloma

Both criteria must be met –

  • Serum monoclonal protein (IgG or IgA)>30g/L or urinary monoclonal protein >500mg per 24h and/or clonal bone marrow plasma cells 10-60%
  • Absence of myeloma-defining events or amyloidosis



  • Clonal bone marrow plasma cells 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events:
    • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
    • Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
    • Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177mol/L (>2mg/dL)
    • Anemia: hemoglobin valure of >20g/L below the lowest limit of normal, or a hemoglobin value <100g/L
    • Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
  • Any one or more of the following biomarkers of malignancy (MDEs):
    • 60% or greater clonal plasma cells on bone marrow examination
    • Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100mg/L (a patients involved free light chain either kappa or lambda is the one that is above the normal reference range; the uninvolved free light chain is the one that is typically in, or below, the normal range)
    • More than one focal lesion on MRI that is at least 5mm or greater in size.


Investigations – IMWG 2010 guidelines

If there is a suspicion that a patient with a paraprotein may have myeloma/smouldering myeloma they should have

  • FBC with diff and blood film
  • Biochemistry panal including calcium
  • Serum protein electrophoresis and immunofixation
  • Nephelometric quantitation of immunoglobulins
  • Urinalysis, 24 hour urine collection for proteinuria,electrophoresis and immunofixation
  • Quantification of both urine M-component level and albuminuria
  • Bone marrow
    • Aspirate, trephine, immunophenotyping and tests for cytogenetics and FISH
  • Imaging
    • Skeletal survey including skull, pelvis, humeri, femurs, spine
    • Low dose whole body CT or MRI is recommended in the work up of smouldering myeloma
    • If smouldering myeloma is suspected, PET CT, Low dose whole body CT or MRI can be done dependant on local availability


Risk factors for progression

Factors that can increase likelihood of progression from the MAYO clinic and Spanish study group for MGUS:

  • none IgG paraprotein
  • Monoclonal paraprotein >15g/L
  • abnormal SFLC ratio
  • DNA aneuploidy
  • >95% aberrant plasma cell population (of total plasma cells)demonstrated by flow. (Aberrant plasma cell populations express dim CD38, CD56+, lack of CD19−, and/or absence of CD45.)



The IMWG 2010 guidelines suggested that monitoring of patients with MGUS could be guided based on risk stratification.

Patients who were low risk by the Mayo clinic criteria (IgG paraprotein < 15 g/L with normal SFLC ratio) could be monitored 6 monthly initially and then 2-3 yearly if stable. Patients who were higher risk should have a baseline bone marrow and cytogenetic analysis. If this is consistent with MGUS then 6 monthly monitoring for the first year, with annual monitoring of serum protein electrophoresis biochemistry/FBC.

Many advances have been made in the last 10-20 years giving us more effective treatments for myeloma. As cytogenetic/molecular genetic advances are made, patients with MGUS who may be at greater risk of progression could be identified and this may enable more effective monitoring and timely treatment strategies.


Further reading

  • International myeloma working group 2010 guidelines
  • Multiple Myeloma: Diagnosis and Treatment, S. Vincent Rajkumar, Shaji Kumar – Mayo clinic proceedings
  • How I manage monoclonal gammopathy of undetermined significance – Ronald S. Go and S. Vincent Rajkumar – Blood 2018 131:163-173; doi:
  • Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies – N.korde et al Blood. 2011 May 26; 117(21): 5573–5581.

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