Risk for Monoclonal Gammopathy of Undetermined Significance (MGUS) is age-dependent. Population studies suggest that risk relates to about:
- 3% > 50 years old
- 5% > 70 years old
- 7.5% > 85 years old
- Multiple Myeloma (0.5-1% per year)
- Plasma Cell Cytoma (plasmacytoma)
- Amyloid
- Follicular Lymphoma
- Chronic Lymphocytic Leukaemia (CLL)
- Waldenstrom’s Macroglobulinaemia
The higher the monoclonal (M) spike and free light-chain burden in the patient, the greater the risk.
Investigations:
Assess these patients clinically, by working them up with:
- ‘CRAB’:
- Calcium
- Renal (Creatinine)
- Anaemia (Hb)
- Bone or back pain
- Lymphadenopathy
- Urinary protein electrophoresis (UPEP)
- Free light-chain assay
- Immunofixation assay (IFE)
Then refer them to the Haematology Clinic for serum-protein monitoring at 3 and 6 months to establish a firm diagnosis of monoclonal gammopathy of undetermined significance (MGUS), a situation which requires ongoing monitoring. If paraprotein levels remain stable, they may be checked annually or even biannually thereafter. Obviously instances where indices instead are doubling or increasing, warrant more intensive investigation looking for one of the causes mentioned above.
Serum PEP (SPEP) and Urinary PEP (UPEP) pick up gammopathies in the order of 50 x normal or more, while an immunofixation assay (IFE) is more sensitive, detecting gammopathy levels about 15 times normal or more. More sensitive still, a free-light chain assay will pick up any increase above normal. Recall, however, in amyloidosis, for instance, much of the extra immunoglobulin is deposited in tissues, and SPEP may remain normal.
Once a working diagnosis of MGUS is established, options include continued watchful waiting (guidelines suggest lifelong follow-up, including BMD measurements) or treatment, depending on circumstance. Immunisations, including vaccination against influenza, remain important considerations prior to commencing any treatment.
Apart from bisphosphonate therapy, most MGUS is watched rather than treated. Where treatment is considered necessary, drug therapy reflects those compounds used in treating multiple myeloma.
Treatment:
- Chemotherapy
- Autologous Bone Marrow (Stem-Cell) Transplant
- Immunomodulators — watch for shingles and pneumocystis pneumonia infections during therapy
- thalidomide
- CC-5013 (Revimid)
- PS 341 (Velcade)
- Oprozomib (monoclonal antibody proteasome inhibitor)
Plasma cell diseases have been linked to environmental exposures; including radiation, organophosphates (especially Agent Orange, a powerful herbicide used in the Vietnam War for defoliation of enemy cover and destruction of enemy provisions), possibly viruses, and potentially in relation to any disease causing a chronic immune stimulation.
Annotation
A monoclonal gammopathy (paraprotein) may be a pre-malignant finding, before its ultimate manifestation of any of the conditions identified earlier. Occasionally, a spike will be seen in β or α2, rather than γ, region of the EPG. Such a spike is due to production of a single heavy chain (immunoglobulin), and will be associated with either kappa (κ) or lambda (λ) light chain production. Clearly, not all monoclonal gammopathies—i.e. not all patients with single sharp, well-defined band (spike) on EPG representing the immunoglobulin end product of a single clone of plasma cells—go on to malignancy.
According to Professor Joseph Mikhael at the Mayo College of Medicine, Phoenix, AZ, as of 2014, the International Myeloma Working Group has added three additional criteria to this definition. These three criteria include clonal bone marrow plasma cell percentage of ≥ 60 percent; involved/uninvolved serum-free light chain (FLC) ratio ≥ 100 (involved FLC level must be ≥ 100 mg/L); and more than one focal lesion on magnetic resonance imaging (MRI) studies (at least 5 mm in size).
These additional criteria are validated in at least two large clinical databases and they reflect a move from the conceptualisation that only those with established end organ damage be treated for myeloma. The implication is (obviously) important: patients with these three criteria have pending organ damage that, left untreated, may develop into irreversible organ injury. Such sentiment has motivated the shift in clinical management, categorising a small subset of the “smoldering myeloma” patient to that of active myeloma warranting treatment.
Dr Mikhael uses the following acronyms to help recall of the additional criteria:
“SLiM”
- 60 percent plasma cells
- > 100 light chains involved/uninvolved
- MRI evidence of one or more focal lesions
“SLiM CRAB”
- multiple myeloma
Note: the terms Monoclonal protein, Paraprotein, M-protein/band/spike, Monoclonal gammopathy, are all used interchangeably.
Patient Information
- MGUS (monoclonal gammopathy of undetermined significance) – Melbourne Haematology
Further Reading
-
James R. Berenson, Anderson, Kenneth C., and Audell, Robert A. “Monoclonal gammopathy of undetermined significance: a consensus statement.“
B J Haem 150(1); July 2010: Pages 28-38. https://doi.org/10.1111/j.1365-2141.2010.08207.x.
- Study Suggests MGUS Patients Receive Inadequate Evaluation, Follow-Up, And Treatment – The Myeloma Beacon, August 22, 2011
- Monoclonal Gammopathies of Undetermined Significance – Medscape, November 6, 2016
- Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®) — Health Professional Version – National Cancer Institute, November 4, 2016
References
- A Diagnostic Approach to Patients with an IgM Monoclonal Protein, Joseph Mikhael, MD, MEd, FRCPC, FACP. Professor of Medicine.
- SV, Kyle RA, Buadi FK. Advances in the Diagnosis, Classification, Risk Stratification, and Management of Monoclonal Gammopathy of Undetermined Significance: Implications for Recategorizing Disease Entities in the Presence of Evolving Scientific Evidence – Mayo Clin Proc. 2010 Oct; 85(10): 945–948.
- Making Sense of Serum Protein Bands – Best Tests, July 2011
