The risk of a person having a Monoclonal Gammopathy of Undetermined Significance (MGUS) is age-dependent. Population studies show the risk to be:

  • 3% > 50 years old
  • 5% > 70 years old
  • 7.5% > 85 years old

Paraproteinaemia on electrophoretogram (EPG) [Image: Robbins Pathologic Basis of Disease,]
If a serum protein EPG detects a monoclonal gammopathy, monitor that patient because 27-30% will go on to one of the following —

  • Multiple Myeloma (0.5-1% per year)
  • Plasma Cell Cytoma
  • Amyloid
  • Follicular Lymphoma
  • CLL
  • Waldenstrom’s Macroglobulinaemia

And the higher the monoclonal (M) spike and free light chains, the greater the risk.

Assess these patients clinically, working them up for —

  • CRAB — Calcium, Renal (Creatinine), Anaemia (Hb), Bone or back pain
  • Lymphadenopathy
  • UPEP (urinary PEP)
  • Free light-chain assay
  • Immunofixation assay (IFE)

— and then refer to Haematology Clinic where the serum protein will be checked after 3 months and then again at 6 months to establish a firm diagnosis of MGUS. If the paraprotein has remained stable it may be checked annually or biannually thereafter (cf. if indices are doubling / increasing).

SPEP and UPEP pick up gammopathies in the order of 50 x normal or more, while IFE picks up those with 15 x normal or more (i.e. more sensitive). A free-light chain assay will pick up any increase above normal. Consider that, for instance, much of the immunoglobulin in amyloidosis is deposited in tissues, and so SPEP is often normal.

Once disease is established, the options include continued watchful waiting (current guidelines suggest lifelong follow-up, including BMD measurements) or treatment, depending on the circumstances. Immunisations and flu shots are important considerations prior to commencing treatment.

Apart from giving bisphosphonates, most MGUS is watched rather than treated. If treatment is considered necessary, similar drugs are used as those for multiple myeloma.

  1. Chemotherapy
  2. Autologous Bone Marrow (Stem-Cell) Transplant
  3. Immunomodulators — thalidomide, CC-5013 (Revimid), PS 341 (Velcade)
    1. watch for shingles / pneumocystis pneumonia
  4. Oprozomib (proteasome inhibitor)

Environmental exposure has been linked to plasma cell diseases — radiation, organophosphate exposure (especially Agent Orange), viruses (?), chronic immune stimulation (?).

Keeping it simple

Here is a video by Dr James Berenson which gives a nice overview of MGUS.

  • A monoclonal gammopathy (paraprotein) may be a pre-malignant finding, before its ultimate fulfillment as any of the conditions identified below. Occasionally a spike will be seen in the β or α2 region, rather than the γ region of the EPG. The spike is due to a single heavy chain (immunoglobulin) production; which will be associated with either a kappa (κ) or lambda (λ) light chain production. Not all monoclonal gammopathies (immunoglobulin representing end product of a single clone of plasma cells — producing a single sharp, well-defined band on EPG) by any means will go on to malignancy.
  • Three additional criteria have now been added to this definition as endorsed by the International Myeloma Working Group, published in late 2014. 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). Each of these criteria was validated by at least two large databases. They do reflect a change in the concept that one must have “established end organ damage” to be treated for myeloma; this is important, as patients with these three criteria have pending organ damage, and if untreated, that damage may be permanent. It has therefore shifted a small subset of smoldering myeloma patients to active myeloma warranting treatment. I remember these three criteria with the acronym “SLiM” (60 percent plasma cells; more than 100 light chains involved/uninvolved; MRI evidence of one or more focal lesions) now creating the overall acronym SLiM CRAB for multiple myeloma. ——[A Diagnostic Approach to Patients with an IgM Monoclonal Protein, Joseph Mikhael, MD, MEd, FRCPC, FACP. Professor of Medicine, Mayo College of Medicine, Phoenix, AZ]

  • Note: the terms Monoclonal protein, Paraprotein, M-protein/band/spike, Monoclonal gammopathy, can all be used interchangeably.
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