AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Monoclonal gammopathy of undetermined significance (MGUS) is the most common of a spectrum of diseases called plasma cell dyscrasias. The term MGUS denotes the presence of a monoclonal immunoglobulin (Ig), also called an M-protein, in the serum or urine in persons without evidence of multiple myeloma (MM), Waldenström macroglobulinemia (WM), amyloidosis (AL) or other lymphoproliferative disorders. MM is a uniformly lethal disease that varies from a disease that does not need therapy at first to an advanced or aggressive stage that requires therapy. Distinguishing between MM and MGUS is critical because patients with MGUS are conservatively treated and do not need chemotherapy.

Pathophysiology

The reason for the monoclonal expansion of a single Ig-secreting plasma cell population in what appears to be a nonmalignant manner is unknown in most cases. Most cases involve IgG or IgA monoclonal cell populations. About 15-20% are composed of IgM monoclonal cells.

Kyle et al reported that the cells in IgG and IgA MGUS arise from a mature, somatically mutated, postswitch plasma cell. About 50% of cases have evidence of translocation in the Ig heavy-chain region at 14q32. In contrast, IgM MGUS is described as arising from somatically mutated, postgerminal center B lymphocytes that have not undergone isotype class switching and therefore do not have the 14q32 translocation. These translocations are thought to be important in initiating and sustaining clonal proliferation (Kyle, 2003).

The risk of progression to MM or other lymphoproliferative disorder is present at a constant rate throughout the remainder of a patient's life. This observation suggests that the second event responsible for progression is a random event and not cumulative.

Frequency

United States

MGUS represents two thirds of all plasma cell dyscrasias. The incidence increases with age. MGUS occurs in 1% of the population older than 50 years and in 3% of the population older than 70 years.

International

International frequency is the same as stated in US frequency.

Mortality/Morbidity

• Patients with MGUS tend to do well when treated conservatively.
• Regular surveillance is required to assess for progression to either a lymphoproliferative disorder or to MM.

Race

A recent retrospective study by the Veteran's Administration revealed that the age-adjusted prevalence ratio of MGUS in African American patients was 3.0 compared with Caucasians (Landgren, 2006).

Sex

The disease is more prevalent in men than in women, and the prognosis for men was worse than that of women in some studies.

Age

• The median age of patients with the disease is 65 years; however, most physicians are observing patients younger than this, possibly because of improved screening rather than an increased incidence of the process.
• The incidence of MGUS is higher in older patients than in younger patients. Of patients older than 80 years, the available literature suggests as many as 10-15% may have an M-protein.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The finding of MGUS is usually an unexpected event during an evaluation for an unrelated disorder.
• The advances in quantification of an M-spike by immunofixation contribute to the increasing number of patients identified as having MGUS.
• MGUS is characterized by the following:
• • Serum M-protein value less than 3 g/dL
  • Fewer than 10% plasma cells in the bone marrow
  • No or only small amounts of Bence-Jones protein in the urine
  • Absence of lytic bone lesions
  • No related anemia, hypercalcemia, renal failure, or any related end-organ damage

Physical

• No specific abnormalities are detected on physical examination in patients with MGUS.
• Several syndromes of polyneuropathies are associated with plasma cell dyscrasias, including MGUS.

Causes

The cause of MGUS is unknown, though the same theories that apply to the pathogenesis of MM may be valid in MGUS.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Amyloidosis
Waldenström macroglobulinemia

MM must be differentiated from MGUS and smoldering MM (SMM). Asymptomatic patients with an M-component of less than 3 g/dL; fewer than 10% bone marrow plasma cells; and no osteolytic lesions, anemia, hypercalcemia, or renal function impairment have MGUS.

Asymptomatic patients who have an M-component higher than 3 gm/dL or more than 10% but less than 20% bone marrow plasma cells fulfill the criteria for SMM. These patients do not have anemia, renal failure, hypercalcemia, osteolytic bone lesions, or other clinical manifestations related to the monoclonal protein. In clinical and biologic terms, SMM is closer to MGUS than to overt MM. Recognition of patients with SMM is extremely important because they should not be treated with chemotherapy until progression occurs. No particular laboratory parameter or clinical factor differentiates MGUS or SMM from overt MM. Decreased levels of uninvolved Igs are not a useful criteria for differentiation because 30-40% of patients with MGUS also have decreased levels of the uninvolved Ig.

Although Bence-Jones proteinuria suggests MM, finding small amounts of monoclonal light chains in the urine of patients with MGUS is not unusual. Lytic bone lesions on the skeletal survey strongly suggest MM. In patients recently diagnosed with MGUS, serum electrophoresis should be repeated after 3 months to exclude early myeloma, and, if the results are stable, the test should be repeated in 6 months. Patients should be aware that the evolution of MGUS to MM can be abrupt; therefore, they should be reexamined promptly if their clinical condition deteriorates.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Complete metabolic panel (eg, to evaluate renal function, calcium, uric acid, and lactate dehydrogenase [LDH])
• Determination of CBC with differential to evaluate for anemia, thrombocytopenia, and neutropenia
• Tests for beta2 microglobulin and C-reactive protein for prognostic information
• Serum and urine electrophoresis with immunofixation (diagnostic test of choice)
• Quantitative immunoglobulin measurements to follow up the progress of the monoclonal gammopathy
• Measurement of the proliferative rate of the plasma cells or plasma cell labeling index (Value is low.)
• Serum electrophoresis
• • In patients with recently diagnosed MGUS, serum electrophoresis should be repeated after 3 months to exclude early myeloma, and, if the results are stable, the test should be repeated in 6 months.
  • Patients should be aware that the evolution of MGUS to MM can be abrupt; therefore, they should be reexamined promptly if their clinical condition deteriorates.
• Serum free light chain (FLC) assay (This is beneficial for prognostic purposes.)

Imaging Studies

• Complete skeletal survey to assess for lytic lesions

Procedures

• Unilateral bone marrow aspiration and biopsy to quantify the percentage of plasma cells and to assess for abnormal cytogenetics
• Determination of plasma cell labeling index

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• If a patient has no other features of a plasma cell dyscrasia and if a serum M-spike is detected, complete assessment of the patient's general medical status is needed.
• • Include baseline measurements of serum B12 and RBC folate levels and a hypercoagulation profile.
  • In addition, specific workup relative to the gammopathy should include a bone marrow examination, skeletal radiography (including single views of the humeri and femurs and complete spinal with optional lateral views), and a 24-hour urine collection for protein quantitation.
  • Serum protein electrophoresis should be repeated in 3 months after diagnosis. If the results are stable, medical assessment should be performed every 6-12 months.
• If a patient has an IgM M-protein, aspiration and biopsy of the bone marrow and CT scanning of the abdomen may be useful in detecting WM or other lymphoproliferative disorders. If all these results are satisfactory, serum electrophoresis should be repeated in 2-3 months at the earliest, and, if the finding is stable, the test should be repeated at 6- to 12-month intervals.
• Serum and urine electrophoresis with immunofixation should be performed if the serum M-protein value increases or if other evidence of evolving MM or WM is observed.
• No treatment is recommended for patients with MGUS. However, if preventive clinical studies are available, patients should be encouraged to participate in such studies.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No treatment is recommended for patients with MGUS.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• Follow-up care includes observing the patient for evolution of MGUS to MM, AL, WM, or other malignant lymphoproliferative disorders.
• The risk of venous thromboembolism (VTE) is increased.
• • In a study by Srkalovic et al (2004), 13% of patients with MGUS developed VTE.
  • Univariate correlates of VTE in patients with MGUS included a family or medical history of VTE, immobility, a low serum albumin level, and a high leukocyte count.

Prognosis

• The annual risk of MM, AL, WM, or other lymphoproliferative disorder is 1% with IgG or IgA MGUS. This risk is 1.5% with IgM MGUS.
• A high plasma cell labeling index suggests active disease.
• Circulating plasma cells is an adverse predictor of progression.
• In patients with IgM MGUS, both serum monoclonal protein concentrations and serum albumin levels at time of diagnosis are independent predictors of progression to a malignant plasma-cell dyscrasia. At 10-year follow-up, progression resulted in 14% of patients having M-protein values <0.5 g/dL and in 41% of patients with M-protein values >2.5 g/dL (Kyle, 2003).
• Rajkumar et al, found that the risk of progression in patients with an abnormal serum FLC ratio was significantly higher than the risk in patients with a normal ratio (P <.001). The authors proposed a risk-stratification model for MGUS based on the serum FLC ratio (Rajkumar, 2005).
• At present, no definitive findings predict malignant plasma-cell proliferative disorders in patients with MGUS.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Misdiagnosis of a true case of MGUS as MM (for IgG or IgA MGUS) or WM (for IgM MGUS) may lead to unwarranted and potentially harmful therapy.
• Patients with MGUS and evidence of end-organ damage related to the plasma cell dyscrasia should be classified as having active MM, and therapy is warranted to prevent further deterioration.
• Failure to monitor MGUS over time may result in failure to diagnose progression to a more serious disorder, such as MM or WM.
• Failure to diagnose a malignant plasma-cell disorder in a timely manner may interfere with the clinician's ability to prevent associated complications, such as renal failure, hypercalcemia, or skeletal fractures.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Chng WJ, Van Wier SA, Ahmann GJ, et al. A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood. Sep 15 2005;106(6):2156-61.
• Davies FE, Dring AM, Li C, et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood. Dec 15 2003;102(13):4504-11.
• Feinman R, Sawyer J, Hardin J, Tricot G. Cytogenetics and molecular genetics in multiple myeloma. Hematol Oncol Clin North Am. Feb 1997;11(1):1-25. [Medline].
• Kumar S, Rajkumar SV, Kyle RA, et al. Prognostic value of circulating plasma cells in monoclonal gammopathy of undetermined significance. J Clin Oncol. Aug 20 2005;23(24):5668-74.
• Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. Feb 21 2002;346(8):564-9. [Medline].
• Kyle RA, Therneau TM, Rajkumar SV, et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood. Nov 15 2003;102(10):3759-64. [Medline].
• Landgren O, Gridley G, Turesson I, et al. Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood. Feb 1 2006;107(3):904-6.
• Rajkumar SV. MGUS and Smoldering Multiple Myeloma: Update on Pathogenesis, Natural History, and Management. Hematology (Am Soc Hematol Educ Program). 2005;340-5.
• Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. Aug 1 2005;106(3):812-7.
• Srkalovic G, Cameron MG, Rybicki L, et al. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer. Aug 1 2004;101(3):558-66.

Article Last Updated: Jun 5, 2006