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Keywords:

  • monoclonal gammopathy of undetermined significance;
  • myeloma;
  • macroglobulinaemia;
  • prognosis;
  • amyloidosis;
  • lymphoma

Summary

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References

Significant advances have been made in our understanding of the natural history, pathogenesis, mechanisms of progression and prognosis of monoclonal gammopathy of undetermined significance (MGUS). Although the overall incidence of MGUS progression is 1 per year, it is now possible to more accurately predict the risk of progression based on a new risk-stratification model. However, it is still hard to design chemopreventive trials given that the absolute risk of progression per year is low, even in the high-risk group. Therefore, further improvements in estimating the risk of progression are needed. Roughly 50% of MGUS may originate from primary translocation events at the heavy-chain immunoglobulin locus at chromosome 14q32. In most of the remaining MGUS patients, the initiating event is associated with genomic instability that results in hyperdiploidy of certain odd numbered chromosomes. Cytogenetically distinct subtypes of MGUS may carry significant differences in the risk of progression to malignancy. New markers, such as measures of bone marrow angiogenesis and circulating plasma cells may be additional prognostic factors. A better understanding of the mechanisms underlying the transition of normal plasma cells to the MGUS phenotype, and the transition of MGUS to myeloma or related malignancy, will help identify new risk factors for progression and new targets for chemopreventive interventions.

Monoclonal gammopathy of undetermined significance (MGUS) is the most common plasma cell disorder and is a potential precursor of multiple myeloma (MM). The plasma cell disorders are classified in Table I. MGUS is defined by a monoclonal immunoglobulin in serum amounting to 30 g/l or less; the absence of lytic bone lesions, anaemia, hypercalcaemia and renal insufficiency related to the monoclonal plasma cell proliferation, and 10% or fewer plasma cells in the bone marrow. At the Mayo Clinic, more than 50% of patients with a monoclonal gammopathy have MGUS (Fig 1A) and IgG constitutes the most common type of M protein (Fig 1B).

Table I.   Classification of monoclonal gammopathies.
  1. Ig, immunoglobulin; M protein, monoclonal protein.

Monoclonal gammopathy of undetermined significance (MGUS)
Benign (IgG, IgA, IgD, IgM, and rarely, free light chains)
Associated with neoplasms of cell types not known to produce M-proteins
Biclonal and triclonal gammopathies
Idiopathic Bence Jones proteinuria
Malignant monoclonal gammopathies
Multiple myeloma (IgG, IgA, IgD, IgE and free κ or λ light chains)
 Overt multiple myeloma (MM)
 Smouldering MM
 Plasma cell leukaemia
 Non-secretory myeloma
 IgD myeloma
 POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (osteosclerotic myeloma)
Plasmacytoma
 Solitary plasmacytoma of bone
 Extramedullary plasmacytoma
Malignant lymphoproliferative disorders
Waldenström macroglobulinaemia (primary macroglobulinaemia)
Malignant lymphoma
Chronic lymphocytic leukaemia or lymphoproliferative disorders
Heavy-chain diseases
 γ Heavy-chain disease
 α Heavy-chain disease
 μHeavy-chain disease
Amyloidosis (AL)
image

Figure 1.  (A). Monoclonal gammopathies diagnosed at the Mayo Clinic during 2005. Macro, macroglobulinaemia; MGUS, monoclonal gammopathy of undetermined significance; SMM, smouldering multiple myeloma. (B) Type of monoclonal protein detected at the Mayo Clinic during 2005.

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MGUS has been referred to by other terms in the past, such as ‘essential hyperglobulinaemia’ that was introduced by Waldenström more than 50 years ago to describe the patients with a small serum protein electrophoretic spike but no evidence of MM, Waldenström macroglobulinaemia (WM), primary amyloidosis (AL) or related disorder. He emphasised the constancy of the size of the protein spike, and used the term ‘benign monoclonal gammopathy’ contrasting it with the increasing quantity of the monoclonal protein (M protein) in patients with MM or WM (Waldenstrom, 1960–1961). The term ‘benign’ monoclonal gammopathy is misleading because of the risk of symptomatic MM, WM, AL or a related disorder during the follow-up. Thus, the term MGUS is currently used (Kyle, 1978; Kyle et al, 2002a).

Smouldering (asymptomatic) MM, smouldering (asymptomatic) WM and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome (osteosclerotic myeloma) are not discussed in this review.

Recognition of monoclonal gammopathies

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References

Serum protein electrophoresis and immunofixation

A sensitive, rapid, dependable screening method to detect the presence of an M protein and a specific assay to identify its heavy-chain class and light-chain type in serum or in urine is essential (Kyle, 1999; Kyle et al, 2002b). Agarose gel serum protein electrophoresis is the preferred method of detection and also allows the quantification of the M protein size. After recognition of a localised band on electrophoresis, immunofixation is necessary to confirm the presence of an M protein and to determine its immunoglobulin heavy- and light-chain types. Immunofixation should also be performed when MM, WM, AL or a related disorder is suspected because small amounts of M protein might not be detected with serum protein electrophoresis (Keren et al, 1999).

Quantitative immunoglobulin studies

Quantification of immunoglobulins should be performed with a rate nephelometer because it is not affected by molecular size and accurately measures 7S IgM, polymers of IgA and aggregates of IgG. One must keep in mind that levels of IgM obtained with nephelometry may be 10–20 g/l higher than that expected on the basis of the serum protein electrophoretic tracing (Riches et al, 1991). The nephelometric values of IgG and IgA levels may also be increased.

Urine protein electrophoresis and immunofixation

It is important to study the urine in patients with monoclonal gammopathies. All patients with a serum M protein concentration >15 g/l should have electrophoresis and immunofixation of a concentrated aliquot from a 24-h urine specimen. Electrophoresis of urine should also be performed in all patients with MM, WM, AL and heavy-chain diseases or when these entities are expected. Patients who are older than 40 years of age with a nephrotic syndrome of unknown cause should also have immunofixation, because the presence of a monoclonal light chain is a strong indication of AL or light-chain deposition disease. A 24-h urine specimen should be collected so that the amount of M protein can be measured. This provides a measure of the patient's tumour mass and is useful in monitoring the course of the disease.

Serum-free light-chain (FLC) assay

Measurement of the serum-FLC has been introduced into clinical practice (Katzmann et al, 2002). This automated nephelometric assay measures the level of free kappa and lambda light-chains in the serum. The normal ratio for FLC-kappa/lambda is 0·26–1·65. In a series of 1020 patients at Mayo Clinic in whom an FLC assay was requested, 88% had a monoclonal plasma cell disorder. All 121 patients who did not have a monoclonal gammopathy had a normal FLC-kappa/lambda ratio. Among 110 untreated patients with AL, the FLC-kappa/lambda ratio was abnormal in 91% compared with 69% for immunofixation of serum, and 83% for immunofixation of urine. A combination of immunofixation and serum FLC detected an abnormal result in 99% of patients with AL (Katzmann et al, 2005).

The presence of an M protein or abnormal FLC ratio in the tests discussed above indicates the presence of MGUS, or a more serious plasma cell disorder, such as MM, WM, AL, etc. A search for monoclonal gammopathies with the above tests should be entertained in any patient who has unexplained the weakness or fatigue, anaemia, back pain of unknown cause, osteoporosis, osteolytic lesions or fractures, hypercalcaemia, renal insufficiency, Bence Jones proteinuria or an increase of the erythrocyte sedimentation rate. It should also be performed in adults with unexplained sensorimotor peripheral neuropathy, carpal tunnel syndrome, refractory congestive heart failure, nephrotic syndrome, orthostatic hypotension or malabsorption because a localised band or spike may indicate possible AL. Testing should also be done in patients with enlargement of the tongue or change in their voice, increased bruising or bleeding, or steatorrhoea. Even when the electrophoretic pattern appears normal, immunofixation should be performed whenever MM, WM, AL or a related disorder is suspected clinically.

Prevalence of MGUS

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References

Monoclonal proteins have been reported without evidence of MM or WM in approximately 3% of persons >70 years of age in Sweden, the USA and France (Axelsson et al, 1966; Kyle et al, 1972; Saleun et al, 1982). MGUS is more common among older patients and was found in 3·6% of 816 patients ≥70 years of age in North Carolina (Cohen et al, 1998).

The first population-based study using the sensitive laboratory techniques to detect monoclonal gammopathies was recently reported (Kyle et al, 2006). Serum samples were obtained from 21 463 (77%) of the 28 038 enumerated residents of Olmsted County, Minnesota who were 50 years of age or older (Table II). MGUS was identified in 694 (3·2%) of these patients. Age-adjusted rates were greater in men than in women, 4·0% vs. 2·7% (P < 0·001) (Table III, Fig 2). The prevalence of MGUS was 5·3% among persons 70 years or older and 7·5% among those 85 years or older. The concentration of monoclonal immunoglobulins was <10 g/l in 63·5% and ≥20 g/l in only 4·5% of the 694 patients. The concentration of uninvolved immunoglobulins was reduced in 28% of 447 persons tested (Table IV). Of 79 patients tested, 21% had monoclonal urinary light chain.

Table II.   Results of requests for serum samples.*
Type of contactPermission grantedPermission refused ‡numberOther‡Permission granted %Total No.
Face-to-face244NANA100244
Status already knownNANA473NA473
Letter to patient
 1st12 9896255895·013 672
 2nd21772717486·32522
 3rd885541193226·33358
 Letter to family1901810460·1312
 Total16 4851455264180·120 581
 Percentage80·17·112·8100 
ResultsNo. of patientsNo. of patients with MGUS
  1. *NA denotes not applicable.

  2. †‘Other’ includes patients classified as ‘missing’, ‘do not contact’ and ‘refused research’, as well as those who did not respond.

  3. ‡Patient-specific information was removed before electrophoresis.

  4. ¶Nine patients had Bence Jones proteinuria.

  5. §Of these 20 581 patients, 4069 had blinded samples.

  6. #Patients were not contacted for the following reasons: 1609 had died, 262 had declined to provide authorisation for research, 116 could not be contacted, 93 had moved out of Olmsted county and 31 had known MGUS, but were not seen at Mayo Clinic.

Patients with samples analysed
 Identified in central processing laboratory20 581§460
 Previously known229¶220
 Patients responded to letter at end of accrual65314
 Total21 463694
Patients with no samples analysed
 Patient or family did not respond to letter4464NA
 Patient could not be contacted2111#NA
 Total6575NA
 Total population28 038NA
Table III.   Prevalence of MGUS by age group and gender.
Age (years)Number/total number (%)*
MaleFemaleTotal
  1. *The percentage was calculated as the number of patients with MGUS divided by the number who were tested.

  2. †Prevalence was age-adjusted to the 2000 USA total population as follows: men, 4·0% (95% confidence interval, 3·5–4·4); women, 2·7% (95% CI, 2·4–3·0); and total, 3·2% (95% CI, 3·0–3·5).

  3. ‡ Prevalence was age- and sex-adjusted to the 2000 USA total population.

50–5982/4038 (2·0)59/4335 (1·4)141/8373 (1·7)
60–69105/2864 (3·7)73/3155 (2·3)178/6019 (3·0)
70–79104/1858 (5·6)101/2650 (3·8)205/4508 (4·6)
≥8059/709 (8·3)111/1854 (6·0)170/2563 (6·6)
Total350/9469 (3·7) †344/11994 (2·9) †693/21463 (3·2)†‡
image

Figure 2.  Prevalence of MGUS according to age. Six hundred and ninety-four of 21 463 residents ≥50 years of age had M protein. The I bars represent 95% CI. Years of age > 90 have been condensed to 90 years of age (x-axis). From ref. Kyle et al (2006). Copyright © 2006 Massachusetts Medical Society.

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Table IV.   Characteristics of patients with MGUS among residents of Olmsted county, Minnesota.
CharacteristicNon-blinded sample (n = 385)*Blinded sample (n = 89)†Clinical sample (n = 220) ‡Total (n = 694)
  1. *Patients in the non-blinded sample gave permission to have their serum sample studied. A monoclonal immunoglobulin was found in the serum of 371 of the 16 485 participants who had given permission (2·3%), as well as in 14 of the 653 who responded to our letters at the end of the accrual period (2·1%). NA, not applicable.

  2. †Serum samples from patients who did not give permission to have their samples studied were blinded. A monoclonal immunoglobulin was found in the serum of 89 of the 4069 with blinded samples (2·2%). NA denotes not applicable.

  3. ‡Patients in the clinical sample were known to have MGUS at entry into the study. Of 229 patients who were thought to have MGUS at study entry, 220 (96·1%) had the disorder and 9 (3·9%) had Bence Jones proteinuria.

Male sex (%)54464550
Age (years)
 Median68NA7570
 50–59 (%)24·723·611·420·3
 60–69 (%)29·613·523·625·7
 70–79 (%)28·134·030·029·5
 ≥80 (%)17·728·135·024·5
Immunoglobulin isotype (%)
 IgG68·168·270·968·9
 IgA11·49·110·510·8
 IgM16·918·217·317·2
 Biclonal3·64·61·43·0
Monoclonal protein (g/l)
 Median55105
 RangeUnmeasurable-29·4Unmeasurable-21·4Unmeasurable-27·6Unmeasurable-29·4
Reduced concentration of uninvolved immunoglobulins (%)
 075·3NA62·872·3
 119·8NA28·321·9
 24·9NA8·95·8

The incidence of MGUS is higher in black patients than in white patients. The prevalence of an M protein was 8·6% in 916 black patients compared with 3·6% in white patients (Cohen et al, 1998). In a large study of inpatients from the US Veteran Affairs hospitals, the age-adjusted prevalence rate for MGUS was 3·0-fold higher in African-Americans than in white people (Landgren et al, 2006).

Long-term outcome of MGUS

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References

Monoclonal gammopathy of undetermined significance is a common finding in the medical practice of all physicians. Determining whether MGUS will remain stable or progress to MM or a related disorder is important for both the patient and physician.

Mayo Clinic referral population

The outcome of patients with MGUS who were evaluated at the Mayo Clinic between 1956 and 1970 has been described (Kyle, 1978; Kyle et al, 2004a). Two hundred and forty-one patients were followed for 3579 person-years (median: 13·7 years; range: 0–39 years). Only 14 (6%) were alive and had no substantial increase in M protein during a median follow-up of 33 years (Table V). Twenty-five patients (10%) developed a serum M protein value of 30 g/l or more, but did not require chemotherapy for MM, WM or AL. All 25 patients in this group have died. One hundred and thirty-eight patients (57%) died without evidence of symptomatic MM, WM, AL or a related disorder. The major causes of death included cardiac disease, cerebrovascular disease or a non-plasma cell malignancy. MM, WM, AL or a lymphoproliferative disease developed in 64 patients (27%). Patients in this group were followed up for a median of 10·4 years (range: 1–32 years) before diagnosis of the lymphoplasma cell proliferative disorder. The actuarial rate of progression was 17% at 10 years, 34% at 20 years and 39% at 25 years, a rate of approximately 1·5% per year (Fig 3). Of the 64 patients with progression, 44 (69%) developed MM. The interval from diagnosis of MGUS to diagnosis of MM ranged from 1 to 32 years (median: 10·6 years) (Table VI). AL was found in eight patients 6–19 years (median: 9 years) after the serum M protein was recognised. WM developed in seven patients 4–16 years (median: 10·3 years) after the M protein was detected and a lymphoproliferative disorder developed in five other patients (malignant lymphoma, three; chronic lymphocytic leukaemia, one; and atypical malignant lymphoproliferative disorder, one).

Table V.   Course of 241 patients with MGUS.
GroupDescriptionNo. (%) of patients at follow-up*
  1. *Person-years follow-up = 3579 (median: 13·7, range: 0–39 years).

1Living patients with no substantial increase of monoclonal protein14 (6)
2Monoclonal protein value ≥30 g/l but no myeloma or related disease25 (10)
3Died of unrelated causes138 (57)
4Developed myeloma, macroglobulinaemia, AL, or related disease64 (27)
Total 241 (100)
image

Figure 3.  Rate of development of multiple myeloma (MM) or related disorders in 241 patients with monoclonal gammopathy of undetermined significance. from ref. Kyle et al (2004a) (see comment).

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Table VI.   Development of myeloma or related diseases in 64 patients with MGUS.
DiseasePatientsInterval to diagnosis, years*
No.%MedianRange
  1. *Actuarial rate was 17% at 10 years and 34% at 20 years.

MM446910·61–32
Macroglobulinaemia71110·34–16
AL8129·06–19
Lymphoproliferative disorder588·04–19
Total6410010·41–32

Southeastern Minnesota population-based study

To confirm the findings of the 241 Mayo Clinic patients from the USA and other countries, which may be subject to referral bias, we conducted a study of 1384 patients with MGUS from the 11 counties from Southeastern Minnesota evaluated at Mayo Clinic from 1960 to 1994 (Kyle et al, 2002a). Median age at diagnosis was 72 years, which is 8 years older than the 241 cohort, while 54% were male. Only 2% were younger than 40 years at diagnosis and 59% were 70 years or older. The M protein value ranged from unmeasurable to 30 g/l. The M protein was IgG in 70%, IgM in 15%, IgA in 12% and biclonal in 3%. A reduction of uninvolved (normal or background) immunoglobulins was found in 38% of 840 patients who were evaluated. Of the 418 patients who had immunofixation of urine, 31% had a monoclonal light chain. The bone marrow contained 0–10% plasma cells (median: 3%) in the 160 patients who underwent the procedure.

The 1384 patients were followed for a total of 11 009 person-years (median: 15·4 years; range: 0–35 years) and 963 (70%) died. During follow-up MM, AL, lymphoma with an IgM serum protein, WM, plasmacytoma or chronic lymphocytic leukaemia (CLL) developed in 115 patients (8%) (Table VII). The cumulative probability of progression to one of these disorders was approximately 1% per year. The rate was 10% at 10 years, 21% at 20 years and 26% at 25 years (Fig 4). It must be emphasised that patients were at risk for progression of stable MGUS even after more than 25 years. An additional 32 patients were identified in whom the serum M protein value increased to >30 g/l or the percentage of bone marrow plasma cells increased to >10% but in whom symptomatic MM did not develop. These findings confirmed the results of the initial Mayo Clinic study of 241 patients.

Table VII.   Risk of progression among 1384 residents of southeastern Minnesota in whom MGUS was diagnosed between 1960 and 1994.
Type of ProgressionPatients, nRelative risk (95% CI)
ObservedExpected*
  1. CI, confidence interval.

  2. *Expected numbers of cases were derived from the age- and sex-matched white population of the surveillance, epidemiology, and end results program in Iowa, except for primary AL, for which data are from Kyle et al (1992).

  3. †All 19 patients had serum IgM monoclonal protein. If the 30 patients with IgM, IgA, or IgG monoclonal protein and lymphoma were included, the relative risk would be 3·9 (95% CI, 2·6–5·5).

  4. ‡All three patients had serum IgM monoclonal protein. If all six patients with IgM, IgA, or IgG monoclonal protein and chronic lymphocytic leukaemia were included, the relative risk would be 1·7 (95% CI, 0·6–3·7).

  5. Data originally reported by Kyle et al (2002a).

MM753·025·0 (20–32)
Lymphoma19†7·82·4 (2–4)
Primary AL101·28·4 (4–16)
Macroglobulinaemia70·246·0 (19–95)
Chronic lymphocytic leukaemia3‡3·50·9 (0·2–3)
Plasmacytoma10·18·5 (0·2–47)
Total11515·87·3 (6–9)
image

Figure 4.  Probability of progression among 1384 residents of southeastern Minnesota in whom MGUS was diagnosed between 1960 and 1994. The top curve shows the probability of progression to a plasma-cell cancer (115 patients) or of an increase in the monoclonal protein concentration to more than 30 g/l or the proportion of plasma cells in bone marrow to more than 10% (32 patients). The bottom curve shows only the probability of progression of MGUS to MM, IgM lymphoma, primary amyloidosis (AL), macroglobulinaemia, chronic lymphocytic leukaemia, or plasmacytoma (115 patients). The bars show 95% CI. From ref. Kyle et al (2002a) Copyright © 2002 Massachusetts Medical Society.

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The number of patients with progression to a plasma cell disorder (115 patients) was 7·3 times the number expected (Table VII). The risk of developing MM was increased 25-fold, WM 46-fold and AL 8·4-fold. The risk of lymphoma was moderately increased at 2·4-fold, but this risk was underestimated because only lymphoma associated with an IgM protein was counted in the observed number, whereas the incidence rates for lymphoma associated with IgG, IgA, and IgM proteins were used to calculate the expected number.

The 75 patients in whom MM developed accounted for 65% of the 115 patients who progressed to a plasma cell disorder. Characteristics of these 75 patients were comparable with those of the 1027 patients with newly diagnosed MM who were referred to the Mayo Clinic between 1985 and 1998, except that the Southeastern Minnesota population was older (median: 72 years vs. 66 years) and had a smaller percentage of men (46% vs. 60%) (Kyle et al, 2003a).

Other series

Several other series have reported similar findings as discussed above. Of the 64 patients with MGUS in a Swedish study, 11% had some evidence of progression during 20 years of follow-up (Axelsson, 1986). In another series, 13 of 128 patients with MGUS developed a malignant disease during the median follow-up of 56 months (Blade et al, 1992). van de Poel et al (1995) reported that 6·6% of 334 patients with MGUS had a malignant transformation after a median follow-up of 8·4 years. In another study, 6·8% of 335 persons with MGUS progressed during a median follow-up of 70 months (Baldini et al, 1996). In a series of 263 patients with MGUS, the actuarial probability of development of malignancy was 31% at 20 years (Pasqualetti et al, 1997). In a cohort of 1324 patients with MGUS in North Jutland, Denmark, malignant transformation was the cause of death in 97 patients compared with the 4·9 deaths expected (Gregersen et al, 2001). In the Danish Cancer Registry, 64 new cases of malignancy (five expected; relative risk, 12·9) were found among 1229 patients with MGUS (Gregersen et al, 2000). The risk of developing MM, WM or non-Hodgkin lymphoma was 34·3-fold, 63·8-fold and 5·9-fold, respectively. In a series of 504 patients with MGUS from Iceland, a related malignancy developed in 51 (10%) after a median follow-up of 6 years (Ogmundsdottir et al, 2002).

In summary, the reported series essentially confirmed the risk of progression from MGUS to MM or a related disorder of approximately 1% per year. This risk does not disappear even after long-term follow-up.

Pathogenesis of progression of MGUS

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References

The events responsible for malignant progression of MGUS are not well understood. Genetic changes, bone marrow angiogenesis, various cytokines related to myeloma bone disease and possibly infectious agents may all play a role in the progression of MGUS to MM or a related disorder (Kyle & Rajkumar, 2005).

Genetic changes

Cytogenetic changes are common in MM and in MGUS. Sixty per cent of patients with myeloma have IgH (14q32) translocation with fluorescence in situ hybridisation (FISH) (Avet-Loiseau et al, 1998). These translocations are also present in MGUS. In one series (Avet-Loiseau et al, 1999a), IgH translocations were found in 46% of patients with MGUS. In another study utilising the cytoplasmic Ig FISH, 27 of 59 patients (46%) with MGUS had IgH translocations consisting of t(11;14)(q13;q32) in 25%, t(4;14)(p16.3;q32) in 9% and t(14;16)(q32;q23) in 5% (Fonseca et al, 2002). These translocations lead to the dysregulation of oncogenes such as cyclin D1 (11q13), C-MAF (16q23), FGF-R3/MMSET (fibroblast growth factor receptor 3/MM SET domain); (4p16.3) and cyclin D3 (6p21) and may be involved with the initiation of the MGUS clone rather than progression of MGUS to MM. It has been recently reported that 11 of 28 (40%) (Chng et al, 2005) patients with smouldering MM (SMM) or MGUS had hyperdiploidy. This is very similar to the percentage of hyperdiploid MM reported in the literature and suggests that hyperdiploid MM originates early during the disease evolution. Thus, it appears that almost all MGUS is associated with evidence of genomic instability, that is manifested as primary IgH translocations in roughly 50% (IgH translocated MGUS) and hyperdiploidy in most of the remaining patients (IgH non-translocated MGUS).

Deletions of chromosome 13, which have an adverse prognostic association in MM, are found in similar frequencies in both MM and MGUS (Avet-Loiseau et al, 1999b). Although deletions of chromosome 13 detected by conventional cytogenetics is associated with an adverse effect on MM, it is not clear whether the rate of progression from MGUS to MM is accelerated because the frequency of deletion of chromosome 13 is similar in both MGUS and MM.

Epigenetic changes, such as aberrant methylation of the 5′ gene promoter regions of tumour suppressor genes, have been observed at the MGUS stage, although they are lower in frequency compared with myeloma (Takahashi et al, 2004). The role of these changes in the progression of MGUS is not clear.

Angiogenesis

Bone marrow angiogenesis is increased in MM and has prognostic value (Vacca et al, 1994; Rajkumar et al, 2000). We studied the bone marrow angiogenesis in 400 patients who had MGUS, SMM, newly diagnosed active MM, relapsed MM and AL. The median microvessel density (in vessels per high-power field) was 1·3 in the 42 normal controls, 1·7 in AL, 3 in MGUS, 4 in SMM, 11 in MM and 20 in relapsed MM. Thus, bone marrow angiogenesis increased progressively from the more benign MGUS stage to advanced MM (Rajkumar et al, 2002a), but it is not known if it plays an aetiological role. Using a chick embryo chorioallantoic membrane angiogenesis assay, Vacca et al (1999) reported that 76% of myeloma bone marrow samples had increased angiogenic potential compared with 20% of MGUS patients. The finding that increased angiogenesis is more common in myeloma suggests that it may play a role in progression of MGUS to MM.

The increase in angiogenesis that occurs with progression does not appear to be related to overexpression of any single proangiogenic cytokine by neoplastic plasma cells, but rather to an alteration in the balance between pro- and antiangiogenic effects. Perhaps increasing tumour burden rather than increased expression of cytokines by individual plasma cells plays a role. Furthermore, there appears to be a loss of angiogenesis inhibitory activity with disease progression from MGUS to MM, which may account for the increase in angiogenesis in MM. In another study, 63% of MGUS serum samples inhibited angiogenesis, while 43% of SMM and 4% of MM serum samples (4%; P < 0·001) did so. This inhibitory activity was heat stable and not overcome by the addition of VEGF (Kumar et al, 2004). Loss of an endogenous angiogenesis inhibitor may be involved in the increased angiogenesis that occurs with disease progression.

Myeloma bone disease

The most important features that differentiate MM from MGUS are the occurrence of lytic bone lesions, osteopenia, hypercalcaemia and pathological fractures in MM. However, in a study of 488 Olmsted County residents with MGUS, we found a 2·7-fold increase in axial fractures but no increase in limb fractures (Melton et al, 2004).

The development of bone lesions with progression of MGUS to MM is caused by osteoclast activation as well as inhibition of osteoblast differentiation. Osteoclast activation in myeloma is caused by overexpression of various cytokines, most importantly receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage inflammatory protein 1-alpha (Roodman, 2002). RANKL is modulated by a decoy receptor, osteoprotegerin (OPG). Consequently, myeloma bone disease can occur from excess RANK-L or reduced levels of OPG (Croucher et al, 2001). Interleukin-1beta is produced by plasma cells in virtually all cases of MM and has strong osteoclast-activating factor activity (Lust & Donovan, 1998). Other cytokines, such as tumour necrosis factor-alpha and interleukin-6 (IL-6), have also been implicated.

Helicobacter pylori

Malik et al (2002) reported that 39 of 59 patients (66%) with MGUS had Helicobacter pylori infection and that 11 of 39 patients treated for H. pylori had a reduction of M spike. On the other hand, serological testing for H. pylori showed that 30% of 93 MGUS patients, who were residents of Olmsted County, MN, had positive results, as did 32% of 98 control subjects from the same population. In addition, 51 of 154 patients (33%) from Mayo Clinic with MGUS were positive for H. pylori as were 365 of 1103 (33%) without MGUS. Thus, controversy exists about the role, if any, of H. pylori infection in MGUS (Rajkumar et al, 2002b).

Predictors of progression of MGUS

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References

At the time of recognition of MGUS, one cannot distinguish a patient whose condition will remain stable from one in whom progression to a plasma cell malignancy will develop. Some parameters are useful for predicting the likelihood of progression from MGUS to MM.

Size of serum M protein

In a series of 1384 patients with MGUS from Southeastern Minnesota, the M-protein value at diagnosis was the most important predictor of progression to a plasma cell disorder. The risk of progression to MM or a related disorder 20 years after the diagnosis of MGUS was 14% for patients with an initial M-protein value ≤5 g/l and 49% for those presenting with an M-spike of 25 g/l (Fig 5). The risk of progression of a serum M-protein value of 15 g/l was almost twice the risk of progression with a value of 5 g/l and the risk of progression with 25 g/l was 4·6-times that of a value of 5 g/l. Age, sex, presence of hepatosplenomegaly, levels of haemoglobin, serum creatinine and serum albumin; presence, type and amount of urinary light chain; numbers of bone marrow plasma cells; and reduction of uninvolved immunoglobulins was not predictors for progression (Kyle et al, 2002a).

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Figure 5.  Actuarial risk of full progression by serum monoclonal protein (M-protein) value (g/dl) at diagnosis of MGUS in persons from southeastern Minnesota. From: ref. Kyle and Rajkumar (2003). With permission of Blackwell Publishing.

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Type of M protein

Blade et al (1992) reported that patients with an IgA MGUS had a greater probability for development of MM than those who did not. In our large series of 1384 Mayo Clinic patients, those with an IgM or an IgA M protein had an increased risk of progression compared with patients who had an IgG (P = 0·001) protein.

Bone marrow plasma cells

The number of plasma cells in the bone marrow is helpful in predicting the progression. Baldini et al (1996) reported a transformation rate of 6·8% when the bone marrow plasma cell level was <10%. Cesana et al (2002) found that more than 5% bone marrow plasma cells were an independent risk factor for progression.

Abnormal serum-FLC ratio

In a large study, serum samples obtained within 30 d of diagnosis were available in 1148 of 1384 patients with MGUS from Southeastern Minnesota. An abnormal FLC ratio was detected in 379 patients (33%). At a median follow-up of 15 years, malignant progression occurred in 87 patients (7·6%). The risk of progression in patients with an abnormal FLC ratio was significantly higher than in patients with a normal ratio (hazard ratio 3·5; P < 0·001) and was independent of the size and type of serum M protein.

Risk-stratification model for MGUS

A new risk-stratification model for determining the risk of progression for MGUS was developed in that study. Patients with risk factors consisting of an abnormal serum FLC, non-IgG MGUS, and an elevated serum M-protein value (≥15 g/l) had a risk of progression at 20 years of 58%, compared with 37% with any two risk factors present, 21% with one risk factor present, and 5% when none of the risk factors was present (Table VIII, Fig 6). The risk of progression was only 2% at 20 years when competing causes of death were taken into account (Rajkumar et al, 2005). We hypothesise that the production of excess monoclonal FLC in MGUS is probably a reflection of plasma cells bearing a higher degree of cytogenetic abnormalities. This is manifested by an increased risk of progression observed in MGUS patients with an abnormal FLC ratio.

Table VIII.   Risk-stratification model to predict progression of MGUS to myeloma or related disorders.
Risk groupNo. of patientsRelative risk Absolute risk of progression at 20 years %Absolute risk of progression at 20 years accounting for death as a competing risk %
  1. This table is adapted from one originally published in Blood. From ref. Rajkumar et al (2005)© the American Society of Hematology.

Low-risk (Serum M protein <15 g/l, IgG type, normal free-light chain ratio (0·26–1·65)449152
Low-intermediate-risk (Any one risk factor abnormal)4205·42110
High-intermediate-risk (Any two risk factors abnormal)22610·13718
High-risk (All three risk factors abnormal)5320·85827
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Figure 6.  Risk of Progression of MGUS to myeloma or related disorder. The top curve illustrates the risk of progression with time in patients with all three risk factors, namely an abnormal serum kappa lambda-free light-chain ratio (<0·26 or >1·65), a high serum monoclonal protein level (≥1·5 gm/dl) and non-IgG MGUS; the second gives the risk of progression in patients with any two of these risk factors; the third curve illustrates the risk of progression with one of these risk factors; the bottom curve is the risk of progression for patients with none of the risk factors. This figure was originally published in Blood. From ref. Rajkumar et al (2005)© the American Society of Hematology.

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In the management of patients with MGUS, one must be aware that death from other diseases (cardiovascular or cerebrovascular diseases and non-plasma cell malignancies) is greater than that from MGUS. After 20 years of follow-up in the Southeastern Minnesota series, plasma cell disorders had developed in 10% of patients whereas 72% had died of other causes (Fig 7).

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Figure 7.  Rate of death from non-plasma cell disorders compared with progression to plasma cell disorders in 1384 patients with MGUS from southeastern Minnesota. From: ref. Kyle and Rajkumar (2003). With permission of Blackwell Publishing.

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Differentiation of MGUS from MM

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References

Differentiating a patient with MGUS from one with MM may be difficult at the time of initial presentation and is based on the clinical and laboratory findings. One should obtain a complete blood count (CBC), serum creatinine, serum calcium and a complete radiographic bone survey, including the long bones. A bone marrow aspirate and biopsy are indicated in all patients with an M-protein value ≥15 g/l, patients with an IgA or an IgM MGUS, patients with an abnormal FLC ratio and all persons who have an abnormality in the CBC, creatinine or calcium levels or an abnormal radiographic bone survey. The size of the serum and urine M protein, haemoglobin concentration, percentage of bone marrow plasma cells, presence of hypercalcaemia or renal insufficiency and the presence of lytic bone lesions are helpful in the differential diagnosis.

A serum M-protein level ≥30 g/l and/or bone marrow plasma cells ≥10% in the absence of anaemia, renal insufficiency, hypercalcaemia, lytic bone lesions or other clinical manifestations related to a malignant plasma cell proliferative disorder are considered SMM (Kyle & Greipp, 1980). SMM is associated with a higher risk of malignant transformation than MGUS. However, patients with SMM must not be treated with chemotherapy until progression occurs because they may remain stable for many years.

A reduction of uninvolved (polyclonal or background) immunoglobulins cannot be used to differentiate MM from MGUS. Although more than 90% of patients with MM have a reduction of one or more immunoglobulins (Kyle et al, 2003a), 30–40% of patients with MGUS also have a decrease in uninvolved immunoglobulins (Blade et al, 1992; Baldini et al, 1996; Kyle et al, 2002a, 2004a). Similarly, the presence of an M protein in the urine (Bence Jones proteinuria) cannot be used to distinguish MGUS and MM; monoclonal light chains are present in patients with MGUS. In our series of 1384 patients with MGUS from Southeastern Minnesota, 31% of the 418 tested patients had a monoclonal light chain in the urine.

The plasma cell labelling index may be useful in differentiating MGUS or SMM from symptomatic MM (Greipp et al, 1987). An elevated value strongly suggests that the patient has or will soon have symptomatic MM and these patients should be followed more closely. However, more than one-third of patients with symptomatic MM have a normal plasma cell labelling index and the test is not widely available. Presence of circulating plasma cells in the peripheral blood is also an indicator of active disease. Sixty-three of 325 (19%) patients with MGUS had circulating plasma cells by the slide-based immunofluorescence method. Patients with circulating plasma cells were twice as likely (hazard ratio 2·1) to progress compared those without circulating plasma cells (P = 0·03). In patients with circulating plasma cells, the median progression-free survival was 138 months compared with a median not yet reached for those without circulating plasma cells (P = 0·028) (Kumar et al, 2005).

Ocqueteau et al (1998) found a population of polyclonal plasma cells with CD 38 expression and low forward light scatter. A monoclonal cell population showed a lower CD38 expression and a higher forward light scatter. Ninety-eight per cent of patients with MGUS had more than 3% normal polyclonal plasma cells and only 1·5% of patients with MM had the same findings.

Although the presence of lytic bone lesions on the skeletal survey in patients suspected to have MGUS is strongly suggestive of MM, one must exclude coincidental metastatic carcinoma. Bellaiche et al (1997) found normal results with magnetic resonance imaging in all 24 patients with MGUS, but abnormalities were found in 86% of 44 patients with MM. Increased levels of C-terminal telopeptide of type I collagen, osteocalcin and serum bone-specific alkaline phosphatase may be present in patients with MM, but these abnormalities are not reliable for distinguishing MM from MGUS (Vejlgaard et al, 1997).

Increased serum levels of IL-6, expression of CD56 or increased levels of beta-2-microglobulin are not useful for differential diagnosis. Conventional cytogenetic studies are not useful for diagnosis because abnormal karyotypes are rarely seen in MGUS because of the small number of plasma cells and their low proliferative rate. Further, several cytogenetic abnormalities occur at the MGUS stage.

Ultimately, the differentiation of active MM from MGUS/SMM depends on the presence or absence of end-organ damage, respectively. MGUS and SMM are differentiated from each other based on the size of the serum M protein and bone marrow plasma cell percentage.

Management of MGUS

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References

Patients with MGUS need indefinite follow-up. Typically, serum protein electrophoresis should be repeated in 6 months and if stable, annually thereafter. Patients who meet the criteria for low-risk MGUS (serum M protein <15 g/l; IgG subtype; normal FLC ratio) can be followed less often (Rajkumar et al, 2005). In the latter setting, routine skeletal radiography, bone marrow examination, and a 24-h urine collection for immunofixation are rarely necessary.

One should perform a bone marrow and metastatic bone survey in patients who have increased risk factors for progression, such as a serum M-protein value ≥15 g/l, non-IgG MGUS or an abnormal FLC ratio. A bone marrow is also indicated in patients who have unexplained anaemia, renal failure, hypercalcaemia or bone lesions on a metastatic bone survey. Determination of the plasma cell labelling index, search for circulating plasma cells in the peripheral blood and cytogenetic studies should be done if available. If the patient has an IgM protein, computed tomography of the abdomen may be considered as clinically indicated. Patients should always be instructed to contact their physicians if there is any change in their clinical condition.

Variants of MGUS

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References

IgM MGUS

In the 430 patients with a monoclonal IgM serum protein seen at Mayo Clinic between 1956 and 1978, 56% had MGUS (Kyle & Garton, 1987). In a more recent study, IgM MGUS was reported in approximately 20% of patients with MGUS and 30% of patients with an IgM paraprotein (Gobbi et al, 2005).

IgM MGUS was diagnosed in 213 Mayo Clinic patients who resided in the 11 counties of Southeastern Minnesota (Kyle et al, 2003b). Non-Hodgkin lymphoma (n = 17), WM (n = 6) and CLL (n = 3) or AL (n = 3) developed in 29 (14%) of the 213 IgM patients with a relative risk of 15-, 262-, 6- and 16-fold, respectively. Progression occurred at a rate of 1·5% per year and this risk persisted even after 20 years of follow-up (Fig 8). A higher initial level of the serum M protein and a lower serum albumin level at diagnosis were independent predictors of progression.

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Figure 8.  Probability of progression in 213 patients with IgM MGUS. Patients were residents of southeastern Minnesota in whom MGUS of IgM class was diagnosed between 1960 and 1994. Curve shows the probability of progression of MGUS to lymphoma, Waldenström macroglobulinaemia, primary AL, or chronic lymphocytic leukaemia. Bars show 95% CI. Numbers at bottom of the horizontal axis are numbers of patients at risk at each interval.

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In a group of 138 patients with IgM MGUS who had remained stable for 12 months, 14 (10%) evolved after a median follow-up of 75 months (Morra et al, 2005). In a group of 83 patients with an IgM-related disorder, type I cryoglobulinaemia was present in 19, type 2 cryoglobulinaemia in 56, peripheral neuropathy in five and idiopathic thrombocytopenia in three. Eight (8·4%) evolved to overt WM or a related disorder, during a median of 62 months of follow-up.

Biclonal gammopathies

Biclonal gammopathies are characterised by the presence of two different M proteins and occur in 2–6% of patients with monoclonal gammopathies. Of 57 patients with a biclonal gammopathy, 37 (65%) had biclonal gammopathy of undetermined significance (Kyle et al, 1981). The clinical findings in biclonal gammopathies were similar to those in monoclonal gammopathies, in that the median age was 67 years and 35% of the 57 patients had MM, WM, or another malignant lympho-plasma cell proliferative disorder. Two localised bands were found in only 18 patients with electrophoresis on cellulose acetate; in the others, a second M protein was not recognised until immunoelectrophoresis or immunofixation was performed. In a series of 1135 patients with monoclonal gammopathy, Riddell et al (1986) found 2·5% with a biclonal gammopathy.

Triclonal gammopathies

Grosbois et al (1997) described a patient with triclonal gammopathy (IgM kappa, IgG kappa and IgA kappa). In a review of 24 cases from the literature, they reported that 16 cases of triclonal gammopathy were associated with a malignant immunolymphoproliferative disorder, five occurred in non-haematological diseases and three were of undetermined significance.

Idiopathic Bence Jones (light chain) proteinuria

Although Bence Jones proteinuria is thought to occur in MM, AL, WM and other malignant lympho-plasma cell disorders, occasionally patients may produce large amounts of Bence Jones protein (monoclonal light chain) in the absence of end-organ damage. In one report, two patients with a stable serum M-protein level excreted 0·8 g/24 h of Bence Jones protein for more than 17 years without disease progression (Kyle et al, 1973). Seven other patients who were presented with Bence Jones proteinuria (>1·0 g/24 h) but in whom no serum M protein was found and who had no evidence of MM or a related disorder were described (Kyle & Greipp, 1982). MM developed in two of the seven, SMM in one, and AL in another, while two patients died of unrelated causes. One of these patients excreted up to 1·8 g of κ light chain every 24 h for 37 years without developing renal insufficiency. This patient died of a sudden cardiac arrhythmia and at autopsy no evidence of systemic AL or MM was found. Although idiopathic Bence Jones proteinuria may remain stable for years, MM or AL often results and consequently, these patients must be followed-up indefinitely.

IgD MGUS

The presence of an IgD M protein almost always indicates the presence of MM, AL or plasma cell leukaemia. However, MGUS of IgD type has been reported. O'Connor et al (1991) described a patient with an IgD lambda protein of 5 g/l who was followed-up for more than 6 years without evidence of progression. We followed a patient with IgD lambda MGUS for more than 8 years without development of MM or AL (Blade & Kyle, 1994).

Association of MGUS with other diseases

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References

As might be expected in an older population, certain diseases are associated with MGUS. The association of two diseases depends on the frequency with which each occurs independently. In addition, an apparent association may occur because of the difference in the referral practice or in other selected patient groups. Epidemiological and appropriate statistical methods must be used to evaluate these associations. The need for an appropriate control population cannot be overemphasised. A more detailed review of the association of an M protein with non-plasma cell disorders has been published (Kyle et al, 2004b; Kyle & Rajkumar, 2005).

Lymphoproliferative disorders

Azar et al (1957) reported that malignant lymphoma and lymphatic leukaemia were associated with a myeloma-type serum protein. Kyle et al (1960) described six patients with lymphoma who had serum electrophoretic patterns consistent with those of MM. In a large series of 1150 patients with lymphoma or CLL, an M protein was found in 49 patients: IgM in 29, IgG in 15 and not typed in five (Alexanian, 1975). Among the 292 patients with nodular lymphoma, four had an M protein while only one of 218 patients with Hodgkin disease had a monoclonal gammopathy. In contrast, 44 of 640 patients (7%) with diffuse non-Hodgkin lymphoma or CLL had an M protein.

In the series with an IgM monoclonal gammopathy at the Mayo Clinic, we reported that 62 patients with a malignant lymphoproliferative disorder (WM, lymphoma, CLL, AL and MGUS were excluded) required therapy because of anaemia or constitutional symptoms. The patients with a malignant lymphoproliferative disorder had a median survival similar to patients with WM (5·5 vs. 5·0 years, respectively). During the follow-up, 40 of 242 patients (17%) with IgM MGUS developed a malignant lymphoid disorder that required therapy (Kyle & Garton, 1987).

In another series of 382 patients with a lymphoid neoplasm and an associated IgM paraprotein, 59% had lymphoplasmacytic/WM. The remainder consisted of CLL/small lymphocytic lymphoma (SLL) (20%), marginal zone lymphoma (7%), follicular lymphoma (5%), mantle cell lymphoma (3%), diffuse large B-cell lymphoma (2%) and miscellaneous (4%) (Lin et al, 2005). Seven of 26 patients, (27%) with an extra nodal marginal-zone lymphoma had an M protein. There was a strong correlation between the involvement of the bone marrow and the presence of an M protein (Asatiani et al, 2004).

Leukaemia

In a series of 100 patients with CLL and associated monoclonal gammopathy, the type of serum M component was IgG (51%), IgM (38%), light chain only (10%) and IgA (1%). (Noel & Kyle, 1987). No clinical differences were found depending on whether the patient had an IgG or an IgM M protein. In another report, 46 patients with CLL/SLL with an IgM M protein and were compared with 52 patients with CLL/SLL without an IgM M protein. There was no difference in survival between the two groups (Yin et al, 2005). Monoclonal gammopathies have also been reported in acute leukaemia, hairy cell leukaemia, T-cell leukaemia and chronic myelocytic leukaemia.

Other haematological diseases

Acquired von Willebrand's disease may be associated with a monoclonal gammopathy. In a group of seven patients with acquired von Willebrand's disease, MGUS and clinical bleeding, the infusion of i.v. gamma globulin had a longer-lasting effect than did an infusion of von Willebrand's factor concentrate (Lamboley et al, 2002). Patients with monoclonal gammopathy and lupus anticoagulant activity have been recognised. Monoclonal gammopathies have also been reported with pernicious anaemia, refractory anaemia, pure red cell aplasia, polycythaemia vera, idiopathic myelofibrosis, congenital dyserythropoietic anaemia III and Gaucher's disease. In a recent series, 31 of 258 (12%) monoclonal gammopathy patients had macrocytosis; 14 had no apparent cause of macrocytosis and the authors attributed it to the M protein. There was no correlation of macrocytosis with vitamin B12 levels (Horstman et al, 2005).

Connective tissue disorders

Monoclonal gammopathies have been reported in patients with rheumatoid arthritis (Zawadzki & Benedek, 1969). MGUS has also been reported with lupus erythematosis, scleroderma, polymyositis, inclusion body myositis, discoid lupus erythematosis and ankylosing spondylitis. Polymyalgia rheumatica has also been described with MGUS. However, because these connective tissue disorders occur more commonly in older populations, it is not clear if the relationship is causal or coincidental.

Neurological disorders

Of 279 patients with a sensory motor peripheral neuropathy of unknown cause, 16 (6%) had MGUS (Kelly et al, 1981). In another series, 16 of 56 patients had MGUS and peripheral neuropathy. The frequency of an M protein in peripheral neuropathy is variable and depends on patient selection, the vigour with which an M protein is sought, and whether peripheral neuropathy is diagnosed on the basis of clinical features or electrophysiological examination. The association of neuropathy and monoclonal gammopathies has been the subject of an excellent review (Ropper & Gorson, 1998).

IgM is the most common protein found in peripheral neuropathy. In approximately one-half of patients with IgM MGUS and peripheral neuropathy, the M protein binds to myelin-associated glycoprotein (MAG). The IgM protein may also bind to gangliosides, glycolipids or chrondroitin sulphate. The clinical significance of the binding of the M protein to these components is not clear. An extensive review of antibodies associated with peripheral neuropathy has been published (Quarles & Weiss, 1999).

In our series of 65 patients with MGUS and sensory motor peripheral neuropathy, 31 had IgM, 24 had IgG and 10 had IgA. There was no difference in the type or severity of neuropathy in patients who did or those who did not have anti-MAG activity. There was no correlation between the level of the M protein and severity of the neuropathy (Gosselin et al, 1991).

Neuropathy associated with AL and POEMS syndrome must be differentiated from MGUS-associated neuropathy. Postural hypotension, sphincter dysfunction, anhidrosis and heart or kidney failure often occur in AL, but are not part of MGUS-associated neuropathy.

Patients with MGUS neuropathy have a more indolent course, less severe weakness and more frequent sensory loss than those with chronic inflammatory demyelinating polyneuropathy (CIDP) (Simmons et al, 1993). In addition, CIDP is more likely to occur at a younger age and have more motor than sensory involvement, a greater tendency for a relapsing course, and no evidence of a monoclonal gammopathy. In another report, clinical neuropathy was found in 74% and electrodiagnostic findings in 89% of 27 patients with hepatitis C-related mixed cryoglobulinaemia. At the last follow-up, 93% had evidence of neuropathy. In general, the peripheral neuropathy progressed despite treatment with alpha-2 interferon or corticosteroids (Ammendola et al, 2005).

Treatment of peripheral neuropathy and monoclonal gammopathy is challenging. Plasmaphaeresis has been of benefit for some patients (Dyck et al, 1991; Mazzi et al, 1999). Rituximab, i.v. gamma globulin, fludarabine and alkylating agents have all produced some benefit, but the overall results are disappointing.

Motor neuron and other neurological diseases

Eleven of 120 patients (9%) with motor neuron disease had an associated M protein. Ten of the 11 patients had amyotrophic lateral sclerosis and one had progressive spinal muscular atrophy (Younger et al, 1990). Nemaline (rod) myopathy has been reported with an IgG monoclonal gammopathy. Ataxia-telangiectasia has also been reported with MGUS (Sadighi Akha et al, 1999).

Dermatological diseases

Lichen myxedematosus (papular mucinosis and scleromyxedema) is a rare dermatological condition usually associated with a cathodal IgG lambda protein (James et al, 1967). Pyoderma gangrenosum, an ulcerative disease of the skin, was associated with MGUS in eight of 67 (12%) patients (Powell et al, 1983). An IgG M protein was recognised in 16 of 22 patients (73%) with necrobiotic xanthogranuloma (Finan & Winkelmann, 1986).

In a report of 10 patients with subcorneal pustular dermatosis, an IgA M protein was found in three and an IgG protein in one of seven patients tested. Schnitzler syndrome, characterised by chronic urticaria and an IgM monoclonal gammopathy, has been reported in 36 patients. Plane xanthomatosis may also be associated with MGUS. A detailed review of monoclonal gammopathies in skin disorders has been published (Daoud et al, 1999).

Endocrine disorders

MGUS has been reported in patients with hyperparathyroidism. We reviewed the records of 911 patients at Mayo Clinic who had hyperparathyroidism who were ≥50 years of age and in whom electrophoresis and immunoelectrophoresis was performed. Nine of the 911 patients (1%) had MGUS, a prevalence similar to that in a normal population (Mundis & Kyle, 1982). In another report, 20 of 101 patients with hyperparathyroidism had an M protein compared with only two of 127 controls (Arnulf et al, 2002). Consequently, the association of hyperparathyroidism and MGUS is not resolved.

Liver disease

There is an association between Hepatitis C virus (HCV) and monoclonal gammopathy, as well as non-Hodgkin lymphoma. In a series of patients with chronic liver disease, an M protein was found in 11% of 239 HCV-positive patients, but in only 1% of 98 HCV-negative patients (Andreone et al, 1998). Although polyclonal increases in immunoglobulins are characteristic of chronic liver disease, an M protein was reported in 11 of 31 patients with chronic active hepatitis.

Immunosuppression

Monoclonal gammopathies are frequently found after transplantation. In a series of 201 liver transplant patients, 28% had a monoclonal gammopathy (Badley et al, 1996). Abnormal protein bands were found in 10% of 550 MM patients who had received autologous stem cell transplantation (Zent et al, 1998). Of 182 patients with a kidney transplant, 30% had an M protein. In another report, 25% of 308 patients with a heart transplant had an M protein (Caforio et al, 2001). Allogeneic bone marrow transplantation was associated with an M protein in 12 of 47 patients; 11 of the 12 had a cytomegalovirus infection.

In a report of five patients with MGUS undergoing transplantation, SMM developed in two and another had an increase in the serum M protein (Rostaing et al, 1994).

Miscellaneous conditions

A wide variety of other diseases have been reported to have an association with MGUS. Gelfand et al (1979) described a patient who had angioedema and acquired deficiency of C1 esterase inhibitor and reviewed the records of 14 other patients from the literature. Twelve of 19 patients in another series with acquired angioedema type II had MGUS (Fremeaux-Bacchi et al, 2002). All 21 patients with systemic capillary leak syndrome had an M protein; all but 1 were IgG type (Droder et al, 1992). Thirteen patients with idiopathic focal and segmental glomerulosclerosis had MGUS (n = 9) and MM (n = 4). Treatment of myeloma resulted in an improvement of the patient's renal lesion (Dingli et al, 2005).

The association of MGUS with silicone breast implants has been reported, but in another study, five of 288 women with silicone breast implants had MGUS while an M protein was found in four of 288 patients without implants (Karlson et al, 2001). Corneal crystal deposits have been found in patients with MGUS (Bourne et al, 1989). Binding of calcium by an M protein may produce hypercalcaemia without pathological consequences because the ionised calcium is normal (Annesley et al, 1982). Copper, transferrin or serum phosphorous may also bind to M proteins.

Monoclonal gammopathies have been reported in patients with many other conditions, such as Hashimoto's thyroiditis, purpura fulminans, Henoch–Schoenlein purpura, septic arthritis, idiopathic pulmonary fibrosis, pulmonary alveolar proteinosis, idiopathic pulmonary haemosiderosis, sarcoidosis, thymoma, hereditary spherocytosis and hyperlipoproteinaemia. The relationship to MGUS to these conditions is not clear and may simply be coincidental.

Monoclonal proteins may be associated with antibody activity: actin, von Willebrand's factor, thyroglobulin, insulin, riboflavin, dextran, antistreptolysin-O, antinuclear activity, double-stranded DNA, apolipoprotein, thyroxin, cephalin, lactate dehydrogenase, and several antibiotics have shown unusual specificities to M proteins (Merlini et al, 1986).

References

  1. Top of page
  2. Summary
  3. Recognition of monoclonal gammopathies
  4. Prevalence of MGUS
  5. Long-term outcome of MGUS
  6. Pathogenesis of progression of MGUS
  7. Predictors of progression of MGUS
  8. Differentiation of MGUS from MM
  9. Management of MGUS
  10. Variants of MGUS
  11. Association of MGUS with other diseases
  12. Acknowledgement
  13. References
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