Monoclonal gammopathies of undetermined significance (MGUS)

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Chapter

19

SECTION 2C - Other diseases with monoclonal free light chains

Monoclonal gammopathies of undetermined significance (MGUS)

Contents

Summary: Elevated monoclonal serum FLCs:-
  1. Are found in 0.5-1% of elderly individuals and 30-60% of MGUS individuals.
  2. May identify individuals with MGUS missed by IFE.
  3. Indicate poor outcome in MGUS.
  4. Have been incorporated into a risk-stratification model for progression in association with the monoclonal immunoglobulin class and concentration.
  5. FLC only MGUS may progress to light chain only plasma cell dyscrasias.

19.1. MGUS: Definition and frequency

MGUS denotes the unexpected presence of an intact immunoglobulin monoclonal protein in individuals who have no evidence of MM, AL amyloidosis, Waldenström's macroglobulinaemia, lymphoproliferative disorders, plasmacytoma or related conditions. The term, monoclonal gammopathy, unattributed/unassociated, (MG[u]), is also used.

MGUS is defined as follows:-
  • M-protein in serum <30 g/L
  • Bone marrow clonal plasma cells <10% and low level of plasma cell infiltration in a trephine biopsy (if done)
  • No evidence of other B-cell proliferative disorders
  • No related organ or tissue impairment

MGUS may be found in 1% of the population over 50 years, 3% over 70 years and up to 10% over 80 years of age [1][2][3], is 2-fold higher in African-Americans [4], and is associated with inflammatory and infectious disorders [5]. Because of the frequency of MGUS, between 50-65% of all monoclonal proteins detected fall into this category and vast numbers go undetected. In a Mayo Clinic study, 73% were IgG, 14% IgM, 11% IgA and 2% biclonal [2]. Rarely, high concentrations of FLC MGUS are found in the urine [6].

19.2. MGUS and monoclonal free light chains

Figure 19.1. Serum FLCs in patients with MGUS. (Courtesy of H Lachmann).
Figure 19.2. Risk of progression based the presence or absence of an abnormal FLC κ/λ ratio. (This research was originally published in Blood [7] © the American Society of Hematology).

Although most people with MGUS die from unrelated illnesses, MGUS may transform into malignant monoclonal gammopathies. Patients should, therefore, be monitored on a regular basis to identify early signs of progression. In order to minimise therapeutic harm, treatment is given only when disease develops. During this monitoring phase, symptoms, signs and markers of malignancy are carefully observed, paying particular attention to serum and urine monoclonal proteins.

In a long-term study of outcome in MGUS patients at the Mayo Clinic, 1,384 patients with MGUS have been continually monitored [8]. Since enrolment between the years 1960 and 1994, 115 had progressed, a rate of approximately 1% per year. The most important prognostic factor for progression was the initial size of the serum monoclonal spike. Immunoglobulin class was also important; individuals with IgM and IgA, but not IgG, monoclonal proteins were 5 times more likely to progress. In a recent study by Kyle et al. [9], looking specifically at 213 patients with IgM MGUS, there was a very high relative risk of progression to Waldenström’s macroglobulinaemia (262 fold) or lymphoma (15 fold). Neither study showed any increased relative risk associated with the various immunoglobulin subclasses or urine FLC excretion.

In contrast, other studies have indicated that urine FLC excretion may be an important prognostic marker [10][11]. In an Italian study of 1,231 patients, Bence Jones proteinuria was an independent risk factor for malignant transformation [12].

Since the amounts of FLC in the urine are restricted by renal catabolism, serum concentrations might be a more reliable predictor of disease progression. Initial studies have indicated that FLC concentrations are raised in the serum of many patients with MGUS [13]. Examples from 31 patients are shown in Figure 19.1. 50% of the sera contained monoclonal FLCs as indicated by abnormal κ/λ ratios. Several others had raised concentrations of both FLCs because of renal impairment (Chapter 20).

In a study by Tate et al. [14], serum FLC concentrations and/or κ/λ ratios were abnormal in 26 of 32 MGUS patients. Serum intact immunoglobulin M-protein concentrations ranged from 1.0 to 22g/L. 9 patients had abnormal serum κ/λ ratios but a further 5 with normal serum FLCs had small amounts of urine monoclonal FLCs identified by electrophoretic tests. Presumably, the levels of monoclonal FLCs were insufficient to cause serum abnormalities but accompanying renal leakage allowed detectable amounts to enter the urine. In contrast, when patients with MM have good renal function, urine tests may be negative for monoclonal FLCs, while serum monoclonal FLC concentrations are relatively high. The same applies to patients with MGUS. It should be born in mind that in patients with MM, sFLC abnormalities rather than urine FLCs are a more reliable measure of outcome (Chapters 8 and 11) and presumably the same applies to FLCs in MGUS. In addition, the urine IFE tests may be falsely identifying intact monoclonal immunoglobulins or ladder-banding as monoclonal FLCs (Chapter 6.6) .

19.3. Risk stratification of MGUS using serum FLC concentrations

Figure 19.3. Effect of increasingly abnormal FLC κ/λ ratio on the relative risk of progression of MGUS. (This research was originally published in Blood [7] © the American Society of Hematology).
Figure 19.4. Effect of increasingly abnormal FLC κ/λ ratio on the relative risk of progression of MGUS. (This research was originally published in Blood [7] © the American Society of Hematology).

Rajkumar et al. [15][7], reported a large series of MGUS patients (1,148) in 2004. Results showed that the risk of progression in patients with abnormal FLC κ/λ ratios was significantly higher (hazard ratio 2.6) than in patients with normal ratios and was independent of the quantity and type of MGUS (Figure 19.2). Furthermore, the risk of progression increased as κ/λ ratios became more extreme (Figure 19.3).

The data was used to produce a risk-stratification model based upon immunoglobulin MGUS class, its quantity above or below 15g/L and the presence or absence of an abnormal FLC κ/λ ratio (Table 19.1 and Figure 19.4). The risk of progression, with time, after MGUS identification is shown in Figure 19.4. Another smaller study has reported similar results [16].

The explanation for the increased risk from abnormalities of sFLC ratios may relate to the clonal evolution of the plasma cells. Genetic and molecular events involved in the transformation of MGUS to MM presumably lead to disordered heavy and light chain immunoglobulin synthesis and abnormal monoclonal FLC production [17].

These important data have been widely reported and led to considerable debate regarding management guidelines for MGUS [18][19][20].

Typical historical practice has been to monitor all individuals on an annual basis in order to anticipate and prevent debilitating disease progression. Now, it may be preferable to monitor only those individuals at intermediate or high risk. Low risk patients (~ 40%) could be reassured about their test results and not followed up on a long term basis. Their MGUS might be only reassessed when they attend for other illnesses. In contrast, those at high risk might enter drug trials to prevent disease progression.

Risk of Progression No. of Abnormal Risk Factors No. Patients Absolute risk of progression at 20 years*
Low 0 449 2%
Low intermediate 1 420 10%
High intermediate 2 226 18%
High 3 53 27%

Table 19.1. Risk stratification model to predict progression of MGUS.
* Accounting for death as a competing risk

Possible guidelines were discussed in the UK and are shown below (Table 19.2). These have yet to be formally adopted.


1. Low risk - normal ratio, IgG isotype, M-spike <15g/L. Reassurance and discharge. Review MGUS when attending for other illnesses.*
2. Intermediate risk - one or two risk factors present. Annual follow-up.+
3. High risk - abnormal ratio, non-IgG isotype, M-spike >15g/L, 6/12 m follow-up.

Table 19.2. Possible guidelines for monitoring patients with MGUS

* For younger patients - follow-up as for intermediate risk.
+ No benefit from more frequent early monitoring following diagnosis.
Higher risk associated with higher and/or rising levels of M-spike and more abnormal sFLC ratios. High sFLC concentrations also associated with risk of renal impairment.


In spite of these significant predictive factors for progression, there is insufficient data for preventative treatment of high-risk patients. In order to increase predictive value further studies have been performed. Rawstron et al. [21], recently reported, in a small study, the addition of plasma cell phenotype (CD138/38/45 expression) to sFLCs and noted they were independent and complementary. Results of a larger study are awaited.

19.4. Serum free light chain MGUS

Figure 19.5.Serum and urine IFE on a patient with isolated urine FLC excretion.Serum analysis for FLCs showed an abnormal κ/λ ratio. TP: urine protein excretion. (Courtesy of JA Katzmann).

Since the monoclonal proteins in MGUS are intact immunoglobulins (by definition) and these patients progress to intact immunoglobulin plasma cell dyscrasias, what is the precursor protein for LCMM and AL amyloidosis? Occasional reports have described individuals with “idiopathic” Bence Jones proteinuria who progress to MM [6]. However, it is probable that FLC MGUS exists as serum FLC κ/λ ratio abnormalities that are undetected by current serum and urine electrophoretic tests. An example of such an individual is shown in Figure 19.5. Isolated, minimal urine FLC excretion is usually considered insignificant, but analysis of the corresponding serum indicated an abnormality of the κ/λ ratio in this patient.

The existence of FLC MGUS is also apparent from screening studies for monoclonal gammopathies that have incorporated serum FLC measurements. Some individuals have grossly abnormal serum FLC κ/λ ratios but completely normal serum and urine electrophoretic tests (Chapter 23) .

The frequency of serum FLC MGUS in a general population was initially addressed in a pilot survey at the Mayo Clinic [22]. 901 sera from the Olmsted County MGUS epidemiological study were investigated. All sera selected were defined as negative for serum or urine monoclonal immunoglobulins by IFE. However, 18 of the samples were abnormal when assessed for serum FLCs. 12 of the sera, with the most abnormal FLC κ/λ ratios (<0.2 or >2.0) were carefully re-assessed by IFE.

One sample had a small IgA band and another a small IgM band hidden in the β region of the gel; 4 had monoclonal λ FLC bands; 3 were equivocal for monoclonal FLCs and 3 were negative. Thus, a total of 7 samples (0.78%) probably had only monoclonal FLCs. These FLC-only MGUS might be the “missing” individuals with preclinical, LCMM or AL amyloidosis. Interestingly, this 0.78% is approximately 20% of the total MGUS incidence in such an age group - a similar percentage to the number of MM patients that are FLC-only (LCMM). This further supports the hypothesis that FLC MGUS are preclinical FLC plasma cell dyscrasias. Of importance is the observation that the FLC assays identified 2 patients with intact immunoglobulin monoclonal proteins that had been missed in the initial IFE tests. This is an additional reason to use FLC assays in a screening mode.

This study has now been extended to 16,637 individuals [23]. 317 had an abnormal sFLC κ/λ ratio with no accompanying intact monoclonal immunoglobulin, producing an incidence of FLC MGUS of 2%. Of these individuals 217 were κ and 100 λ with concentrations between 1.18mg/L and 2,700mg/L. κ/λ ratios were between 1.67- 511.0 for κ and 0.014-0.253 for λ. In 35 samples the presence of the monoclonal FLC was apparent by IFE. Progression to MM had occurred in 4 individuals at the time of reporting and 2 further people had developed CLL, both rates considerably higher than expected by chance.

Remaining questions include:-

  1. Are urine FLC concentrations increased in these patients?
  2. What is the overall incidence of progression per year?
  3. Do serum FLC MGUS also progress to AL amyloidosis?
  4. Are patients with FLC only MGUS at greater risk of progression to FLC monoclonal gammopathies than intact immunoglobulin MGUS?

Further evidence of FLC MGUS may come from studies of chronic inflammatory conditions [5] and chronic renal failure populations (Chapter 20). Hutchison et al. [24][25], showed a high prevalence of monoclonal FLCs in patients with severe renal failure and speculated that there might be a causal link between more rapid deterioration of renal function and FLC toxicity.

Test Questions
  1. How should patients with a serum FLC MGUS be managed?
  2. What clinical decisions should be made about MGUS patients who have associated monoclonal serum FLCs??
  3. Why are FLC MGUS rarely seen with SPE and IFE testing of serum and urine?
  4. What are the clinical benefits of MGUS risk stratification?



Chapter 18 Back to Contents Page Chapter 20

References

  1. ↑ Kyle RA, Rajkumar SV. Monoclonal gammopathies of undetermined significance. Hematol Oncol Clin North Am 1999; 13: 1181 – 202 PMID: 10626144
  2. ↑ 2.0 2.1 Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance. Br J Haematol 2006; 134: 573 – 89 PMID: 16938117
  3. ↑ Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, Melton LJ, 3rd. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346: 564 – 9 PMID: 11856795
  4. ↑ Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D, 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 2006; 107: 904 – 6 PMID: 16210333
  5. ↑ 5.0 5.1 Brown LM, Gridley G, Check D, Landgren O. Risk of multiple myeloma and monoclonal gammopathy of undetermined significance among white and black male United States veterans with prior autoimmune, infectious, inflammatory, and allergic disorders. Blood 2008; 111: 3388 – 94 PMID: 18239085
  6. ↑ 6.0 6.1 Kyle RA, Greipp PR. "Idiopathic" Bence Jones proteinuria: long-term follow-up in seven patients. N Engl J Med 1982; 306: 564 – 7 PMID: 7057813
  7. ↑ 7.0 7.1 7.2 7.3 Rajkumar SV, Kyle RA, Therneau TM, Melton LJ, 3rd, Bradwell AR, Clark RJ, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005; 106: 812 – 7 PMID: 15855274
  8. ↑ Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, Melton LJ, 3rd. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346: 564 – 9 PMID: 11856795
  9. ↑ Kyle RA, Therneau TM, Rajkumar SV, Remstein ED, Offord JR, Larson DR, et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood 2003; 102: 3759 – 64 PMID: 12881316
  10. ↑ Dimopoulos MA, Moulopoulos A, Smith T, Delasalle KB, Alexanian R. Risk of disease progression in asymptomatic multiple myeloma. Am J Med 1993; 94: 57 – 61 PMID: 8420300
  11. ↑ Baldini L, Guffanti A, Cesana BM, Colombi M, Chiorboli O, Damilano I, Maiolo AT. Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy. Blood 1996; 87: 912 – 8 PMID: 8562962
  12. ↑ Cesana C, Klersy C, Barbarano L, Nosari AM, Crugnola M, Pungolino E, et al. Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. J Clin Oncol 2002; 20: 1625 – 34 PMID: 11896113
  13. ↑ Marien G, Oris E, Bradwell AR, Blanckaert N, Bossuyt X. Detection of monoclonal proteins in sera by capillary zone electrophoresis and free light chain measurements. Clin Chem 2002; 48: 1600 – 1 PMID: 12194945
  14. ↑ Tate JR, Gill D, Cobcroft R, Hickman PE. Practical considerations for the measurement of free light chains in serum. Clin Chem 2003; 49: 1252 – 7 PMID: 12881439
  15. ↑ Rajkumar SV. MGUS and smoldering multiple myeloma: Update on pathogenesis, natural history and management. Hematology Am Soc Hematol Educ Program 2005: 340 – 5 PMID: 16304401
  16. ↑ Giarin MM, Giaccone L, Caracciolo D, Bruno B, Falco P, Omedè P, et al. Serum free light chains (SFLC) assay: a suggestive new criteria for evaluating disease response, progression and relapse in plasma-cell disorders (PD) and a prognostic factor in monoclonal gammopathy of undetermined significance (MGUS). Haematologica 2006; 91: 151a
  17. ↑ Cavallo F, Rasmussen E, Zangari M, Tricot G, Fender B, Fox M, et al. Serum free-lite chain (sFLC) assay in Multiple Myeloma (MM): Clinical correlates and prognostic implications in newly diagnosed MM patients treated with Total Therapy 2 or 3 (TT2/3). Blood 2005; 106: 974a
  18. ↑ Blade J. Clinical practice. Monoclonal gammopathy of undetermined significance. N Engl J Med 2006;355: 2765 – 70 PMID: 17192542
  19. ↑ Jagannath S. Value of serum free light chain testing for the diagnosis and monitoring of monoclonal gammopathies in hematology. Clin Lymphoma Myeloma 2007; 7: 518 – 23 PMID: 18021469
  20. ↑ Rajkumar SV, Lacy MQ, Kyle RA. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Blood Rev 2007; 21: 255 – 65 PMID: 17367905
  21. ↑ Rawstron AC, Davis B, D. DS, de Tute RM, Kerr MA, Owen RG, Ashcroft AJ. Plasma cell phenotype and SFLC provide independent prognostic information in MGUS. Haematologica 2007; 92: PO907a
  22. ↑ Katzmann JA, Clark RJ, Rajkumar VS, Kyle RA. Monoclonal free light chains in sera from healthy individuals: FLC MGUS. Clin Chem 2003; 49: A74a
  23. ↑ Rajkumar SV, Kyle RA, Plevak M, Clark RJ, Larson D, Therneau T, et al. Prevalance of light-chain monoclonal gammopathy of undetermined significance (LC-MGUS) among Olmsted Country, Minnesota residents aged 50 years of greater. Blood 2006; 108: 5060a
  24. ↑ Hutchison CA, Harding S, Basnayake K, Townsend J, Landray M, Mead GP, et al. Increased MGUS prevelance in chronic kidney disease patients. Haematologica 2007; 92: PO905a
  25. ↑ Hutchison CA, Mead G, Chandler K, Harper J, Bradwell AR, Cockwell P. Free light chain abnormalities in patients with chronic kidney disease. J Am Soc Nephrol 2006; 17: PUB393a

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