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

Elevated monoclonal serum free light chains:
  1. Are found in 0.5-1% of elderly individuals and in 30-60% of individuals with monoclonal gammopathy of undetermined significance.
  2. May identify individuals with MGUS missed by immunofixation electrophoresis.
  3. Indicate poor outcome in monoclonal gammopathy of undetermined significance.
  4. Have been incorporated into a risk-stratification model for progression in association with the monoclonal immunoglobulin class and concentration.
  5. Free light chain-only monoclonal gammopathy of undetermined significance 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 multple myeloma (MM), AL amyloidosis, Waldenström's macroglobulinaemia (WM), lymphoproliferative disorders, plasmacytoma or related conditions.

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

MGUS is present in approximately 3.2% of individuals 50 years of age or older, and in 5.3% of those 70 years or older [1]; it is 2-fold higher in African-Americans [2] and is associated with inflammatory and infectious disorders [3]. 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% of monoclonal proteins identified were IgG, 14% IgM, 11% IgA and 2% biclonal [4]. Rarely, high concentrations of FLC MGUS are found in the urine [5].

19.2. MGUS and monoclonal FLCs

Serum free light chain ratios are abnormal in approximately one third of monoclonal gammopathy of unknown significance patients
Figure 19.1 sFLCs in patients with MGUS. (Courtesy of H Lachmann).
An abnormal serum free light chain ratio is associated with increased risk of progression of monoclonal gammopathy of uncertain significance to multiple myeloma or related conditions
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 [6] © 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 (for recent guidelines see Chapter 25). In order to minimise therapeutic harm, treatment is given only when disease develops. During this monitoring phase, symptoms, signs and markers of malignancy are observed carefully, paying particular attention to serum and urine monoclonal proteins.

The long-term outcome of 1,384 patients with MGUS was studied at the Mayo Clinic [7]. Patients enrolled between 1960 and 1994 were followed up for a median time of 15.4 years (range: 0–35 years), during which time 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 detailed and specific study of 213 IgM-MGUS patients [8], a very high relative risk of progression to WM (262-fold) or lymphoma (15-fold) was documented. 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 [9][10]. In an Italian study of 1,231 patients, Bence Jones proteinuria was an independent risk factor for malignant transformation [11].

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 [12]. Examples from 31 patients are shown in Figure 19.1. The sera of 50% of these contained monoclonal FLCs, as indicated by abnormal κ/λ ratios. Several other patients had raised concentrations of both FLCs due to renal impairment (Chapter 20).

In a study by Tate et al. [13] sFLC concentrations and/or κ/λ ratios were abnormal in 26 of 32 MGUS patients. Serum intact immunoglobulin monoclonal protein concentrations ranged from 1.0 to 22g/L. Nine patients had abnormal serum κ/λ ratios and a further 5 with normal sFLCs 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, a situation that also applies to patients with MGUS. It should be noted that in patients with MM, sFLC abnormalities rather than urine FLCs are the more reliable measure of outcome (Chapters 8 and 11), a scenario that presumably applies also to FLCs in MGUS. In addition, 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 sFLC concentrations

The probability of progression of monoclonal gammopathy of unknown significance increases in relation to the degree of abnormality of the sFLC κ/λ ratio
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 [6] © the American Society of Hematology).
Risk of monoclonal gammopathy of uncertain significance progression to multiple myeloma or related conditions according to three risk factors: baseline serum free light chain ratio, serum monoclonal protein size and serum monoclonal protein type
Figure 19.4 Risk of progression to myeloma or related condition in 1148 patients with MGUS. (This research was originally published in Blood [6] © the American Society of Hematology).

Rajkumar et al. [14][6] reported data from a large series of MGUS patients (1,148) in 2005. 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 were 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 subsequent to MGUS identification is shown in Figure 19.4. Similar results have also been reported in a separate smaller study [15]. Indeed, these observations were included in the 2010 IMWG MGUS guidelines [16], which direct that patients with MGUS should be risk stratified at diagnosis and their follow up determined by a 'Risk-stratification model', outlined in Table 25.1. The 2009 IMWG guidelines on the use of sFLC [17] recommend sFLC determination at baseline for MGUS prognosis (Chapter 25).

The explanation for the increased risk arising from abnormal 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 [18].

These important data have been reported widely and led to considerable debate regarding management guidelines for MGUS [19][20][21]. Typical historical practice has been to monitor all individuals on an annual basis in order to anticipate and prevent debilitating disease progression. The more recent consensus statement on MGUS [22] states that all patients should be followed initially at 3-6 months; however, the frequency over time may vary depending upon the size of the monoclonal protein and other risk factors for progression (Table 25.1). Low risk patients (~40%) could be reassured about their test results and followed up on a more infrequent basis (every 2-3 years) or when they attend for other illnesses. In contrast those at high risk might enter drug trials to prevent disease progression.

The UK Myeloma Forum and Nordic Myeloma Study Group published guidelines in 2009 [23], further detailed in Chapter 25 on the investigation of newly detected monoclonal proteins and management of MGUS.

Risk of progression No. of abnormal risk factors No. of 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

Despite the existence of these significant predictive factors for progression, there are insufficient data on the preventative treatment of high-risk patients. In order to increase predictive value, further studies have been performed. Rawstron et al. [24] in a recently reported small study, showed that plasma cell phenotype (CD138/38/45 expression) and sFLCs provide independent and complementary prognostic information on the risk of progression. Results of a larger study are awaited.

19.4. Serum free light chain MGUS

serum and urine immunofixation electrophoresis in a patient with idiopathic Bence Jones proteinuria
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).
Involved serum free light chain concentrations plotted against serum free light chain ratio in patients with free light chain-monoclonal gammopathy of unknown significance
Figure 19.6 FLC MGUS as defined by the normal sFLC ratio reference range (0.26-1.65) compared with the renal reference range ratio (0.37-3.10). (Reproduced with permission from the Lancet [25]).

Monoclonal proteins in MGUS were historically considered to be intact immunoglobulins, as these patients progress to intact immunoglobulin plasma cell dyscrasias. So, what is the precursor protein for light chain multiple myeloma (LCMM) and AL amyloidosis? Occasional reports have described individuals with “idiopathic” Bence Jones proteinuria who progress to MM [26]. However, it is probable that FLC MGUS exists as serum FLC κ/λ ratio abnormalities that are undetected by 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 sFLC measurements. Some individuals have grossly abnormal sFLC κ/λ ratios but completely normal serum and urine electrophoretic tests (Chapter 23) .

The frequency of FLC MGUS in a general population was initially addressed in a pilot survey at the Mayo Clinic [27], in which 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, and the 12 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 been extended to a much larger proportion of the Olmsted County MGUS epidemiology survey [28] originally consisting of 21,463 residents. More recent analysis of the data led to the proposal for a light chain equivalent of conventional MGUS as a new clinical entity [25]. The authors defined this as an abnormal sFLC ratio with an increased concentration of the involved light chain and no expression of the intact immunoglobulin.

The study included 18,357 individuals, 610 of whom had an abnormal ratio; 213 of these had an intact immunoglobulin MGUS. Of these, 57 had not been detected with serum protein electrophoresis (SPE) as the screening test and so the prevalence of conventional MGUS in this population was revised from 3.2% to 3.4% (95% CI 3.2-3.7). Of the remaining 397 individuals, 146 had an increase of at least one FLC, resulting in a calculated prevalence of FLC MGUS of 0.8% (95% CI 0.7-0.9), resulting in an overall MGUS prevalence of 4.25% (95% CI 3.9-4.5). Of the FLC MGUS individuals 108 were ĸ and 38 λ. Figure 19.6 illustrates the observed ranges of FLC levels in FLC MGUS. Both ĸ and λ FLCs are raised in renal diseases (Chapter 20) and so the authors examined the application of the FLC renal reference ranges (Figure 19.6). This led to the exclusion of 69 individuals with apparent ĸ FLC MGUS and 57 with λ, including one patient who subsequently progressed to IgG λ MM. An association of renal diagnosis with FLC MGUS was noted; however, as medical information was not available for all patients the prevalence data was not calculated.

Interestingly, the authors showed a 0.3% (95% CI 0.1-0.8) risk per 100 person years of progression for FLC MGUS to MM and related disorders. This is lower than the overall progression rate of MGUS (1.0%), although this did not differ from patients with low-risk conventional MGUS. The authors speculated that the transformation events resulting in either FLC MGUS or conventional MGUS may be the same and that their presence in combination may indicate a step closer to full transformation to MM or a related disorder.

Further evidence of FLC MGUS may come from studies of chronic inflammatory conditions [3] and chronic renal failure populations (Chapter 20). Notably, 23% of FLC MGUS individuals identified by Dispenzieri et al.[25] had an incidental renal diagnosis either at the time of sample acquisition or subsequently. Hutchison et al.[29][30] 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.

19.5. MGUS as the precursor condition for MM and related disorders

MGUS patients have an increased risk of developing MM and related disorders. Patients may be risk stratified based on the number of risk factors present (Table 25.1). Until recently there has been little evidence supporting the supposition that MM always arises from an MGUS disorder or alternatively that MM more typically arises de novo. Such available evidence would provide important information for the study of MGUS and in developing new approaches to management.

Recently, Landgren et al. [31] examined the records from 77,469 healthy adults enrolled in the US PLCO (Prostate, Lung, Colorectal, and Ovarian) cancer screening trial, to identify individuals who developed MM. Serum samples were available from 2 to 10 years prior to MM diagnosis for 71 individuals. Analysis by SPE, IFE and sFLC assay was carried out to define the prevalence of MGUS prior to MM diagnosis (MGUS was defined as having a monoclonal protein visible by SPE or IFE, an abnormal sFLC ratio or both). The prevalence of MGUS was 100.0%, 98.3%, 97.9%, 94.6%, 100%, 93.3% and 82.4% at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis (Table 19.2).

In a similar, but smaller study Weiss et al. [32] demonstrated that 27 of 30 MM diagnoses were preceded by MGUS in a group of autologous stem cell transplant patients. Monoclonal proteins were identified by SPE/IFE in 21 individuals (77.8%) and by sFLC ratio alone in 6 (22%). Of the 3 individuals in whom no pre-existing plasma cell disorder was shown, one had a single prediagnostic sample from 9.5 years prior to diagnosis and the other two were IgD MM patients with available samples 3.5 and 5 years prior to MM diagnosis. The true incidence of MGUS prior to MM diagnosis may therefore have been higher than the 27/30 indicated.

In a retrospective study of 20 patients with AL amyloidosis, MGUS was detected prior to diagnosis in all cases [33]. A median of 3 pre-diagnostic samples were obtained 0.23 to 19.3 years prior to diagnosis. The monoclonal protein type was FLC MGUS in 11/20 (55%) cases, and intact immunoglobulin MGUS in 9/20 (45%) cases. The prevalence of MGUS was 100%, 80% and 42% at <4, 4 to 11, and >11 years prior to diagnosis.

Blood draw prior to
MM diagnosis		 M-Spike Abnormal κ/λ
FLC ratio		 MGUS
By year n % n % n %
2 25/27 92.6 23/27 85.2 27/27 100.0
3 54/58 93.1 46/58 79.3 57/58 98.3
4 45/48 93.8 29/46 63.0 47/48 97.9
5 34/37 91.9 25/37 67.6 35/37 94.6
6 25/25 100.0 19/25 76.0 25/25 100.0
7 14/15 93.3 11/15 73.3 14/15 93.3
8 or more 13/17 76.5 8/17 47.1 14/17 82.4

Table 19.2. Prevalence of serum protein abnormalities prior to MM diagnosis. (Adapted from [31]). These data are based on the actual available serum sample at a given time point as opposed to inferred data from earlier time points. M-Spike is defined as a monoclonal immunoglobulin being detected by SPE, IFE, or both. The normal sFLC ratio reference range (0.26-1.65) was used. For this study MGUS was defined as evidence of an M-spike (as defined above), an abnormal sFLC ratio, or both.


Test Questions
  1. How should patients with a sFLC MGUS be managed?
  2. What clinical decisions should be made about MGUS patients who have associated monoclonal sFLCs??
  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, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006;354:1362-9 PMID: 16571879
  2. ↑ 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
  3. ↑ 3.0 3.1 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
  4. ↑ Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance. Br J Haematol 2006;134:573–89 PMID: 16938117
  5. ↑ 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
  6. ↑ 6.0 6.1 6.2 6.3 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, Merlini G, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010;24:1121-7 PMID: 20410922
  17. ↑ Dispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, Hajek R, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 2009;23:215-24 PMID: 19020545
  18. ↑ 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
  19. ↑ Blade J. Clinical practice. Monoclonal gammopathy of undetermined significance. N Engl J Med 2006;355:2765–70 PMID: 17192542
  20. ↑ 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
  21. ↑ Rajkumar SV, Lacy MQ, Kyle RA. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Blood Rev 2007;21:255–65 PMID: 17367905
  22. ↑ Berenson JR, Anderson KC, Audell RA, Boccia RV, Coleman M, Dimopoulos MA, et al. Monoclonal gammopathy of undetermined significance: a consensus statement. Br J Haematol 2010;150:28-38 PMID: 20507313
  23. ↑ Bird J, Behrens J, Westin J, Turesson I, Drayson M, Beetham R, et al. UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected monoclonal proteins and the management of monoclonal gammopathy of undetermined significance (MGUS). Br J Haematol 2009;147:22-42 PMID: 19673884
  24. ↑ 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
  25. ↑ 25.0 25.1 25.2 Dispenzieri A, Katzmann JA, Kyle RA, Larson DR, Melton LJ, 3rd, Colby CL, et al. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet 2010;375:1721-8 PMID: 20472173
  26. ↑ 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
  27. ↑ Katzmann JA, Clark RJ, Rajkumar VS, Kyle RA. Monoclonal free light chains in sera from healthy individuals: FLC MGUS. Clin Chem 2003;49:A74a
  28. ↑ 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
  29. ↑ 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
  30. ↑ 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;17:899a
  31. ↑ 31.0 31.1 Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009;113:5412-7 PMID: 19179464
  32. ↑ Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009;113:5418-22 PMID: 19234139
  33. ↑ Weiss BM, Hebreo J, Cordaro D, Roschewski MJ, Abbott KC, Olson SW. Monoclonal gammopathy of undetermined significance (MGUS) precedes the diagnosis of AL amyloidosis by up to 14 years. Blood 2011;118:1827a

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