Monoclonal gammopathies of undetermined significance (MGUS)

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SECTION 5 - Monoclonal gammopathy of undetermined significance

Monoclonal gammopathies of undetermined significance (MGUS)


Monoclonal serum free light chains:
  1. Are found in approximately one third of individuals with intact immunoglobulin monoclonal gammopathy of undetermined significance, and in an additional 0.8% of individuals aged 50 years or older in the general population.
  2. May identify individuals with monoclonal gammopathy of undetermined significance missed by immunofixation electrophoresis.
  3. Indicate poor outcome in patients with 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.

19.1. MGUS: Definition and frequency

MGUS denotes the unexpected presence of a monoclonal protein in the serum of individuals who have no evidence of multiple myeloma (MM), AL amyloidosis, Waldenström's macroglobulinaemia (WM), lymphoproliferative disorders, plasmacytoma or related conditions.

MGUS is defined as follows (all criteria must be met):

  1. Serum monoclonal protein <30 g/L
  2. Clonal bone marrow plasma cells <10%
  3. Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, and bone lesions that can be attributed to the plasma cell proliferative disorder.

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 has a 2-fold higher incidence 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. Historically, the monoclonal protein in individuals with MGUS has been characterised as a serum intact immunoglobulin. In a Mayo Clinic study, 70% of monoclonal proteins identified were IgG, 15% IgM, 12% IgA and 3% biclonal [4]. MGUS patients have an increased risk of developing MM and related disorders, however, only 80% of cases of MM are associated with an intact immunoglobulin monoclonal protein. Recently, a new category of free light chain-only MGUS (FLC MGUS) has been recognised [5], which accounts for approximately 20% of MGUS cases, consistent with the proportion of light chain MM (LCMM) among newly diagnosed cases of MM (Chapter 8).

19.2. Risk factors for MGUS progression

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). To minimise therapeutic harm, treatment is only commenced once disease is evident. 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 [6]. Patients enrolled between 1960 and 1994 were followed up for a median 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 [7], 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 [8][9]. In an Italian study of 1,231 patients, Bence Jones proteinuria was an independent risk factor for malignant transformation [10]. More recently, sFLC abnormalities have been identified as a more reliable measure of outcome, and are described below.

19.3. Monoclonal sFLCs and MGUS progression

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 19.1. Risk of progression based the presence or absence of an abnormal FLC κ/λ ratio. (This research was originally published in Blood [11] © the American Society of Hematology).
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 19.2. Effect of increasingly abnormal FLC κ/λ ratio on the relative risk of progression of MGUS. (This research was originally published in Blood [11] © 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 19.3. Risk of progression to myeloma or related condition in 1148 patients with MGUS. (This research was originally published in Blood [11] © the American Society of Hematology).

In the largest study reported to date by Rajkumar et al., sFLC measurements were characterised in a series of 1,148 individuals with MGUS [11]. At baseline, an abnormal κ/λ sFLC ratio (<0.26 or >1.65) was detected in 379 (33%) cases. At a median follow-up of 15 years, malignant progression to MM or a related condition had occurred in 87 (7.6%) patients. The risk of progression in patients with abnormal sFLC κ/λ ratios was significantly higher (hazard ratio 2.6) than in patients with normal ratios and was independent of the size and type of the monoclonal protein (Figure 19.1). Furthermore, the risk of progression increased as κ/λ ratios became more extreme (Figure 19.2). These data are supported by the findings of a separate smaller study [12]. 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 [13].

Rajkumar et al. [11] used their data to produce a MGUS risk-stratification model based upon the immunoglobulin class, its concentration (above or below 15g/L) and the presence or absence of an abnormal κ/λ sFLC ratio (Table 19.1 and Figure 19.3). Using this model, low-risk patients were characterised as those with a small (<15 g/L) IgG monoclonal protein and a normal sFLC ratio. Such patients have a 2% absolute risk of disease progression at 20 years when competing causes of death are taken into account. Importantly, this low-risk group accounted for approximately 40% of the cohort, who could be reassured to a great extent. A smaller group of high-risk patients were identified as those with a large (>15 g/L) IgA or IgM monoclonal protein and an abnormal sFLC ratio. These patients have a 27% absolute risk of progression at 20 years and could be selected to be monitored more closely for signs of progression.

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%
* Accounting for death as a competing risk.
The three risk factors are defined as an abnormal κ/λ sFLC ratio (<0.26 or >1.65), a high serum monoclonal protein concentration (>15 g/L), and a non–IgG subtype (IgA or IgM).

Table 19.1. Risk stratification model to predict progression of MGUS.

A large independent study of 728 Swedish MGUS patients has recently validated the prognostic value of the sFLC ratio at diagnosis [14]. In this study, patients were followed up for up to 30 years (median 10 years), during which time 84 patients developed a lymphoid disorder, with MM accounting for the majority (53/84) of cases. The sFLC ratio was abnormal in 47% of the patients. Three risk factors were significantly associated with progression: an abnormal sFLC ratio, monoclonal protein concentration (>15 g/L) and a reduction of 1 or 2 non-involved immunoglobulin isotypes (immunoparesis). No association was found between the monoclonal protein isotype and risk of progression, which is in contrast to some previous reports [4][15][16], but in keeping with the Spanish PETHEMA group [17]. This Spanish group also previously identified immunoparesis as a significant risk-factor for MGUS progression in univariate but not multivariate analysis [17].

Turesson et al. concluded that a-risk stratification model in which the 3 Mayo clinic risk factors (abnormal sFLC ratio, monoclonal protein concentration and monoclonal protein isotype) were combined with immunoparesis had higher discriminatory power than other models, although the differences were not statistically significant [14].

International Myeloma Working Group (IMWG) guidelines [18] now recommend that patients with MGUS should be risk stratified at diagnosis to optimise counselling and follow-up, using the risk-stratification model outlined in Table 19.1 (Chapter 25). For patients with low-risk MGUS, follow-up is recommended at 6 months initially, and if stable, every 2-3 years or when symptoms suggest evidence of a plasma cell malignancy. For these patients, a baseline bone marrow examination or skeletal radiography is not routinely indicated. For patients with intermediate- and high-risk MGUS, follow-up is recommended at 6 months initially, and then annually and upon any change in the patient's clinical condition. A bone marrow aspirate and biopsy should also be carried out at baseline to rule out any underlying plasma cell malignancy [18].

Despite the existence of these significant predictive factors for progression, there are insufficient data on the preventative treatment of high-risk patients. In the future, additional markers may be added to risk stratification models to better define high-risk patients. Rawstron et al. [19], 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 19.4. 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 19.5. 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 [5]).

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? Historical case reports have described individuals with “idiopathic” Bence Jones proteinuria who progress to MM [20]. However, more recently, large population screening studies support the definition of FLC MGUS as a distinct clinical entity [5]. An example of such an individual is shown in Figure 19.4. No abnormality was detected by serum protein electrophoresis (SPE) or urine protein electrophoresis (UPE), but an abnormal sFLC κ/λ ratio confirmed the presence of monoclonal FLCs. This finding was supported by the detection of urinary λ Bence-Jones protein by urine immunofixation electrophoresis (uIFE).

In the largest study to date, Dispenzieri et al. [5] assessed the prevalence and risk of progression of FLC MGUS in a cohort of 18,357 residents of Olmstead County, Minnesota, who were aged 50 years or older. Of the 610 (3.3%) individuals who had an abnormal sFLC ratio, 213 had an intact immunoglobulin MGUS. This included 57/213 additional patients whose monoclonal intact immunoglobulin had not already been detected by screening with SPE (see Chapter 23), and so the prevalence of conventional MGUS in this population was revised from 3.2% to 3.4% (95% CI 3.2-3.7). FLC MGUS was defined as an abnormal sFLC ratio with an increased concentration of the involved light chain and no expression of monoclonal intact immunoglobulin. Of the 397 individuals with an abnormal sFLC ratio but no abnormality detected by SPE, a total of 146 met the definition of FLC MGUS, resulting in a calculated prevalence of FLC MGUS of 0.8% (95% CI 0.7-0.9) and an overall MGUS prevalence of 4.25% (95% CI 3.9-4.5). A similar incidence of FLC-MGUS (0.7%) was confirmed by a European study of 4,702 individuals aged 45-75 years [21]

Of the 146 individuals with FLC MGUS in the Olmstead County study, the light chain type was identified as κ in 108 and λ in 38 individuals. Figure 19.5 illustrates the observed ranges of FLC levels. Interestingly, a quarter of FLC-MGUS patients had some form of renal diagnosis that was not recognised as being related to a plasma cell dyscrasia. However, given the increasing understanding of the renal toxicity of monoclonal FLCs, Leung et al. [22] have now suggested that MGUS should not be used to describe hematologic disorders associated with kidney disease. Instead, a new term, “monoclonal gammopathy of renal significance (MGRS)” has been proposed. This highlights that renal impairment is likely to be linked to the underlying haematological disorder, even if it fails to meet the standard definitions for MM or SMM (see Chapter 25). Interestingly, Hutchison et al. [23]. have shown a high prevalence of monoclonal FLCs in patients with severe renal failure and have speculated that there might also be a causal link between more rapid deterioration of renal function and FLC toxicity (Section 20.5).

Dispenzieri et al. 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 [5]. This is lower than the overall progression rate of MGUS (1.0%), although this did not differ from that for 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 the presence of an abnormal sFLC ratio in patients with conventional MGUS may indicate a step closer to full transformation to MM or a related disorder.

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

In approximately half of monoclonal gammopathy of undetermined significance patients, involved serum free light chain concentrations increase prior to the diagnosis of multiple myeloma
Figure 19.6. Involved sFLCs prior to MM diagnosis. (This research was originally published in Blood [24] © the American Society of Hematology).

The findings of Dispenzieri et al. [5] have been confirmed by two recent reports [24][25], which demonstrated that conventional or FLC MGUS precedes the diagnosis of MM, that is often present many years before the diagnosis of malignant disease. A further study by Weiss et al. demonstrates that MGUS may also precede a diagnosis of AL amyloidosis [26].

Landgren et al. [24] 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 2 to 10 years prior to MM diagnosis for 71 individuals. Study subjects had an average of 3 pre-diagnostic samples available (range 1-6) on which by SPE, IFE and sFLC assays were performed (MGUS was defined as having a monoclonal protein visible by SPE or IFE, an abnormal sFLC ratio or both). The study concluded that MM is consistently preceded by MGUS, with up to 75% of patients having a detectable monoclonal protein 8 or more years prior to the diagnosis of malignancy. Whilst at a group level, median monoclonal protein concentrations (detected by electrophoresis) increased over time prior to the diagnosis, the proportion of individuals with an abnormal κ/λ sFLC ratio varied between 47 and 85%, with no statistical association over time. However, in approximately half of the individuals, the involved sFLC ratio (defined as κ/λ in κ patients and λ/κ in λ patients) showed a year-by-year increase (Figure 19.6), whilst ratios in the other half remained largely stable. A similar trend was observed for monoclonal protein concentrations prior to MM diagnosis.

In a similar, but smaller study, Weiss et al. [25] 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%). In all four patients diagnosed with LCMM or NSMM, disease evolved from a light chain MGUS. The temporal changes in monoclonal proteins were well-characterised in 7 patients, and demonstrated that substantial increases in the sFLC ratio may precede the diagnosis of MM, either with or without a corresponding change in the intact immunoglobulin.

In a retrospective study of 20 patients with AL amyloidosis, MGUS was detected prior to diagnosis in all cases [26]. 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.

Test Questions
  1. How should patients with MGUS be managed?
  2. Why are FLC MGUS rarely seen with SPE and IFE testing of serum and urine?
  3. What are the clinical benefits of MGUS risk stratification?

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