CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Serum free light chain ratio is an independent risk factor for progression
in monoclonal gammopathy of undetermined significance
S. Vincent Rajkumar, Robert A. Kyle, Terry M. Therneau, L. Joseph Melton III, Arthur R. Bradwell, Raynell J. Clark, Dirk R. Larson,
Matthew F. Plevak, Angela Dispenzieri, and Jerry A. Katzmann
We hypothesized that the presence of
monoclonal free kappa or lambda immunoglobulin light chains in monoclonal
gammopathy of undetermined significance (MGUS), as detected by the serum
free light chain (FLC) assay increases the
risk of progression to malignancy. Of
1384 patients with MGUS from Southeastern Minnesota seen at the Mayo Clinic
from 1960 to 1994, baseline serum
samples obtained within 30 days of diagnosis were available in 1148. At a median
follow-up of 15 years, malignant progression had occurred in 87 (7.6%) patients.
An abnormal FLC ratio (kappa-lambda
ratio < 0.26 or > 1.65) was detected in
379 (33%) patients. The risk of progression in patients with an abnormal FLC
ratio was significantly higher compared
with patients with a normal ratio (hazard
ratio, 3.5; 95% confidence interval [CI],
2.3-5.5; P < .001) and was independent of
the size and type of the serum monoclonal (M) protein. Patients with an abnormal
serum FLC ratio, non–immunoglobulin G
(non-IgG) MGUS, and a high serum M
protein level (> 15 g/L) had a risk of
progression at 20 years of 58% (high-risk
MGUS) versus 37% with any 2 of these
risk factors (high-intermediate risk), 21%
with one risk factor (low-intermediate
risk), and 5% when none of the risk factors were present (low risk). (Blood. 2005;
106:812-817)
© 2005 by The American Society of Hematology
Introduction
Monoclonal gammopathy of undetermined significance (MGUS) is
a premalignant plasma cell proliferative disorder found in approximately 3% of the general population 50 years of age and older.1 The
hallmark of MGUS is the presence of a monoclonal immunoglobulin in the serum, commonly referred to as a monoclonal (M)
protein. By definition, patients with MGUS have a serum M protein
less than 30 g/L, bone marrow plasma cells less than 10%, and no
anemia, hypercalcemia, lytic bone lesions, or renal failure that
would be indicative of a malignant plasma cell disorder.2-4 Since
MGUS is asymptomatic, diagnosis is usually the result of a
screening serum protein electrophoresis performed as part of a
diagnostic work up by primary-care providers. MGUS is associated
with progression to multiple myeloma or related malignancy at a
rate of 1% per year.5,6 Thus the risk of malignancy for a 50-year-old
patient with a 25-year life span is 25%. However, the risk of
progression does not diminish even after 25 to 35 years, making
lifelong follow-up by primary-care providers necessary in all
persons diagnosed with MGUS.5,7
Since myeloma is incurable and has a median survival of
only 3 to 4 years,8-10 delaying or preventing the progression of
MGUS assumes great significance. However, given the potential
adverse effects of prophylactic approaches and the duration for
which such interventions will be needed, only patients at a high
risk for progression can be considered candidates for testing
preventive strategies. Conversely, low-risk patients must not be
subjected to potentially harmful or expensive tests or preventive
interventions. It is therefore important to identify risk factors
that can accurately predict the subset of patients with the
greatest likelihood of progression. Unfortunately, such risk
factors have been very difficult to identify. In a large populationbased study of MGUS, we evaluated more than 13 potential risk
factors, but only the size and type of M protein (IgM and IgA
subtypes) were predictive of progression.5 In another study,
Cesana and colleagues reported that a bone marrow plasma cell
percentage of 6% to 9% carried twice the risk of progression
compared with marrow involvement that is 5% or less.11 Clearly,
additional laboratory predictors of progression of MGUS to
myeloma are needed.
A novel, highly sensitive serum free light chain (FLC) assay is
now available for clinical practice.12 It allows quantitation of free
kappa (␬) and lambda (␭) chains (ie, light chains that are not bound
to intact immunoglobulin) secreted by plasma cells. An abnormal
kappa-lambda FLC ratio indicates an excess of one light chain type
versus the other, and is interpreted as a surrogate for clonal
expansion based on extensive testing in healthy volunteers, and
patients with myeloma, amyloidosis, and renal dysfunction.13,14
From the Division of Hematology, Department of Laboratory Medicine and
Pathology, Division of Biostatistics and Division of Epidemiology, Mayo Clinic
College of Medicine, Rochester, MN; University of Birmingham and The
Binding Site Ltd, Birmingham, United Kingdom.
S.V.R., R.A.K., J.A.K., A.R.B., and L.J.M.III participated in the study concept,
data analysis, study design, and writing of the report; M.F.P., D.R.L., and T.M.T.
were involved in data collection, data analysis, and manuscript review; A.D.
was involved in data analysis and manuscript review; R.J.C. was involved in
performing the free light chain assays, data collection, and manuscript review.
Submitted March 15, 2005; accepted April 10, 2005. Prepublished online as
Blood First Edition Paper, April 26, 2005; DOI 10.1182/blood-2005-03-1038.
Supported in part by research grants CA 107 476 and CA 62 242 from the
National Cancer Institute.
One of the authors (A.R.B) has declared a financial interest in The Binding Site
Ltd, Birmingham, United Kingdom, whose product, the serum free light chain
assay, was studied in the present work.
812
An Inside Blood analysis of this article appears in the front of this issue.
Reprints: S. Vincent Rajkumar, Division of Hematology, Mayo Clinic, 200 First
St SW, Rochester, MN 55905.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2005 by The American Society of Hematology
BLOOD, 1 AUGUST 2005 䡠 VOLUME 106, NUMBER 3
BLOOD, 1 AUGUST 2005 䡠 VOLUME 106, NUMBER 3
PROGNOSIS OF MGUS
Table 1. Clinical characteristics of 1148 southeastern Minnesota
patients with monoclonal gammopathy
of undetermined significance
Characteristic
No. patients (%)
Sex
Male
622 (54)
Female
526 (46)
813
eloma.12,14,15 The presence of a monoclonal FLC in MGUS may be
a marker of clonal evolution in the neoplastic plasma cell since it
likely indicates a loss of control over the proportion of heavy and
light chains synthesized. We undertook this study to test the
hypothesis that an abnormal FLC ratio at baseline is a risk factor for
the progression of MGUS to malignancy.
Age, y
0-49
66 (6)
50-59
123 (11)
60-69
286 (25)
70⫹
673 (59)
Serum monoclonal protein heavy chain type
IgG
806 (70)
IgA
135 (12)
IgM
182 (16)
Biclonal
25 (2)
Serum monoclonal protein level, g/L
ⱕ5
287 (25)
6-10
229 (20)
11-20
604 (53)
21-30
28 (2)
The assay is performed on automated chemistry analyzers, is
widely available, and is commonly used to monitor patients with
oligo-secretory or nonsecretory myeloma and primary amyloidosis,
as well as patients with the light-chain only form of my-
Figure 1. Risk of progression to myeloma or related disorder in 1148 patients
with monoclonal gammopathy of undetermined significance. (A) The upper
curve illustrates risk of progression of all patients without taking into account
competing causes of death. The lower curve illustrates risk of progression after
accounting for other competing causes of death. (B) The upper curve illustrates risk of
progression of monoclonal gammopathy of undetermined significance in patients
with an abnormal serum kappa-lambda FLC ratio (⬍ 0.26 or ⬎ 1.65). The lower curve
illustrates the risk of progression in patients with a normal ratio.
Materials and methods
The study cohort was derived from persons who resided in the 11 counties
in southeastern Minnesota who met previously established diagnostic
criteria for MGUS at the Mayo Clinic from January 1, 1960, through
December 31, 1994.5 Of 1384 patients with MGUS diagnosed during this
period, a cohort whose baseline characteristics, methods of detection,
follow-up, and risk of progression have been well described by us earlier,5
1148 patients who had cryopreserved serum samples collected within 30
days of the MGUS diagnosis were studied. Follow-up was through the
review of each patient’s complete medical records at the Mayo Clinic. The
study was approved by the Mayo Institutional Review Board.
The FLC level in serum collected at the time MGUS was first
recognized was determined on all 1148 patient samples using the FLC assay
(Freelite; The Binding Site, Birmingham, United Kingdom) performed on a
Dade-Behring Nephelometer (Deerfield, IL).12-14 It consists of 2 separate
measurements, one to detect free-kappa (normal range, 3.3-19.4 mg/L) and
the other to detect free-lambda (normal range, 5.7-26.3 mg/L) light
chains.16 In addition to measuring the absolute levels of FLC, the test also
allows the assessment of clonality based on the ratio of kappa-lambda light
Figure 2. Effect of increasingly abnormal FLC ratio on the relative risk of
progression of monoclonal gammopathy of undetermined significance to
multiple myeloma or related disorder. This figure illustrates that as the serum
kappa-lambda FLC ratio becomes increasingly abnormal, the risk of progression
increases (A) and that this effect is present even after adjusting for differences in the
serum monoclonal protein spike among patients (B). The middle curve in both figures
represents relative risk; upper and lower curves represent 95% confidence intervals.
814
BLOOD, 1 AUGUST 2005 䡠 VOLUME 106, NUMBER 3
RAJKUMAR et al
chain levels (normal reference range, 0.26-1.65).13 Patients with a kappalambda FLC ratio less than 0.26 are typically defined as having monoclonal
lambda FLC and those with ratios greater than 1.65 are defined as having a
monoclonal kappa FLC. If the FLC ratio is greater than 1.65, kappa is
considered to be the “involved” FLC and lambda the “uninvolved” FLC,
and vice versa if the ratio is less than 0.26.
The normal reference range of 0.26 to 1.65 for the free-kappa–lambda
ratio in the FLC assay reflects a higher serum level of free-lambda light
chains than would be expected given the usual kappa-lambda ratio of 2 for
intact immunoglobulins. This occurs because the renal excretion of free
kappa (which exists usually in a monomeric state) is much faster than free
lambda (which is usually in a dimeric state).13,14
FLCs
The prognostic effect of abnormal kappa-to-lambda FLC ratio on progression of MGUS was studied. We also examined whether the risk of
progression varied depending on the extent to which the FLC ratio was
abnormal. To estimate the continuous risk effect of the FLC ratio, a
smoothing spline as previously described17 was used in univariate and
multivariate Cox proportional hazards models.18 The risk of progression
depending on extent to which the FLC ratio was abnormal was also
estimated after adjusting for the size of the serum monoclonal protein to the
mean monoclonal protein level. The primary end point was progression to
multiple myeloma or a related disorder. Progression endpoints were
examined both as cumulative probability of progression and cumulative
incidence. The former was computed using an ordinary Kaplan-Meier
estimate19 where patients who die are censored; curves were compared
using the log-rank test. The effects of potential risk factors on progression
rates were examined using a Cox proportional hazards model.18 The
cumulative incidence curve, on the other hand, explicitly accounts for death
from other causes (such as cardiovascular disease, cerebrovascular disease,
or unrelated malignancy) as a competing risk and was estimated using the
method of Gooley.20
Results
Clinical characteristics
The median age at diagnosis of MGUS was 72 years. The median
serum M protein at diagnosis was 12 g/L. Urine electrophoresis and
immunoelectrophoresis or immunofixation was done in 370
patients. Of these, a monoclonal light chain was detected in 110 patients
(30%). Additional patient characteristics are given in Table 1.
Serum FLC assay
The free-kappa light chain values ranged from 0.1 mg/L to 1210
mg/L (median, 20 mg/L), whereas the free-lambda light chain
values ranged from 0.1 mg/L to 10 100 mg/L (median, 20 mg/L).
There were 737 patients (64%) who had elevated levels of kappa or
lambda FLC. The kappa-to-lambda ratio ranged from 0.002 to 94.2
(median, 1.0). Based on the normal reference range for kappalambda ratio currently in use for clinical practice (0.26-1.65),13 an
abnormal FLC ratio (indicating the presence of monoclonal FLCs)
was detected in 379 (33%) patients. Of these, the FLC was of the
same isotype (kappa or lambda) as the corresponding serum M
protein in 371 (98%) of the patients. A higher proportion of patients
with a positive urinary monoclonal protein had an abnormal FLC
ratio (55%) compared with patients with no detectable monoclonal
proteins in the urine (32%) (P ⬍ .001).
Outcomes
These 1148 patients were followed for a total of 8982 person years
(median, 15 years). There were 783 patients (68%) who were
followed until death. During this period of observation, 87 (7.6%)
patients experienced progression: multiple myeloma (53 patients),
IgM lymphoma (17 patients), primary amyloidosis (6 patients),
macroglobulinemia (6 patients), chronic lymphocytic leukemia (3
patients), and plasmacytoma (2 patients). The cumulative probability of progression was 9% at 10 years, 20% at 20 years, and 30% at
25 years, or approximately 1% per year (Figure 1). Because
patients who die are censored, the upper curve in this figure reflects
the probability that a patient who has not died of other causes will
experience plasma cell progression at each point in the follow-up; it
therefore represents the natural history of the disease assuming
patients do not die of other causes prior to progression. The risk of
progression is lower if competing causes of death are taken into
account, 11.2% at 25 years, as illustrated by the lower curve in
Figure 1A.
Risk of progression based on FLC assay
In a Cox proportional hazards model, the risk of progression in
patients with an abnormal FLC ratio was significantly higher
compared with patients with a normal ratio (hazard ratio, 3.5; 95%
Table 2. Absolute risk of progression of MGUS to myeloma or related disorders based on the serum FLC ratio
Risk based on FLC (kappa-lambda) ratio
using the current diagnostic
reference range
Normal ratio
0.26-1.65*
Abnormal ratio
< 0.26 or > 1.65†
Risk based on increasingly abnormal
FLC (kappa-lambda) ratio
FLC ratio
0.25-4‡
FLC ratio 0.1250.25 or 4-8§
FLC ratio
< 0.125 or > 8㥋
Absolute risk of progression, % of patients
(95% CI)
Time of follow-up
5y
2.5 (1.3-3.8)
8 (4.8-11)
3.1 (1.9-4.4)
9.4 (2.4-15.9)
13.5 (4.3-22.5)
10 y
5.3 (3.2-7.4)
16.7 (11.4-21.7)
6.4 (4.4-8.4)
19.3 (8.5-31.3)
31.7 (13.5-46.1)
6.6 (4-9.8)
15 y
20 y
Cumulative annual rate of progression, %/y
29.9 (21.1-37.8)
9.6 (6.5-12.6)
42.3 (20.1-60.4)
47.3 (18.6-67.1)
12.6 (4.5-20.7)
35 (23.6-45)
15.8 (8.5-22.7)
42.3 (20.1-67.2)
60.5 (19.3-82.7)
0.6
1.8
0.8
2
3
0.3
0.8
0.4
1
1.3
Cumulative annual rate of progression, after
adjusting for competing risk of death,
%/y
*n ⫽ 769.
†n ⫽ 379.
‡n ⫽ 977.
§n ⫽ 95.
㛳n ⫽ 76.
BLOOD, 1 AUGUST 2005 䡠 VOLUME 106, NUMBER 3
PROGNOSIS OF MGUS
Table 3. Multivariate analysis of prognostic factors for progression
of monoclonal gammopathy of undetermined significance
Hazard ratio (95%
confidence interval)*
Prognostic factor
Abnormal FLC ratio
2.6 (1.7-4.2)
Serum M protein size
2.4 (1.7-3.5)
IgA, IgM, or biclonal IgA plus IgM
2.6 (1.7-4.0)
*P ⬍ .001 for each variable.
confidence interval [CI], 2.3-5.5; P ⬍ .001). The risk of progression to myeloma or related malignancy at 10 years was 17% with
an abnormal ratio compared with 5% with a normal ratio;
corresponding rates at 20 years were 35% and 13%, respectively
(Figure 1B).
There was a good correlation between increasingly abnormal
FLC ratio and the relative risk of progression (Figure 2A). The
absolute risk of progression at 5, 10, 15, and 20 years for varying
FLC ratios is given in Table 2.
An increased risk of progression was also noted when the
analysis was done using absolute levels of serum FLC. Patients
with elevated levels of kappa or lambda FLC had a significantly
higher risk of progression compared with those with lower levels
(hazard ratio, 2.1; 95% CI, 1.3-3.5; P ⫽ .002). There were 61
patients (5%) who had suppressed levels of the uninvolved FLC in
the absence of elevated involved FLC levels; no increased risk of
progression was seen in this group (hazard ratio, 1.2; 95% CI,
0.5-2.6; P ⫽ .65).
Of 379 patients with an abnormal FLC ratio, the abnormal ratio
was due to elevated involved FLC alone in 309 patients; the risk of
progression in this group was significantly higher compared with
patients with a normal ratio (hazard ratio, 3.5; 95% CI, 2.2-5.5;
P ⬍ .001). An abnormal ratio was solely due to suppressed
uninvolved FLC in 32 patients whereas it was due to combined
elevated involved FLC and suppressed uninvolved FLC in 20
patients. The hazard ratio for the risk of progression in these 2
groups was 1.4 and 10.5, respectively, but interpretation is
restricted by the small sample size. An abnormal FLC ratio
occurred with normal levels of both uninvolved and involved
FLC in 18 patients.
815
Multivariate analysis and proposed model for predicting risk
of progression of MGUS
The effect of an abnormal FLC ratio on risk of progression was
independent of the size of the M protein, as illustrated in Figure 2B,
which has been adjusted for the size of the serum M protein. After
adjusting for the size and type of the serum M protein on
multivariate analysis, the hazard ratio for progression associated
with an abnormal FLC ratio was only slightly reduced (hazard
ratio, 2.6; 95% CI, 1.7-4.2; P ⬍ .001) as delineated in Table 3. In
this multivariate model the hazard ratio for the size of the serum M
protein was 2.4 (P ⬍ .001) and that for a non–IgG type MGUS was
2.6 (P ⬍ .001).
Risk stratification model for MGUS
The FLC ratio added additional prognostic value to all 3 subgroups
of MGUS stratified by the 2 known prognostic factors, the size and
type of M protein (Table 4). We constructed a model for predicting
the risk of progression of MGUS based on the size of the serum M
protein, the type of immunoglobulin, and the presence of an
abnormal FLC ratio (⬍ 0.26 or ⬎ 1.65). The use of these 3 risk
factors identified 4 cohorts of patients with MGUS with significantly different rates of progression (Table 4; Figure 3). In fact,
when competing causes of death are taken into account, the true
lifetime risk of progression decreases to 2% for patients in the
low-risk group.
Discussion
The term “MGUS” was first coined at the Mayo Clinic more than
25 years ago,21 and our studies have shown that the risk of
progression of MGUS to myeloma or related malignancy is
approximately 1% per year.5-7 However, distinguishing the patient
with a stable monoclonal gammopathy from one in whom multiple
myeloma or related disorders will eventually develop is difficult
when MGUS is originally recognized. Moreover, there is no
decline in the risk of progression over time,5,6 necessitating lifelong
follow-up, usually performed by primary-care providers. Patients
are referred to hematologists typically in the face of a rising M
Table 4. Risk-stratification models to predict progression of monoclonal gammopathy of undetermined significance
to myeloma or related disorders
Risk group
No.
patients
Relative risk,
95% CI
Absolute risk of
progression at
20 years, %
Absolute risk of
progression at 20 years
accounting for death as a
competing risk, %
Addition of FLC ratio to known prognostic categories
Low risk (serum M protein ⬍ 15 g/L and IgG subtype)
Normal FLC ratio
449
1
Abnormal FLC ratio
142
7.4
5
2
27
12
Intermediate risk (either serum M protein ⱖ 15 g/L or non-IgG subtype)
Normal FLC ratio
278
1
22
9
Abnormal FLC ratio
184
2.2
37
17
High risk (serum M protein ⱖ 15 g/L and non-IgG subtype)
Normal FLC ratio
42
1
37
23
Abnormal FLC ratio
53
1.5
58
27
Risk stratification model incorporating all 3 predictive factors
Low risk (serum M protein ⬍ 15 g/dL, IgG subtype, normal FLC ratio [0.26-1.65])
449
1
5
2
Low-intermediate risk (any 1 factor abnormal)
420
5.4
21
10
High-intermediate risk (any 2 factors abnormal)
226
10.1
37
18
53
20.8
58
27
High risk (all 3 factors abnormal)
816
BLOOD, 1 AUGUST 2005 䡠 VOLUME 106, NUMBER 3
RAJKUMAR et al
Figure 3. Risk of progression of MGUS to myeloma or related disorder using a
risk-stratification model that incorporates the FLC ratio and the size and type of
the serum monoclonal protein. The top curve illustrates risk of progression with
time in patients with all 3 risk factors, namely an abnormal serum kappa-lambda FLC
ratio (⬍ 0.26 or ⬎ 1.65), a high serum monoclonal protein level (ⱖ 15 g/L), and
non–IgG MGUS; the second gives the risk of progression in patients with any 2 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.
protein on follow-up, or when other symptoms and signs suggestive of myeloma or related malignancy develop.
Given the uncertainty that follows the diagnosis of MGUS and
the need for long-term follow-up, clinical management would be
greatly enhanced by identification of factors that more accurately
predict progression or stability. We recently conducted a small
case-control study to determine if the presence of an abnormal FLC
ratio was associated with progression of MGUS.22 There were 47
patients with MGUS who had progression to myeloma or related
disorder who served as cases, while 50 patients with MGUS
without evidence of disease progression served as controls. The
presence of an abnormal FLC ratio was associated with a 2.5-fold
increased risk of progression. Given the significant clinical implications of this finding, the present study was undertaken with the goal
of validating and confirming these findings in a large, wellestablished population-based cohort of patients with MGUS in
whom long-term follow-up was available.5
The results of this study confirm our hypothesis that an
abnormal FLC ratio is an important risk factor for progression and
is independent of the size and type of the serum M protein, 2 known
prognostic factors.5 The relative risk of progression is related to the
extent to which the ratio is abnormal. We also show that the size
and type of the M protein and the serum FLC ratio can be combined
to yield a powerful risk-stratification model for the progression of
MGUS. This model identifies a group of patients with low-risk
MGUS (constituting almost 40% of the cohort) who have only a
5% risk of progression at 20 years, and a lifetime risk of 2% when
competing causes of death are taken into account. Clearly, this
group of patients can be reassured to a great extent. In fact, the
serum M protein levels may need to be rechecked in this group only
if symptoms of myeloma or related disorder become apparent. On
the other hand, the smaller group of high-risk patients needs to be
monitored more closely before pathologic fractures, hypercalce-
mia, renal failure, paraplegia from extramedullary plasmacytoma,
primary amyloidosis, overwhelming infection, or other serious
complications develop.
Another goal of the study was to identify patients in whom
prophylactic interventions can be justified. Low-risk patients
should clearly be excluded from preventive strategies and trials that
typically carry adverse effects and cost. However, even in the
high-risk group with both a high serum M protein and an abnormal
FLC ratio, the risk of progression is only 3% per year, making it
hard to justify preventive strategies. It is important in this context to
realize that 3% percent of the general population over the age of 50
years has MGUS, whereas the annual incidence of myeloma is only
4 per 100 000,23 and that the vast majority of patients with MGUS
(approximately 75%-90%)5,6 will not develop myeloma or a related
disorder in their lifetime. A risk of progression of 3% per year is, in
our opinion, insufficient to warrant large preventive trials in MGUS
in the absence of effective drugs with low long-term toxicity.
Clearly, additional risk factors are needed, and we are currently
exploring factors such as bone marrow microvessel density,
marrow angiogenic potential, and presence of circulating plasma
cells in predicting progression of MGUS. The high-risk patients
with MGUS identified in this study will serve as the base from
which additional risk factors can identify a suitable cohort for
chemoprevention trials.
Recent studies show that loss of heavy chain expression in
myeloma is related to cytogenetic events in the heavy chain locus
on chromosome 14 (14q32).24 We hypothesize that clonal evolution
of the neoplastic plasma cell may be marked by imbalance in heavy
and light chain production, and the results of this study lend support
to this theory. Whether the expression of excess clonal FLCs in
MGUS evolves from a cell that has undergone additional cytogenetic changes, or represents a clone that has aberrant light chain
overexpression from the outset, needs further investigation.
The serum FLC assay used in this study is currently used
clinically to monitor response to therapy in patients with myeloma
who present with unmeasurable levels of monoclonal protein in
serum and urine protein electrophoresis studies (oligo-secretory or
nonsecretory disease).12 In these patients, the serum FLC levels are
often elevated, decreasing the need for serial bone marrow
biopsies. It is also used in a similar manner in patients with primary
amyloidosis who often have low or unmeasurable levels of
monoclonal protein by electrophoresis.15 The FLC assay is also
being investigated as a replacement to 24-hour urine electrophoresis studies to monitor light chain excretion in the urine.14,16 Criteria
to assess response using the serum FLC assay have been proposed,25 but need further validation.
The presence of an abnormal FLC ratio is a clinically and
statistically significant predictor of progression in MGUS. We
identify a low-risk subset of patients with MGUS with a remarkably small lifetime risk of progression in whom less frequent
follow-up can be justified. Since this subset accounts for almost
40% of all patients, this is a finding of significant importance for
the management of MGUS.
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PROGNOSIS OF MGUS
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