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ORIGINAL ARTICLE
Extensive bone marrow infiltration and abnormal free
light chain ratio identifies patients with asymptomatic myeloma
at high risk for progression to symptomatic disease
E Kastritis
1
, E Terpos
1
, L Moulopoulos
2
, M Spyropoulou-Vlachou
1
, N Kanellias
1
, E Eleftherakis-Papaiakovou
1
,
M Gkotzamanidou
1
, M Migkou
1
, M Gavriatopoulou
1
, M Roussou
1
, A Tasidou
3
and MA Dimopoulos
1
Asymptomatic multiple myeloma (AMM) is characterized by a constant risk of progression to symptomatic myeloma. To evaluate
previously recognized risk factors and to identify high-risk features we analyzed 96 patients with AMM and at least 18 months of
follow-up. The progression rate at 1,2, and 3 years was 8%, 15% and 26%, respectively, and the projected 5-year progression rate
was 38%. Extensive bone marrow (BM) infiltration, abnormal free light chain (FLC) ratio and serum monoclonal (M)-proteinX3 gr/dl
were the most significant factors for progression, whereas the type of heavy (IgG vs IgA) or light chain or immunoparesis of the
uninvolved immunoglobulins were not. Abnormal marrow signal of magnetic resonance imaging of the spine was associated with a
significant risk of progression (median 15 months, P¼0.001). Extensive BM infiltration X60% (hazard ratio, HR: 13.7, Po0.001) and
FLC ratioX100 (HR: 9, P¼0.003) independently identified a ‘very high-risk’ group, which included 12.5% of patients with AMM and
who progressed p18 months from initial diagnosis. Development of anemia and/or lytic bone lesions were the most common
features of symptomatic progression. In conclusion, there is a subgroup of patients who have a substantial risk of progression to
symptomatic disease that can be detected at diagnosis (either by extensive BM infiltrationX60% or FLC ratioX100) and may be
considered for immediate treatment.
Leukemia (2013) 27, 947–953; doi:10.1038/leu.2012.309
Keywords: free light chains; risk; smoldering myeloma; bone marrow; trephine biopsy; immunoparesis
INTRODUCTION
Asymptomatic multiple myeloma (AMM) is a proliferative but
asymptomatic plasma cell disorder, which is characterized
by a constant risk of progression to symptomatic myeloma.
1,2
According to the definition by the International Myeloma Working
Group (IMWG), AMM is characterized by the presence of either
3 gr/dl or more of M-protein in the serum and/or 10% or more of
clonal plasma cells in the bone marrow (BM), whereas there is no
related organ or tissue impairment (that is no end-organ damage)
or symptoms.
1
According to the current recommendations, which
have been recently updated,
3
patients with AMM should be followed
without treatment until they develop symptomatic disease.
The risk of progression of AMM to symptomatic myeloma varies
between different series, depending also on the criteria for the
characterization of asymptomatic myeloma and the criteria for
progression to symptomatic disease requiring therapy.
3,4
Furthe-
rmore, there are significant differences in the risk of progression
for individual patients: some individuals may not require therapy
for several years, even decades, whereas others may progress to
symptomatic myeloma within months. Several factors which are
associated with an increased risk of progression have been
identified, the most established being BM plasmacytosis X10%
and serum monoclonal (M)-protein levelsX3 gr/dl.
2,5
In the series
by Kyle et al.
2
the overall risk of progression was 10% per year for
the first 5 years, B3% per year for the next 5 years and 1% per
year for the past 10 years; however, the median time to
progression for patients with BM plasma cells X10% and
M-protein level, X3 g/dl was 27 months, for patients with BM
plasma cells X10% but M-protein level o3 g/dl was 93 months
and for those with plasma cells o10% but a M-protein level X3g/
dl exceeded 220 months. The first two groups included 40% and
50%, respectively, of those with AMM in this report. Additional
factors that have been identified include an abnormal free light
chain (FLC) ratio,
5
uninvolved immunoglobulin suppression,
6
the
presence of aberrant plasma cells by multiparametric flow
cytometry,
6
an abnormal magnetic resonance imaging (MRI)
7
or
the ‘evolving’ type characterized by the gradual increase of
M-protein.
8
Both for prognostic reasons and for monitoring planning,
treatment strategy and intervention, it is important to identify
those patients who are at a very high risk for early progression and
which may be considered for immediate treatment. Thus, we
considered that patients who progress to symptomatic multiple
myeloma (MM) early that is within 18 months from the diagnosis
of AMM, as ‘very high-risk’ group. The aim of our analysis was to
identify features that could help in the identification of this group
of individuals with ‘very high-risk’ AMM.
PATIENTS AND METHODS
Our analysis included 96 patients with AMM and a minimum follow-up of
at least 18 months.
1
Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece;
2
Department of Radiology, University of Athens School of Medicine, Athens,
Greece and
3
Department of Hemopathology, Evangelismos Hospital, Athens, Greece. Correspondence: Professor MA Dimopoulos, Department of Clinical Therapeutics, University
of Athens School of Medicine, 80 Vas. Sofias Avenue, Athens 115 28, Greece.
E-mail: mdimop@med.uoa.gr
Received 5 September 2012; revised 11 October 2012; accepted 16 October 2012; accepted article preview online 6 November 2 012; advance online publicatio n, 27 N ovember 2012
Leukemia (2013) 27, 947– 953
&
2013 Macmillan Publishers Limited All rights reserved 0887-6924/13
www.nature.com/leu
AMM was defined as serum M-protein (IgG or IgA) level of X3 g/dl and/
or BM plasma cells X10%, in the absence of end-organ damage, such as
lytic bone lesions, anemia, hypercalcemia or renal failure, that can be
attributed to a plasma cell proliferative disorder.
1
Progression of asymptomatic to symptomatic myeloma was defined
according to the IMWG criteria.
1,3
More specifically the development of any
of the following was considered as progression to symptomatic disease:
serum calcium 41 mg/dl above the upper limit of normal or411 mg/dl,
increased serum creatinine42 mg/dl (when no other obvious cause was
present), development of anemia (hemoglobin p2 g/dl below the
lower limit of normal or o10 g/dl), development of lytic bone lesions or
osteoporosis with compression fractures, development of symptomatic
hyperviscosity, amyloidosis, or of a new soft tissue plasmacytoma.
In all cases the BM biopsies were assessed for clonality of plasma cells to
ensure that the clonal plasma cell population was X10% and were
reviewed by an experienced haemopathologist (AT).
Evaluation of MRI pattern of marrow infiltration
Patients had an MRI of the spine for the evaluation of BM involvement. T1-
weighted (TR/TE: 641/10, turbo factor: 4), Short TI Inversion Recovery (STIR)
(TR/TE/TI:2000/70/150) and contrast-enhanced T1-weighted magnetic
resonance (MR) images (TR/TE were obtained in the sagittal plane for
the thoracic spine and for the lumbar spine and in the axial plane for the
pelvis with a 1.5T unit (Phillips Medical Systems, Eindhoven, The
Netherlands). MR images were analyzed for pattern of myelomatous
involvement. The pattern of marrow involvement on MR images was
characterized as: (1) normal when there was no evidence of abnormal
signal intensity; (2) focal, which consisted of localized areas of abnormal
marrow; the lesions are darker than yellow marrow and slightly darker than
or isointense to red marrow on T1-weighted images, whereas on T2-weighted
images focal lesions are brighter than both red and yellow marrow, and on
enhanced T1-weighted images they enhancetovariousdegrees;(3)diffuse,in
which normal BM signal intensity is completely absent; the intervertebral disks
appear brighter than or isointense to thediseasedmarrow;thereisadiffuse
decrease in the BM signal intensity of the marrow on T1-weighted images, a
variable increase in the signal intensity of abnormal marrow on T2-weighted
images, and after the administration of intravenous contrast, the abnormal
marrow enhances and the intervertebral disks appear darker than the
enhanced spine; and finally(4) variegated that consists of innumerable small
foci of disease on a background of intact marrow, with small dark lesions on
T1-weighted images, which become bright on T2-weighted image and
enhanceaftertheadministration of intravenous contrast.
9–11
Statistical analysis
For comparisons of differences among various groups we used the w
2
-test
for categorical variables (using Fisher’s exact test when appropriate) and
with the Mann–Whitney test or analysis of variance for continuous
variables. Time to progression to symptomatic myeloma was calculated
from the date of initial diagnosis of AMM until the date when criteria for
progression were first met. Death before progression to symptomatic
myeloma was treated as competing risk and the cumulative incidence
estimate is provided.
12
Survival after progression to symptomatic myeloma
was calculated from the date of treatment initiation until the date of death
or last follow-up. Time to event curves were plotted with the Kaplan–Meier
method and comparisons were made with log rank test. Multivariate
analysis was performed with the use of Cox proportional hazards. Receiver-
operating characteristic analysis was used to identify optimal cutoffs for
progression to symptomatic myeloma at 18 months.
RESULTS
The characteristics of the 96 patients who were included in the
analysis are depicted in Table 1. Median age was 63 years (range
33–88 years); 7 (7%) were p40 years of age. Median hemoglobin
was 12.6 gr/dl and 96% had hemoglobin 410 gr/dl. For patients
presenting with anemia (hgbo10 gr/dl), extensive investigation
excluded the myeloma as the cause of their anemia. In all cases the
patients were heterozygotes of beta-thalassemia, a common trait in
the Greek population. Median BM infiltration in patients with a
hemoglobino12 gr/dl was 15% and for patients with X12 gr/dl was
20% and this difference was not significant. Similar results were
obtained when we used as a cutoff value of 14 gr/dl for hemoglobin.
Median serum M-protein was 1.65 gr/dl (range 0.1–5 gr/dl),
whereas 12% of patients had M-protein levels X3 gr/dl. In 15%
urine immunofixation was positive for either kor llight chains,
whereas median levels of Bence Jones proteinuria was 85 mg/day;
monoclonal urine protein X200 mg/day was not detected in any
patient. Median epidermal growth factor receptor at the time of
diagnosis was 81 ml/min/1.73 m
2
(range 15–167 ml/min/1.73 m
2
);
only 17% of the patients had epidermal growth factor receptor
o60 ml/min/1.73 m
2
(chronic kidney disease (CKD) stage 3 or
greater) and only 3 (3%) patients had serum creatinine X2 mg/dl.
In all these patients renal dysfunction was due to a cause other
than myeloma. In 86 (91%) of the patients a BM trephine biopsy
was available. Median BM infiltration was 20% (range 20–90%).
Progression to symptomatic MM and risk factors for progression
After a median follow-up of 45 months (a cumulative of 381
person/years, median 3 person/years), 38 patients have pro-
gressed to symptomatic MM (35 patients) or light chain (AL):
amyloidosis (three patients). Two patients died before the
development of symptomatic myeloma. The respective rates of
progression, accounting for death as a competing risk, at 1, 2 and
3 years was 8%, 15% and 26%, respectively; the projected 5-year
progression rate is 38% and the median time to progression is
estimated at 66 months (Figure 1). Thus, during the first 5 years
after the diagnosis of AMM the rate of progression to symptomatic
MM is about 8% per year. However, after about 8 years the curve
becomes less steep and the rate of progression is slower.
Several factors that have been associated with increased risk of
progression to symptomatic MM were validated in our patients
(Table 2). The extent of BM infiltration was the most significant
factor for progression to symptomatic disease. Median time to
progression for patients with a BM infiltration 10–19% was 90
months (95% confidence interval (CI) 62–117) vs 42 months (95%
CI 20–60) for patients with a BM infiltration 20–49% and 31
months (95% CI 13.5–49) for patients with BM infiltration X50%
(Po0.001) (Figure 2a). An increase of the BM infiltration by 10%
was associated with a 57% increase (95% CI 33–85%, Po0.001) of
the risk for progression to symptomatic disease.
In univariate analysis the type of heavy chain (IgG vs IgA) or
light chain (kvs l) were not associated with increased risk of
progression to symptomatic myeloma. Patients with X3 gr/dl of
M-protein had a significant risk of progression vs those with
p3 gr/dl (hazard ratio (HR): 2.36, 95% CI 1.001–5.4; P¼0.046). In
patients with BM plasma cells X10% and M-protein level X3 g/dl
Table 1. Characteristics of the patients (N¼96)
Median age 63 (33–88)
Male/female 45%/55%
Hemoglobin (gr/dl) 12.6 (9–16.1)
IgG 69%
IgA 26%
Light chain only 3%
Biclonal 2%
Kappa/lambda 61.5%/
37.5%
M-protein (gr/dl) 1.65 (0.1–5)
M-proteinX3 gr/dl 12%
Absolute FLC ratio (k/lor l/k) 2.9 (1–167)
Immunoparesis of X1 uninvolved immunoglobulin 61%
Proteinuria (mg/day) 85 (0–588)
Bone marrow PC 10–19% 59%
Bone marrow PC 20–49% 29%
Bone marrow PC X50% 12%
Bone marrow PC X60% 8%
Abnormal MRI (N¼37) 21%
Abbreviations: FLC, free light chain; MRI, magnetic resonance imaging;
PC, plasma cells.
AMM final
E Kastritis et al
948
Leukemia (2013) 947 – 953 &2013 Macmillan Publishers Limited
median time to progression was 19 months and for patients with
BM plasma cells X10% but M-protein level o3 g/dl was 73
months. All our patients had BM infiltration X10% so we could
not validate the risk of progression for patients with o10%
infiltration and X3 gr/dl of M-protein.
Immunoparesis of at least one of the uninvolved immunoglobu-
lins (defined as IgGo700 mg/dl, IgAo70 mg/dl or IgMo40 mg/dl)
has been recognized as a risk factor for progression;
6
however, in
our patients we did not found any significant impact on the risk of
progression (Table 2). Immunoparesis of both the uninvolved Igs
was present in 37% of our patients and was not associated with
increased risk of progression to symptomatic disease (median TTP
56 months for both Igs suppressed vs 73 months for 1 Ig
suppressed vs not reached if there was no suppressed Ig, P¼0.608).
We then explored the importance of 425% decrease below the
lower limit of normal of the uninvolved Igs: 48% of our patients had
a decrease of at least one uninvolved Ig 425% below the lower
limit of normal. In this case there was a trend for shorter TTP in
patients with severely decreased (o25% below lower normal limit)
at least one of the uninvolved Igs (median TTP 43 months vs 73
months, P¼0.062). Then we analyzed patients that had both
uninvolved immunoglobulins 425% below the lower limit: 16% of
our patients had two uninvolved Igs 425% below lower limit and
the median TTP was 56 months (95% 22–91 months).
A pattern of progressive increase of the levels of the M-protein
8
was also associated with a shorter time to development of
symptomatic myeloma: patients who had an increase X10% in at
least two consecutive visits within the first year from diagnosis
had a shorter time to progression compared with those without
an increase of M-protein (35 vs 66 months, P¼0.1).
Abnormal FLC ratio has been considered as a risk factor
for progression to symptomatic myeloma and a FLC ratio X8
(either k/lor l/k) has been used to identify patients at risk:
5
we
also found that a FLC ratio X8 (orp1/8) was associated with
Months
192168144120967248240
% developing symptomatic disease
1.0
0.8
0.6
0.4
0.2
0.0
Figure 1. Progression to symptomatic myeloma for patients with
AMM and a minimum follow-up of at least 18 months.
Table 2. factors associated with progression to symptomatic
myeloma for patients with AMM
Time to progression to
symptomatic myeloma
(median in months)
P-value
Male 70 0.860
Female 67
HemoglobinX12 gr/dl 70 0.971
Hemoglobinp12 gr/dl 66
IgG 72
IgA 68 0.585
Other (IgD, light chain
only)
NR
Kappa light chain 65 0.772
Lambda light Chain 87
M-peakX3 gr/dl 19 0.033
M-peako3 gr/dl 73
FLC ratioo8 55 0.005
FLC ratioX873
FLC ratioo100 73 0.001
FLC ratioX100 8
Immunoparesis of at least
one uninvoled Ig
56 0.217
No immunoparesis NR
Bone marrow PC 10–19% 90
Bone marrow PC 20–49% 42 o0.001
Bone marrow PC X50% 31
Bone marrow PC X60% 15 o0.001
Bone marrow PC o60% 90
Abnormal MRI of the
spine
15 0.001
Normal MRI of the spine
(N¼37)
Not reached
Abbreviations: FLC, free light chain; MRI, magnetic resonance imaging;
PC, Plasma Cells.
Months
120
10080604020
0
% with progression to symptomatic
myeloma
1.0
0.8
0.6
0.4
0.2
0.0
BM plasma cells 10-19%
BM plasma cells 20-49%
BM plasma cells >=50%
progtime
120100806040200
% with progression to symptomatic
myeloma
1.0
0.8
0.6
0.4
0.2
0.0
BM plasma cells >= 60%
BM plasma cells <60%
Figure 2. (a) Progression to symptomatic myeloma for patients with
BM plasma cell infiltration 10–19%, 20–49% and X50% (b)
progression to symptomatic myeloma for patients with BM plasma
cell infiltration X60% vs o60%.
AMM final
E Kastritis et al
949
&2013 Macmillan Publishers Limited Leukemia (2013) 947 – 953
increased risk for progression to symptomatic MM. Thus, patients
with FLC ratio X8 (orp1/8) had a median time to progression of
55 months vs 73 months for those with FLC ratio o8 (or 41/8)
(P¼0.005) (Figure 3a). In accordance with the risk stratification
model proposed by Dispenzieri et al. those with two of three risk
features (BM plasma cells X10%, FLC ratio X8 and M-protein
X3 gr/dl) had a median time to progression of 55 months vs 73
months for those with one risk factor. The number of patients with
all three risk factors was very small.
Thirty seven patients had available MRI at diagnosis and 8 (22%)
had an abnormal MRI signal (either focal (n¼2) or diffuse pattern
(n¼6)
9
). Abnormal MRI was associated with a significant risk of
progression (median time to progression 15 months, HR: 5.8, 95%
CI 1.84–18.35; P¼0.001) and 5 of 8 patients with abnormal MRI
progressed within 18 months (Figure 4). There was also a
significant correlation of abnormal MRI signal with extensive BM
infiltration X60% (P¼0.001) and abnormal FLC ratio (P¼0.038).
Patterns of disease progression
Among the 35 patients who progressed to symptomatic myeloma,
17 (47%) developed at least one bone lesion, 1 (3%) developed
also hypercalcemia, 20 (55%) developed anemia and 4(11%) had
an increase of their serum creatinine (median serum creatinine at
progression in these patients 3.1 mg/dl, range 2.1–6.2 mg/dl)
(Table 3). Among the four patients who developed renal
dysfunction, all had positive urine immunofixation for clonal light
chains and estimated glomerular filtration rate (eGFR) p60 ml/
min/1.73 m
2
at diagnosis of AMM, due to unrelated conditions;
only one of the patients who developed renal dysfunction
required dialysis, but she had preexisting stage 4 kidney disease
due to diabetes and hypertension.
The median survival after initiation of therapy, for the patients
(n¼35) who progressed to symptomatic myeloma was 85 months.
The median survival of patients with symptomatic myeloma treated in
our center in the same time period was 47 months. However, at
progression to symptomatic MM, 31% of the patients were Inter-
national Staging System (ISS)-1, 56% were ISS-2 and only 12.5% ISS-3.
We then analyzed our data in order to identify whether certain
factors at diagnosis of AMM were predictive of the development
of specific myeloma-defining features. The development of bone
lesions was more common in patients who had abnormal MRI
signal at diagnosis of AMM (71% vs 34%, P¼0.1); the develop-
ment of renal dysfunction was more common in patients with
lambda light chain myeloma (15% vs 0%, P¼0.13), whereas
extensive BM infiltration and M-proteinX3 gr/dl were more
commonly associated with the development of anemia.
Characteristics of patients at ‘very high risk’ and identification of
prognostic features
Owing to the heterogeneity of the natural history of AMM, it is
important to identify those patients who are at high risk for early
progression and for whom immediate treatment may be
appropriate. Thus, we considered patients who progressed within
the first 18 months from the initial diagnosis as a ‘very high-risk’
group and we sought to identify their characteristics and factors
that are associated with this type of rapidly progressing AMM.
We identified 12 (12.5%) patients who progressed within 18
months from initial diagnosis (‘very high-risk’ group); their
characteristics are depicted in Table 4. We also identified 15
(16%) patients with AMM who have not progressed to sympto-
matic disease after at least 5 years of follow-up and their
characteristics are also presented in Table 2. Patients who
remained stable without progression for at least 5 years have
significantly less-extensive BM infiltration, lower levels of M-pro-
tein, usually normal MRI and a normal FLC ratio.
Months
120100806040200
Progression to symptomatic Myeloma
1.0
0.8
0.6
0.4
0.2
0.0
FLC ratio >=8 or =<1/8
FLC ratio <8 and >1/8
Months
120100806040200
Progression to symptomatic Myeloma
1.0
0.8
0.6
0.4
0.2
0.0
FLC ratio >=100 or =<1/100
FLC ratio <100 and >=1/100
Figure 3. (a) Progression to symptomatic myeloma for patients with
a FLC ratio X8 vs those with FLC ratio o8(b) progression to
symptomatic myeloma for patients with a FLC ratio X100 vs those
with FLC ratio o100.
Months
120
100806040200
Progression to symptomatic myeloma
1.0
0.8
0.6
0.4
0.2
0.0
Abnormal MRI (focal or diffuse)
Normal MRI
Figure 4. Progression to symptomatic myeloma for patients with
abnormal MRI vs patients with normal MRI.
AMM final
E Kastritis et al
950
Leukemia (2013) 947 – 953 &2013 Macmillan Publishers Limited
To identify the best cutoff for the recognition of patients at high
risk we used receiver-operating characteristic analysis for progres-
sion at 18 months. A BM infiltration 60% or higher had a specificity
of 95.5% to identify patients who progressed at 18 months.
Among eight patients with a BM infiltration X60% all have
progressed to symptomatic myeloma and median time to
progression to symptomatic disease was 15 months (range from
3 to 56 months); however, three patients with BM infiltration
X60% progressed 430 months after initial diagnosis (Figure 2b).
A BM infiltration 70% or higher had a specificity of 99% to identify
patients who progressed at 18 months (median time to
progression to symptomatic myeloma was 10 months, range
3–30 months), however, only 4% of our patients with AMM had
BM infiltration X70%. We performed similar analysis to identify
cutoffs for FLC ratio for progression to symptomatic disease within
18 months. A FLC ratio X50 had 88% specificity and a FLC ratio
X100 had 98% specificity for progression at 18 months: 20% of
patients had FLC ratio X50 and only 7% FLC ratio X100
(Figure 3B). Median time to disease progression for patients with
FLC ratio X100 was 13 months (95% CI 3–23 months). An analysis
to identify optimal cutoffs for progression within 24 months
resulted in similar cutoff values.
We then performed a multivariate analysis, in which a highly
abnormal FLC ratio (X100 or p1/100) (P¼0.003, HR: 9, 95% CI
2.15–39) and BM infiltration X60% (Po0.001, HR: 13.7, 95% CI
4.44–42.2) were the only independent risk factors for progression.
In multivariate analysis for progression at 18 months (very high-
risk AMM), the only independent factors that identified these
patients were again FLC ratio X100 (OR: 17, 95% CI 1.4–212;
P¼0.028) and BM infiltration X60% (OR: 12.5, 95% CI 1.7–91;
P¼0.013). Thus, median time to progression for patients without
any of the above risk factors was 73 vs 18 months for patients with
any one of the above risk factors vs 8 months for patients with
both risk factors present (Po0.001). Among patients with none of
the above risk factors, 10% progressed within 18 months, among
those with any one of the above factors 66% progressed at
18 months and of those with both these risk factors present, all
progressed within 18 months.
DISCUSSION
In recent years an increasing number of patients are diagnosed by
chance with AMM. The risk of progression to symptomatic
myeloma for patients with AMM is substantial compared with
the general population, about 180–1000-fold higher.
2
We found
that the risk of progression is about 8% per year after the
diagnosis of AMM, at least during the first 5 years, a rate which is
not different than the one reported by Kyle et al. (about 10% per
year in the first 5 years)
2
or Musto et al. (about 8% per year).
13
However, the natural history of asymptomatic MM is
heterogeneous. Thus, a major task is the identification of those
individuals with the highest risk of progression to the
symptomatic state in which case very close monitoring and/or
therapeutic intervention is required; on the other hand, in patients
at low risk for progression it is important to avoid unnecessary
treatments and interventions and to reduce the frequency of
monitoring. The aim of our analysis was to identify factors that
could improve the detection of patients which are at highest risk
of progression.
Several earlier studies have identified several factors that are
associated with increased risk of progression to symptomatic
myeloma. In their seminal work, Kyle et al.
2
from Mayo Clinic
found that patients with both plasmacytosisX10% and an
M-peakX3 gr/dl have significantly higher risk for progression to
symptomatic disease compared with patients with either of the
above. In our cohort, 12% of patients could be considered as high
risk based on the above criteria with a median time to progression
of 19 months (vs 27 months in the series of Kyle et al. and
25 months in the control arm of the randomized study by Mateos
et al.
14
). In our cohort no patients had X3 gr/dl of M-protein with
o10% of plasma cells. In the study by Kyle et al.
2
o10% of the
patients had plasma cells o10% and M-protein 43 gr/dl.
However, in our study, 91% of patients had available BM
trephine biopsy, which is more sensitive to identify patients with
410% plasma cells and it also assesses clonality, in contrast to
morphology only by optical microscopy of the BM aspirate. Thus,
our study had perhaps higher sensitivity in detecting patients with
X10% of plasma cells, which is consistent with published data,
which indicate that BM biopsy is more sensitive for direct
Table 4. Characteristics of patients with ‘very high-risk’ AMM, who
progressed within 18 months from diagnosis and comparison with
patients who have not progressed after at least 5 years of follow-up
Progressed
p18 months
(N¼12)
No progression
after X5 years
(N¼15)
P-value
Age 60 (33–77) 0.516
Male/female 50%/50% 20%/80% 0.1
IgG 75% 60% 0.554
IgA 25% 33%
Other (IgD, light
chain only)
–7%
Kappa light
chain
67% 47% 0.299
Lambda light
chain
33% 53%
Bone marrow PC
10–19%
25% 80%
Bone marrow PC
20–49%
42% 20% 0.008
Bone marrow PC
X50%
33% 0
Bone marrow PC
X60%
33% 0 0.015
FLC ratioX8 75% 0 0.004
FLC ratioX100 25% 0 0.022
M-proteinX3 gr/
dl
33% 7% 0.07
Immunoparesis 42% 60% 0.292
Abnormal MRI 5 (83%) (N¼6) 1 (17%) (N¼6) 0.021
Clinical presentation at progression
Lytic bone
disease
33% NA NA
Hypercalcemia 8%
Anemia 50%
Increased
serum
creatinine
8%
Abbreviations: FLC, free light chain; MRI, magnetic resonance imaging;
PC, Plasma Cells.
Table 3. Patterns of disease progression in 38 patients who
developed symptomatic myeloma (35 patients) or systemic light chain
amyloidosis (3 patients)
Clinical presentation at
progression
N (%)
Lytic bone disease 17 (49)
Hypercalcemia 1 (3)
Anemia 20 (57)
Increased serum
creatinine
4 (11)
Amyloidosis 3 (8)
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estimation of the tumor load in MM compared with BM aspirates,
especially in patients with a focal growth pattern.
15–17
The median
time to progression for the other patients (that is those with
M-peako3 gr/dl but BM plasmacytosis X10%), which are rated as
‘intermediate risk’ had a median time to progression of 73 months
(95% CI 61–85 months) compared with 93 months in the series of
Kyle et al.
2
Dispenzieri et al.
5
from the same group added the
immunoglobulin FLC ratio X8 (or p1/8) in the previous criteria
and stratified patients into three groups.
Perez-Persona et al.
6
have used multiparametric flow cytometry
to identify patients with AMM at high risk for progression. The
authors reported also that immunoparesis was associated with
increased risk of progression. However, multiparametric flow
cytometry is not widely available and a certain degree of expertise
and standardization is required. In our series we did not find that
immunoparesis was a significant risk factor for progression to
symptomatic MM. An evolving pattern of AMM has also been
recognized by Rosinol et al.,
8
in which patients with gradual
increase of M-protein levels progress to symptomatic myeloma
sooner and at higher rates that those with non-increasing
M-protein. We also found that patients who had an increase
X10% of their M-protein in at least two consecutive visits within
the first year from diagnosis had a shorter time to progression
compared with those without an increase of M-protein (35 vs 66
months, P¼0.1), but this variable cannot be used at diagnosis to
discriminate high-risk patients.
Recently, the Mayo Clinic group recognized that 3.2% of patients
with a diagnosis of AMM had extensive plasmacytosis X60% and
were at very high risk for early progression (median 7 months) and
they proposed that these patients should be considered for
immediate therapy at the time of diagnosis.
18
In our series, we
identified that 8% of patients had X60% of plasma cells at
diagnosis of AMM and that these patients had a median time to
disease progression of 15 months. On the basis of our data and the
Mayo group data
18
we believe that such patients with extensive
plasmacytosis, which have a short time to disease progression,
should not be considered ‘asymptomatic’ but rather ‘pro-
symptomatic’ and may be candidates for immediate treatment. If
such a patient is not treated promptly, more extensive workup,
probably including MRI of the spine, whole-body MRI or positron
emission tomography–computed tomography should be consid-
ered. Frequent hematologic assessment should also be considered
because anemia develops commonly in patients with extensive BM
infiltration and descending levels of hemoglobin should alert the
physician to initiate treatment even before clinically significant
anemia or other complications develop.
We also found that aberrant FLC ratio was associated with a
higher risk of progression, but we further identified that a FLC
ratio X100 (or p1/100) is also associated with a substantial risk of
progression within 18 months from the initial diagnosis of AMM.
The highly abnormal FLC ratio with a similar cutoff has also been
identified as a predictor of imminent progression in patients with
AMM.
19
An extensive BM infiltration, especially by X60% clonal
plasma cells and a highly abnormal FLC ratio (X100 or p1/100)
may identify a subgroup of patients with a substantial risk of
progression within 18 months from diagnosis; actually all patients
with both risk features present at the time of diagnosis progressed
within 18 months. These two variables are readily and widely
available. Furthermore, we found that abnormal signal of MRI of
the spine may help identify patients at imminent risk for
progression, but further validation in a larger number of
patients is needed. Notably, abnormal MRI was also associated
with the development of lytic bone lesions at the time of
progression to symptomatic MM.
The development of symptomatic bone lesions such as
compression fractures of the spine or fractures of long bones is
associated with significant morbidity and compromises the
patients’ quality of life. The use of bisphosphonates may reduce
the risk of a skeletal complication in patients with AMM but do not
alter the natural history of the disease.
13,20
Currently, the use of
bisphosphonates is not recommended in all patients with
asymptomatic myeloma but only in those with osteoporosis.
3,4
However, significant additional prognostic information can be
obtained by MRI of the spine.
9
In our patients with available MRI of
the spine an abnormal signal was associated with a very high risk
of progression and also with the development of lytic bone
lesions. The importance of the presence of focal MRI lesions as a
major adverse prognostic factor for the progression of AMM to
symptomatic myeloma has also been published by Hillengass
et al.,
7
which reported that patients with more than one focal
lesion in whole-body MRI had a median time to progression of 13
months, whereas a diffuse infiltration pattern of the BM was an
additional independent risk factor. Recently, data from the SWOG
S0120 Observational Trial were presented which showed that focal
lesions in MRI of the spine were associated with 425-fold increase
in the risk of progression to symptomatic myeloma.
21
Thus, in
patients with AMM MRI of the spine can guide the physicians to
institute bisphosphonates therapy, monitor the patient closely for
the development of bone disease and start therapy before a
devastating skeletal complication occurs.
It is also important to note that only 4 (11%) of our patients
developed renal dysfunction and all were patients who had
preexisting renal dysfunction for reasons other than myeloma. This
indicates that with standard follow-up of patients with AMM,
significant renal dysfunction should not be a common complication.
The IMWG has recently published recommendations on the
monitoring and management of patients with AMM.
3
According to
these recommendations, patients with AMM should have a blood
tests (including protein serum protein electrophoresis) every 2–3
months for the first year, followed by every 4–6 months for 1 year,
with eventual 6- to 12-month evaluations if clinically stable thereafter;
an MRI of the spine and pelvis is advised because it can detect occult
lesions and, if present, predict for a more rapid progression to MM.
We believe that for patients at high risk for progression close
monitoring, every 1–2 months for 1–2 years and MRI of the spine at
diagnosis should be considered. Also, we believe that a FLC
measurement should be performed at least at initial evaluation,
and that at initial assessment and at 3–6 month intervals all patients
should have a 24 h urine collection for protein electrophoresis. The
development of amyloidosis should also be considered as a
complication of a long-standing plasma cell dyscrasia. The role of
positron emission tomography–computed tomography needs to be
further evaluated, but data indicate that may increase significantly
the sensitivity of detection of extramedullary disease,
22
although may
be less sensitive for spine involvement.
23
In conclusion, in our series of patients the 3-year probability of
progression to symptomatic myeloma is 26% and 5-year about
40%, corresponding on a risk of progression of about 8% per year.
There is a subgroup of patients with extensive BM infiltration
(X60%) and/ or highly abnormal FLC ratio (X100), who have a
substantial risk of progression to symptomatic disease within the
first two years from the diagnosis of AMM. These high-risk patients
may also have other features such as abnormal MRI of the spine.
Patients at very high risk for progression should be considered for
immediate treatment.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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