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The Role of Serum Immunoglobulin Free Light Chain (sFLC) in response and
progression in Waldenstrom Macroglobulinemia (WM)
Xavier Leleu1,3*, Wanling Xie
2*
, Meghan Bagshaw1, Ranjit Banwait1, Renee Leduc1,
Nitin Roper1, Edie Weller2, and Irene M. Ghobrial1
* XL and WX contributed equally to this work.
1 Department of Medical oncology, Dana-Farber Cancer Institute and Harvard Medical
School Boston, MA, USA.
2 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute
and Harvard School of Public Health Boston, MA, USA.
3 Service des Maladies du Sang, Hôpital Huriez, CHRU, Lille, France
Corresponding author:
Irene M. Ghobrial, MD
Department of Medical oncology, Dana-Farber Cancer Institute, 44 Binney Street, Mayer
1B127,
Boston, MA, 02115. Phone: (617)-632-4198. Fax: (617)-632-4862.
Email: [email protected]
Running title: sFLC in Waldenstrom Macroglobulinemia
Scientific heading: Neoplasia
Key words: Waldenstrom Macroglobulinemia, Involved Serum Free Light Chain,
response, progression.
Abstract: 150; Tables: 2; Figures: 1; Word count: 2659; References: 12
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Abstract
Introduction: The serum free light chain (sFLC) has been widely used in the assessment
of response in patients with multiple myeloma and other plasma cell dyscrasias.
However, its use in Waldenstrom Macroglobulinemia (WM) has not been previously
assessed. We sought to examine the role of sFLC in response and progression of patients
with WM.
Methods: This study was performed in a cohort of 48 patients diagnosed with WM,
untreated (N=26) or relapsed/refractory (N=37), prospectively treated on a bortezomib
and rituximab trial.
Results: Involved (i)FLC response occurred in 79% patients versus 60% by M-spike
protocol criteria. The median time to response was shorter with iFLC than per protocol,
2.1 and 3.7 months (p=0.05). Progression using iFLC also correlated well to progression
in the protocol (kappa=0.63). However, the median time to progression (TTP) was more
rapid by iFLC than per protocol, 13.7 and 18.9 month. We also confirmed a flare by iFLC
in post-rituximab therapy did not correlate with lack of response or shorter time to
progression.
Conclusion: Involved sFLC may be a useful marker of tumour measurement
demonstrating earlier response and progression compared to IgM or M-spike
measurements.
STATEMENT OF TRANSLATIONAL RELEVANCE
The serum free light chain (sFLC) has been widely used in the assessment of response in
patients with multiple myeloma and other plasma cell dyscrasias. However, its use in
Waldenstrom Macroglobulinemia (WM) has not been previously assessed. In this study,
we show that sFLC can be a useful marker of tumor measurement demonstrating early
assessment of tumor response and early progression compared to IgM or M spike
measurements. The use of sFLC in the measurement of tumor response in WM is
warranted.
2
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Introduction
Waldenstrom macroglobulinemia (WM) is a low grade B cell lymphoma characterized by
bone marrow infiltration of lymphoplasmacytic cells that secrete IgM in the serum(1-3).
The current consensus recommendations use the serum monoclonal protein to determine
response and progression(4, 5). However, the IgM level lacks sensitivity due to its
prolonged half-life(3). In addition, in about 50% of patients receiving rituximab therapy,
the IgM increases temporarily, a term called IgM flare. This leads to discontinuation of
therapy in some patients. Therefore, there is a need to identify new markers reflective of
tumor burden in WM. The serum free light chain (sFLC) assay is a nephelometric
measurement of kappa and lambda light chains. 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(6-9). The assay is performed
on automated chemistry analyzers, is widely available, and is commonly used to monitor
patients with multiple myeloma, oligosecretory myeloma, and primary amyloidosis, as
well as patients with the light-chain only form of myeloma. The sFLC assay has shown
significant application in response, progression and prognosis of plasma cell dyscrasias,
specifically in MM(6-12). However, the role of sFLC in the measurement of tumor
response in WM has not been previously examined. We previously showed that using
involved sFLC values accurately diagnosed patients with WM and differentiated them
from patients with IgM-MGUS5-6.
In this study, we hypothesized that sFLC can be used in the assessment of response and
progression of patients with WM. This study represents the first prospective assessment
of the role of sFLC in patients with WM.
Patients and methods
Patients. This study was performed using serum prospectively collected and analyzed
from a cohort of WM patients, uniformly treated in the protocol NCT00422799, phase 2
trial of bortezomib with rituximab (bortezomib 1.6mg/m2 at days 1, 8, 15 q28 days x6
cycles and rituximab 375 mg/m2 at days 1, 8, 15, 22 on cycles 1 and 4). 63 patients were
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enrolled from August 2006 to April 2009: previously untreated (N=26) or relapsed and/or
refractory (N=37). The inclusion criteria included a measured creatinine <2.5 times the
upper limit of the normal range. Approval of this protocol was obtained from DanaFarber Cancer Institute and was in accordance with the Declaration of Helsinki.
Eligible patients must have had measurable sFLC levels at baseline. Patients were
excluded for normal iFLC at baseline (N=12), no baseline or cycle 1 sFLC data (N=1), or
no follow up data available after therapy initiation (N=2). A total of 48 patients were
included in this study.
Serum FLC assay. The serum free kappa and lambda light chain levels were measured
using the serum free light chains assay (Freelite®, The Binding Site Ltd, UK) (13). The
clonal FLC (either kappa or lambda depending on the type of light chain involvement)
was considered the involved immunoglobulin FLC (iFLC) 9. The DFCI laboratory normal
ranges are as follow: Kappa: 3.3 - 19.4 mg/L; Lambda: 5.7 - 26.3 mg/L; Ratio, K/L: 0.26
- 1.65. IgM normal range (nephelometry): 40-230mg/dL. Abnormal serum iFLC value is
defined as greater than the ULN of Kappa or Lambda value depending on the type of
clonal serum light chain. Abnormal FLC ratio is defined as off the normal range of ratio
(<0.26 or >1.65).
Response. The serum iFLC test was used for response and progression evaluation.
Response per protocol was defined according to consensus recommendations
10
. Serum
iFLC and IgM response (nephelometry) was defined as achievement of PR and better (at
least 50% decreases from baseline in the iFLC level and in the IgM value or
normalization of the level).
Progression. Progressive disease (PD) was defined according to consensus
recommendations
10
, e.g. at least 25% increase in serum monoclonal M-spike using
SPEP, or progression of symptoms attributable to WM, and confirmed by a second
measurement at least 2 weeks apart. Various definitions of progression have been
described by use of serum iFLC. Therefore, we have examined two iFLC definitions, a
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25% or a 50% increase in the level of serum iFLC from nadir with an increase to a value
greater than the ULN. IgM progression was defined using similar terms.
Statistical analysis. Response rate was summarized as percent of patients with the 90
percent confidence intervals. Concordance between serum iFLC, IgM and protocol (Mspike) response rate was evaluated using Kappa statistics. The level of agreement for the
kappa statistic was: <=0 poor, 0.0-0.2 slight, 0.2-0.4 fair, 0.4-0.6 moderate, 0.6-0.8
substantial and 0.8-1.0 almost perfect. We also calculated the maximum percent decrease
in the iFLC and IgM levels; their correlation was evaluated using Spearman correlation
coefficient. For responders by both iFLC and IgM criteria or responders by both iFLC
and M-spike criteria, we calculated time to response (defined as months from therapy
initiation to the date of response); comparisons were conducted using Wilcoxon signedrank test. Time to progression (defined as months from therapy initiation to the date of
progression, censored at last known to be in remission or date of initiation of new
therapy) were estimated using Kaplan-Meier methodology. We also did landmark
analysis to compare overall response rate and time to progression by FLC or IgM
response status at 2 months after therapy initiation; Fisher Exact test or Log-rank test
were used. The statistical analysis was performed using SAS version 9.2 (SAS Institute
Inc., Cary, NC). All p-values are two-sided.
Results
Patient characteristics. Baseline characteristics of these patients (N=48) are described in
Table 1A. There was no difference in the baseline serum FLC levels between patients on
the upfront arm of the study or those with relapsed/refractory disease (data not shown).
Serum iFLC response. 29 (60%, 90% CI: 48%, 72%) patients responded as per protocol
response criteria using the SPEP. The iFLC response occurred in 38 (79%, 90% CI: 67%,
88%) patients with 21 (44%) having 50% reduction and 2 (4%) having normalization of
iFLC values, and 15 (31%) meeting both criteria. Using serum IgM protein measurement
by nephelometry, 35 (73%, 90% CI: 60%, 83%) patients responded with a PR or better.
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Previous studies examined other FLC response definitions using FLC kappa/Lambda
ratio or the difference between involved FLC and uninvolved FLC (dFLC) 1. Here, 12/47
(26%, 90% CI: 15%, 38%) patients achieved normal FLC ratio. Of these, 11 (92%)
achieved response by iFLC response criteria. Using dFLC criteria, 36 (75%) patients
showed a 50% decrease in dFLC, of which 35 (97%) also had iFLC response
(kappa=0.89, 95% CI: 0.74, 0.99). We therefore considered serum iFLC measurement not
inferior to the FLC kappa/Lambda ratio, and to the dFLC value for this study.
Correlation of iFLC with IgM and M-spike response. Table 1B compared iFLC
response with IgM and protocol response criteria (M-spike by SPEP). Concordance of
iFLC response and protocol response was fair (kappa=0.38, 95% CI 0.13-0.64). Of note,
iFLC response rate was 3/3 (100%) in CR, 24/26 (92%) in PR, 9/13 (69%) in MR and 2/5
(40%) in SD per protocol. Lack of concordance occurred as 11 patients had iFLC
response but did not reach response as per SPEP in the protocol. We believe this relates
to the high sensitivity of serum iFLC test, and might accentuate lack of sensitivity of the
SPEP technique. Interestingly, an agreement between serum iFLC and IgM response
occurred in 41 (85%) patients, 33 responders and 8 non-responders (kappa=0.60, 95%CI
0.34-0.86). Of the 5 patients that achieved iFLC response but not IgM response, 3 had
IgM reduction of greater than 45% but less than 50% compared to baseline. There was
high concordance between IgM response and protocol M-spike response (kappa=0.63,
95%CI 0.41-0.85, data not shown). There was significant correlation between maximum
percentage reduction in iFLC and IgM (Spearman correlation coefficient=0.64,
p<0.0001). Maximum reduction using iFLC and IgM by protocol response using SPEP
M-spike is shown in Figures 1A and 1B, respectively.
Time to iFLC response. Time to iFLC response was compared to IgM (N=33, Figure
1C) and SPEP response (N=27, Figure 1D) among patients who achieved response by
both criteria. Median time to iFLC response was 1 month earlier than either IgM
(nephelometry) or SPEP, 2.1 months (range 0.9-28.7) versus 3.0 months (0.9-14.7)
(p=0.07) and 3.7 months (p=0.05), respectively. Sixteen (48%) patients achieved iFLC
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response earlier in comparison to IgM. Only 5 (21%) patients achieved earlier IgM
response, and 10 (30%) patients achieved IgM and iFLC response at the same time.
Serum iFLC progression. Based on protocol criteria of progression, 23 (48%) patients
showed progression. We examined two iFLC definitions that were previously described,
50% and 25% increase in the level of iFLC from nadir with increase to a value greater
than the ULN. Twenty eight (58%) patients and 23 (48%) showed progression using
iFLC 25% and 50% increase criteria, Table 2B. There was significant correlation
between progression by iFLC >25% increase and M-spike, having concordance with both
markers in 39 (81%) patients, (Kappa=0.63, 95% CI: 0.41-0.84). The 25% iFLC increase
criteria showed better concordance compared to 50% definition (kappa=0.58, 95% CI:
0.35, 0.81). Similar trends were observed using IgM progression criteria. We therefore
propose the use of 25% increase in iFLC from nadir as the progression definition in WM.
Median follow up was 19.1 months (range: 5.2-43.5 months). Median time to progression
per the protocol was 18.9 months (95% CI: 10.5-NR), and was 13.7 months (95% CI:
10.9-19.4) and 14.6 months (95% CI: 9.5-19.1) using iFLC >25% and IgM >25% criteria,
respectively. These results demonstrate more rapid detection of progression by iFLC
compared to M-spike and IgM measurements. Therefore, iFLC appears a sensitive
marker to determine progression earlier in WM.
Early response by iFLC. We examined whether response 2 months after therapy
initiation (early response) using iFLC can predict overall response to therapy by
landmark analysis. Seventeen patients (35%) achieved early iFLC response. Early iFLC
response was not associated with baseline iFLC levels. Interestingly, patients with early
iFLC response had intermediate/high ISS-WM stage, elevated β-2 microglobulin or low
hemoglobin <11.5 g/dL (p<0.05). Early iFLC response was related to overall IgM
response (p=0.02). We could not detect significant association between early iFLC
response and overall response by M-spike. Early iFLC response did not predict time to
progression by either M-spike or iFLC and IgM criteria (Log rank p>0.75).
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Multivariable analysis was conducted since we observed patients with early iFLC
response had worse prognostic factors compared to those who did not achieve early
response. In multivariable models when adjusting for ISS stage, B2M, or hemoglobin,
there was no significant association between early iFLC response and time to progression
either by M-spike, iFLC or IgM criteria.
Serum iFLC flare. We examined correlation between IgM flare and iFLC flare. We
defined flare as 15% increase from the prior value. Flare occurred during cycles 2 and 3
and during cycles 5 and 6 since rituximab was given in cycles 1 and 4. Based on this, 11
(23%) patients had iFLC flare only, 8 (17%) had IgM flare only, and 6 (13%) had both
iFLC and IgM flare. There were 23 (48%) patients who did not flare by either iFLC or
IgM. An early flare occurred in only 35% of patients following the first cycle of
rituximab. These results confirm that iFLC can show flare in post-rituximab therapy, with
a lack of correlation between IgM and iFLC in the post-rituximab flare. Therefore, serum
iFLC cannot replace IgM to differentiate progression from flare when patients are treated
with rituximab therapy.
Furthermore, the iFLC flare status prior to cycle 3 did not relate with overall iFLC
response (response rate: 86% in non-flare and 62% in flare, p=0.11), overall M-spike
response (response rate: 69% in non-flare and 38% in flare, p=0.10) or overall IgM
response (p=0.73). Additionally, early iFLC flare status did not predict for time to
progression defined by either M-spike, or iFLC and IgM criteria (p>0.15). These results
demonstrate occurrence of flare post-rituximab therapy does not correlate with lack of
response or shorter time to progression and increased occurrence of relapse.
Correlation with progression free survival and time to progression.
At the time of analysis, there were only 2 deaths out of 48 patients in this analysis
population. Therefore, there is limited power to evaluate correlations of variables,
including response, with overall survival or progression free survival (PFS). In the
context of this limited power, we evaluated whether there is correlation of FLC/IgM/Mspike response with time to progression (TTP) using the landmark analysis methodology.
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Overall, we did not detect any significant association between FLC/IgM/M-spike
response and TTP defined by protocol (supplement table I), no matter which landmark
time-point was chosen. Results were similar if TTP was defined by FLC or IgM criteria
(25% or 50% increase, data not shown).
Given the good concordance between the FLC response and the IgM or M-spike
response, there are a very few patients who had response by just one criteria (table 2).
Therefore, we compared time to progression between patients who had both FLC and
IgM response versus all others (FLC response only, IgM response only, non-response by
both criteria), and no significant association was detected (supplemental table I). Results
were similar if we compared TTP between patients who had both FLC and protocol (Mspike) response versus all others. However, we acknowledge the sample size is limited to
draw definite conclusions in this study.
In this study, 12 patients with normal iFLC level were excluded from analysis. When
comparing response and TTP (by protocol criteria), we did not find any difference
between patients with normal or abnormal iFLC level at baseline, data not shown.
Discussion
The serum free light chain (sFLC) assay is a nephelometric measurement of kappa and
lambda light chains that circulate as light chain monomers or dimmers and that are not
bound to immunoglobulin heavy chain. The sFLC assay has shown significant clinical
application in plasma cell dyscrasias, specifically in MM, primary systemic amyloidosis
and MGUS. In MM, sFLC is used to monitor response to therapy and is included in the
response criteria (14) based on its sensitivity to assess lower tumor burden compared to
serum protein electrophoresis. However, empiric definition of sFLC response was
proposed for patients with MM in the international uniform response criteria, but was not
validated. Another possible advantage of the measurement of clonal light chain over IgM
M-spike is that light chain has a significantly shorter half-life (10).
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This study described the role of sFLC in WM. Here, we analyzed the sFLC in a
prospective study of patients treated uniformly in a clinical trial of bortezomib and
rituximab. The median iFLC values were higher in our study compared to previously
published studies in MM
5-6
. This may be because we have only included patients with
abnormal sFLC values at baseline in our study. Interestingly, involved sFLC values range
were not as wide in WM as in myeloma 1, although the overall number of patients studied
is too small to draw definite conclusions. iFLC response was comparable to the response
obtained using SPEP or IgM measurement by nephlometry, indicating that it can be used
in the future as a reliable measurement of disease response. Seventy nine % of patients
achieved an iFLC response compared to 60% of patients achieving response, using SPEP.
Previous studies have examined other FLC response definitions using the FLC
kappa/Lambda ratio or the difference between involved FLC and uninvolved FLC
(dFLC). In this study, we found that serum iFLC measurement is not inferior to the FLC
kappa/Lambda ratio and to the dFLC value for this study.
The median time to iFLC response was one month earlier than either IgM (nephelometry)
or SPEP, indicating that this test can be used to assess response earlier than current
measurements of disease. Similarly, iFLC >25% showed a more rapid detection of
progression compared to M-spike and IgM measurements. Therefore, iFLC appears a
sensitive marker to determine response and progression earlier in WM. These results are
comparable to studies performed in MM.
Interestingly, patients with early iFLC response were more likely to have
intermediate/high ISS-WM stage, elevated beta 2 microglobulin or low hemoglobin
<11.5 g/dL. These results may be similar to those observed by Van Rhee et al(15),
indicating that high sFLC and rapid reductions after therapy could reflect a more
aggressive disease. Further studies are warranted to examine the role of sFLC and early
sFLC response and its correlation with time to progression and progression-free survival.
Finally, we examined whether sFLC measurement can be used in patients with an IgM
flare post-rituximab to predict whether those patients will respond post the flare. In this
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study, we observed that iFLC can show a flare in post-rituximab therapy, with a lack of
correlation between IgM and iFLC in the post-rituximab flare. Therefore, serum iFLC
cannot replace IgM to differentiate progression from flare when patients are treated with
rituximab therapy. In addition, the iFLC flare status prior to cycle 3 did not correlate with
a lack of response or a shorter time to progression or an increased occurrence of relapse.
In summary, iFLC may be a useful and sensitive marker of tumor measurement in WM
that correlates well with IgM and M-spike measurements. The serum iFLC marker
showed a more rapid time to response and and time progression compared to IgM or Mspike measurements. We propose to study sFLC measurement in future large prospective
trials to further confirm whether early determination of sFLC will help in making
decision of treatment modification during the course of therapy.
Author contribution:
XL, WX, IMG wrote the manuscript
WX, EW performed statistics
MR, RL, RB, NR, collected data
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Table 1A. Patient Characteristics at baseline (N=48)
N
%
31
65
0
20
42
1 and 2
15
31
≥3
13
27
11
23
7
15
19
40
2
4
30
63
29
60
unknown
3
6
> 3 mg/L
26
54
Median
range
2.6
0.5-5.3
103.5
22.5-3540
mg/L
91.8
12.4-3535
Kappa/Lambda ratio
13.5
0.01-665
IgM, mg/dL
3995
537-10800
Gender: male
No. of prior treatment
ECOG PS
≥1
IPSS
High Risk
Intermediate Risk
Soft Tissue Assessed by CT
Not Done
Evidence of Disease
Hemoglobin
≤11.5 g/dL
beta 2 microglobulin
M-spike, gm/dL
Involved FLC. mg/L
Difference of involved-uninvolved,
*Normal range at DFCI: Kappa: <19.4 mg/L; Lambda<26.3 mg/L; Kappa/Lambda ratio:
0.26-1.65.
14
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Table 1B Comparing iFLC response (A) and progression (B) with IgM and protocol
criteria
N
%
N (%) of
Kappa
agreement
(95% CI)
41 (85)
0.60 (0.34,
A. Response
Comparing iFLC and IgM response
iFLC and IgM response
33
69
iFLC and IgM non-response
8
17
iFLC response only
5
10
IgM response only
2
4
0.86)
Comparing iFLC and protocol
response (PR or better)
iFLC and protocol response
27
35 (73)
56
iFLC and protocol non-response
8
17
iFLC response only
11
23
protocol response only
2
4
iFLC and IgM PD
21
44
iFLC and IgM non-PD
14
29
iFLC PD only
7
15
IgM PD only
6
13
iFLC and protocol PD
21
44
iFLC and protocol non-PD
18
38
iFLC PD only
7
15
protocol PD only
2
4
0.38 (0.13,
0.64)
B. Progression disease (PD)
Comparing iFLC and IgM PD*
35(73)
0.45(0.19,0.70)
39(81)
0.63(0.41,0.84)
Comparing iFLC and protocol PD
* iFLC and IgM progression was defined as 25% increase from nadir with value greater
than ULN.
15
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Figure legend.
Figure 1.
Boxplot: iFLC (A) and IgM (B) maximum reduction (%) by protocol response per Mspike criteria.
Cumulative response rates after therapy initiation: (C) per iFLC and IgM criteria (n=33)
and (D) per iFLC and M-spike (protocol) criteria (N=27).
16
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The Role of Serum Immunoglobulin Free Light Chain (sFLC) in
response and progression in Waldenstrom Macroglobulinemia
(WM)
Xavier P Leleu, Wanling Xie, Meghan Bagshaw, et al.
Clin Cancer Res Published OnlineFirst March 17, 2011.
Updated version
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