International Journal of Myeloma 8(3): 5–10, 2018
©Japanese Society of Myeloma

ORIGINAL

Early normalization of the serum free light chain ratio
predicts ­prolonged progression-free survival among patientswith multiple myeloma
Toshihiro MATSUKAWA, Keito SUTO, Kazuo OSHIMI and Takuto MIYAGISHIMA
Background: Serum free light chain (sFLC) is a widely used marker for assessing treatment response among patientswith multiple myeloma (MM). The International Myeloma Working Group has defined normalization of the sFLC
ratio (rFLC) as a criterion for stringent complete response (sCR), which is associated with good survival outcomes.
This study aimed to identify whether sFLC measurements could predict prognosis after patients achieved partial
response (PR) and very good PR (VGPR).
Methods: We retrospectively analyzed data from 51 patients with MM who received first-line bortezomib- or­lenalidomide-based chemotherapy between January 2012 and September 2016 at Kushiro Rosai Hospital.
Patients were excluded if they had only light chain MM.Results: The patients’ median age was 73 years (range: 39–87 years), and the median follow-up duration was 19.8
months (range: 1.6–61.3 months). The patients’ baseline characteristics did not significantly predict the achievementof PR. However, after achieving PR, progression-free survival (PFS) was significantly longer among patients withnormalized rFLC than with abnormal rFLC (P = 0.0017), although this difference was marginal for overall survival (OS)(P = 0.064). Among patients who achieved VGPR, no significant rFLC-related differences were observed in PFS or OS.
In the univariate analysis, rFLC and β2-microglobulin (>3.5 mg/L) were risk factors for PFS of <1 year after achieving
PR, with the multivariate analysis revealing that rFLC was an independent risk factor.
Conclusion: These results suggest that rFLC measurement can help predict prognosis among patients with MM whoachieve PR.
Key words:

free light chain, early response, response assessment

Introduction

their monoclonal myeloma cells. The serum FLC (sFLC) assay
provides a measure of this monoclonality, and 89–97% of

Multiple myeloma (MM) is caused by monoclonal plasma

patients with immunoglobulin secretory MM have an imbal-

cells and is characterized by hypercalcemia, renal dysfunction,

anced sFLC ratio (rFLC) [1–3]. This is because the clonal plasma

anemia, lytic bone lesions and other symptoms (the CRAB

cells’ production is overwhelmed by the production of the­features). Similar to immunoglobulin, free light chain (FLC) is

monoclonal plasma cells, which produce more light chain than

produced by B-cells, with twice as much kappa as light chain

heavy chain and the excessive light chain production subse-

versus lambda light chain being produced in healthy people.

quently affects the rFLC. The International Myeloma Working

The ratio of these components remains stable in healthyGroup (IMWG) has defined stringent complete response (sCR)­people with normal renal function, although the light chain

as complete response (CR) with normalization of the rFLC in

production becomes skewed in patients with MM because of

the presence of measurable disease [4]. In addition, Kapoor et
al. reported that sCR after autologous transplantation was

Received May 9, 2018, accepted August 9, 2018
Department of Hematology, Kushiro Rosai Hospital, Kushiro, Japan
Corresponding author: Toshihiro MATSUKAWA
Department of Hematology, Kushiro Rosai Hospital, 13-23,
Nakazono-cho, Kushiro 085-8533, Japan
Email: t-matsukawa@hokkaido.med.or.jp

associated with longer progression-free survival (PFS) andoverall survival (OS) than CR [5]. However, sFLC measurements
are not recommended by IMWG in the absence of measurable
disease, although the introduction of novel agents for treating
MM has permitted the targeting of deeper responses. Thus,
the clinical strategy should be guided by the detection ofminimal residue disease (MRD), which should be actively

International Journal of Myeloma

vol. 8 no. 3 (2018)5

MATSUKAWA et al.

­monitored at each disease stage, especially for CR or deeper

Table 1.

responses, such as, immunophenotypic or molecular CR [6].
In this context, sFLC is assumed to be a short-term prognostic

Sexmale/female

24 (47.1)/27 (52.9)

factor for patients with MM, based on it only circulating for 2–6

Age, years

73 (39–87)

Heavy chain
IgG/IgA/IgD

31 (60.8)/19 (37.3)/1 (2.0)

whether sFLC was useful for predicting treatment response

Light chain
kappa/lambda

33 (64.7)/18 (35.3)

and prognosis among patients with MM.

Follow-up, months

19.8 (1.6–61.3)

ISS
I/II/III6 (11.8)/23 (45.1)/22 (43.1)

R-ISS
I/II/III

3 (5.9)/47 (92.2)/1 (2.0)

Cytogenetic risk
high/normal/missing

10 (19.6)/34 (66.7)/7 (13.7)

Extramedullary disease
yes/no4 (7.8)/47 (92.2)

Lytic bone lesions
yes/no31 (60.8)/20 (39.2)

Treatmentbortezomib-/lenalidomide-based

45 (88.2)/6 (11.8)

h after production [7], and there are limited data regardingwhether sFLC monitoring is a useful measure of treatment
response. Therefore, the present study aimed to determine

Patients and Methods
Patients
This study’s retrospective protocol was approved by the
Kushiro Rosai Hospital Institutional Review Board and complied with Declaration of Helsinki. The study evaluated 51 with
newly diagnosed MM who received first-line bortezomib- or
lenalidomide-based chemotherapy as first-line therapy being
treated at Kushiro Rosai Hospital between January 2012 andSeptember 2016. All patients had measurable disease, which
was defined as a serum M protein concentration of >1 g/dL.
Patients with only light chain (LCMM) were excluded from thistrial. High cytogenetic risk was defined as the presence ofBaseline characteristics of the 51 patients

Data are shown as number (%) or median (range).
ISS: International Staging System, R-ISS: Revised-ISS.

del(17q), t(4;14), and/or t(14;16), as previously described [8].
Response assessment and FLC testing
The patients’ medical records were searched to identify theirfor poor PFS, which was defined as <1 year after achieving
PR or VGPR.

responses, which were judged based on the IMWG uniform

Results

response criteria for measurable disease [4]. The patients’sFLC concentration had been regularly measured during atleast monthly follow-up appointments using Freelite® system

The patients’ baseline demographics and disease character-(The Binding Site, Birmingham, United Kingdom). Normal con-istics are shown in Table 1. The median age was 73 years

centration were defined as 3.3–19.4 mg/L for sFLCκ, 5.7–26.3(range: 39–87 years), and the median follow-up duration was

mg/L for sFLCλ, and 0.26–1.65 for rFLC [9]. Our hospital has

19.8 months (range: 1.6–61.3 months). Table 2 and 3 show

checked FLC routinely for outpatients. Normalization of rFLC

comparison of the patients who achieved PR and VGPR,

was required at least two consecutive assessment of normal

respectively. The best responses, based on IMWG uniform cri-rFLC apart from 4 weeks, and we regulated normalization ofteria, were sCR for 2 patients (3.9%), CR for 4 patients (7.8%),

rFLC at the first point of achieving normal rFLC, simultaneously

VGPR for 21 patients (41.2%), PR for 22 patients (43.1%), stablechecked partial response (PR) or very good PR (VGPR).

disease (SD) for 1 patient (2.0%), and progressive disease (PD)for 1 patient (2.0%). Thus, 49 patients (96.1%) achieved at least

Statistical analysis

PR and 25 patients (49.0%) achieved at least VGPR. The two

All statistical analyses were performed using EZR (Saitama

patients who experienced SD or PD had received bortezomib-

Medical Center, Jichi Medical University, Saitama, Japan) [10],based treatment. Normalization of the rFLC was observed forand differences were considered statistically significant at

20 of 49 patients (40.8%), who achieved at least PR and for 17

P-values of <0.05. Gray’s method and the log-rank test wereof 25 patients (63.0%), who achieved at least VGPR. No signifi-

used to compare survival based on PFS and OS. Univariatecant changes were detected in the characteristic of patients

2

analyses were performed using the χ -test or Fisher’s exact

who achieved at least VGPR excluding International Staging

test, as appropriate, and factors with P-values of <0.20 were

System Score (P = 0.046), hemoglobin (P = 0.022), serum β2-­

included in the multivariate analyses. Stepwise multivariate

microglobulin (β2-MG) (P = 0.0078), and lactate dehydrogenaselogistic regression models were used to analyze risk factors(P = 0.018).

6

International Journal of Myeloma

vol. 8 no. 3 (2018)

Serum free light chain ratio and myeloma

Table 2. Baseline characteristics of the 49 patients who achieved apartial response

Table 3. Baseline characteristics of the 27 patients who achieved avery good partial response
Normal rFLC
(n = 17)

Abnormal rFLC
(n = 10)Sex
male/female

8/9

4/6

0.23

Age, years

70 (39–87)

74 (63–80)

1

Heavy chain
IgG/IgA/IgD

8/9/0

6/3/1

Light chain
kappa/lambda

10/7

7/3

0.82

Hemoglobin (g/dL)

9.15 (7.2–12.8)

8.4 (6.5–12.3)

0.37

ISS
I/II/III

4/8/5

0/4/6

R-ISS
I/II/III

2/15/00/10/00.37

β2-MG (mg/L)

4.25 (1.7–7.5)

7.45 (3.8–29.3)

10.5 (9.0–11.9)

0.11

Corrected Ca (mg/L)

10.05 (8.9–15.7) 10.05 (9.0–11.9)

0.96

173 (96–1155)

184 (93–356)

0.30

LDH (IU/L)

173.5 (93–200)

192.5 (147–356)

0.018

0.84
5/12/3

5/20/4

Cytogenetic risk
high/normal/NA

4/11/2

1/7/2

Normal rFLC
(n = 20)

Abnormal rFLC
(n = 29)

Sex
male/female

8/12

14/15

Age, years

70.5 (39–87)

74 (55–87)

Heavy chain
IgG/IgA/IgD

12/8/017/11/1

Light chain
kappa/lambda

12/8

20/9

Hemoglobin (g/dL)

9.3 (7.2–12.8)

8.4 (6.5–13.5)

ISS
I/II/III

4/9/7

2/13/14

R-ISS
I/II/III

1/18/1

2/27/0β2-MG (mg/L)

4.5 (1.5–38.7)

5.0 (1.5–29.3)

Corrected Ca (mg/L)

9.8 (8.9–15.7)

LDH (IU/L)
Cytogenetic risk
high/normal/NA

P-value
0.77

0.56

0.74

Extramedullary disease
yes/no
2/18

1
2/27

P-value
1
0.51
0.23
0.69
0.022
0.046
0.74
0.00780.72

Extramedullary disease
yes/no2/15

1
1/9

Data are shown as number (%) or median (range).
ISS: International Staging System, R-ISS: Revised-ISS, β2-MG: serum β2microglobulin, LDH: lactate dehydrogenase.

Data are shown as number (%) or median (range).
ISS: International Staging System, R-ISS: Revised-ISS, β2-MG: serum β2microglobulin, LDH: lactate dehydrogenase.

After achieving PR, the survival curve analyses revealed that

After relapse, light chain escape can be detected based on

patients with normalized rFLC had significantly longer medianincrease in FLC without a corresponding increase in monoclo-

PFS than patients with abnormal rFLC (28.2 months vs. 10.2

nal immunoglobulin, with 3–10% of patients with MM having

months, P = 0.0018), although the difference was marginallight chain escape at the point of paraprotein relapse [10, 11].

for median OS (median OS: not reached vs. 35.7 months, P =Regular monitoring of sFLC may be performed at this time,

0.064) (Fig. 1). After achieving VGPR, no significant differences

although light chain escape is less frequently evaluated [12].

according to rFLC normalization were observed for median

The IMWG recommends monitoring sFLC after the diagnosis

PFS (27.8 months vs. 17.8 months, P = 0.069) or median OS (notto detect monoclonal gammopathies [13], while urine electro-

reached vs 35.2 months, P = 0.19) (Fig. 2). In the univariate

phoresis or sFLC can also be used residual disease among

analyses, rFLC and β2-MG (>3.5 mg/L) were risk factors for PFS

LCMM [14]. However, it remains unclear whether sFLC is a use-of <1 year after achieving PR (Table 4), although only rFLC was

ful marker for predicting therapeutic response and prognosis,

a significant risk factor in the multivariate analysis (Table 5).

as it has a much shorter half-life than immunoglobulin. A rapid
response to chemotherapy can lead to favorable outcomes

Discussion[2, 14], and our data suggest that sFLC normalization may predict a good likelihood of achieving PR. Similarly, Iwama et al.

The present study revealed that rFLC normalization pre-reported that rFLC normalization was associated with a good

dicted relatively good PFS after patients with MM achieved PR.

prognosis, including LCMM [16]. In this context, rFLC reflectsThus, rFLC appears to be a useful prognostic factor for patientslight chain clonality and is strongly related to be the effective-

who have achieved PR. However, no significant differences inness of LCMM treatment, which is why LCMM cases were

PFS or OS were observed after the patients achieved VGPR,

excluded from our study. Alhaj Moustafa et al. have also

regardless of the patients’ rFLC status. This discrepancy may bereported that, after excluding LCMM cases, rFLC normalization

related to the small sample size, short follow-up duration,

after first line chemotherapy was associated with an improved

and/or retrospective study design.

prognosis [17]. In contrast, a study of 260 consecutive MM

International Journal of Myeloma

vol. 8 no. 3 (2018)7

MATSUKAWA et al.

Figure 1. Overall survival and progression-free survival for patients who achieved partial response.

Figure 2.

Overall survival and progression-free survival for patients who achieved very good partial response.

cases, including patients with LCMM, did not reveal that rFLC

dance may be related to the timing of evaluation, as sFLC wasnormalization after 6 cycles of chemotherapy was associatedmonitored at least once per month in our study versus weekly

with an improved prognosis [18]. Previous reports have indi-

evaluations in previous studies [16]. More frequent examina-

cated that rFLC normalization can predict the achievement oftions may improve sensitivity for predicting the response toCR [4, 15, 16], although Paiva et al. have reported that sCR was

chemotherapy, although more frequent tests are also associ-not ­necessarily superior to CR, which conflicts with the IMWG

ated with increased costs and inconvenience.

­uniform criteria [18]. Moreover, patients with a high rFLC attheir diagnosis may have less favorable prognosis [19].

Various approaches are being used to detect MRD inpatients with MM [22], as MRD negativity predicted good PFS

Other reports suggested that early sFLC normalization or an

and OS outcomes in a previous meta-analysis [23]. In addition,

FLC reduction could predict favorable outcomes after patients

heavy + light chain (HLC) monitoring can be used to evaluateachieved VGPR [20, 21]. However, our results do not support

plasma cell function and predict clinical outcomes among

this association after patients achieved VGPR. This discor-patients who have achieved PR or CR [24]. Other methods for

8

International Journal of Myeloma

vol. 8 no. 3 (2018)

Serum free light chain ratio and myeloma

Table 4. Univariate Cox regression analysis of factors that predicted
progression-free survival of <1 year

detecting MRD include the polymerase chain reaction [25],P-valuecytometry analysis [27, 28], although these data cannot ben

PFS <1 yr

OR

95%CI

Age
≤75
>75

30
17

14 (46.7%)
8 (47.1%)

1
1.02

Sex
FemaleMale26
21

13 (50.0%)
9 (42.9%)1
0.75

0.20–2.76

β2-MG (mg/dL)
<3.5
≥3.5

11
36

3 (27.3%)
19 (52.8%)

1
2.91

0.58–19.83

FLC ratio
normalabnormal20
27

6 (30.0%)
17 (63.0%)

1
4.91

1.22–22.97

ISS
1 or 23

27
20

12 (44.4%)
10 (50.0%)1
1.24

0.33–4.64

Cytogenetic risk
standard
high

37
10

17 (45.9%)
5 (50.0%)1
1.17

0.23–6.07

Extramedullary disease
no
43
yes
4

21 (48.8%)
1 (25.0%)1
0.36

0.0063–4.85

Creatinine (mg/dL)
<2
40
≥2
7

17 (42.5%)5 (71.4%)

1
2.99

0.47–38.57

Hemoglobin (g/dL)
≥10
9
<10
38

5 (55.6%)
17 (44.7%)

1
0.65

0.11–3.57

Bone lesionnoyes

7 (36.8%)
15 (53.6%)

1
1.95

0.52– 7.79

Corrected calcium (mg/L)<11
36 16 (44.4%)≥11
11
6 (54.5%)

1
1.49

0.31–7.41

LDH
normalabove the ULN

1
1.15

0.14–9.68

next-generation sequencing [26], and multi-parameter flow
easily analyzed in many institutions.

19
28

41
6

19 (46.3%)
3 (50.0%)1
0.26–3.92
0.77

patients with MM.

Conflicts of Interest
0.18

The authors declare that they have no competing financial
interests.

0.017

0.77

1

0.61

0.23

0.77

0.37

0.73

1

Data are shown as number (%) or median (range).
ISS: International Staging System, R-ISS: Revised-ISS, β2-MG: serum β2microglobulin, LDH: lactate dehydrogenase, ULN: upper limit of
normal.
Table 5. Multivariate Cox regression analysis of factors that pre­dicted progression-free survival of <1 year
OR

95%CI

P-value

β2-MG (mg/dL)
<3.5
≥3.5

1
2.68

0.56–12.90

0.22

FLC ratio
normalabnormal

1
4.86

1.32–17.80

0.017

FLC: free light chain, β2-MG: serum β2-microglobulin.

In conclusion, our findings indicate that sFLC monitoring
may be useful and sensitive early-phase assessment for

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