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Abstract

BACKGROUND:

The neutrophil-to-lymphocyte ratio (NLR) at diagnosis has been identified as an independent prognostic marker in several malignancies. Recently, a few studies have reported that an elevated pretreatment NLR is associated with poor survival among multiple myeloma (MM) patients. However, the role of NLR at diagnosis in patients with MM treated with regimens containing bortezomib has been less explored.

OBJECTIVE:

We aimed to investigate the relationships between NLR and overall survival (OS) in newly diagnosed patients receiving bortezomib-based therapy for MM.

METHODS:

A total of 76 newly diagnosed patients with MM treated with bortezomib-based regimes were analyzed retrospectively. NLR was calculated from whole blood counts prior to therapy and subsequently correlated with OS.

RESULTS:

Complete remission (CR) was seen in 39.2% of patients with NLR $<$ 2.95 compared to 20% in the group with NLR $\geqslant$ 2.95 ( $P=$ 0.094). NLR was lower in CR patients in comparison to Non-CR subjects ( $P=$ 0.044). Patients with a NLR $\geqslant$ 2.95 experienced inferior median survival compared to those with NLR $<$ 2.95 (4-year OS rates were 30.9% and 64.8%, respectively, $P=$ 0.029). In multivariate analysis, only elevated LDH and IgA MM were factors predicting inferior OS.

CONCLUSIONS:

Elevated NLR was associated with poor OS in MM patients receiving induction therapy with bortezomib-based regimens, but it was not an independent prognostic factor in this patient cohort.

Keywords

Bortezomib multiple myeloma neutrophil-to-lymphocyte ratio prognostic

1. Introduction

Multiple myeloma (MM) is a disease resulted from malignant disorder of plasma cells, which mainly occurs among elderly patients [1]. As a result of novel agents including proteasome inhibitors and immunomodulator agents, the overall survival of patients with MM has significantly improved in the last decade [2]. Bortezomib, the first potent therapeutic proteasome inhibitor, has become an important therapeutic drug in MM, and several bortezomib-based combination therapies have resulted in high response rates for newly diagnosed as well as relapsed disease [3].

Table 1
Patients’ characteristics by neutrophil-to-lymphocyte ratios

Characteristics	Total (%)	NLR $<$ 2.95 (%)	NLR $\geqslant$ 2.95 (%)	$P$ value
Number of patient	76	51/67.1	25/32.9
Median age (year)	63 (40–79)	62 (40–78)	65 (41–79)	0.281
Male	41/53.9	28/54.9	13/52	0.812
Myeloma type				0.593
IgG	28/36.8	19/37.3	9/36
IgA	26/34.2	19/37.3	7/28
Light chain	16/21.1	9/17.6	7/28
Non-secretory	4/5.3	2/3.9	2/8
Others	2/2.6	2/3.9	0/0
ISS Stage				0.409
I	3/3.9	3/5.9	0/0
II	35/46.1	22/43.1	13/52
III	38/50	26/51	12/48
NLR (Median, range)	2.2 (0.2–14.6)	1.8 (0.2–2.9)	4.1 (3–14.6)	0.000
CRP, mg/L (mean $\pm$ SD) protein	14.3 $\pm$ 21.3	15.3 $\pm$ 23.4	12.1 $\pm$ 16.3	0.54
Hemoglobin $<$ 10 g/L	56/73.7	36/70.6	20/80	0.381
Albumin $<$ 3.5 g/L	67/88.2	45/88.2	22/88	0.976
lactate dehydrogenase $>$ normal	16/21.1	8/15.7	8/32	0.101
Creatinine $>$ 177 $\mu$ mmol/L	21/27.6	13/25.5	8/32	0.551
Calcium $>$ 2.75 mmol/L	14/18.4	7/13.7	7/28	0.131
WHO performance status $\geqslant$ 3	21/27.6	13/25.5	8/32	0.551
Median follow-up months, range	34 (1–93)	38 (3–93)	25 (1–72)	0.027
from diagnosis to RRMM, range

Ig: Immunoglobulin, ISS: International Staging System; WHO: World Health Organization, NLR: Neutrophil-to-lymphocyte ratio, CRP:C-reactive protein.

Traditionally, the factors that influence the risk and prognosis in myeloma are mainly based on disease-related factors and patient-related factors, such as International Staging System (ISS), cytogenetic results, lactate dehydrogenase level, and serum free light chain ratio [4]. In light of new data, the factors related to tumor microenvironment have been enrolled [5].

Neutrophil-to-lymphocyte ratio (NLR) is an easily available marker of the systemic inflammatory response. NLR as a simple, inexpensive tool has been increasingly reported to have predictive and prognostic value in various types of tumors [6]. The values of baseline NLR was prognostic for survival in patients with multiple myeloma (MM) [7, 8, 9, 10, 11]. In the review of the literature, the role of NLR at diagnosis in patients with MM treated with regimens containing bortezomib, has been less explored. Therefore, the present study was performed to investigate whether NLR at diagnosis in patients receiving induction therapy with bortezomib-based regimens for MM is associated with outcome.

2. Patients and methods

2.1 Study population

In this retrospective study, 108 consecutive patients with MM received induction therapy with bortezomib-based regimens at Wuxi people’s hospital between January 1, 2007 and December 31, 2015. Patients with amyloidosis at the time of diagnosis were excluded. In order to eliminate the possibility of affecting the systemic inflammatory response, exclusions comprised diabetes mellitus ( $n=$ 12), chronic pulmonary disease ( $n=$ 2), coronary or congestive heart diseases ( $n=$ 5), and hepatocirrhosis ( $n=$ 1). Seven patients presented with infectious events and 5 for solid tumor were also excluded. Finally, 76 patients were eligible for the analysis and were followed until November 30, 2016. The study was approved by the ethics committee in the Wuxi People’s Hospital and carried in accordance with the Helsinki Declaration.

2.2 Data collection and definition

In all patients recruited, demographic and clinical variables were collected by reviewing medical charts and electronic records. White blood cell (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), were obtained from a standard complete blood count (CBC) obtained at the time of diagnosis by Sysmex XN-9000/5000. NLR was defined as an absolute neutrophil count divided by an absolute lymphocyte count using the data obtained from CBC. Clinical stages were determined based on ISS [12]. Because fluorescent in-situ hybridization (FISH) was not available in our hospital, we had not carried out the cytogenetic risk stratification of the patients.

Bortezomib-based regimens included VD (Bortezo- mib-dexamethasone), VTD (Bortezomib-thalidomide-dexamethasone), PAD (bortezomib-doxorubicin-dexa- methasone) [13, 14]. Following the induction of therapy, 4 patients received autologous stem cell transplantation. Treatment responses were evaluated according to the International Myeloma Working Group (IMWG) criteria [15].

Figure 1.

(a) Treatment response in patients with different baseline neutrophil-to-lymphocyte ratio (NLR) and (b) Baseline NLR in patients according to treatment response.

2.3 Statistical analyses

All analyses were performed using SPSS statistical software (version 19.0). $P$ -values $<$ 0.05 were considered statistically significant. Continuous variables were summarized as median and extreme values or Mean $\pm$ SD; categorical data as absolutes and percentages. The significant differences between the groups were compared using the chi-square test and $t$ -test as appropriate. The cutoff value for the NLR as a predictor for OS was determined through a receiver operating characteristic (ROC) curve with calculation of the area under curve (AUC). The optimum cut points were the point on ROC curve which yielded the highest specificity and sensitivity. Overall survival (OS) was calculated from the time of diagnosis of symptomatic myeloma to the time of death or last follow-up. Survival analysis was constructed according to the Kaplan-Meier method, and differences between survival curves were analyzed using the log-rank test. The prognostic impact of different variables in terms of OS was performed using a Cox proportional hazard regression.

3. Results

3.1 Patient characteristics

The baseline characteristics of the patients and their distribution are shown in Table 1. The median age of patients in this study was 63 (range, 40–79) years. The major type of MM included IgG ( $n=$ 28, 36.8%), IgA ( $n=$ 26, 34.2%). 56.6% of patients received VTD treatment. The median follow-up of all patients was 34 (range, 1–93) months, and 35 of 76 (46.1%) patients died at the time of data collection. Median NLR was 2.2 (range 0.2–14.6). NLR $\geqslant$ 2.95 was selected as the cut-off point based on ROC analysis. The patients were grouped as NLR $<$ 2.95 ( $n=$ 51) and NLR $\geqslant$ 2.95 ( $n=$ 25). Although patients with NLR $\geqslant$ 2.95 showed elevated lactate dehydrogenase (LDH) more often (32%, 15.7%) and rising calcium levels (28%, 13.7%), the differences across groups were not significant (Table 1).

3.2 Response and NLR

Complete remission (CR) after bortezomib-based treatment was observed in 25 (32.9%) patients, very good partial remission (VGPR) in 29 (38.2%) patients and partial remission (PR) in 19 patients (25%). Persistent disease was found in 3 patients (3.9%). We explored the impact of NLR on the response to bortezomib-based treatment, however, there was no any difference between NLR $<$ 2.95 and NLR $\geqslant$ 2.95 groups ( $P=$ 0.229, Fig. 1a). CR was seen in 39.2% of patients with NLR $<$ 2.95 compared to 20% in the group with NLR $\geqslant$ 2.95 ( $P=$ 0.094). In the entire cohort, the groups of CR and Non-CR were distinguished according to NLR. NLR was lower in CR patients in comparison to Non-CR subjects ( $P=$ 0.044, Fig. 1b).

Table 2
Univariate and Multivariate analysis of factors associated with Overall survival

	Univariate analysis		Multivariate analysis
	OR (95% CI)	$P$ Value	OR (95% CI)	$P$ value
Age (yr) $\geqslant$ 70	2.88 (0.877–9.454)	0.081	2.166 (0.742–6.322)	0.157
Men	1.96 (0.781–4.918)	0.152	2.174 (0.753–6.279)	0.151
IgA	4.368 (1.578–12.086)	0.005	5.604 (1.892–16.603)	0.002
ISS III	0.727 (0.294–1.798)	0.49
NLR $\geqslant$ 2.95	1.818 (0.691–4.781)	0.225
WHO performance status $\geqslant$ 3	0.638 (0.228–1.783)	0.391
C-reactive protein $\geqslant$ 10 mg/L	1.273 (0.492–3.291)	0.619
Hemoglobin $<$ 10 g/L	1.059 (0.38–2.954)	0.912
Albumin (g/L) $<$ 3.5 g/L	1.076 (0.266–4.364)	0.918
Lactate dehydrogenase $>$ normal	3.3 (1.018–10.703)	0.047	4.758 (1.331–17.003)	0.016
Creatinine $>$ 177 $\mu$ mmol/L	0.873 (0.304–2.305)	0.73
Calcium $>$ 2.75 mmol/L from	0.593 (0.178–1.97)	0.393
diagnosis to RRMM, range

ISS: International staging system, WHO: World Health Organization, OR: Odds ratio, CI: Confidence interval.

Figure 2.

Overall survival according to neutrophil-to-lymphocyte ratio (NLR) at diagnosis.

3.3 Overall survival and NLR

The median OS of the entire cohort was estimated as 59 months (95% CI: 45.2–72.8). The 2-year OS estimates for the group with NLR $<$ 2.95 was 82% versus 62.6% for the group with NLR $\geqslant$ 2.95. The 4-year OS estimates of the two groups was 64.8% and 30.9%, respectively. The median OS was 69 months (95% CI: 55.2–82.8) in patients with low NLR and 40 months (95% CI: 20.1–59.9) in the rest of the cohort ( $P=$ 0.029, Fig. 2).

When the patients were assessed for the ISS stages, although a decreasing OS rate was observed with the higher ISS, the difference had no statistical significance ( $P=$ 0.869). We further analyzed whether theNLR could improve the prognostic impact of ISS stages. NLR was assessed separately for ISS stages II and III. We did not analyze the OS for the ISS I stage due to the few cases (only three). We did not find a significant difference between the OS in the NLR $<$ 2.95 and NLR $\geqslant$ 2.95 groups in each of the ISS stage ( $P=$ 0.157 for ISS II, and $P=$ 0.055 for ISS III stages, respectively).

4. Prognostic factors

Risk factors influencing OS in newly diagnosed patients with MM receiving bortezomib-based therapy were reported in Table 2. In univariate analysis, LDH and IgA MM were risk factors poorly impacting OS, but not with NLR $\geqslant$ 2.95 ( $P=$ 0.225). All variables with $P<$ 0.2 in univariate analysis were included in the multivariate logistic regression model. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from backward stepwise Cox proportional analysis. In multivariate analysis, elevated LDH and IgA MM were factors predicting inferior OS. The higher NLR was not an independent prognostic factor for poor survival.

5. Discussion

The host immune system and bone marrow microenvironment plays a pivotal role in MM pathogenesis, which induce tumor growth, progression, and cell adhesion mediated-drug resistance, as well as immune suppression [16]. Myeloid derived suppressor cells (MDSC) are heterogeneous, immature, myeloid progenitor cells, which can induce MM cell proliferation and exert an immunosuppressive activity mainly on T lymphocytes. Accumulation of MDSCs has been described in the peripheral blood of MM patients having an adverse effect on survival [17, 18]. However, consists of T-cell clonal expansions, a higher T helper 17, and lower T-regulatory cells may be related to a longer survival in patients with MM because of antitumor activity [19]. The peripheral absolute neutrophil count may symbolize the MDSCs, and the absolute lymphocyte count may be related to the T-cell activity, making NLR a potential marker to measure both [7].

Bortezomib is a first-class inhibitor of the ubiquitin-proteasome for the treatment of MM, which can target the tumor and its microenvironment, and induce T and NK cell-mediated antitumor response and modulate cytokine signaling [20]. A retrospective analysis included 97 relapsed MM patients reported that a low ALC before bortezomib-dexamethasone therapy was associated with a poor prognosis [21]. They thought that a high ALC containing a high fraction of NK cells before bortezomib containing therapy could be an important predictive factor for OS.

Romano et al. [9] retrospectively analyzed the NLR in 309 newly diagnosed patients whom treated upfront with novel agents. In this study, 157 patients (51%) received bortezomib, 91 (29%) received lenalidomide or thalidomide, 61 (20%) bortezomib with lenalidomide or thalidomide; 113 (37%) patients underwent to autologous stem cell transplantation as consolidation therapy. Among younger patients (age $<$ 65 years, $N=$ 179), NLR $\geqslant$ 2 was an independent predictor of OS, while NLR values did not add any significant impact on outcome in elderly MM patients. In addition, a higher NLR did not correlate with the type of induction regimen or an adverse karyotype.

A study of 559 patients with MM receiving thalido- mide-based or bortezomib-based treatment, showed that elevated NLR was associated with high beta-2 microglobulin, but low frequency of high-risk cytogenetic abnormalities. The pretreatment NLR was an independent, significant predictor of long-term survival [11]. Another study that investigated pretreatment NLR values of 52 MM patients in Turkey concluded that patients with NLR $>$ 1.72 had significantly worse stages, performance status, kidney functions and poorer OS rates when compared to those with a NLR $\leqslant$ 1.72. The predictive value of the NLR in 18 (35%) patients with MM whom treated upfront with bortezomib was also examined. Because only one patient had died in the bortezomib group, the estimated OS could not be reached [7].

Our study retrospectively evaluated the predictive significance of NLR in newly diagnosed MM patients treated upfront with bortezomib-based regimens. In our study, although evaluated NLR was associated with poor OS in MM patients receiving induction therapy with bortezomib-based regimens, it was not an independent prognostic factor, and NLR also did not predict overall response rates to initial therapy. This suggests that NLR might not be the best inflammatory markers in understanding the potential antimyeloma mechanisms, in specific clinical setting. Previous studies have shown that bortezomib treatments improve CR and OS in patients with MM regardless of ISS and chromosomal abnormalities at diagnosis [3]. It is possible that the unique mechanism of bortezomib overcomes the impact of the adverse prognostic factors. The other prognostic factors are needed in such a population.

Our study had some limitations. First, it was a collection of retrospective data from a single center. We did not describe lymphocyte subsets such as the T/NK cell subset or assessed their relationship to clinical outcome, because these were not routinely analyzed in MM. Second, sample size was relatively small and genetic markers were not available for most of the patients. In addition, NLR did not have a standardized cut off, and the different cut-off values of NLR as a prognostic marker were used in survival analysis [7, 8, 9, 10, 11].

In summary, our study showed that a high NLR ( $\geqslant$ 2.95) was associated with poor OS in MM patients upfront with bortezomib-based regimens, but it was not an independent prognostic factor in this patient cohort. Due to the heterogeneity of MM and various influencing factors of NLR measurement, the prognostic role of NLR in this subject should be further investigated in a large series of prospective studies.

Footnotes

Acknowledgments

The authors thank all of the doctors and nursing staff of Department of Hematology in Wuxi People’s Hospital for their dedicated patient care.

Conflict of interest

The authors declare that they have no conflict of interest.

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Evaluation of neutrophil-to-lymphocyte ratio in newly diagnosed patients receiving borte- zomib-based therapy for multiple myeloma

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

Table 1 Patients’ characteristics by neutrophil-to-lymphocyte ratios

2.1 Study population

2.2 Data collection and definition

3. Results

3.1 Patient characteristics

3.2 Response and NLR

Table 2 Univariate and Multivariate analysis of factors associated with Overall survival

4. Prognostic factors

5. Discussion

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Patients’ characteristics by neutrophil-to-lymphocyte ratios

Table 2
Univariate and Multivariate analysis of factors associated with Overall survival