Peripheral Blood Lymphocyte-to-Monocyte Ratio as a Useful Prognostic Factor in Newly Diagnosed Multiple Myeloma

The survival of individuals with tumors may be predicted by the peripheral blood lymphocyte-to-monocyte ratio (LMR) upon diagnosis in recent studies. For patients with multiple myeloma (MM) in the era of novel agents, the prognostic significance of LMR remains unclear. In this study, the prognostic impact of LMR is evaluated by 285 patients with MM who are treated with proteasome inhibitor and/or immunomodulatory drug. LMR is a proven predictor of survival using the receiver operating characteristic curve, with 4.2 as the cutoff point. Patients with LMR ≤ 4.2 at diagnosis had poorer overall survival (OS) and progression-free survival (PFS) than those with LMR > 4.2. In addition, multivariate analysis showed that LMR less than 4.2 is an independent predictor for the OS (hazard ratio [HR]: 1.703; 95% confidence interval [CI]: 1.020–2.842; P = 0.042) and PFS (HR: 1.831; 95% CI: 1.098–3.053; P = 0.021). According to the test, the LMR at diagnosis, which functions as a simple index reflecting host systemic immunity, can predict clinical outcomes in patients with MM who are treated with new agents.


Introduction
Multiple myeloma (MM) is the second most common hematological malignancy, which accounts for nearly 10% of all hematological malignant disorders and 0.9% of all cancer deaths each year [1,2]. For newly diagnosed MM patients, the proteasome inhibitor and/or immunomodulatory drugbased chemotherapy is combined with autologous stem cell transplantation (ASCT) if eligible. Outcome of patients with MM was improved with these new therapies [3]. However, it is worth noting that MM remains incurable, and accurate and practical prognostic indicators for predicting survival will be used for MM patients.
At present, the International Staging System (ISS) [4] is the primary tool to predict the prognosis of MM patients. The Revised-International Staging System (R-ISS) was developed as a newly revised tool in which cytogenetics and lactate dehydrogenase (LDH) are used as the prognostic factors that are independent of the ISS staging system [5]. The R-ISS is proven effective in improving the stratification of patients into more homogeneous risk groups, and it has a better discriminative power than the ISS for MM patients who were treated with novel agents as the primary therapy [6].
The immune system is an important factor in tumor pathogenesis. Immune biomarkers which reflect the baseline host immune status, for example, lymphocyte-to-monocyte ratio (LMR) may be related to the poor prognosis of various tumors [7]. Shi has reported that LMR is associated with the survival of MM patients and is an independent prognostic factor for OS [8]. However, studies on LMR for newly diagnosed MM patients who were treated with novel agents are limited.
This study aimed to investigate the prognostic value of peripheral blood LMR, combined with iFISH in newly diagnosed MM patients.
The study was censored on December 31, 2017. The study was approved by the ethics committee of Beijing Chao-Yang Hospital.

Statistical Analysis.
All patients were treated with at least one novel agent, followed by ASCT if eligible. During the study, the patients were evaluated for CBC, serum albumin, LDH, creatinine, calcium, and 2-microglobulin, serum and urine M protein, bone marrow and multiparametric flow cytometry every 3 months. The overall survival (OS) is defined as the time from diagnosis to death from any cause. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of disease progression, death from any cause, or the last contact, whichever occurred first. Kaplan-Meier analysis was conducted to estimate the survival of patients, and log-rank test was used for comparison. P values < 0.05 were considered statistically significant. The 2 test (nonparametric analysis) was adopted to evaluate the differences between groups. In the multivariate analysis, a Cox proportional hazards model was used. Receiver operating characteristic curves (ROC) and area under the curve (AUC) were used to determine the best cutoff values for survival that is indicated by the LMR. A statistical analysis was performed using the IBM Statistical Package for the Social Sciences software (SPSS Inc, Chicago, IL, USA) or R 3.3.1 software (Institute for Statistics and Mathematics, Vienna, Austria; http://www.r-project.org/).

Characteristics of the Patients.
In this retrospective analysis 285 newly diagnosed MM patients, baseline clinical and laboratory characteristics are listed in Table 1. The median follow-up duration was 48 (range: 2-84) months. The 3-year OS and PFS of the entire cohort were 69.8% and 50.0%, respectively.
The median LMR at diagnosis was 6.18 (range: 0.60-118.00). Using the data from the entire cohort, we selected the cutoff points of the LMR for predicting the survival outcomes in the ROC curve analysis. The most discriminative cutoff value of LMR was 4.2, with an AUC value of 0.607 (95% confidence interval [CI]: 0.529-0.685; Figure 1). Table 1 shows the patients' characteristics according to the LMR at diagnosis. Patients with a LMR ≤4.2 had elevated levels of serum LDH (P < 0.001), creatinine (P = 0.006), calcium (P = 0.003), and 2-microglobulin (P = 0.035), and they had a higher incidence of relapse (P = 0.001) than those with a LMR >4.2. The results also showed that patients with LMR >4.2 had a higher incidence of t (11;14) than those with LMR ≤4.2 (24.8% vs. 13.6%, P = 0.018).

Prognostic Impact of the Lymphocyte/Monocyte Ratio on Different ISS and R-ISS.
Further analysis showed that LMR ≤4.2 had a negative prognostic impact on both PFS and OS in ISS stages II and III, while it could not in ISS stage I (see Figure 3). Moreover, LMR ≤4.2 had a negative prognostic impact on both PFS and OS in R-ISS stage II, while it could not in R-ISS stages I and III (see Figure 4).

Discussion
As a marker of host antitumor immunity, absolute lymphocyte count (ALC) has been widely studied in hematologic and solid malignancies [10]. In MM, ALC recovery after ASCT has significant prognostic value [11,12]. Moreover, another study has shown that ALC at diagnosis was associated with survival in patients with newly diagnosed MM [13].   The BM micro-environment plays a critical role in the development of MM from its precursor condition, monoclonal gammopathy of undetermined significance (MGUS), in part by allowing immune tumor evasion [14]. In addition, it can support the growth and survival of myeloma cells and influence their migration and drug resistance [15,16]. Inflammatory cells are essential in tumor progression [17,18]. Tumor-associated macrophages (TAMs), which constitute a significant proportion of tumor-related inflammatory cells, contribute to the growth, angiogenesis, and metastasis of a variety of tumors [19].
TAMs play an important prognostic role in patients with classical Hodgkin lymphoma (HL) [20][21][22], follicular lymphoma (FL) [23], and MM [24][25][26]. Derived from the circulating monocytes, TAMs are recruited to the tumor site by tumor-derived chemotactic factors [27]. Tumor-derived chemotactic factors can influence the number of circulating monocytes and the TAMs, the level of TAM recruitment can be reflected by the peripheral blood absolute monocyte count (AMC), and it may be considered as an important surrogate marker for TAMs. AMC is a poor prognostic factor in diffusing large B-cell lymphoma (DLBCL) [28], FL [29], extranodal natural killer/T-cell lymphoma (ENKL) [30], HL [31], and MM [24].
Based on these results, the ALC-to-AMC ratio may be considered as a symbol of the relative strength of the host BioMed Research International 5  immune system to tumor-induced immune dysfunction. A lower LMR has a negative prognostic impact on several solid tumors and hematologic malignancies [7,32,33]. A recent study has reported that LMR < 3.6 can be considered a bad prognostic factor for PFS in patients with MM [34].
Therefore, LMR has been associated with the prognosis of patients with several tumors.
In this paper, the prognostic impact of the LMR in newly diagnosed MM patients was treated by proteasome inhibitor and/or immunomodulatory drug-based chemotherapy was  retrospectively evaluated. The result showed that LMR was an independent predictor for OS and PFS, and patients with LMR ≤4.2 had significantly elevated serum LDH, creatinine, calcium, and 2-microglobulin levels and a higher incidence of relapse. In addition, patients with LMR >4.2 had a higher incidence of t (11;14). However, Dosani et al. have found that LMR independently predicted del(17p) and t(4;14), rather than t(11;14) [35]. This may be due to differences in the study population and may also be related to differences in the selected cutoff values. Thus, prospective studies with a larger sample size must be conducted to validate the results.
Considering the significance of LMR in clinical outcomes, certain tests have also been conducted to validate whether LMR could improve the prognostic impact of the ISS and R-ISS. Interestingly, based on the test results, the addition of LMR to the ISS further defined prognosis, particularly in stages II and III, whereas those to the R-ISS further defined prognosis in stage II. The combination of ISS or R-ISS and LMR improved the predictive value in patients treated with novel agents beforehand.

Conclusions
The LMR at diagnosis, which is a simple index reflecting host systemic immunity, can predict clinical outcomes in patients with MM who were treated with novel agents. In addition, LMR is an objective and cost-effective test result, and it can be easily obtained from CBC results. Owing to its significant value in clinical treatment, further studies on LMR must be conducted to better understand the roles of peripheral lymphocytes and monocytes in individuals with MM.

Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest
The authors declare that they have no conflicts of interest.