INTRODUCTION
Multiple myeloma (MM) is a hematological disease with the accumulation of monoclonal plasma cells in the bone marrow characterized by anemia, hypercalcemia, bone failure, and renal dysfunction.[1] MM is a heterogeneous disease with varied patient outcomes. Different staging systems useful in predicting prognosis are Durie and Salmon,[2] International Staging System,[3] and Revised International Staging System,[4] which includes parameters such as serum albumin, ß2 microglobulin, lactate dehydrogenase (LDH), conventional cytogenetics, and fluorescence in situ hybridization. These methods are usually complex and too expensive, and the staging system does not consider the tumor microenvironment.[5,6]
Inflammation is considered one of the distinctive features of cancer. The interaction between the bone marrow microenvironment and myeloma cells plays a crucial role in the pathogenesis of MM and stimulates the secretion of autocrine or paracrine mediators. The tumor microenvironment is primarily orchestrated by inflammatory cells and signaling molecules inducing the proliferation and survival of cancer cells. The inflammatory cells secreted by the tumor induce genomic instability and promote angiogenesis and metastasis.[6,7] High levels of interleukin-6 (IL-6), IL-16, IL-17, hepatocyte growth factor, epidermal growth factor, and interferon-γ are displayed by MM subjects. These factors are considered markers of systemic inflammation.[7,8] The inflammatory markers indirectly reflect the status of the bone marrow micro-environment and are considered to be cost-effective and easily detected prognostic markers. Neutrophils are the most common type of leukocytes; they ensure rapid neutralization and clearance of pathogens.[9] Neutrophils and lymphocytes are inflammatory and regulatory markers activating major cell types involved in acute and chronic inflammation.[10] Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) obtained from complete blood count (CBC) are identified as prognostic markers for both solid tumors and hematological malignancies.[11,12] These markers are inexpensive, easily reproducible, and involved in the disease's outcome for different cancer types. As the efficacy of PLR in patients with MM is less known, the study aimed to assess the NLR and PLR in pretreated MM patients and investigate its correlation with clinical and hematological parameters.
METHODS
A total of 50 patients diagnosed with MM at the Department of Oncology at K. S. Hegde Charitable Hospital were enrolled in the study. MM was diagnosed based on the presence of hypercalcemia, anemia, renal failure, and lytic bone lesions and persistent plasmacytosis in the bone marrow aspirates. The study was approved by the Institutional Ethics Committee, and patients' informed consent was taken. The data were reviewed and collected from patient case history, which included age, gender, total protein, albumin, globulin, A/G ratio, bilirubin total, bilirubin direct, bilirubin indirect, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), alkaline phosphatases, blood urea, uric acid, creatinine, calcium, sodium, potassium, and CBC. The NLR ratio was calculated by dividing absolute neutrophil count (ANC) to absolute lymphocyte count (ALC). The PLR ratio was calculated by dividing platelet count to absolute lymphocyte count using the data obtained from CBC.
Ethical consideration
The present study was approved by the Central Ethics Committee, NITTE (Deemed to be) University. Ref: NU/CEC/2019/0224. Dated: 20/03/2019. Each patients informed consent was obtained.
Statistical analysis
The relationship between clinical characteristics, NLR and PLR, was analyzed using Chi-square and independent t-test. The correlation between clinical characteristics, NLR and PLR, was carried out using Pearson's correlation. P < 0.05 was considered to be statistically significant. The data were analyzed using Statistical Package for Social Sciences (SPSS 16.0, IBM, Chicago, IL, US).
RESULTS
A total of 50 MM patients were enrolled in the study. The median age of the patients was 60 years ranging from 42 to 75 years. Out of them, 56% were male and 44% were female. The median Hb was 9.5 g/dL, with a range from 4.9 to 14.8 g/dL. The median absolute lymphocyte count was 1.68, with a range from 0.31 to 80.3. The median ANC was 4.16 ranging from 0.81 to 470. The other characteristics are listed in [Table 1]. The median NLR was 2.6 (range: 0.3–18.8) and the median PLR was 124.45 (range: 2.14–509.6).
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Table 1: The baseline characteristics of the patients
The histograms of PLR and NLR are shown in [Figure 1]. The median NLR was 2.6 (range: 0.3–18.8) and the median was PLR 124.45 (range: 2.14–509.6).
Figure 1: (a) Histogram of neutrophil-to-lymphocyte ratio and (b) Histogram of platelet-to-lymphocyte ratio in patients with multiple myeloma
Patients' characteristics according to neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio
The patients were divided into two groups based on the cutoff values for NLR and PLR. Based on previously published reports, we chose an NLR cutoff of 2.86 and 157.66 for PLR.[13] Thirty patients presented values NLR <2.86 and twenty patients presented values NLR >2.86. Thirty-six patients presented values PLR <157 and 14 patients presented PLR >157.
The association between the clinical characteristics and NLR is shown in [Table 2]. The myeloma case group consists of 28 (56%) males and 22 (44%) females. There was no significant difference in age, gender, Hb, erythrocyte sedimentation rate (ESR), total protein, albumin, globulin, bilirubin direct, bilirubin indirect, bilirubin total, SGOT, SGPT, calcium, sodium, potassium, uric acid, and creatinine. However, patients with high NLR presented high blood urea (P = 0.0018) and platelet count (P = 0.0442) compared with low NLR. No statistically significant difference was found between patients with high PLR and low PLR for clinical parameters [Table 3]. The association between the clinical characteristics and PLR is shown in [Table 3].
Table 2: Patients' characteristics by neutrophil-to-lymphocyte ratio
Table 3: Patients characteristics by platelet-to-lymphocyte ratio
Correlation between clinical parameters and neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio
We noted a statistically significant positive correlation between blood urea and NLR [rho = 0.55, P ≤ 0.0001; Figure 2a]. In addition, uric acid positively correlated with NLR [rho = 0.27, P = 0.049; Figure 2b]. Furthermore, blood urea correlated positively with PLR [rho = 0.34, P = 0.0139; Figure 2c]. The correlation results are shown in [Table 4].
Figure 2: (a) Pearson's correlation between blood urea and neutrophil-to-lymphocyte ratio (NLR), (b) Pearson's correlation between uric acid and NLR, (c) Pearson's correlation between blood urea and platelet-to-lymphocyte ratio
Table 4: Correlation between clinical parameters and neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio
DISCUSSION
Predicting the prognosis of the disease is one of the important workups required in any treatment strategy. Oncogenesis involves genetic basis and inflammatory responses toward disease. NLR and PLR are the inflammatory responses of the host toward the development and progression of the neoplasm. These are simple prognostic markers providing information in malignancies. The mechanism of destruction of malignant cells is hampered by lymphopenia or thrombocytopenia or by an increase in the number of neutrophils.[14] When the tumor load is high, lymphopenia and thrombocytopenia are the most common features displayed.
MM is a complex disease with an interaction between the bone marrow microenvironment and myeloma cells. The stromal environment consists of bone marrow stromal cells (BMNCs), endothelial cells, and adhesion molecules. Interaction between the pro-inflammatory markers and myeloma cells induces proliferation during the course of the disease.[15] Patients with high clonal T-cell expansion, T helper 17, and low T regulatory cells seem to survive longer. In MM, T-cell function is suppressed by a small population of neutrophils and immature myeloid cells, also called myeloid-derived suppressor cells (MDSCs). Absolute lymphocyte count is associated with T-cell activity, and absolute lymphocyte count represents MDSCs, making NLR a potential prognostic marker.[16] Thrombocytosis being a marker of systemic inflammation, is common in patients with solid tumors. In MM, thrombopoiesis is inhibited by malignant plasma cells and leading to thrombocytopenia therefore, reflecting the tumor burden. In addition, the half-life of platelets is being reduced in MM.[17]
In our study, we sought to investigate the potential correlation between NLR, PLR, and hematological parameters. Fifty myeloma patients were recruited for the study. The median age in our study was 60 years which matched with previously published data.[13,18] We classified the patient groups into high NLR and PLR and low NLR and PLR based on the cutoff taken from the previously published data. Here, we observed that ESR, blood urea, uric acid, platelet count, and ANC were higher in patients with high NLR than low NLR patients. ESR is a classical cost-effective, reliable inflammatory marker, and elevated ESR is associated with the advanced stage.[19] Studies have shown that CRP, NLR, and platelet count might significantly affect newly diagnosed patients.[20]
CONCLUSION
In patients with high PLR, blood urea was higher than the patients with low PLR. Correlation analysis between NLR, PLR, and clinical parameters revealed a positive correlation between blood urea, uric acid, and NLR. Positive correlation was seen between PLR and Blood urea. The study suggested an association between blood urea, uric acid, and NLR and PLR. ALC is a surrogate marker of the antitumor immune system, a decrease in ALC leads to NLR elevation. High NLR is an independent prognostic marker and an additional parameter to design therapeutic strategies in MM.[7,21,22]
The prognosis of the disease for planning the treatment efficacy plays an important role in MM patients.
Therefore, we could conclude that NLR and PLR can be considered independent prognostic markers in clinical outcome and predicting survival in MM.[7,23]
Limitation of study
Due to insufficient data regarding follow up and treatment regimens, the survival analysis and outcome of the patients couldn't be predicted.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
The authors are grateful to all study participants.
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