Patients with MM suffered immune deficiency in varying degrees, which increased the risk of severe infections [3, 4, 24]. Similar to the previous studies [6, 8, 19, 22, 25-27], infection was common in newly diagnosed patients with MM and appeared to be the initial manifestation and the leading cause of death, mainly occurred in the elderly. In order to provide ideas for the assessment, prevention and treatment of infection in newly diagnosed MM patients without the antitumor therapy, we explored the characteristics and risk factors of infection in 161 patients who were first hospitalized in our department.
According to our cases, infections occurred in 78.3% cases of newly diagnosed patients with MM in our ward from May 2013 to December 2018. Respiratory infections were in the majority (64.7%), which was in concordance with the existing data [19, 25, 26, 28]. Urinary, digestive and circulatory systems were more likely to cause the microbial infection (P=0.001, P=0.027, P=0.046, respectively), which may be related to the placement of catheters. Additionally, we found viral (43.9%) and bacterial (36.6%) infections represent a major threat to MM patients, as reported by Blimark et al. . For the first time, the viruses overtook bacteria and occupied the first place, meanwhile, EBV and HBV accounted for the major proportion in our study, which was different from the known research [28-31] (considered that gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa are the leading pathogens). However, whether there is an upward trend in the infection rate of the virus remains to be verified.
Patients with multiple myeloma are more susceptible to the virus . Blimark et al.  showed that the risk of developing viral infection in patients with MM was 10 times higher compared with matched controls. Through molecular analysis, a recent study  displayed a significant EBV DNA in malignant plasma cell disorders, especially in MM and MGUS (monoclonal gammopathy of undetermined significance) patients. Bosseboeuf et al.  demonstrated that EBV was the most frequent target of purified monoclonal IgG which produced by patients with MGUS or MM. They considered that chronic stimulation by infectious Ag may promote MGUS and MM. It can be concluded that EBV has been associated with MM. An early study  confirmed that HBV was lymphotrophic, and was able to infect and replicate in human lymphocytes and monocytes. A study in Japan  reported that the rate of HBV infection in patients with MM was 3.2%, higher than that in the group of healthy subjects (1.2%). Huang et al.  found that the patients with MM had significantly higher HBV carrier rate than acute leukemia, and patients with MM who were HBV carriers were at significantly higher risk of having hepatic injury than non-carriers. Coinciding with the views of early researchers, we believed that viruses play an important role in patients with MM, especially the EBV and HBV in our study. Therefore, the prevention and treatment of the virus in newly diagnosed patients with MM is essential. If an underlying chronic infection was cleared up early enough in disease progression, it could perhaps offer the possibility to prevent MGUS transition to SM and MM in the first place . In addition, we agree with the point that newly diagnosed patients with MM should be screened for serum hepatitis B viral markers universally in HBV endemic areas .
In our research, according to the univariate and multivariate analysis, we demonstrated that advanced ISS stage (ISS stage Ⅲ), more severe anemia (Hb<90 g/L) and the elevation of CRP (>10 mg/L) were identified as independent determinants of infection patients with MM. Meanwhile, poor performance status (ECOG>2), advanced DS stage (DS Ⅲ) and the presence of catheter were the influencing factors of infection. Nevertheless, ANC and ALC did not display significant difference. Compared with the previous report in recent years, Huang et al.  showed that advanced ISS stage (ISS stage Ⅲ) and poor ECOG performance status (ECOG>2) were the independent risk factors of blood stream infections (BSI) in patients with newly diagnosed MM, and more severe anemia (Hb<100 g/L) and worse renal function (Cr≥177 μmol/L) were influencing factors associated with BSI. In addition, ALC showed no significant difference. However, they did not include DS stag, ANC, CRP and catheter in univariate and multivariate analysis, blood stream was the only discussed infection site, and patients received antitumor therapy, which may be the cause for the difference in risk factors of the final model between our researches.
The ISS stage is a widely accepted staging system based on serum levels of albumin and β2-MG . Serum albumin level is inversely correlated with healthy dietary and has been recognized as a sign of rapid tumor growth . In addition, serum β2-MG level is elevated in patients with MM due to renal insufficiency as well as tumor burden. In an unselected cohort, Caravita et al.  reported that only ISS resulted as risk factor affecting severe infection development. Isoda et al.  indicated that advanced ISS stage was an independent risk factor associated with severe (grade C 3) bacterial infection in MM patients. A large number of studies [19, 28, 29] have shown that the advanced ISS stage was an important risk factor of infection in MM patients. In agreement with previous reports, advanced ISS stage appeared to be associated with a higher incidence of infection in our cases as well. In consequence, similarly we hold the opinion that the patients with ISS-Ⅲ stage, mostly morbid patients with high disease activity, not only have poorer prognosis, but also are susceptible to serious infection complications .
The decrease of hemoglobin content, on the one hand, reduces the concentration of respiratory enzyme, mitochondrial oxidase and myoglobin, thus resulted in the deficiency in oxygen supply, decrease of aerobic metabolism and accumulation of lactic acid, on the other hand, affects the immune response and phagocytosis , which in turn leads to the depression of immune functions and disturbances of immune regulation, subsequently increases the risk of infection . It has been found that anemia is a risk factor for accompanying infection in patients with MM, Dumontet et al.  included hemoglobin in the predictive model of first treatment-emergent (TE) grade ≥ 3 infection in the first 4 months in patients with MM, TE infections were defined as infections that occur or worsen on or after the first dose of any drug and within 28 days after discontinuation of treatment. Similar to early research, lower hemoglobin level also showed a significant correlation with infection in our study, although the patients were not received treatment previously. Therefore, according to European Myeloma Network , we consider that patients with persistent symptomatic anemia (hemoglobin <10g/dL) without other cause may initiate treatment with erythropoietic-stimulating agents.
CRP is an acute phase reaction protein (APRP) synthesized by liver cells in response to inflammatory stimuli such as microbial invasion or tissue damage. CRP increases within the first few hours of inflammation and peaks at 48 hours, which is not affected by radiotherapy, chemotherapy or corticosteroid therapy. Rintala et al.  demonstrated that CRP was a reliable and readily available method to differentiate between bacterial infections and other causes of fever in patients with malignant hematological diseases. What’s more, Apewokin et al.  concluded that the elevated CRP in patients with hematological malignancies could be used as a sensitive screening index for viral infection. In our research, the elevation of CRP was observably related to the risk of infections, and 12 (57.1%) patients with viral infection were accompanied with the elevated CRP, while the rate of increased CRP was 38.6% in patients without viral. So, for severely infected patients with elevated CRP, using antibacterial drugs is not effective, the viral infection should be taken into account.
Numerous previous studies have suggested that neutropenia is a risk factor for infection with MM. High-dose alkylating agents and new drugs can lead to myelosuppression and agranulocytosis, especially in combination . In this study, absolute neutrophil counts (ANC) were all pre-treatment data, 80.1% (100/126) of infected patients were in a normal ANC, and neutropenia accounted for only 11.9% (15/126). Although the occurrence of neutropenia may also due to the disease itself, but it was not reflected in this study, possibly because the remaining myeloid progenitor cells of MM patients still balanced the production and consumption of neutrophil, or the stored mature neutrophil in bone marrow still replenished for the circulating. Moreover, the hematopoietic function was suppressed in patients with MM, and neutrophilia was not necessarily observed during infection. Only 8.7% (11/126) of the patients had neutrophilia in our analysis. As a result, for the newly diagnosed MM patients, the decrease or increase of ANC can’t be used as an indicator of infection. The absolute lymphocyte count (ALC) as a marker of host immunity has been widely studied in a variety of malignancies. Although its role on infections in newly diagnosed MM patients remains indeterminate, the significance on infection risk and survival has been associated with MM during bortezomib treatment [30, 48]. However, ALC did not show any remarkable difference in infections in this research, which may attribute to the fact that patients were not accepted previous treatment.
Newly diagnosed patients with MM have variable survival, ranging from a few days to more than a decade [49, 50]. A large number of studies [1, 2, 7, 8, 27, 30] confirm that infections represent a major threat to patients with MM. A single institution study  pointed out that infections contributed most to the early mortality. Caravita, et al.  attested that the overall survival (OS) of MM patients with infections was significantly shorter compared to that without infections. The same conclusion was reached in our study of newly diagnosed MM patients with infection compared with that without infection (P=0.033). And the median OS of patients with independent risk factors was significantly shorter than that without independent risk factors (P=0.011), among the risk factors, mainly more advanced stage (ISS stag Ⅲ, P=0.008) and more severe anemia (Hb<90 g/L, P=0.039) were significantly associated with the poor prognosis. It can be seen that infection is a significant cause of death in patients with MM, and the existence of independent risk factors of infection seriously affects the prognosis of newly diagnosed MM patients, especially the ISS-Ⅲ stage and the lower hemoglobin level.
There are several limitations of our research. Firstly, the retrospective designed study may have selection biases of patients, and the number of participants is limited. Besides, the performance of interphase fluorescence in situ hybridization (iFISH) in MM patients is not common due to various reasons, such as the expensive price, resulting in a serious lack of information on cytogenetic, so the data of r-ISS stage is not analyzed in our study. However, considering the broadscale clinical application, ISS stage may be of a higher practical value in predicting infection at present. On account of the more important role in evaluating the prognosis of patients with MM, R-ISS also need to be included in the analysis with the popularization of cytogenetic detection technology.