In the era of emerging novel treatments, the clinical outcomes of patients with MM have improved greatly to a five-year survival rate of 60% [4]. However, MM remains notorious for placing patients at high risk of infection, thanks to the impairment of host defenses, and ensuring treatment-related immunosuppression. Importantly, the risk of infection is the highest within the first four months after the initial diagnosis. Furthermore, infection contributes to approximately 45% of early deaths [2]. Although the transition from chemotherapy to novel agents has caused a marked decrease in the incidence of severe pneumonia, heightened rates of early infection and pneumonia persist. Nearly all recent studies investigating MM-related infection focused on patients with refractory and relapsed MM [10–15]. As compared with these patients, those newly diagnosed with MM also experience the same risk of infection [19]. Therefore, it is imperative to prevent the occurrence of infection in all patients with MM, particularly early infection within the first four months after diagnosis.
As the vast majority of infections are bacterial in nature, it is reasonable, logically, to administer antibiotics for the prevention of infection in patients with MM. A phase III study explored the effects of oral antibiotic prophylaxis, i.e., ciprofloxacin or trimethoprim-sulfamethoxazole, for the first two months on the incidence of infection in patients with newly diagnosed MM; however, this study showed that routine use of prophylactic antibiotics did not reduce the incidence of infection among patients with MM receiving induction chemotherapy [7]. Another retrospective study investigated the effect of levofloxacin prophylaxis for the prevention of severe infections in patients with MM being treated using bortezomib-based regimens and supports the prophylactic use of levofloxacin in MM cases due to the marked decrease in severe infection observed relative to the control group (30.9% vs. 17.5%; p = 0.037) [20]. A prospective phase III study (TEAMM) also revealed that prophylactic administration of levofloxacin during the first 12 weeks of anti-myeloma therapy significantly reduced the number of febrile episodes and deaths as compared with the control group (27% vs. 19%; p = 0.0018) [21]. Despite such positive results, the use of antibacterial prophylaxis for infection remains to be viewed with caution due to the limitation of about 50% of patients withdrawing from the TEAMM study [21]. Moreover, prophylactic antibiotics can also increase the risk of Clostridioides difficile infection and antibiotic resistance. The discrepancy highlighted above was largely attributed to the significant differences in therapeutic regimens and enrolled patients with MM. Hence, available data on prophylactic antibiotics for early infection remain inconsistent and should not be considered to indicate the best course of action in patients with MM [19]. Currently, prophylactic antibiotics for early infection should be limited to use in high-risk patients who have the heightened potential to experience severe-grade and prolonged neutropenia during anti-myeloma treatment [22].
In the clinical setting, neutropenia has been strongly associated with the incidence of infection in patients with MM [23, 8]. Owing to the fragile performance status and multiple comorbidities (e.g., diabetes) of patients with MM, neutropenia-related infection may be a potentially life-threatening condition in such patients, which also results in treatment delay and the final outcome. Thus, the idea of G-CSF as a feasible treatment option has emerged to prevent neutropenia-related infections in those with MM. As noted previously, long-acting G-CSF has been documented for prophylaxis of infection mainly in refractory and relapsed patients with MM [10–15]. Enlighted by such previous findings, we investigated the effect of long-acting G-CSF on preventing infection among those with newly diagnosed MM.
In our study, the incidence rates of early infection and treatment delay were markedly lower in the long-acting G-CSF group than in the standard G-CSF group. The underlying mechanisms were attributed to the longer circulation half-life and lower immunogenic activity of long-acting G-CSF in comparison with standard G-CSF [24]. However, we detected no significant difference in FN between the two groups (6.1% vs. 17.1%; p = 0.297). This result indicated that neutropenia can be classified as one of the causes of infection. Additionally, there were many other risk factors for early infection, such as hypoalbuminemia, the complications of diabetes, and the late staging of ISS in our patients with MM [25]. Further analysis reported that the common types of early infection included pneumonia, colitis, and fever of unknown origin. Of note, pneumonia was the most frequent type of infection, accounting for more than 50% of early infections in our study. This finding was consistent with the results of other research, such as that by Lavi et al. [26], who strongly recommended chest computed tomography as a routine examination for patients with MM at high risk of infection.
In the present study, the BLD regimen was chosen as the front induction therapy due to the reported pronounced improvements in overall response rate, progression-free survival, and overall survival, especially among patients with high-risk features [27]. As for clinical efficacy, there were no significant differences between the long-acting and standard G-CSF groups. All of our participants achieved PR or better outcomes following the BLD plus G-CSF regimen. The favorable efficacy was partially ascribed to the chemo-sensitization activity of G-CSF to bortezomib via the blockade of stromal cell-derived factor-l/CXC receptor 4 (SDF-1/CXCR4) between myeloma and stromal cells [28, 29].