MM is a common hematological cancer. The OS rate of individuals with MM has risen significantly in the previous decade, primarily as a result of the advent and advancements of innovative treatments. As a consequence, given the possibility that cancer will progress to the stage of chronic illness, it is essential to pay close attention to the patient's QoL. Medical oncologists and other healthcare providers who treat MM patients currently focus on ways to create a balance between effective tumor control and minimal toxicity .
PLD is one of the main therapeutic drugs used to treat MM . According to the literature, HFS is the most prevalent complication of PLD-based chemotherapy, with an occurrence rate ranging from 18–45% in solid-tumor patients. In the present study, 13.3% of patients with MM who received PLD developed HFS, which is less than the reported incidence in the literature, and no grade 3 HFS occurred. Some studies suggest that patients with hematological malignancies have a reduced risk of HFS . MM patients who were treated with PLD were all given dexamethasone. However, steroid use was an exclusion criterion in other studies, which could factor in to the occurrence of HFS. Since dexamethasone is an important part of the chemotherapy regimen for MM patients, in our study, we could not exclude the influence of steroids.
While HFS is neither a life-threatening condition, HFS might reduce health-related QoL in many different ways, due to the associated swelling, pain, and loss of the capacity to participate in normal activities, emotional impairment, and social isolation. Therefore, the prevention of HFS is of substantial clinical significance. Because there is a shortage of reliable data on the pathophysiology and management of HFS, therapeutic recommendations have relied primarily on professional judgment. The most effective management approach continues to be dosage titration or treatment discontinuation, both of which have the capacity for lowering the overall effectiveness of the chemotherapy treatment that is being planned .
A number of studies and anecdotal evidence have proposed that diverse approaches should be used to reduce the occurrence rate of HFS. However, while pyridoxine, commonly referred to as vitamin B6, is routinely utilized as an oral medication to treat and prevent HFS, the evidence demonstrating that it has created advantages for patients is controversial and limited at present. Despite advances in science, the specific mechanism through which pyridoxine acts in HFS remains largely unknown. Denda et al.  postulated that the mode of action of pyridoxine could be via the inhibition of the P2X purinergic receptor, which speeds up the restoration of the epidermal barrier once it has been disrupted and inhibits epithelial hyperplasia. Therefore, we conducted an open-label randomized investigation designed to provide information about the effectiveness of pyridoxine for preventing PLD-induced HFS in MM patients.
Our study suggests that pyridoxine prophylaxis effectively reduces the rate of HFS and delays the onset of HFS induced by PLD in MM patients. To the best of our knowledge, this is the first research report that offers proof of the prophylactic efficacy of oral pyridoxine in MM patients. However, the findings of previous studies demonstrated conflicting findings with regard to the clinical application of pyridoxine in preventing PLD-induced HFS. A number of case reports and preclinical studies have demonstrated that pyridoxine is an effective therapeutic or preventative agent for PLD-induced HFS . However, some contemporary double-blind randomized studies demonstrated that pyridoxine was not satisfactory in preventing HFS in ovarian, breast, or endometrial cancer patients treated with PLD [18, 19]. A number of factors could be at play in this difference, such as distinct cancer types, differences in statistical analysis methodologies, and differences in sample sizes. Furthermore, the data might deviate from ours due to variability in the sex ratio. It was demonstrated that women are more concerned than men are about the state of the skin on their feet and hands, in general . Most of the patients included in these previous trials were women, but in our study, most patients were men. We hypothesize that this is among the major reasons for the differences between our results and those of earlier studies. It is also possible that other factors are at play, such as the change in pyridoxine dosage. Several different pyridoxine dosages have been studied by researchers (between 50 mg and 800 mg each day) . Regarding the dose of pyridoxine given, different doses of pyridoxine achieve different results. In our study, we inferred that 200 mg of pyridoxine could well be the optimum dosage for preventing HFS in MM patients. Another outcome of the present research related to the HFS grade. The findings revealed the absence of a statistically significant difference between the two subgroups in terms of the reduction in PPE grade after the intervention (p = 0.725). This finding is in agreement with the assertions of a meta-analysis, which found that there was no overall correlation between prophylactic pyridoxine supplementation (oral usage) and HFS grade . The mechanism is not clear.
Our data indicate an obvious beneficial outcome of pyridoxine prophylaxis in preventing PLD-related HFS in MM patients. In certain trials, however, it was discovered that long-term usage of vitamin B6 had an effect on the treatment responsiveness in some cancer patients [8, 21]. If high-dose pyridoxine has an adverse effect on the effectiveness of chemotherapy drugs, this has not yet been proven. According to our findings, there were no statistically significant differences in response between the cohorts in the present study (p = 0.690). There is almost no significant concern regarding the potential of adverse effects related to prophylaxis pyridoxine for the preventative measures of PLD-induced HFS, as it is only administered for short durations.
Although the above results demonstrated that prophylactic pyridoxine reduced the rate of HFS, many studies have shown that prophylactic pyridoxine is not the only contributing factor [21, 22]. In our study, we found that in the absence of pyridoxine prophylaxis, more cycles of PLD chemotherapy (> 3) and low albumin levels were significant risk factors for HFS.
In terms of the number of PLD cycles, according to related literature reports, the intensity of the dosage independently serves as a risk variable that influences the occurrence rate of HFS; the greater the intensity of the dosage is, the greater the possibility of developing HFS. In our study, the PLD dose and schedule were the same among the different treatment regimens (40 mg/m2, d1, d2), and PLD was used every four weeks; therefore, the number of PLD cycles influenced the dose intensity of PLD. More cycles of PLD chemotherapy (> 3) are related to a high rate of HFS. Furthermore, in this study, the results of the analysis showed that the albumin level was another risk factor for the occurrence of HFS. The lower the albumin level was, the greater the probability of HFS was, which has not been reported in other studies. This may be because if a patient has a low albumin level, it can influence the proliferation of skin cells, resulting in a greater susceptibility to HFS . Referring to baseline albumin-related biomarkers could therefore be beneficial for preventing HFS and making appropriate modifications to the PLD dosage.
There are several drawbacks related to the present research. First, this was a single-center investigation. The research findings could be skewed and should be validated in multicenter, prospective investigations. Second, we did not evaluate QoL; if we had, we might have found other benefits of pyridoxine. Third, this study was designed without a placebo; hence, the statistical power had to be lower for the purpose of generating a confirmatory finding. Nevertheless, to the best of our knowledge, this study is among the largest on PLD-related HFS in MM patients, and it identifies risk factors for HFS among MM patients instead of simply reporting the HFS incidence.
In conclusion, the present study is the first randomized, open-label clinical experiment with the aim of examining the effects of pyridoxine prophylaxis on HFS induced by PLD in MM patients. The administration of pyridoxine reduced the rate and delayed the occurrence of HFS. Nevertheless, prevention with pyridoxine is not the only variable affecting the occurrence and progression of HFS. The albumin level and the number of PLD cycles are also risk factors for HFS in MM patients, and the management of these factors may be helpful for the prevention of HFS.