ABSTRACT
Objective
To research the effects of autonomic neuropathy of the digestive system induced by bortezomib on clinical efficacy and quality of life.
Methods
A total of 150 patients with newly diagnosed multiple myeloma (MM) were hospitalized in our department from January 2018 to December 2021, and treated with bortezomib-based combination regimens. To observe the incidence of autonomic neuropathy of the digestive system and analyse the correlations between the severity of autonomic neuropathy and the efficacy, survival, age, underlying diseases and personal history.
Results
The incidence of autonomic neuropathy of the digestive system was 60.0%. The overall response rate (ORR), 2-year progression-free survival (PFS) rate and 2-year overall survival (OS) rate in the grade 3 group of autonomic neuropathy were significantly lower than those in the grade 1–2 group, and the differences were statistically significant (P < 0.05). Age, constipation, diabetes, fracture/spinal cord compression in bed and history of alcoholism were positively correlated with the risk of autonomic neuropathy of the digestive system (P < 0.05). The autonomic neuropathy of the digestive system was significantly alleviated in most patients after the timely adjustment of the treatment regimen, and bortezomib could continue to be administered.
Conclusions
The incidence of autonomic neuropathy of the digestive system induced by bortezomib is high, and its severity is closely related to efficacy, advanced age, constipation, diabetes, fracture/spinal cord compression in bed and history of alcoholism. Early detection and early treatment are necessary to better treat the disease and reverse the autonomic neuropathy.
Introduction
Multiple myeloma (MM) is a malignant tumour characterized by abnormal proliferation of monoclonal plasma cells, and the clinical manifestations are anaemia, bone destruction, impairment of renal function and immune dysfunction [Citation1]. MM accounts for 10−15% of haematological malignancies, with high heterogeneity, and tends to occur in middle-aged and elderly persons [Citation2]. In recent years, with the wide administration of proteasome inhibitors, especially bortezomib, the prognosis of MM patients has been significantly improved, the 5-year survival rate is 60% and the 10-year survival rate is 30% [Citation3]. However, the adverse effects of bortezomib are gradually attracting attention, among which the incidence of bortezomib-induced peripheral neuropathy (BIPN) is approximately 40−60%, presenting as sensory, motor and autonomic neuropathy [Citation4,Citation5]. Autonomic neuropathy of the digestive system is very common, which can lead to paralytic ileus and endanger the patient's life in severe cases [Citation6]. There are no more case reports and standard treatment methods for autonomic neuropathy of the digestive system at home and abroad. In this study, we collected information from 150 newly diagnosed MM patients in our hospital and retrospectively analysed the effects of autonomic neuropathy of the digestive system induced by bortezomib on the efficacy and quality of life, to further optimize the treatment of MM.
Materials and methods
Patients’ eligibility
One hundred and fifty newly diagnosed MM patients were enrolled in our department from January 2018 to December 2021. They were hospitalized in our department and received at least one cycle of bortezomib-based combination chemotherapy. The diagnosis of patients was performed according to the diagnostic criteria of the International Myeloma Working Group (IMWG) for active myeloma [Citation7].
Treatment regimens
All of the enrolled patients received subcutaneous bortezomib-based chemotherapy regimens, e.g. BD (bortezomib 1.3 mg/m2, d1, 4, 8, 11; dexamethasone 20 mg, d1–2, 4–5, 8–9, 11–12), PAD or PDD (bortezomib 1.3 mg/m2, d1, 4, 8, 11; dexamethasone 20 mg, d1–2, 4–5, 8–9, 11–12; epirubicin 9-10 mg/m2/d, d1-4 or liposome doxorubicin 30 mg/m2/d, d4), BCD (bortezomib 1.3 mg/m2, d1, 4, 8, 11; dexamethasone 20 mg, d1–2, 4–5, 8–9, 11–12; cyclophosphamide 300 mg/m2/d, d1, 8, 15), and every 4 weeks is a treatment cycle.
Assessment of efficacy and safety
Blood samples and 24-h urine samples were collected for assessing efficacy before and after each cycle of treatment. The response was categorized according to the efficacy evaluation criteria developed by IMWG, including strict complete remission (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), disease stability (SD) and disease progression (PD) [Citation8]. The overall response rate (ORR) was defined as a summation of sCR, CR, VGPR and PR. The toxicity of bortezomib was closely monitored in patients, and the adverse events of the digestive system were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTC AE 5.0) [Citation9].
Statistical analysis
All statistical procedures were performed with SPSS 22.0. The Chi-square test was employed to compare the classification data among different groups, and Logistic regression analysis was used to test the risk factors of adverse events in the digestive system. The Kaplan–Meier method was used for survival analysis. The variable screening method used was forward, and P values < 0.05 were considered statistically significant.
Results
Patient characteristics
Clinical characteristics of the newly diagnosed MM patients are shown in . The study comprised 150 patients, including 91 males (60.7%) and 59 females (39.3%), with a median age of 62 years (range 25–81), and 82 patients (54.7%) were ≥ 60 years old. There were different types of myeloma, 65 patients (43.3%) were IgG, 41 patients (27.3%) were IgA, one patient (0.7%) were IgD and 43 patients (28.7%) were light chain type. According to the Durie–Salmon staging system (D-S), there were 29 patients (19.3%) in stage I, 43 patients (28.7%) in stage II and 78 patients (52.0%) in stage III. According to the International Staging System (ISS), 33 patients (22.0%) were stage I, 41 patients (27.3%) were stage II and 76 patients (50.7%) were stage III. According to the Revised ISS (R-ISS), 46 patients (30.7%) were stage I, 54 patients (36.0%) were stage II and 50 patients (33.3%) were stage III. Of all the patients, 35 patients (23.3%) had a history of hypertension, 17 patients (11.3%) had a history of diabetes, 16 patients (10.7%) had a history of constipation (defecation less than three times a week, difficult defecation, lasting more than twelve weeks), 9 patients (6.0%) had a history of alcoholism, 48 patients (32.0%) accompanied by hyper-calcaemia, 32 patients (21.3%) accompanied by abnormal renal function, 105 patients (70.0%) developed different degrees of anaemia, 5 patients (3.3%) combined with bone lesions and fracture/spinal cord compression in bed, 37 patients (24.7%) administered oral opioid analgesics, and 12 patients (8.0%) administered antiemetic drugs.
Table 1. The baseline characteristics of 150 MM patients.
Adverse events of the digestive system
Among the 150 MM patients treated with bortezomib-based chemotherapy, 21 patients (14.0%) developed adverse events of the digestive system in the first or second cycles of treatment, 69 patients (46.0%) developed adverse events of the digestive system in the third to fifth cycles of treatment, and the overall incidence was 60.0%. The main adverse events of the digestive system in these patients are detailed in . The main manifestations were anorexia (17 patients, 11.3%), nausea and vomiting (11 patients, 7.3%), diarrhoea (13 patients, 8.7%), constipation (21 patients, 14.0%), and intestinal obstruction (28 patients, 18.7%), of which two patients developed severe paralytic intestinal obstruction. Adverse events of the digestive system were classified according to NCI-CTC AE version 5.0, 63 patients (42.0%) developed grade 1–2 adverse events, and 27 patients (18.0%) developed grade 3 adverse events. In a word, if there are adverse events in the digestive system during the treatment with bortezomib, the mild ones will influence the treatment process, and the severe ones will endanger the patient's life. Therefore, early detection and early management are particularly important. This study recommended grading the autonomic neuropathy of the digestive system related to bortezomib according to NCI-CTC AE version 5.0, and adjusting the treatment regimen in time according to the severity of neuropathy (). Ninety patients (60.0%) developed adverse events in the digestive system, of which 42 patients (28.0%) could continue to be treated with the original regimen, 21 patients (14.0%) in grade 2 were given bortezomib reduced to 1.0 mg/m2 or extended the interval of administration. Twenty-seven patients (18.0%) in grade 3 received symptomatic support treatment, such as fasting water, rehydration, acupuncture, antidiarrheal, catharsis, enema, gastrointestinal decompression and so on, after the symptoms were significantly alleviated to grade 2 or below, bortezomib was given a reduction to 1.0 mg/m2 with an interval of one week. Among the patients with intestinal obstruction, 26 patients (17.3%) were cured by conservative treatment, and 2 patients (1.3%) were ineffective and died from giving up further treatment. Although adverse events of the digestive system were very common, most patients could maintain stability without aggravation after intervening in treatment and adjusting the regimen in time, especially reduced the dose or the frequency of bortezomib.
Table 2. Severity classification and specific symptoms of 90 MM patients with various degrees of digestive system adverse events.
Table 3. Severity classification of MM patients with digestive system adverse events and adjustment of treatment dose and frequency.
Logistic regression analysis was used to analyse the correlations between age, gender, underlying diseases, personal history and the incidence of autonomic neuropathy in the digestive system induced by bortezomib. The results suggested that patients with age > 50 years old, previous history of diabetes, constipation, fracture/spinal cord compression in bed and alcoholism were positively correlated with the risk of autonomic neuropathy of the digestive system (P < 0.05), while other factors, including CRAB (hyper-calcaemia, renal insufficiency, anaemia, bone lesions) symptoms of MM disease itself, were not significantly correlated ().
Table 4. Logistic regression analysis of the correlation between multivariate factors and autonomic neuropathy of the digestive system in 150 MM patients.
Responses and survival
All the patients received bortezomib-based treatment, with a median of two cycles (range 1–6), and the ORR of 150 patients was 89.3%. Of the patients who responded to treatment, 37 patients (24.7%) were CR, 45 patients (30.0%) were VGPR, and 52 patients (34.7%) were PR. 90 MM patients developed autonomic neuropathy of the digestive system, and the treatment responses of these patients are summarized in to explore the influence of severity on efficacy. The ORR of the grade 1–2 digestive system adverse event group was 95.2%, and that of the grade 3 digestive system adverse event group was 63.0%. The ORR of the grade 1–2 group was significantly higher than that of the grade 3 group (P < 0.05). The median follow-up for the whole group was 20 months (range 2–50). The 2-year progression-free survival (PFS) rate and 2-year overall survival (OS) rate were 79.2% and 87.8% in the grade 1–2 group, whereas the 2-year PFS rate and 2-year OS rate were 67.4% and 73.1% in the grade 3 group. The rates of 2-year PFS and 2-year OS in the grade 1–2 group were significantly higher than those in the grade 3 group, and the differences were statistically significant (P < 0.05).
Table 5. Summary of treatment responses in 90 MM patients with different degrees of digestive system autonomic neuropathy.
Discussion
Bortezomib, as the first-line drug for MM in clinical, has a significant curative effect and the prognosis of patients is significantly improved. However, the incidence of treatment-related BIPN is very high, among which the autonomic neuropathy of the digestive system gradually attracts the attention of researchers [Citation10]. A total of 150 MM patients in this study were treated with bortezomib-based chemotherapy, the incidence of autonomic neuropathy of the digestive system was 60%. The main symptoms were anorexia, nausea, vomiting, diarrhoea, constipation, intestinal obstruction and other gastrointestinal symptoms. The majority of patients were in grades 1–2, and the incidence rate was 42.0%. The incidence of grade 3 was 18.0%, but the incidence of paralytic intestinal obstruction was 1.3%, which was consistent with the results reported in the literature [Citation11]. Although previous research studies suggested that the digestive symptoms also could be induced by MM disease itself, such as nausea, anorexia, diarrhoea and constipation, they were associated with CRAB, the symptoms were relatively mild and the incidence was usually low [Citation12]. Gastrointestinal symptoms would be alleviated after the primary disease was controlled [Citation13, Citation14]. However, the incidence of adverse events in the digestive system was significantly increased after combination treatment of bortezomib, and some patients developed serious or even life-threatening symptoms. Although the complications of chemotherapeutic agents such as cyclophosphamide and epirubicin include gastrointestinal mucositis, which represents injury of the rest of the alimentary tract beyond oral mucositis, this condition is most prominent in the small intestine, but it also occurs in the aesophagus, stomach and large intestine. Gastrointestinal mucositis induced by chemotherapy is associated with alterations of intestinal barrier function due to the potential damage induced by the anti-cancer drugs on the epithelial cells of the intestinal mucosa. Cytotoxic drugs impair the turn-over of intestinal epithelia and induce flattening of the villi and increased exposure of luminal contents to crypts. These alterations may be involved in the frequent recurrence of gastrointestinal symptoms, such as abdominal pain and diarrhoea in patients undergoing chemotherapy [Citation15]. The gastrointestinal reactions caused by chemotherapeutic agents usually recover within 1–3 days after withdrawal, while the digestive side effects caused by bortezomib generally disappear 3–5 days after withdrawal in mild cases, and gradually recover in 1–2 weeks in severe cases, because the average elimination half-life of bortezomib after repeated administration is longer than that of chemotherapeutic agents [Citation16, Citation17]. Although the administration of chemotherapeutic agents such as cyclophosphamide and epirubicin also contributed to digestive symptoms, the recovery time of digestive symptoms was more than 3 days in this study. In addition, patients who received the BD regimen alone without chemotherapeutic agents still developed digestive system symptoms of different degrees. Therefore, it could conclude that bortezomib was the main cause of adverse events in the digestive system.
At present, the mechanism of neurotoxicity of bortezomib on the digestive system is still unclear. Research studies have shown that the autonomic neuropathy of the digestive system is related to the influence of the autonomic nerve by the sympathetic nerve and vagus nerve. The main causes of autonomic neuropathy of the digestive system may be that bortezomib inhibits the proteases of nerve terminations in patients, destroys the transport of normal proteins in the axons of nerve cells, and then induces dysfunction of intestinal autonomic nerve cells, affects local nerve conduction and intestinal smooth muscle contraction [Citation4]. Other possible causes are as follows. The administration of 5-hydroxytryptamine antiemetics in patients further inhibited the peristalsis of the gastrointestinal tract. Patients were given a high protein and a fat diet, insufficient intake of dietary fibre, insufficient drinking water and other unreasonable diets. If patients were nervous and anxious, resulting in gastrointestinal dysfunction, decreased intestinal peristalsis and dry stool. During the treatment period, the gastrointestinal motility drugs and laxative drugs, such as mosapride, lactulose and traditional Chinese medicine were not given in time for oral prevention, and the enema was not applied in time, resulting in prolonged defecation time and constipation. Most patients were in advanced clinical stage and often accompanied by multiple bone destruction, resulting in long-term bed rest, reduced intestinal peristalsis, and gradual constipation and intestinal obstruction. In some patients with intestinal amyloidosis, intestinal peristalsis was further weakened, leading to intestinal dysfunction [Citation18–20]. In recent years, there have been literature reports of gastrointestinal adverse events induced by bortezomib at home and abroad. Fukushim et al. [Citation21] reported that 22 MM patients received a BD regimen, of which seven patients (31.8%) developed gastrointestinal adverse events of grade 3 or above, and one patient (4.5%) died of paralytic intestinal obstruction and sepsis. Qinglan Zhang et al. [Citation22] compared 26 patients with intestinal obstruction who received bortezomib treatment with 26 patients without intestinal obstruction who received bortezomib treatment at the same time. The results confirmed that the CR rate in the therapeutic intestinal obstruction group was significantly lower than that in the control group (11.5% vs 53.8%), and the median PFS was significantly shorter than that in the control group (15.0 months vs 33.0 months). This study reported 150 MM patients received bortezomib-based chemotherapy. The ORR (63.0% vs 95.2%), 2-year PFS rate (67.4% vs 79.2%), and 2-year OS rate (73.1% vs 87.8%) in the grade 3 digestive autonomic neuropathy group were significantly lower than those in the grade 1–2 group. The differences were statistically significant, consistent with the results reported in the literature [Citation21, Citation22]. In addition, previous studies confirmed that bortezomib was combined with other chemotherapy agents, different agents could have synergistic effects on the digestive system [Citation23], and reducing the dose or frequency of bortezomib was helpful to significantly alleviate the symptoms of the digestive system [Citation24], which was consistent with the results of this study. Therefore, bortezomib was the main cause of digestive system neuropathy in the above treatment regimens. The results of this study showed that the severity of autonomic neuropathy of the digestive system influenced the efficacy, 2-year PFS and 2-year OS of MM patients. As a result, the autonomic neuropathy of the digestive system should be emphasized.
MM is more common in the elderly population, with complex manifestations, multiple complications and difficult treatment. Previous research confirmed that age, medical history and complications were the main risk factors for BIPN. The incidence and severity of BIPN significantly increased in MM patients over 50 years old, and the risk increased by 6% every year, indicating that BIPN was positively correlated with age [Citation25]. Most elderly MM patients have severe bone destruction, mobility difficulties, poor gastrointestinal function, and the incidence of constipation significantly increased. With the increase of age, the digestive fluid secreted by the gastrointestinal tract of the elderly is reduced, the intestinal tension and peristalsis are weakened, so that food stays in the intestine tract for too long, water is excessively absorbed, and finally leads to constipation. This study retrospectively analysed 150 MM patients in our hospital, the median age was 62 years old. Five patients (3.3%) with fracture/spinal cord compression in bed developed grade 2–3 constipation, and 16 patients (10.7%) with a history of constipation developed grade 2–3 intestinal obstruction. Moreover, patients with diabetes have a higher risk of autonomic neuropathy. Hyperglycaemia causes multiple system damage, leading to chronic progressive lesions, dysfunction and failure of nerves, blood vessels and other tissues and organs, as well as gastrointestinal dysfunction [Citation26, Citation27]. 17 patients (11.3%) with a history of diabetes all suffered from grade 2–3 diarrhoea or constipation, which was similar to the results reported in the literature [Citation28]. Alcohol can cause chronic damage to the central nervous system, resulting in dysfunction of the digestive and nervous systems [Citation29]. Nine patients (6.0%) with a history of alcoholism all developed grade 1–2 anorexia or nausea and vomiting. The results of this study indicated that age, fracture/spinal cord compression in bed, diabetes, alcoholism and constipation were the main risk factors for autonomic neuropathy of the digestive system, and refractory constipation was a high-risk factor for intestinal obstruction.
Peripheral neuropathy induced by bortezomib is relatively common. With the in-depth study of the clinical characteristics, pathogenesis and treatment measures of sensory and motor neuropathy, the neurological symptoms can be improved to a certain extent. However, there are no effective prevention and treatment measures for autonomic neuropathy of the digestive system. According to NCI-CTC AE version 5.0 and the results of research, our centre suggests evaluating and classifying the adverse effects of the digestive system induced by bortezomib and adjusting the treatment strategy in time on the basis of the severity of autonomic neuropathy. The details are as follows: the dose or frequency of bortezomib is no need to adjust for grade 1, bortezomib is reduced to 1.0 mg/m2 or administered once a week for grade 2, treatment is suspended until the symptoms are significantly alleviated by one level for grade 3, and treatment is terminated for grade 4. In this study, 26 patients with intestinal obstruction were cured after reducing the dose or frequency of bortezomib as shown in and conservative treatment, two patients were ineffective and died after giving up further treatment. Autonomic neuropathy of the digestive system was characterized by rapid progress, severe disease and easy to be ignored. It should be closely monitored, diagnosed and treated early to improve the prognosis of patients.
However, this study was a single-centre, retrospective and non-randomized study, the conclusions need to be further confirmed by multi-centre and large-scale clinical studies. In addition, patients need on-going follow-up to draw a more precise conclusion.
Conclusions
This study reported the correlation between the efficacy of bortezomib-based chemotherapy in the treatment of MM and the autonomic neuropathy of the digestive system. The results confirmed that the incidence of bortezomib-related autonomic neuropathy of the digestive system was high, and its severity was closely related to the efficacy, advanced age, constipation, diabetes, fracture/spinal cord compression in bed, and history of alcoholism. Discovery in time and reasonable treatment are necessary to treat the disease and reverse autonomic neuropathy so that more patients can benefit from it.
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No potential conflict of interest was reported by the author(s).
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References
- Cowan AJ, Green DJ, Kwok M, et al. Diagnosis and management of multiple myeloma: A review. JAMA. 2022 Feb 1;327(5):464–477.
- Padala SA, Barsouk A, Barsouk A, et al. Epidemiology, staging, and management of multiple myeloma. Med Sci (Basel). 2021 Jan;9(1):3.
- Terpos E, Katodritou E, de la Rubia J, et al. Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice. Eur J Haematol. 2018 Oct;101(4):556–565.
- Yamamoto S, Egashira N. Pathological mechanisms of bortezomib-induced peripheral neuropathy. Int J Mol Sci. 2021 Jan;22(2):888.
- Goel L, Gupta P, Pahuja M. Mechanistic involvement of inflammation in bortezomib-induced peripheral neuropathy. Comb Chem High Throughput Screen. 2022;25(10):1595–1600.
- Mele G, Coppi MR, Melpignano A, et al. Paralytic ileus following “subcutaneous bortezomib” therapy: focus on the clinical emergency-report of two cases. Clin Exp Med. 2016 Feb;16(1):99–101.
- Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International myeloma working group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–e548.
- Kumar S, Paiva B, Anderson KC, et al. International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328–e346.
- Freites-Martinez A, Santana N, Arias-Santiago S, et al. Using the common terminology criteria for adverse events (CTCAE-version 5.0) to evaluate the severity of adverse events of anticancer therapies. Actas Dermosifiliogr (Engl Ed). 2021 Jan;112(1):90–92.
- Gressin R, Daguindau N, Tempescul A, et al. A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma. Haematologica. 2019;104(1):138–146.
- Keating M, Dasanu CA. Strategy to reduce bortezomib-induced paralytic ileus in patients with myeloma and impaired renal function. BMJ Case Rep. 2016: bcr2016217000.
- Ramsenthaler C, Kane P, Gao W, et al. Prevalence of symptoms in patients with multiple myeloma: a systematic review and meta-analysis. Eur J Haematol. 2016;97:416–429.
- Tathineni P, Cancarevic I, Malik BH. Uncommon presentations of multiple myeloma. Cureus. 2020 Jun;12(6):e8400.
- Mishra SB, Azim A, Mukherjee A. Multiple myeloma presenting as acute pancreatitis. Am J Emerg Med. 2017;35:1385–1381.
- Kadowaki S, Yamaguchi K. Chemotherapy-induced stomatitis and diarrhea. Gan To Kagaku Ryoho. 2011;38(11):1761–1766.
- Tan CRC, Abdul-Majeed S, Cael B, et al. Clinical pharmacokinetics and pharmacodynamics of bortezomib. Clin Pharmacokinet. 2019 Feb;58(2):157–168.
- Jamieson D, Lee J, Cresti N, et al. Pharmacogenetics of adjuvant breast cancer treatment with cyclophosphamide, epirubicin and 5-fluorouracil. Cancer Chemother Pharmacol. 2014 Oct;74(4):667–674.
- Perfetti V, Palladini G, Brunetti L, et al. Bortezomib-induced paralytic ileus is a potential gastrointestinal side effect of this first-in-class anticancer proteasome inhibitor. Eur J Gastroenterol Hepatol. 2007;19(7):599–601.
- Koda Y, Mori T, Shimizu T, et al. Early onset of paralytic ileus caused by simultaneous administration of bortezomib and azole antifungals in multiple myeloma patients. Rinsho Ketsueki. 2012;53(8):760–764.
- Fukushima T, Iwao H, Sakai T, et al. Once-weekly bortezomib plus dexamethasone therapy induced complete response, reducing severe gastrointestinal adverse events for a patient with relapsed multiple myeloma-a case report. Gan To Kagaku Ryoho. 2012;39(5):805–807.
- Fukushima T, Nakamura T, Iwao H, et al. Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events. Anticancer Res. 2011;31(6):2297–2302.
- Zhang QL, Liu YZ, Lin DQ, et al. Clinical analysis of 26 cases of multiple myeloma with intestinal obstruction treated with bortezomib. Zhonghua Xue Ye Xue Za Zhi. 2017;38(07):625–627.
- Hassan Zafar MS, Khan AA, Aggarwal S, et al. Efficacy and tolerability of bortezomib and dexamethasone in newly diagnosed multiple myeloma. South Asian J Cancer. 2018 Jan–Mar;7(1):58–60.
- Scott K, Hayden PJ, Will A, et al. Bortezomib for the treatment of multiple myeloma. Cochrane Database Syst Rev. 2016 Apr;4:CD010816.
- Lee SE, Choi K, Han S, et al. Bortezomib pharmacokinetics in tumor response and peripheral neuropathy in multiple myeloma patients receiving bortezomib-containing therapy. Anticancer Drugs. 2017;28(6):660–668.
- Marathe CS, Jones KL, Wu T, et al. Gastrointestinal autonomic neuropathy in diabetes. Auton Neurosci. 2020 Dec;229:102718.
- Kuźnik E, Dudkowiak R, Adamiec R, et al. Diabetic autonomic neuropathy of the gastrointestinal tract. Prz Gastroenterol. 2020;15(2):89–93.
- Du YT, Rayner CK, Jones KL, et al. Gastrointestinal symptoms in diabetes: prevalence, assessment, pathogenesis, and management. Diabetes Care. 2018 Mar;41(3):627–637.
- Qamar N, Castano D, Patt C, et al. Meta-analysis of alcohol induced gut dysbiosis and the resulting behavioral impact. Behav Brain Res. 2019 Dec;376:112196.