Bortezomib Group Research Articles

The efficacy of Bortezomib-based regimens on survival state in newly diagnosed multiple myeloma patients.

The prognosis of patients with multiple myeloma (MM) has significantly improved over the past ten years because of several innovative treatments, including the proteasome inhibitor Bortezomib and immunomodulatory drugs (IMiDs) like Thalidomide and Lenalidomide. The present study aimed to determine the effectiveness of Bortezomib-based regimens on survival state of MM patients. This retrospective study included 204 newly diagnosed MM patients who were registered at Nanakali Hospital for Blood Diseases and Cancer, Erbil- Iraq, between April 2008 and April 2022. The patients were split into two primary groups: those receiving treatment with Bortezomib and those not. Clinical and laboratory data, treatment type, responsiveness to induction therapy, and survival results were examined in the enrolled patients' medical records. The mean patient age was 60 years, males constituted 55.8% of the included patients. At the time of diagnosis, 98 individuals (48%) had stage 3 illness. Except for the LDH, which was noticeably higher in the non-Bortezomib group, the patients laboratory results did not substantially change between the Bortezomib and non-Bortezomib groups (p = 0.001). In patients treated with Bortezomib, the complete response (CR) rate following induction was substantially greater (35.2%) than in those treated without Bortezomib (9.1%). Compared to the non-Bortezomib group, the median survival time of the Bortezomib group was considerably greater (p < 0.001). Bortezomib has a significant role in inducing a CR before bone marrow (BM) transplantation, and it has a significant role in the survival outcome in MM.

#1714 The treatment of antibody-mediated rejection in kidney transplantation with recent drugs: a network meta-analysis

Abstract Background and Aims The recent treatments for antibody-mediated rejection (AMR) have been carried out in a small number of controlled clinical trials and are based on limited data. In recent research on AMR treatment, new drugs targeting B cells, plasma cells, the complement system, and IL-6 have been gaining attention. Method Studies on antibody mediated rejection (AMR) treatment were divided into four groups:, 1) rituximab, 2 bortezomib, 3 eculizumab, and 4) tocilizumab. We searched the CENTRAL, MEDLINE, EMBASE, and Science Citation Index Expanded databases from 1970 to February 2023.5. We performed direct and indirect network meta-analyses using Bayesian models and ranked different AMR treatment method using a generation mixed treatment comparison (GeMTC) and Stata version 13. The outcomes included patient survival, graft failure, and bacterial and viral infections Results This analysis included 21 clinical trials with a total of 1217 participants. We focused on graft failure events based on the use of four groups of medications when patients received induction therapy for AMR treatment. There was a lower tendency in graft failure rates in the bortezomib and tocilizumab groups (odds ratio [OR] 0.31, 95% CrI: 0.058-1.4 and OR 0.42, 95% CrI 0.012-7.4), while the eculizumab group showed a higher graft failure rate (OR 2.3, 95% CrI 0.26-31.0) compared to the rituximab using group. However, these study results were not statistically significant. Conclusion When looking at the study results, although not statistically significant, it was observed that bortezomib and tocilizumab, compared to rituximab, showed a tendency to reduce the incidence of graft failure after AMR occurrence. Although this study did not demonstrate statistical significance, it is believed that future research with increased enrollment and additional studies may help identify effective drugs for AMR treatment.

Efficacy and Safety of Bortezomib or Thalidomide Combined with rhEPO in the Treatment of Multiple Myeloma

To explore the efficacy and safety of bortezomib or thalidomide combined with recombinant human erythropoietin (rhEPO) in the treatment of multiple myeloma (MM). A total of 80 patients with MM who were treated in the Second People's Hospital of Wuhu from January 2013 to December 2018 were selected as the research subjects, and they were divided into bortezomib group (n=40) and thalidomide group (n=40) by the simple randomization method. The bortezomib group received bortezomib regimen combined with rhEPO therapy, and the thalidomide group was given thalidomide regimen combined with rhEPO therapy, and all patients were treated for 3 courses with every 3 weeks as a course of treatment. The clinical efficacy after 3 courses of treatment, and tumor-related biochemical indicators [lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), vascular endothelial growth factor (VEGF), apoptosis inhibitory protein Survivin], bone marrow-related indicators [serum M-protein, bone marrow plasma cells, hemoglobin (Hb)] and coagulation function indicators [activated partial thromboplastin time (APTT), prothrombin time (PT), plasminogen activator inhibitor (PAI), total circulating microparticles (TMPs)] before treatment and after 3 courses of treatment were compared between the two groups of patients. The occurrence of adverse reactions during the treatment in the two groups of patients was recorded. After 3 courses of treatment, the ORR rate of 92.5% in bortezomib group was higher than 90.0% in thalidomide group, but the difference was not statistically significant (P >0.05). The levels of LDH, β2-MG, VEGF, Survivin, serum M-protein, bone marrow plasma cells, APTT, PT, PAI and TMPs in the two groups after 3 courses of treatment were significantly lower or shorter than those before treatment, and the above indicators in bortezomib group were significantly lower or shorter than those in thalidomide group (P <0.05). After 3 courses of treatment, the expression level of Hb in the two groups was significantly higher than that before treatment, and the Hb level in bortezomib group was significantly higher than that in thalidomide group (P <0.05). During the treatment process, the incidence rates of adverse reactions in bortezomib group were significantly lower than those in thalidomide group (P <0.05). Thalidomide regimen or bortezomib regimen combined with rhEPO has similar clinical efficacy on MM, but bortezomib regimen combined with rhEPO is more prominent and safer on improving tumor-related biochemical indicators, bone marrow-related indicators and coagulation status in patients with MM.

Neurotropin Alleviates Bortezomib-Induced Neurotoxicity Via Microglial Neuroinflammation

Objective: To investigate the effect of neurotropin (NTP) on the prevention and amelioration of neurotoxicity induced by bortezomib (BTZ)-based chemotherapy regimens and the possible mechanism of action, and to provide new ideas for the prevention mechanism and treatment of bortezomib-induced peripheral neuropathy (BIPN). Methods: The BIPN model was constructed by injecting bortezomib （ BTZ group ）or bortezomib+saline ( BTZ+NS group)into the tail vein of C57BL/6 mice. After successful modeling, NTP was added to take intraperitoneal injections for 4 weeks, which were defined to be NTP group. In order to assess the severity of BIPN, systemic toxicity, pain behavioral and sensorimotor kinetic changes in mice of different group were observed while transmission electron microscopy examination was used to observe the damage of peripheral nerve ultrastructure and myelin thickness. Immunofluorescence staining method was used to detected the activation of spinal cord microglial and their expression level of inflammatory factors such as IL-1β, IL-6 and TNF-α. ELISA was used to detected the expression of IL-1β, IL-6 and TNF-α in the dorsal horn homogenate of the spinal cord; Western blot to detect the protein expression of pathway-associated proteins JAK/STAT. Results: The Compared with the Control group, the BTZ and BTZ+NS groups showed significant decreases in mechanical, thermal pain thresholds and motor coordination compared with the Control group (P&amp;lt;0.05), and ultrastructural damage to the peripheral nerves, with demyelinating lesions and a significant reduction in the overall thickness of myelin sheaths in myelinated fibers (0.62±0.08 Vs 0.56±0.12, P＜0.01). NTP administration significantly improved pain behavioral changes, reduced ultrastructural damage, reversed demyelinating lesions and significantly increased myelin thickness (0.56±0.06 Vs 0.62±0.08, P＜0.01) in model mice compared with BTZ group. Immunofluorescence staining suggested that microglia in the dorsal horn of the spinal cord of mice in the BTZ group and the BTZ+NS group were significantly activated, which were shown the fluorescence ratio of IBA-1 + was significantly increased (2.55±0.61 Vs 0.55±0.04，2.42±0.89 Vs 0.55±0.04，P＜0.0001), while NTP significantly improved the activation of microglia in the model mice (0.71±0.13 Vs 2.55±0.61, 0.71±0.13 Vs 2.42±0.89, P&amp;lt;0.0001). The co-staining results suggest that the increase in inflammatory factors may originate from microglia. ELISA results that the expression level of IL-6 and TNF-α in NTP administration group significantly decreased compared with the group of BTZ group (IL-6: 37.87±23.2 Vs 111.8±6.0, P＜0.05; TNF-α: 547.9±17.11 Vs 998.8±333.4, P＜0.05) and the BTZ+NS group (IL-6: 37.87±23.2 Vs 88.3±15.58, P&amp;lt;0.05; TNF-α: 547.9±17.11 Vs 768.3±37.45, P&amp;lt;0.05) in the dorsal horn homogenate of the spinal cord. The results of spinal cord proteomics showed that neurotropin could induce the changes of differential proteins, such as PI3K-AKT, MAPK, JAK/STAT, which were related to inflammation. Moreover, these differential proteins can be significantly enriched in the JAK/STAT KEGG Pathway. The KEGG pathway of differential protein enrichment in the spinal cord of differential BIPN mice was detected by proteomics chip after NTP treatment, and the JAK/STAT pathway was significantly down-regulated after NTP treatment. Western blot showed that the protein expression of JAK1/STAT3 decreased after NTP administration. Conclusion: Neurotropin alleviates bortezomib induced neurotoxicity through microglial neuroinflammation, and may reduce the release of glial inflammation by regulating JAK1/STAT3 signaling pathway, thus playing a therapeutic role in BIPN. Repeated experiments are needed for further research. Keywords: Neurotropin, Bortezomib, Peripheral neuropathy, Neuroinflammation

Impact of Concomitant Use of Azoles on Bortezomib-related Adverse Drug Reactions Using JADER.

Azoles are widely used for prophylaxis in patients with haematologic malignancies and are well known as selective cytochrome P450 isoenzyme 3A4 inhibitors. Although the interaction between bortezomib and azoles has been reported, most previous studies were case reports or small clinical studies. Hence, we conducted a pharmacoepidemiological study to elucidate the impact of azoles on bortezomib-related adverse reactions, using the Japanese adverse drug event report database (JADER). We extracted 19,567 reports on patients prescribed bortezomib and/or azoles. We classified cases into three groups, namely bortezomib, bortezomib and azoles, and azoles groups. We estimated the odds ratios (OR) for the impact of concomitant azole use on five bortezomib-related adverse drug reactions (peripheral neuropathy, thrombocytopenia, neutropenia, leukopenia, and interstitial lung disease) using logistic regression. The OR for peripheral neuropathy in the 'bortezomib and azoles' group was higher than that in the bortezomib group [OR=2.02, 95% confidence interval (CI)=1.32-3.08]. The magnitude of the interaction was stronger with itraconazole than that with fluconazole (itraconazole, OR=3.22, 95% CI=1.78-5.70; fluconazole, OR=1.56, 95% CI=0.86-2.72). We found an association between concomitant administration of azoles with bortezomib and peripheral neuropathy. Azoles may enhance bortezomib-induced peripheral neuropathy based on their pharmacokinetic properties.

IL-6 Regulates the Chemosensitivity of Drug-Resistant Multiple Myeloma Cell Lines to Bortezomib through STAT3/Notch Signaling Pathway

To investigate the effect of interleukin-6 (IL-6) on the chemosensitivity of drug-resistant multiple myeloma (MM) cell lines to bortezomib (BTZ) and its mechanism. Peripheral blood samples were collected from patients with BTZ-resistant MM before and after treatment. Human MM cell lines KM3 and KM3/BTZ were cultured in vitro. ELISA was used to detect the content of IL-6 in peripheral blood of MM patients, KM3 and KM3/BTZ cells. CCK-8 assay was used to detect the drug sensitivity of KM3 and KM3 / BTZ cells to BTZ. KM3 / BTZ cells were divided into KM3/BTZ control group (normal culture for 48 h), IL-6 neutralizing antibody Anti-IL-6 group (500 ng/ml Anti-IL-6 treated for 48 h), BTZ group (300 ng/ml BTZ treated for 48 h), BTZ + Anti-IL-6 group (300 ng/ml BTZ and 500 ng/ml Anti-IL-6 treated for 48 h). The proliferation activity of KM3 / BTZ cells was detected by CCK-8 assay. The cell cycle distribution of KM3/BTZ cells was detected by flow cytometry. The apoptosis of KM3/BTZ cells was detected by Annexin V-FITC/PI double staining. The mRNA expression levels of IL-6, Notch1, signal transducer and activator of transcription 3 (STAT3) in KM3/BTZ cells were detected by real-time fluorescent quantitative PCR (qRT-PCR), and the protein expression levels of IL-6, Notch1, STAT3 in KM3/BTZ cells were detected by Western blot. The level of IL-6 in peripheral blood of patients with BTZ-resistant MM after treatment was significantly higher than that before treatment (P<0.05). The level of IL-6 in KM3/BTZ cells was significantly higher than that in KM3 cells (P<0.05). The sensitivity of KM3/BTZ cells to BTZ was significantly lower than that of KM3 cells (P<0.05), and the resistance index (RI) was 19.62. Anti-IL-6 and BTZ could inhibit the proliferation of KM3 / BTZ cells, block cell cycle, and induce apoptosis (P<0.05). Compared with single drug treatment, the combined effect of Anti-IL-6 and BTZ was more obvious on KM3/BTZ cells (P<0.05), and significantly down regulated the mRNA and protein expression of IL-6, Notch1 and STAT3 in KM3/BTZ cells (P<0.05). Antagonizing IL-6 can increase the chemosensitivity of MM cells to BTZ, and IL-6 may reduce the sensitivity of MM cells to BTZ through STAT3/Notch signaling pathway.

Effect of bortezomib on fatty liver in a rat model of atherosclerosis

Introduction and Aim: Fatty liver is associated with atherosclerosis even though the exact mechanism remains unknown. Fatty liver and atherosclerosis correlate with inflammation. Interleukin 6 (IL-6) is recognized as an inflammatory marker. Bortezomib is a proteasome inhibitor that will inhibit the proteasome pathway and is expected to inhibit inflammation in atherosclerosis. The current research aimed to investigate the effect of bortezomib on the fatty liver of atherosclerosis rats and to analyze its correlation with serum IL-6 concentration. Materials and Methods: Experimental subjects were 18 male Wistar rats (Rattus novergicus) divided into three treatment groups, namely atherosclerosis group (I), atherosclerosis + bortezomib group (II), and control group (III). Bortezomib (50 ?g/kg BW) was given twice intraperitoneally, on day 1 and day 3. The presence of fatty liver was evaluated using the percentage system. Serum IL-6 concentrations were measured using enzyme-linked immunosorbent assay kits. Results: The highest amount of fatty liver was found in the atherosclerosis group (group I) (38.33%), while the lowest was in the control group (group III) (5.83%). There was a decreasing fatty liver percentage due to bortezomib administration (group II) (29.17%), and it was statistically significant. There is a significant correlation between the degree of fatty liver and serum IL-6 concentration. Conclusion: The administration of bortezomib 50 ?g/kg BW in atherosclerosis model rats can reduce the occurrence of fatty liver by reducing the inflammatory process.

Effect of Bortezomib administration on autophagic cell death in colorectal cancer cells

Colon cancer is the most common cancer type after breast and prostate cancer in humans. Bortezomib is a proteasome inhibitor and is commonly preferred for the treatment of some types of cancer due to its efficiency and lower side effects. This study has investigated the impact of Bortezomib on cell death regarding the stimulation of autophagy. Bortezomib (Velcade) was treated to colorectal cancer cells (HT-29) for 24 hours at different concentrations (10 nM, 20 nM, and 40 nM). MTT analysis was used to determine the viability of Bortezomib-treated HT-29 cells, and immunocytochemical methods were used to determine bortezomib’s effects on the expression of Beclin-1 and LC3 levels in the HT-29 cells. In MTT analysis, viability was decreased with an increase in bortezomib concentration and the lowest viability was found at 40 nM concentration. In the study, Beclin-1 immune reactive cells were seen as higher in 10nM and 40 nM concentrations of Bortezomib than other groups. Additionally, in LC3 evaluation, the immune reactive cell density was the highest at 40 nM concentration of Bortezomib (p&lt;0.05). However, the LC3 immune reactivity was higher at 20nM and 40 nM concentrations of bortezomib groups (p&lt;0.05). The findings revealed that the treatment of Bortezomib leads to an increase in levels of LC3 and Beclin-1 and activate the autophagy in colon cancer cells.

Bortezomib-Induced Ovarian Toxicity in Mice.

Cancer survivors may experience long-term adverse effects of cancer treatments such as premature ovarian failure and infertility. We aimed to investigate the potential effects and toxicity of bortezomib (BTZ) as an effective anticancer drug on ovaries, raise awareness to the negative consequences of the treatment, and help increase the quality of life after treatment. Mice were distributed into bortezomib (BTZ1, BTZ2) and saline-injected control groups (C1, C2) at a dose of 1 mg/kg twice per week for 6 weeks. We sacrificed C1, BTZ1 groups at day 1 and C2, BTZ2 groups at 4 weeks after the last injection. Ovary samples were examined using histopathological and immunohistochemical methods. Ovarian follicle impairment was detected on BTZ-treated mice and was associated with a statistically significant decreased population of primordial and antral follicles compared with control groups. In experimental groups, Caspase-3 and Ki67 expressions were increased, whereas estrogen receptor alpha (ERα) and progesterone receptor (PR) expressions were decreased in various developmental stages of follicles. BTZ specifically targets granulosa cells by inducing granulosa cell apoptosis and may have long-term effects on follicles. Bortezomib treatment may adversely affect ovarian function by accelerating ovarian reserve depletion and changing ERα and PR hormone levels that can cause fertility problems in the long term.

The Prognostic Role of Cyclin D1 in Multiple Myeloma: A Systematic Review and Meta-Analysis.

Purpose: Cyclin D1 has been identified as a proto-oncogene associated with the uncontrolled proliferation of tumor cells. This systematic review and meta-analysis aims to estimate the prognostic significance of cyclin D1 in multiple myeloma (MM) patients. Method: We searched for qualified data in PubMed, Embase, and Web of Science up to February 2020. Data quality was assessed by the Newcastle-Ottawa scale (NOS). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were used to evaluate the relationship between cyclin D1 expression and overall survival (OS), progression-free survival (PFS)/event-free survival (EFS) in patients with MM. Result: A total of 13 studies involving 961 patients were included. Overall, pooled analysis revealed significant heterogeneity between cyclin D1 expression and the prognosis of MM (OS, HR = 1.08, 95% CI: 0.71-1.64, I2 = 67.9%; PFS/EFS, HR = 0.97, 95% CI: 0.49-1.93, I2 = 85.8%). Subgroup analysis revealed that the prolongation of OS was relevant to increased expression of cyclin D1 in MM patients in the relapsed and refractory group (OS, HR = 0.46, 95% CI: 0.24-0.90). Another subgroup assessment of OS established that MM patients with CCND1 overexpression in the bortezomib group had longer survival time (HR = 0.30, 95% CI: 0.11-0.82), whereas, those overexpressing CCND1 in the conventional chemotherapy group had poor prognosis (HR = 2.19, 95% CI: 1.18-4.08). We also found that increased cyclin D1 expression correlated favorably with PFS in the autologous stem cell transplantation (ASCT) (HR = 0.45, 95% CI: 0.28-0.73) or reverse transcription-polymerase chain reaction (RT-PCR) group (HR = 0.41, 95% CI: 0.26-0.64). Conclusion: The result of this meta-analysis suggested that CCND1 overexpression might be a predictive biomarker for MM patients when treated with bortezomib, receiving ASCT, or in relapsed and refractory period.

Effect of Proteasome Inhibitor on Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intercellular Adhesion Molecule-1 (ICAM-1) Expressions in Rat Model of Atherosclerosis.

The effect of proteasome inhibitors on atherosclerosis is known to vary depending on the atherosclerosis stage. Previous studies have shown that the highest proteasome expression in atherosclerotic lesions is at the progression stage. Adhesion molecules play a role in the progression stage of atherosclerosis, but no studies have analyzed the effect of proteasome inhibitors on the expression of adhesion molecules at this stage. This experimental study aimed to analyze the effect of a proteasome inhibitor, namely bortezomib, on the vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule1 (ICAM-1) expressions in blood vessels of rat model of atherosclerosis at the progression stage. This study used 18 male Wistar rats divided into three groups, i.e. group I that is the control group given standard feed, group II induced by atherosclerosis, and group III induced by atherosclerosis and given bortezomib. Atherosclerosis induction was performed using vitamin D3 (700,000 IU/kg) orally by gastric intubation on the 1st day and atherogenic feed given for four days. Bortezomib 50 µg/kgBW/day was administered intra-peritoneally. The expression of VCAM-1 and ICAM-1 molecules was measured using immunohistochemistry and analyzed quantitatively using Adobe Photoshop software. The statistical test showed differences in VCAM-1 expression between atherosclerosis + Bortezomib group and atherosclerosis group, but there were no differences in the expression of ICAM-1 and atherosclerotic lesions between the groups. Administration of bortezomib 50μg/kg for four days in progressive atherosclerosis model rats can inhibit VCAM-1 expression, although it does not affect ICAM-1 expression and cannot inhibit atherosclerotic lesion formation.

Deep Learning-Based CT Imaging in Diagnosing Myeloma and Its Prognosis Evaluation.

Imaging examination plays an important role in the early diagnosis of myeloma. The study focused on the segmentation effects of deep learning-based models on CT images for myeloma, and the influence of different chemotherapy treatments on the prognosis of patients. Specifically, 186 patients with suspected myeloma were the research subjects. The U-Net model was adjusted to segment the CT images, and then, the Faster region convolutional neural network (RCNN) model was used to label the lesions. Patients were divided into bortezomib group (group 1, n = 128) and non-bortezomib group (group 2, n = 58). The biochemical indexes, blood routine indexes, and skeletal muscle of the two groups were compared before and after chemotherapy. The results showed that the improved U-Net model demonstrated good segmentation results, the Faster RCNN model can realize the labeling of the lesion area in the CT image, and the classification accuracy rate was as high as 99%. Compared with group 1, group 2 showed enlarged psoas major and erector spinae muscle after treatment and decreased bone marrow plasma cells content, blood M protein, urine 24 h light chain, pBNP, ß-2 microglobulin (β2MG), ALP, and white blood cell (WBC) levels (P < 0.05). In conclusion, deep learning is suggested in the segmentation and classification of CT images for myeloma, which can lift the detection accuracy. Two different chemotherapy regimens both improve the prognosis of patients, but the effects of non-bortezomib chemotherapy are better.

Comparison of Proteasome Inhibitors-Induced Cardiotoxicity (carfilzomib vs. bortezomib): Insights into the Molecular Mechanisms

Introduction: Proteasome inhibitors are widely used for the treatment of multiple myeloma (MM). Carfilzomib is an irreversible proteasome inhibitor, which has been licensed for the treatment of relapsed/refractory MM. In phase 3 trials, carfilzomib has been associated with higher heart failure and cardiotoxicity rates (grade ≥3: 4-6%) compared with the reversible inhibitor, bortezomib (grade ≥3: <2%). However, the mechanisms of heart damage by carfilzomib have not been fully identified yet. The aim of this study was to investigate the molecular mechanisms of carfilzomib-induced cardiotoxicity compared to bortezomib in vivo .Methods: Male C57BL/6 mice, 12 weeks old, were randomized into the following groups: 1. Control group (Ν/S 0.9%, n=7); 2. Bortezomib group (1mg/kg ip, n=9); 3. Carfilzomib group (8 mg/kg ip, n=8). Drugs were administered every 48 hours for 6 days. At baseline and at the end of treatment the mice underwent echocardiographic assessment. Animals were sacrificed and blood and myocardial tissue samples were obtained for the analysis of proteasome peptidases activity, signaling pathways and molecular mechanisms. Protein kinase Akt, along with its downstream NO synthases; endothelial (eNOS) and inducible (iNOS), were identified as targets of possible endothelial dysfunction and inflammation. Moreover, the transcription factor FOXO1, downstream target of Akt and AMPKα, was identified in order to investigate possible changes in the expression of apoptotic factors. Finally, AMPKα was identified since - besides phosphorylating eNOS and FOXO1 - it functions as a regulator of autophagy. Blood samples were used to measure levels of malondialdehyde (MDA), a marker for oxidative stress (lipid peroxidation).Results: Administration of bortezomib or carfilzomib resulted in significant reduction of the assayed chymotrypsin-like (CT-L) and caspase-like (C-L) proteasomal peptidase activities in the hearts of treated mice vs . controls. Echocardiography at day 6 demonstrated a statistically significant reduction in the fractional shortening (FS) in the carfilzomib group compared to the bortezomib and control groups (39.87±0.47% vs. 42.10±0.82% and 42.05±0.64 respectively, p <0.05). Western blot analysis in the carfilzomib group demonstrated a decrease in pAkt/tAkt (0.54 fold change of control, p<0.05), pAMPKα/tAMPKα (0.05 fold change of control, p<0.001) and peNOS/teNOS (0.41 fold change of control, p<0.05) levels and an increase in the expression of iNOS (5.16 fold change of control, p<0.01) compared to the control group. In contrast, no statistically significant differences were observed in the above mentioned signaling molecules between bortezomib and control. In the carfilzomib group a decrease in pAkt/tAkt (36.73% of bortezomib, p<0.001), pAMPKα/tAMPKα (4.07% of bortezomib, p<0.0001) and an increase in the expression of iNOS (607.06% of bortezomib, p<0.01) compared to the bortezomib group was observed. Levels of pFOXO1/tFOXO1 decreased in both carfilzomib and bortezomib groups versus the control group (0.24 and 0.26 fold change of control respectively, p<0.001). Interestingly, in the bortezomib group, reduction in body weight (median 20.10 mg; range 18.20 to 25.20 mg) versus control (median 24.80 mg; range 24.00 to 26.80 mg; p<0.01) and carfilzomib (median 23.60 mg; range 22.20 to 25.20 mg; p<0.05)) and increased levels of MDA in plasma (median 13.08 uM; range 8.09 to 17.21 uM), versus control (median 8.30 uM; range 5.30 to 10.86 uM; p<0.05) and carfilzomib (median 6.18 uM; range 4.89 to 7.79 uM; p<0.01), combined with a 43.75% increase in mortality (compared to zero mortality in carfilzomib and control groups), were observed.Conclusion: The present study demonstrates that carfilzomib induces cardiac dysfunction via interfering with the Akt/eNOS axis and via simultaneous increase of iNOS, leading to possible endothelial dysfunction and inflammation. Importantly the decrease of phosphorylation of AMPKα observed in the carfilzomib group seems to be an essential mechanism for carfilzomib induced FS reduction. Moreover, AMPKα and Akt inhibition results in decreased FOXO1 phosphorylation with possible induction of apoptosis and autophagy. On the contrary bortezomib seems to cause premature death in the mice through a different mechanism that requires further investigation. DisclosuresKastritis:Takeda: Honoraria; Amgen: Research Funding; Genesis: Honoraria; Janssen: Honoraria, Research Funding. Dimopoulos:Genesis Pharma: Research Funding; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Novartis: Consultancy, Honoraria. Terpos:Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: SC member; GSK: Honoraria; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; Amgen: Honoraria, Other: SC member, Research Funding; BMS: Honoraria; Abbvie: Honoraria.

The Significance of Flow Cytometry and Positron Emission Tomography and Computed Tomography (PET-CT) in the Assessment of the Minimum Residual Disease in Patients with Multiple Myeloma

Background.The minimal residual disease (MRD) status is the single posttreatment predictor of long-term outcomes after treatment in patients with multiple myeloma (MM), regardless of the treatment protocol or the presence of other pre-existing prognostic indicators. Traditionally, the method of evaluating MRD is multicolor flow cytometry (MFC), which has high sensitivity and specificity. Another way of detecting MRD is by the use of positron emission tomography and computed tomography (PET-CT) through the detection of possible patchy bone marrow infiltration or extramedullary involvement with an MRD-negative (MRD-) bone marrow. Aim.To determine the frequency of MRD- status by MFC and PET-CT and evaluate influence of MRD on the progression-free survival (PFS) in multiple myeloma patients. Methods.We analyzed 55 patients with MM (median age 56 years, male/female - 1.4:1). The induction therapy with Bortezomib-based regimens (VD, CVD, VMP, PAD) was used in 37/55 (67.3%) patients, Immunomodulator-based regimens (Thal+D, RD, VRD, PomD) - in 15/55 (27.3%), chemotherapy - in 3/55 (5.4%). Autologous stem cell transplantation (ASCT) was performed 32 (58.2%) patients. For definition of primary tumor cell's phenotype and assessment of MRD we used 5-color flow cytometry with CD38, CD138, CD45, CD19, CD20, CD27, CD56 and CD117 antibodies. MRD status by MCF and/or PET-CT was evaluated after 4-6 cycles of induction therapy or after ASCT, if it (ASCT) was performed. The MFC MRD- response was evaluated as identification less than 0.01% of clonal plasma cells in bone marrow. The PET-CT MRD- response was established if specific accumulation of 18F-fluorodeoxyglucose was absent. Results.The MFC MRD- was reached in 29.1% (16/55): “Bortezomib group” - 35.1% (13/37), “Immunomodulator group” - 13.3% (2/15) (Chi-square=2.472; p>.05). After ASCT MRD- status was achieved in 36.4% (4/11) patients. Maintenance therapy with bortezomib or lenalidomide did not affect the achievement of the MFC MRD- in patients with MRD-positive (MFC MRD+) response. Median PFS in MFC MRD+ group was 21 months, in the MFC MRD- - 66 months (p=.0042). Patients with a low amount residual plasmatic cells after therapy had longer PFS: ˂0.01% - 66 months, 0.01%-0.1% - 48 months at, 0.1%-1% - 22 months, ˃1% - 10.5 months (p=.0002).The PET-CT MRD- was reached in 36.4% (8/22) patients. Median PFS in PET-CT MRD+ group was 20 months, in the PET-CT MRD- - 23 months (p >.05).Integrated assessment of MRD by PET-CT and MFC was performed in 22 patients. Interesting, that median PFS in the MFC MRD- PET-CT MRD- group (n=5) was not achieved, in the other groups (MFC MRD+ PET-CT MRD-, MFC MRD- PET-CT MRD+, MFC MRD+ PET-CT MRD+) was 23 months (n=15) (p=.03). Conclusion .The presence of MRD after induction therapy is unfavorable prognostic factor in patients with multiple myeloma. Currently, multiparameter flow cytometry is the most sensitive approach to detect MRD in bone marrow. The role of PET-CT in the assessment of MRD is not completely understood. However, the combined use of both methods for evaluation of MRD and their prognostic potential is a promising scientific direction. DisclosuresShuvaev:Fusion Pharma LLC: Consultancy.

Efficacy and Toxicity Profile of Carfilzomib Based Regimens for Treatment of Multiple Myeloma, a Systematic Review

Background: Standard induction therapy for Multiple Myeloma (MM) is triple combination therapy based on three classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has serious issues of peripheral neuropathy (PN) with incidence of grade ≥ 3 PN reported between 2% to 23%. A novel proteasome inhibitor, carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PN. CFZ has been approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. We conducted comprehensive literature search to summarize efficacy, dosing and toxicity profile of CFZ in newly diagnosed and relapsed MM.Methods: Database search using PubMed, EMBASE, Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov was performed on 6/5/2017. Phase II/III clinical trials from last 10 years and focusing on CFZ as primary drug therapy were included.Results: Literature search identified a total of 1839 articles. Twenty-six articles met the inclusion criteria (15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group) with a total of 5980 patients (4205 in RRMM and 1775 in NDMM group).For heavily pre-treated RRMM patients with median 5 prior lines of therapy, 20/27 mg/m2 of single agent CFZ produced outcomes ranging from 3.5 to 5.1 months of progression free survival (PFS), 16.7% to 23.7% of overall response rate (ORR) and 16% to 18.3% of partial response (PR). Higher dose 20/56 mg/m2 of CFZ in Kd (carfilzomib + dexamethasone) regimen produced PFS of 4.1 months and ORR of 55% in patients with 5 prior lines of therapy. Even higher 20/70 mg/m2 dose of CFZ in Kd regimen produced ORR of 77% and PFS of 12.6 months in patients with 1 prior therapy. ENDEAVOR and ASPIRE trials reported PFS of 18.7 months with Kd vs 9.4 months with Vd (bortezomib and dexamethasone) and 26.3 months with KRd (carfilzomib, lenalidomide and dexamethasone) vs 17.6 months with Rd (lenalidomide and dexamethasone) respectively, in patients with median 2 prior lines of therapy.CFZ in front line setting achieved high response rates. In NDMM, most commonly studied regimen was CFZ in combination with lenalidomide and dexamethasone (KRd) with 4 phase II and 1 phase I/II trial (n= 268). Their outcomes range from 96% to 98% ORR, 83% to 97% overall survival (OS) and 92% to 97% of 2-year PFS. Likewise, outcomes of other CFZ based regimens, 6 phase II and 3 phase I/II trials (n= 552) range from 72% to 97% ORR. Data on overall survival (OS) and progression free survival (PFS) was either not reported or reported at 2 or 3-year interim analysis. Observed PFS in a recent phase III trial comparing CFZ, melphalan and prednisone (KMP) with bortezomib, melphalan and prednisone (VMP) was 22.3 months vs 22.1 months respectively.Most common grade ≥3 AE were hematologic. Incidences of non-hematologic grade ≥ 3 AE include heart failure (3.4% to 20%), acute renal failure (3.4% to 9%), HTN (4.3% to 25%) and PNP (<1% to 1.1%). ENDEAVOR reported significantly higher incidence of ≥2 PNP in bortezomib group (32%) vs 6% in carfilzomib group. ENDEAVOR trial using serial echocardiograms reported no increased risk of cardiotoxicity and ventricular dysfunction with CFZ vs bortezomib.Conclusion: CFZ demonstrates comparable if not higher efficacy to bortezomib with much favourable adverse effect (AE) profile. Most common grade ≥ 3 AE were hematologic that usually don't require dose changes or discontinuation of therapy. High incidence of grade ≥3 HTN deserves attention and underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20/27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20/56 and 20/70mg/m2 dose of CFZ vs standard 20/27mg/m2 dose.All trials except one on CFZ for NDMM were phase II clinical trials with data available mostly as abstracts. So, there was insufficient data available to compare studies. Deep, rapid and sustainable response with KRd with lower incidence of crippling PN strongly supports extension of KRd therapy to frontline setting. More data from phase III trials is needed for head to head comparison of KRd vs other regimens like bortezomib, lenalidomide and dexamethasone (RVd) for treatment of NDMM. CFZ should be tested in combination with other available drugs like daratumumab and pomalidomide. [Display omitted] DisclosuresAbraham:Janssen Oncology (Johnson & Johnson, LLC): Consultancy.

Suppression of Cdc37 Induces BTZ Resistance through XBP1s Mediated Plasma Cell Immaturation in Multiple Myeloma

Backgrounds: Cell division cycle protein 37 (Cdc37) is considered as a key co-chaperone of heat shock protein 90 (Hsp90), guiding the stabilization and activation of client kinases with time specificity and substrate selectivity. Previous studies have demonstrated that Cdc37 is over-expressed in many kinds of cancers, contributing to the tumorigenesis. However, our previous study suggested that some MM cell population with low expression of Cdc37 was correlated with BTZ resistance in clinical MM samples and in vitro study. The purpose of this study is to investigate how Cdc37 contributes to drug resistance in MM.Materials and methods: Nineteen sequential MM samples with gene expression profiling (GSE19554) obtained from published studies were analyzed. The expression of Cdc37 was investigated in MM cell lines and primary CD138+ cells by qRT-PCR. Cdc37 function was then interrupted by Cdc37 shRNA or Hsp90-Cdc37 inhibitor Celastrol in MM cell line. Sensitivity of BTZ was evaluated. Bone marrow MM cells were enriched and gated into subpopulations by CD38 and CD138 status by FACS. CD38+CD138+ plasma cells, CD38+CD138- plasmablasts and CD38-CD138- B cells were examined for Xbp1s and Cdc37 expression by qRT-PCR and IF. Then cellular morphology, supernatant light chain immunoglobulin and makers of plasma cell maturation were checked when MM cells were exposed to Celastrol or underwent Xbp1s overexpression. Finally, the in vivo verification was carried out in 5TGM1 mouse model.Results: The GEP analysis showed that Cdc37 was down-regulated as the progression of MM (base line, pre-1st transplantation, pre-2nd transplantation, post-2nd transplantation) in 13 out of 19 sequential samples. Our results also showed that some relapsed MM patients had a down-regulated Cdc37 expression compared with newly diagnosed cases (0.78±1.13 vs 0.25±1.05, p <0.05). Moreover, Cdc37 was only suppressed in bortezomib (BTZ) resistant cell line ANBL-6. BR compared with their wild type ANBL-6.WT. While there were no significant differences between doxorubicin-, dexamethasone- resistant cell line. Indeed, suppression Cdc37 in MM cell line by Cdc37-shRNA or Celastrol resulted in a lower apoptosis rate after BTZ treatment. These results indicated that Cdc37 may participate in BTZ resistance.To explore the mechanism of Cdc37 mediating BTZ resistance, we tried to determine if Cdc37 suppression might cause immaturity of plasma cells, which is well established to cause MM cells resistant to BTZ. Cdc37 expression was first found to be positively correlated with Xbp1s in primary MM cells (r=0.61, p <0.001). Then CD38+CD138+ plasma cells, CD38+CD138- plasmablasts and CD38-CD138- B cells were examined for Xbp1s and Cdc37 and showed that Cdc37 and Xbp1s were gradually up-regulated during the maturation of plasma cells in 3/5 patients. The results indicated that Cdc37 may induce BTZ resistancethroughXBP1s mediated plasma cell immaturation.To certify our hypothesis, Cdc37-Hsp90 interaction were interrupted with Celastrol, NCI-H929 cells appeared smaller and rounder with larger nucleus, less cytoplasm, resembling plasmablast. ELISA analysis also demonstrated a decreased secretion of free light chain from MM cells. Partial repression of plasma cell maturation markers, such as Xbp1s, Chop, CD49e were also observed when Cdc37 was inhibited in NCI-H929 cells. However, the above changes were reversed when Xbp1s was overexpressed in MM cells. In vivo, the serum IgG2b level was (146.8±4.0) ng/ml and (166.0±13.0) ng/ml (p<0.05) in BTZ group and BTZ+Celastrol group, respectively. Although statistical significance were not reached, the BTZ+Celastrol group showed a shorter overall survival compared with BTZ group.Conclusion: Our results demonstrated that Cdc37 downregulation may result in BTZ resistance through Xbp1s mediated plasma cell immaturation. These findings provide a certain theoretical reference for the proper combination of BTZ and other therapy, forcing BTZ resistant cells differentiation, to fight against BTZ resistance. More importantly, Cdc37 may provide a diagnostic biomarker for predicting BTZ sensitivity prior to treatment. DisclosuresNo relevant conflicts of interest to declare.

Relapsed or Refractory Multiple Myeloma Patients Treated with Second-Line Carfilzomib and Categorized By Prior Exposure to Bortezomib: A Subgroup Analysis of the Randomized Phase 3 Aspire and Endeavor Trials

Relapsed or Refractory Multiple Myeloma Patients Treated with Second-Line Carfilzomib and Categorized By Prior Exposure to Bortezomib: A Subgroup Analysis of the Randomized Phase 3 Aspire and Endeavor Trials

Encapsulation and pH-responsive release of bortezomib by dopamine grafted hyaluronate nanogels

Hydrophobic drugs loaded nanogels were always associated with low encapsulation efficiency and immature burst release. In this work, dopamine grafted hyaluronate nanogels were designed for bortezomib (BTZ), a hydrophobic anticancer drug and a proteasome inhibitor. It was found that there was a more efficient loading and pH-controlled release of BTZ due to the presence of dopamine groups on the skeleton of the nanogels. The drug loading content (DLC) were up to 8.58% as the nanogels modified with 29% dopamine, compared to the DLC of less than 1% for nanogels without dopamine modification. It was the pH-sensitive nature of the borated bonds between BTZ and catechol groups that endowed the pH-responsive release behavior of BTZ in vitro. In vitro study proved good biocompatibility and efficient cell uptake of the nanogels. In vivo anti-tumor experiments demonstrated that bortezomib loading into the nanogel significantly enhanced the therapeutic effect of the drug. After 14-day treatment, the average tumor volume of BTZ loaded nanogel group was reduced by 200% more than that of free BTZ group. Combined with CD44 receptor targeting ability of hyaluronate and the merits of nanogel, the catechol modified hyaluronate nanogel exhibited as an efficient chemotherapeutic formulation of BTZ for cancer treatment.

PX-12 Promoting Apoptosis of Multiple Myeloma Cell Line H929 Induced by Bortezomib

To study the effect of PX-12 on apoptosis of multiple myeloma (MM) cell line induced by bortezomib. MM cell line H929 cells were divided into PX-12 group, bortezomib group, combination group, and control group. 5.0 μmol/L PX-12, 20 nmol/L bortezomib, combination of the two drugs, and DMSO were given to the above mentioned group, respectively. After culture for 24, 48, and 72 hours, the changes of cell viability were observed, the MM cell activity was detected by MTT method, and the cell cycle distribution and apoptosis of each group was detected by flow cytometry. The intracellular ROS level was measured by H2DCFDA probe labeling. MTT assay showed that after culture for 72 hours, the activity of H929 cells in PX-12 group (P<0.05) and bortezomib group (P<0.01) was significantly lower than that in the control group, while that in the combination group was decreased most significantly (P<0.01). After culture for 48 hours, cells in G1 phase in PX-12 group was decreased to 40%, while cells in S phase and G2/M phase was increased to 28% and 40%, respectively. The cells in bortezomib group also showed a similar distribution after being treated. After treated with PX-12 and bortezomib, the cells in G1 phase were decreased significantly to 19% and 12% in S phase, but increased significantly to 68% in G2/M phase, which was significantly different from PX-12 group and bortezomib group (P<0.01). After culture for 72 hours, the apoptosis rate was 71.3% in the combination group, which was significantly higher than that in PX-12 group, bortezomib group, and control group (20.6%, 33.3%, 10.6%)(P<0.01). After culture for 24 hours, the intracellular ROS level in the combination group was 12015±430.2, which was higher than that in the PX-12 group, bortezomib group, and control group (6729±352.8, 2651±228.3, 1098±164.6, respectively) (P<0.01). PX-12 can increase the apoptosis of MM cell line H929 induced by bortezomib, which may be caused by increasing of ROS level.

Autologous stem cell transplantation vs bortezomib based chemotheraphy for the first-line treatment of systemic light chain amyloidosis in the UK.

The benefit of autologous stem cell transplantation (ASCT) in the treatment of light chain (AL) amyloidosis requires re-evaluation in the modern era. This retrospective case-matched study compares ASCT to bortezomib for the treatment of patients with AL amyloidosis. Newly diagnosed patients with AL amyloidosis treated with ASCT or bortezomib between 2001 and 2018 were identified. Patients were excluded if the time from diagnosis to treatment exceeded 12months. Patients were matched on a 1:1 basis, using a propensity-matched scoring approach. A total of 136 propensity score-matched patients were included (ASCT n=68, bortezomib n=68). There was no significant difference in overall survival at two years (P=.908, HR: 0.95, CI: 0.41-2.20). For ASCT vs bortezomib: overall haematological response rate at 6months was 90.6% vs 92.5%; organ response at 12months: cardiac (70.0% vs 54%, P>.999), renal (74% vs 24%, P=.463) liver (21% vs 22%, P=.048); median progression-free survival (50 vs 42months P=.058, HR: 0.61, CI: 0.37-1.02) and time to next treatment (68 vs 45months, P=.145, HR: 0.61, CI: 0.31-1.19). More patients required treatment in the bortezomib group compared to ASCT group at 24months (41 vs 23, Chi-squared P=.004) and 48months (57 vs 41, Chi-squared P=.004). This small retrospective study suggests that there is no clear survival advantage of ASCT over bortezomib therapy. A prospective randomised controlled trial evaluating ASCT in AL amyloidosis is critically needed.