Administration Of Carfilzomib Research Articles

Preclinical efficacy of carfilzomib in BRAF-mutant colorectal cancer models.

Serine/threonine-protein kinase B-raf (BRAF) mutations are found in 8-15% of colorectal cancer patients and identify a subset of tumors with poor outcome in the metastatic setting. We have previously reported that BRAF-mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. In this work, we tested whether carfilzomib could restrain the growth of BRAF-mutant colorectal tumors not only by targeting cancer cells directly, but also by promoting an immune-mediated antitumor response. In human and mouse colorectal cancer cells, carfilzomib triggered robust endoplasmic reticulum stress and autophagy, followed by the emission of immunogenic-damage-associated molecules. Intravenous administration of carfilzomib delayed the growth of BRAF-mutant murine tumors and mobilized the danger-signal proteins calreticulin and high mobility group box 1 (HMGB1). Analyses of drug-treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3)+ T-cell surface glycoprotein CD4 (CD4)+ T cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF-mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF-mutant colorectal cancer patients.

Oxyphenbutazone ameliorates carfilzomib induced cardiotoxicity in rats via inhibition of oxidative free radical burst and NF-κB/IκB-α pathway

Carfilzomib (CFZ), a chemotherapeutic agent used for multiple myeloma treatments reported to cause high incidence of cardiac events either new onset and/or exacerbate formerly diagnosed heart failure with ventricular and myocardial dysfunction.Purpose: Current research designed to explore and examine the preventive effect of oxyphenbutazone in the CFZ -instigated cardiotoxicity. Methodology: Female Wistar Rats weighing 200–250 g selected randomly and grouped as follows: Group 1 designated as the Normal control and receive normal saline only. Group 2 served toxic control and exposed to CFZ (4 mg/kg, intraperitoneally [i.p.]). Group 3 & 4 served as treatment groups and administered with CFZ concomitantly orally fed with oxyphenbutazone at doses of 35 and 70 mg/kg/three times a week, respectively. The total duration of experimental protocol was of 21 days. After completion of the experiments animals subjected to blood collection using light ether anesthesia and serum was separated for biochemical analysis further. The serum levels of Mg+2, Ca+2 and cardiac enzymes (aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase-MB (CK-MB) levels were estimated. Later animals sacrificed and heart tissue isolated for further examinations. Intracellular proteins NFkB and IkBα were estimated by western blot. Results: The serum analysis revealed that CFZ administration significantly elevated the levels of LDH, CK and CKMB in CFZ exposed animals when compared to normal animals while administration of oxyphenbutazone significantly reduced these biochemical changes, Intracellular antioxidant enzymes and NF-kB in treatment groups as compared to disease control animals. Conclusion: Findings of the research protocol suggests significant injuries to cardiac tissues when animals exposed to CFZ and Oxyphenbutazone protected the cardiac tissues.

Carfilzomib Mitigates Lipopolysaccharide/D-Galactosamine/Dimethylsulfoxide-Induced Acute Liver Failure in Mice.

Acute liver failure (ALF) is a disease accompanied by severe liver inflammation. No effective therapy is available yet apart from liver transplantation; therefore, developing novel treatments for ALF is urgently required. Inflammatory mediators released by NF-кB activation play an essential role in ALF. Proteasome inhibitors have many medical uses, such as reducing inflammation and NF-кB inhibition, which are believed to account for most of their repurposing effects. This study was undertaken to explore the possible protective effects and the underlying mechanisms of carfilzomib, a proteasome inhibitor, in a mouse model of ALF induced by lipopolysaccharide/D-galactosamine/dimethylsulfoxide (LPS/GalN/DMSO). Carfilzomib dose-dependently protected mice from LPS/GalN/DMSO-induced liver injury, as indicated by the decrease in serum alanine aminotransferase and aspartate aminotransferase levels. LPS/GalN/DMSO increased TNF-α, NF-кB, lipid peroxidation, NO, iNOS, cyclooxygenase-II, myeloperoxidase, and caspase-3 levels. Carfilzomib administration mitigated LPS/GalN/DMSO-induced liver damage by decreasing the elevated levels of TNF-α, NF-кB, lipid peroxidation, nitric oxide, iNOS, cyclooxygenase-II, myeloperoxidase, caspase-3, and histopathological changes. A restored glutathione level was also observed in the carfilzomib-treated LPS/GalN/DMSO mice. Our results demonstrate that carfilzomib protects against LPS/GalN/DMSO-induced ALF by inhibiting NF-кB, decreasing inflammatory mediators, oxidative/nitrosative stress, neutrophil recruitment, and apoptosis, suggesting that carfilzomib may be a potential therapeutic agent for ALF.

Thymoquinone Ameliorates Carfilzomib-Induced Renal Impairment by Modulating Oxidative Stress Markers, Inflammatory/Apoptotic Mediators, and Augmenting Nrf2 in Rats.

Chemotherapy-induced kidney damage is an emerging problem that restricts cancer treatment effectiveness. The proteasome inhibitor carfilzomib (CFZ) is primarily used to treat multiple myeloma and has been associated with severe renal injury in humans. CFZ-induced nephrotoxicity remains an unmet medical need, and there is an urgent need to find and develop a nephroprotective and antioxidant therapy for this condition. Thymoquinone (TQ) is a bioactive compound that has been isolated from Nigella sativa seeds. It has a wide range of pharmacological properties. Therefore, this experimental design aimed to study the effectiveness of TQ against CFZ-induced renal toxicity in rats. The first group of rats was a normal control (CNT); the second group received CFZ (4 mg/kg b.w.); the third and fourth groups received TQ (10 and 20 mg/kg b.w.) 2 h before receiving CFZ; the fifth group received only TQ (20 mg/kg b.w.). This experiment was conducted for 16 days, and at the end of the experiment, blood samples and kidney tissue were collected for biochemical assays. The results indicated that administration of CFZ significantly enhanced serum marker levels such as BUN, creatinine, and uric acid in the CFZ group. Similarly, it was also noticed that CFZ administration induced oxidative stress by reducing antioxidants (GSH) and antioxidant enzymes (CAT and SOD) and increasing lipid peroxidation. CFZ treatment also enhanced the expression of IL-1β, IL-6, and TNF-α production. Moreover, CFZ increased caspase-3 concentrations and reduced Nrf2 expression in the CFZ-administered group. However, treatment with 10 and 20 mg/kg TQ significantly decreased serum markers and increased antioxidant enzymes. TQ treatment considerably reduced IL-1β, IL-6, TNF-α, and caspase-3 concentrations. Overall, this biochemical estimation was also supported by histopathological outcomes. This study revealed that TQ administration significantly mitigated the negative effects of CFZ treatment on Nrf2 expression. Thus, it indicates that TQ may have utility as a potential drug to prevent CFZ-induced nephrotoxicity in the future.

Carfilzomib Use Among Patients with Relapsed/Refractory Multiple Myeloma in the Asia Pacific Region: Characteristics and Outcomes By Regimen from a Prospective, Real-World Study

Background: Carfilzomib (CFZ) is a next-generation proteasome inhibitor currently approved in combination with lenalidomide and dexamethasone (KRd) or with dexamethasone alone (Kd) for treatment of multiple myeloma (MM) patients with ≥1 prior line of therapy in the Asia-Pacific (APAC) region. Here, we describe utilization of KRd and Kd in routine clinical practice in APAC, including treatment patterns, patient profile, reasons for discontinuation, clinical outcomes, and frequency of adverse events (AEs). Methods: This prospective, single-arm cohort study recruited adults with relapsed/refractory MM who received ≥1 dose of CFZ in routine clinical practice as either a combination or monotherapy regimen and had received ≥1 prior line of MM treatment before CFZ initiation. Between July 2019 and June 2021, approximately 300 patients were planned to be enrolled in this study. Medical history, patient characteristics, and clinical data are collected at baseline and throughout the 2-year observation period or until death, withdrawal of consent, or loss of follow-up. Follow-up data are collected through chart reviews every 3 months. AEs leading to treatment discontinuation are collected; common AEs associated with drugs/disease were excluded from collection by the protocol (all serious AEs were collected). The study is ongoing, and last patient record for the analysis will be collected no later than Q1 2023. Results: As of data cutoff April 1, 2022, 311 patients were enrolled, of whom 38 are excluded from the present analysis (11 died before waiver of informed consent approval and 27 patients had missing data for the first medical chart review or first CFZ administration). The 273 patients included in this ad hoc interim analysis were enrolled from 5 countries/regions: Australia (n=46), Hong Kong (n=17), Korea (n=172), Singapore (n=13), and Taiwan (n=25). To date, the regimens prescribed were KRd (n=160, 59%), Kd (n=103, 38%), and other CFZ-based regimens (n=10, 4%; monotherapy [n=1]; not classified [1]; or with dexamethasone and cyclophosphamide [5], pomalidomide [2], or daratumumab [1]). Table 1 displays detailed patient and disease characteristics, and Table 2 displays CFZ utilization and response. Overall, 33% of patients reported a history of hypertension, 11% of cardiac disorders, 7% of diabetes mellitus, and 3% of pulmonary embolism, prior to CFZ initiation. On average, patients prescribed KRd were slightly younger than those prescribed Kd. The majority of KRd patients (68%) had received 1 prior line of treatment, whereas one-third of Kd patients (36%) had received ≥4 prior lines of treatment. Similar proportions of KRd (33%) and Kd (34%) populations were bortezomib refractory, and 73% of Kd patients were lenalidomide refractory. The planned CFZ dose at first cycle was in accordance with the local product information and was used in 89% of KRd and 69% of Kd patients (27 and 56 mg/m2 twice weekly, respectively). At data cutoff, 43.1% and 30.1% of KRd and Kd patients, respectively, remained on CFZ treatment. The most common reason for CFZ discontinuation was disease progression/refractory disease. With KRd and Kd, respectively, the best overall response rate was 79.0% (n=94/119) and 54.7% (n=29/53) and median overall survival was 60.9 (95% confidence interval [CI], 55.9-not estimable [NE]) and 54.5 (95% CI, 33.3-NE) months. CFZ-treatment-related AEs of interest occurred in 10 (3.7%) total patients (cardiac arrhythmia, n=1 Kd; cardiac failure, 1 KRd; dyspnea, 2 KRd, 2 Kd, 1 other CFZ; hematopoietic thrombocytopenia, 1 KRd and 1 Kd; ischemic heart disease, 1 KRd; no incidence of treatment-related acute renal failure, hypertension, and peripheral neuropathy). Overall, 10 (3.7%) patients discontinued CFZ owing to an AE. Conclusions: This study investigates the real-world use of CFZ for relapsed/refractory MM in a predominantly Asian patient population across the APAC region. Interim results confirm that the standard dosing schedules for KRd and Kd are well tolerated in real-world practice and suggest a very low rate of discontinuation due to CFZ-related AEs, even in heavily pretreated MM. Further prospective data collection of patients in routine practice is ongoing to assess patterns of longer-term patient management, patterns after CFZ treatment failure, CFZ toxicity according to number of previous lines of therapy, response, survival outcome, and AEs, which will inform optimal use of CFZ. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High-Dose Carfilzomib Recaptures Response in Relapsed/Refractory Multiple Myeloma Resistant to Low-Dose Carfilzomib By Co-Inhibiting β2 Subunit of Proteasome Complex: The First in Human Evidence

BackgroundProteasome, a complex involved in the intracellular protein degradation, consists of multiple subunits, but only three subunits have enzymatic activity to cleave and degrade proteins, namely β1, β2 and β5. Carfilzomib (CFZ), a second-generation proteasome inhibitor (PI), can induce cell death by selective and irreversible inhibition of β5 subunit of proteasome. Preclinical data suggested that high-dose CFZ could co-inhibit predominantly β2 proteasome activity, followed by β1 inhibition (Besse et al, Cell Chem Biol. 2019). Over the past few years, CFZ has become a corner stone for multiple myeloma (MM) therapy. Currently, CFZ is approved by the FDA in different dosing schedules in combination with lenalidomide or daratumumab and dexamethasone. However, the optimal CFZ dosing is still a matter of debate, with the approved dosage ranging from 20to 70mg/m 2 in different regimens. In addition, if response can be recaptured by escalating CFZ dose in patients progressing from low-dose CFZ has yet to be determined. The aim of our current study was to analyse the profile of proteasome inhibition in the respective dose cohorts and to elucidate if high-dose CFZ could recapture response in patients resistant to low-dose CFZ.MethodsWe prospectively collected clinical data and peripheral blood mononuclear cells (PBMC) of 32 patients with relapsed/refractory (RR) MM before and 1-8 hours after CFZ administration. PBMC were lysed and labelled for the activity of individual proteasome subunits using activity based proteasome probes and the proteasome subunits were separated using SDS-PAGE. The activity of constitutive and immunoproteasome β1, β2 and β5 subunits was evaluated by densitometry analysis and combination of the activity of constitutive and immunoproteasome individual subunit was used for further analysis.ResultsOverall, six, nine, twelve and five patients received CFZ at a dose of 20, 27, 36 and 56 mg/m 2, respectively. As expected, the total activity of proteasome decreased with higher doses of CFZ. Significant inhibition (median inhibition > 50%) of β5 subunit was observed already at 20 mg/m 2 dose, while β2 subunit started to be co-inhibited only at a dose of ≥27 mg/m 2. Significant co-inhibition of β2 activity was seen at 36 mg/m 2 dose, at which also β1 subunit started to be co-inhibited. Finally, at 56 mg/m 2, the activity of all active subunits was inhibited with a median inhibition of > 50%, with the strongest inhibition of the β5 subunit, followed by β2 and then β1. When we compared the patient groups low-dose CFZ (20 or 27 mg/m 2) versus high-dose CFZ (36 or 56 mg/m 2), we observed a significant difference in β2 (P=0.002) and β5 (P=0.02) subunit inhibition between the both groups. In terms of total proteasome activity, high-dose CFZ demonstrated a significantly higher proteasome inhibition in comparison with patients receiving low-dose CFZ (P=0.01). In brief, our results suggested that high-dose CFZ, in contrast to low-dose CFZ, could obtain superior proteasome inhibition by co-inhibiting β2 subunit of proteasome complex.In light of this finding, we successfully treated six RRMM patients who were resistant to low-dose CFZ with CFZ dose escalation. All six patients were heavily pretreated with 3-12 lines of therapy including daratumumab, two PIs, two immunomodulatory drugs and autologous stem cell transplant. Additionally, one and two patients received prior treatment with B-cell maturation antigen targeted bi-specific antibody and chimeric antigen receptor modified T-cell, respectively. In the last line of treatment, these six patients showed progression during CFZ based regimens with low-dose CFZ, namely 20 or 27 mg/m 2. We therefore increased the CFZ dose to 36 or 56 mg/m 2 and the doses of agents other than CFZ in the combination regimens remained the same. High-dose CFZ dose recaptured response in all six patients with four and two patients that achieved partial remission and very good partial remission, respectively, and the progression free survival ranged from 1-13 months.ConclusionIn summary, high-dose CFZ, namely ≥ 36mg/m 2, showed more effective proteasome inhibition via blocking β5 and β2 subunits, while low-dose CFZ could not achieve a sufficient inhibition of β2 subunit. We provided the first in human evidence that high-dose CFZ could recapture response in RRMM patients resistant to low-dose CFZ by co-inhibiting the β2 subunit activity of proteasome complex. [Display omitted] DisclosuresEinsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding.

Cardiovascular Toxicity of Carfilzomib: The Real-World Evidence Based on the Adverse Event Reporting System Database of the FDA, the United States.

Background: Carfilzomib, an effective proteasome inhibitor agent for the therapy of relapsed and refractory multiple myeloma, has been related to a significant number of cardiovascular events. However, patterns of cardiovascular complications associated with this agent remain poorly characterized in real-world settings.Objective: To gain further insight into the frequency, spectrum, clinical features, timing, and outcomes of carfilzomib-related cardiovascular toxicities.Methods: This disproportionality (case/non-case) study was conducted leveraging records from FAERS database from 2014 to 2019. Cardiovascular events were defined and broadly categorized eight entities using narrow version of the Standardized MedDRA Queries (SMQs). Reporting odds ratios (ROR) and information component (IC) were calculated to measure disproportionality. Additionally, statistical shrinkage was applied to reduce false-positive signals.Results: The final number of records involved was 28,479,963, with 3,370 records submitted for carfilzomib related cardiovascular events. Significant disproportionality association between carfilzomib administration and cardiovascular events was captured (IC025/ROR025 = 0.85/1.95) when exploring in the entire database. Upon further analysis, all eight broad categories of cardiovascular toxicities were disproportionately associated with carfilzomib with varying frequencies, time-to-onset, and severities. Cardiomyopathy-related complications (N = 1,301, 38.61%), embolic and thrombotic events (N = 821, 24.36%), and cardiac failure (N = 765, 22.70%) largely comprised the reported problems. Notably, the strongest signal was detected for cardiac failure (IC025/ROR025 = 1.33/2.59), followed by pulmonary hypertension (IC025/ROR025 = 1.19/2.34). Median onset time of cardiovascular events was 41days (Q1-Q3: 9-114 days), with the shortest median time being 16 days (Q1–Q3: 4–85 days) for ischemic heart disease, with the longest time being 68 days (Q1–Q3: 21–139 days) for embolic and thrombotic events. Torsade de pointes/QT prolongation was identified as a new complication (IC025/ROR025 = 0.33/1.29) and was particularly noteworthy for highest death proportion (44.11%).Conclusions: Treatment with carfilzomib can lead to severe and versatile cardiovascular events. Early and intensive monitoring is important, particularly in the first 3 months after carfilzomib initiation. Maximizing the benefit while reducing potential cardiovascular harms of carfilzomib should become a priority.

Renal failure among multiple myeloma patients utilizing carfilzomib and associated factors in the "real world".

Carfilzomib, a next-generation proteasome inhibitor, improves outcomes in patients with multiple myeloma (MM); however, a proportion of those treated develop renal failure due to adverse event, comorbidity, or myeloma progression. The rate of renal failure and associated risk factors remains unknown in real-world populations. Adults with relapsed/refractory MM who received carfilzomib between the years 2013 and 2016 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Renal failure was defined using the corresponding International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnostic codes and procedure codes for dialysis. Patients with a pre-existing diagnosis of renal failure were excluded to distinguish an adverse event from comorbidity. Multivariate cox regression analysis was performed to identify the variables independently associated with the development of renal failure among MM patients utilizing carfilzomib. A total of 1950 patients were included in the analysis. Renal failure developed in 22% of patients during the study period. The median time to development of renal failure from first carfilzomib administration was 1.6 months (range < 0.1-23.3). Increasing age (adjusted hazard ratio [aHR] 1.01 per year, p = 0.018), pre-existing heart failure (aHR 1.50, p = 0.005), and pre-existing chronic kidney disease (aHR 2.00, p < 0.001) were associated with a higher risk of developing renal failure. Renal failure occurred in up to 22% of patients on carfilzomib therapy. The exact cause and mechanism of renal failure cannot be determined from our study and may be multifactorial. Future studies are needed to further understand the cause of renal failure among patients on carfilzomib and devise strategies to mitigate the risk.

VRd Versus KRd Safety Profiles in Newly Diagnosed Multiple Myeloma Patients Using Real-World Evidence Data from a Single Institution: VRd Has High Rates of Chronic Neuropathy, and KRd Has Low Rates of Cardiopulmonary or Renal Toxicities When Using Optimized IV Fluid Management Coupled with Baseline Cardiac Workup

VRd Versus KRd Safety Profiles in Newly Diagnosed Multiple Myeloma Patients Using Real-World Evidence Data from a Single Institution: VRd Has High Rates of Chronic Neuropathy, and KRd Has Low Rates of Cardiopulmonary or Renal Toxicities When Using Optimized IV Fluid Management Coupled with Baseline Cardiac Workup

Carfilzomib-Revlimid-Dexamethasone Vs. Carfilzomib-Thalidomide-Dexamethasone Weekly (After 2 Twice Weekly Cycles) Followed By Carfilzomib Maintenance Vs. Control in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) - Interim Efficacy Analysis of Combined Data (AGMT MM-02)

Carfilzomib-Revlimid-Dexamethasone Vs. Carfilzomib-Thalidomide-Dexamethasone Weekly (After 2 Twice Weekly Cycles) Followed By Carfilzomib Maintenance Vs. Control in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) - Interim Efficacy Analysis of Combined Data (AGMT MM-02)

PB2184 CARFILZOMIB OR POMALIDOMIDE IN PATIENTS WITH RELAPSE AND/OR REFRACTORY MULTIPLE MYELOMA: SINGLE CENTER EXPERIENCE

Background:Multiple myeloma (MM) is a neoplastic plasma cell disorder characterized by clonal proliferation of malignant plasma cells in bone marrow and has a high risk for relapse. With more targeted agents in development, the treatment of myeloma patient at relapse has become complicated. Carfilzomib and pomalidomide are new agents for double‐refractory MM.Aims:We aimed to evaluate efficacy and hematological adverse effects of carfilzomib and pomalidomide on relapse and refractory MM (RR‐MM) patients.MethodsFourty RR‐MM patients who treated with carfilzomib or pomalidomide between 2016 and 2018 in Ege University, School of Medicine were screened, retrospectively. Patients seperated into three groups who were treated with carfilzomib (n = 25), pomalidomide (n = 8) or both of two drugs, consecutively (n = 7). Complete blood counts, renal functional tests, serum immunoglobuline heavy and light chain levels, bone marrow aspiration and biopsies, bone lesions, ISS scores at diagnosis, follow up periods, performance status (according to ECOG performance scale), response status to treatment and hematological adverse effects are evaluated.Results:Fourty RR‐MM patients were evaluated. The median age was 65 (range 45‐85) and the median age at diagnosis was 60 (range 42‐80). Mean follow‐up period was 71 months (range 13‐200). The patients were composed of 19 (47.5%) females and 21 (52.5%) males. ECOG performance status of 30 patients were 0, 16 patients were 1, and 2 patients were 2. ISS scores of 16 patients were 1, 13 patients were 2 and 7 patients were 7. Patients had received 4 lines of therapy prior to carfilzomib and the mean number of carfilzomib administration cycle was 6 (range 2‐15). Before pomalidomide treatment patients had received 4 lines therapy and the mean number of pomalidomide treatment was 12 (range 2‐32). Six patients's treatment was changed from pomalidomide to carfilzomib by the reason of disease progression or intolerance, while one patient's treatment was changed carfilzomib to pomalidomide. Six patients died; four of them were under carfilzomib treatment, two of them were treated with pomalidomide. 13 (40.6%) of 32 patients who were treated with carfilzomib had disease progression or had not continued to therapy because of intolerance. Until disease progression, patients were received 4 cycles therapy. At pomalidomide group, 2 of 15 patients had intolerance to therapy and 2 patients were died because of pulmonary infection. 7 patiens had disease progression and patients had taken in average 13.2 cycles therapy until disease progression. The most common hematological adverse effect was thrombocytopenia in both groups. 10 patients (31.2%) in carfilzomib group and 5 patients (33.3%) in pomalidomide group had thrombocytopenia.Summary/Conclusion:Despite of the current report has limitations and small numbers of patients, our results has revealed that carfilzomib and pomalidomide have durable efficacy and well‐tolerated agents for relaps refractory myleoma and the most common hematological adverse effect was thrombocytopenia as also stated in the literature.

Carfilzomib for relapsed and refractory multiple myeloma.

Although the prognosis of multiple myeloma (MM) patients has dramatically improved during recent years, virtually all patients eventually develop relapsed refractory disease. Several new therapeutics have been developed in the last few years, including carfilzomib, a second-generation proteasome inhibitor (PI) that has been approved by the US Food and Drug Administration (FDA) in the setting of relapsed and/or refractory MM, as a single agent with or without dexamethasone, and in combination with lenalidomide in 2012 and 2015, respectively. Other promising combinations with carfilzomib are being investigated. Carfilzomib has shown superiority over the first-generation PI bortezomib on both efficacy and toxicity. In particular, profoundly lower incidence in polyneuropathy compared to bortezomib has been described. However, carfilzomib has a different toxicity profile, with more cardiovascular adverse events. Therefore, caution should be taken with the use of carfilzomib for elderly and cardiovascularly compromised patients. The once-weekly administration of carfilzomib, recently approved by the FDA in combination with dexamethasone, will lead to a lower burden for the patient and caregivers compared to the twice-weekly schemes that were routinely used until recently. This review has a focus on clinical trial data that has led to drug approval, as well as new promising combination studies, and provides advice for treating physicians who are now prescribing this drug to patients.

Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway.

Carfilzomib (CFZ), a proteasome inhibitor approved by the FDA to treat multiple myeloma, may cause nephrotoxicity. Rutin is a bioflavonoid with antioxidant properties. We aimed to examine whether rutin protects the kidney from CFZ-induced nephrotoxicity. This study aimed to demonstrate the effect of rutin on CFZ-induced renal injury via the inhibition of oxidative stress and inflammation. Wistar albino rats were divided into six groups (n = 6): Group 1 (normal control; NC) was administered normal saline for 3weeks; Group 2 (CFZ/toxic group) received CFZ [4mg/kg, intraperitoneal (i.p.) injection] twice weekly for 3weeks; Group 3 (standard treatment group) was administered CFZ (4mg/kg, i.p.) and olmesartan (2mg/kg, p.o.) for 3weeks; Group 4 was administered CFZ (4mg/kg, i.p.) and rutin (10mg/kg, p.o.) for 3weeks; Group 5 was administered CFZ (4mg/kg, i.p.) and rutin (20mg/kg, p.o.) for 3weeks; and Group 6 was administered CFZ (4mg/kg, i.p.) and rutin (40mg/kg, p.o.) for 3weeks. We carried out haematological and biochemical analyses, determined oxidative stress, caspase-3 activity, and protein levels, and performed a histopathological evaluation to confirm CFZ-induced nephrotoxicity and its prevention by rutin administration. Exposure to only CFZ significantly (p < 0.05) increased white blood cell (WBC) count, Hb%, and HTC% concentration; however, these features were significantly decreased (p < 0.05) when olmesartan and rutin were administered. CFZ administration significantly decreased (p < 0.0001) the level of antioxidant enzymes; whereas, administration of olmesartan and rutin significantly reversed (p < 0.05) their levels toward the normal range. The levels of caspase-3 enzyme significantly increased (p < 0.001) in the CFZ group and were reduced toward the normal values by olmesartan and rutin administration. Furthermore, the results of NOS-2, NF-κB, IkBa, and IL-17 protein estimation and the histopathological evaluation strengthened our findings that rutin exhibits a protective effect against CFZ-induced nephrotoxicity. These findings clearly demonstrate that rutin ameliorates CFZ-induced oxidative stress and inflammation in nephrotoxicity via the NOS-mediated NF-κB signaling pathway.

Interim Results of the Observational Study Caro: Twice Weekly Carfilzomib Is a Convenient Treatment Option for Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy

Introduction:Poor adherence and persistence to anticancer treatment are serious issues in the management of cancer patients since nonadherence has been shown to lead to higher treatment failure rates, worse outcome and higher total costs of care. The combination of the proteasome inhibitor carfilzomib (Kyprolis®) with lenalidomide (Revlimid®) and dexamethasone (CAR/LEN/DEX) or with dexamethasone alone (CAR/DEX) is approved for the treatment of patients with multiple myeloma who have received at least one prior therapy. According to the current approved schedule, carfilzomib has to be given twice weekly in both regimens. Real-world data on the implementation of this treatment recommendation are still limited.Methods:The prospective, multicenter, non-interventional, observational CARO study was designed to collect data on 300 patients with multiple myeloma (CAR/LEN/DEX: 200, CAR/DEX: 100) from 90 sites across Germany. Primary objective is patients' adherence and persistence to carfilzomib therapy as prescribed by the treating physician according to current Summary of Product Characteristics (SmPC). Secondary objectives are patients' adherence and persistence to lenalidomide and dexamethasone as well as the real-world implementation of the recommended CAR/LEN/DEX or CAR/DEX dosing regimen in clinical routine (i.e., the comparison of actually administered medication versus recommended medication according to current SmPC). Exploratory objectives are effectiveness, safety and health-related quality of life. The first interim analysis of the CARO study was scheduled to assess the primary and secondary endpoints 12 months after the recruitment of the first patient.Results:Between October 2016 and October 2017, 102 patients had been enrolled, thereof 68 patients into the CAR/LEN/DEX cohort and 32 patients into the CAR/DEX cohort at the time of the pre-specified interim analysis (database cut: 25 October 2017).Here, the focus is on the adherence of the twice weekly carfilzomib schedule in evaluable patients who received CAR/LEN/DEX (N=64) and on the implementation of the SmPC in terms of timing, dosing and frequency. Median age of patients was 72.3 years (range 43.4-84.3), 45.3% were female and 70.3% of the patients had a good performance status (PS) with a Karnofsky PS score of 80 to 100. The relative mean dose intensity of carfilzomib was 88.1%. 1368 of the scheduled 1591 carfilzomib administrations (86.0%) were given in time. 7.9% (n=125) of administrations were omitted, 5.0% (n=80) of administrations were delayed and 1.1% (n=18) of doses were administered earlier. Carfilzomib was omitted at least once in 43.8% of patients (n=28). 62.5% (n=40) and 18.8% (n=12) of patients, respectively, had a delayed or earlier carfilzomib administration documented at least once during their course of treatment. Reasons for deviations from the recommended carfilzomib dosing schedule concerning timing are depicted in Table 1. 1328 of 1466 carfilzomib administrations (90.6%) were given at the recommended dose. 6.2% (n=91) of doses were reduced. The main reason for dose reduction was the occurrence of adverse events (4.0%, n=58). Other reasons were: nonadherence (1.2%, n=18), organizational reasons (0.1%, n=2) and others (0.9%, n=13). 23.4% (n=15) of patients received at least one reduced carfilzomib dose during their course of treatment.The mean adherence to the carfilzomib dosing regimen (i.e., the percentage of doses administered as scheduled by the treating physician and not modified for adherence reasons) was 94.8%.Conclusion:According to our interim results, 86% of carfilzomib administrations were given in time and more than 90% of administrations were given at the recommended dose. Deviations from the recommended carfilzomib regimen were mainly due to safety issues or organizational reasons, but not due to nonadherence. Carfilzomib treatment adherence was almost 95%. Though, despite the required twice weekly dosing schedule, the carfilzomib regimen seems to be a convenient treatment option for multiple myeloma patients. Results have to be confirmed at final analysis. DisclosuresKnauf:Celgene: Consultancy, Honoraria; Roche: Consultancy; Amgen: Consultancy, Honoraria; Mundipharma: Consultancy; Gilead Sciences: Consultancy; AbbVie: Consultancy; Janssen: Consultancy. Marschner:Amgen: Consultancy, Honoraria; IOMEDICO: Employment, Equity Ownership; Sandoz: Honoraria.

Carfilzomib Induces Acute Endothelial Dysfunction Which Correlates with the Occurrence of Cardiovascular Events

Carfilzomib Induces Acute Endothelial Dysfunction Which Correlates with the Occurrence of Cardiovascular Events

Apremilast ameliorates carfilzomib-induced pulmonary inflammation and vascular injuries

Acute lung injury (ALI) due to chemotherapy occurs frequently. It presents a challenge for clinicians managing therapies for different types of cancers. Carfilzomib (Kyprolis™) is a new proteasome inhibitor that shows promise for the treatment of relapsing multiple myeloma. However, several cases of severe ALI have raised concern about the use of carfilzomib against relapsed multiple myelomas. To improve the efficacy of carfilzomib, a new anti-inflammatory drug for psoriasis treatment, apremilast (Otezla™) was investigated for its protective effects against carfilzomib-induced ALI in rats. RT-PCR analyses revealed that carfilzomib administration in rats markedly increased the levels of tumor necrosis factor-alpha and nuclear factor-kappa B and myeloperoxidase activity with a concomitant increase in lipid peroxidation. The anti-inflammatory cytokine, interleukin-10, was downregulated following carfilzomib administration. Reduction in glutathione levels indicated diminished cellular antioxidant defenses in response to carfilzomib-induced ALI. ALI was confirmed by histopathological observations in lung tissue slices. Apremilast administration reduced lung inflammation in terms of reduction in myeloperoxidase activity and levels of tumor necrosis factor-alpha and alveolar infiltrating cells. Apremilast reversed all observed toxic effects of carfilzomib and prevented ALI in rats.

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials

AbstractCarfilzomib is a selective proteasome inhibitor approved for the treatment of relapsed and/or refractory multiple myeloma (RRMM). It has significantly improved outcomes, including overall survival (OS), and shown superiority vs standard treatment with lenalidomide plus dexamethasone and bortezomib plus dexamethasone. The incidence rate of cardiovascular (CV) events with carfilzomib treatment has varied across trials. This analysis evaluated phase 1-3 trials with >2000 RRMM patients exposed to carfilzomib to describe the incidence of CV adverse events (AEs). In addition, the individual CV safety data of >1000 patients enrolled in the carfilzomib arm of phase 3 studies were compared with the control arms to assess the benefit-risk profile of carfilzomib. Pooling data across carfilzomib trials, the CV AEs (grade ≥3) noted included hypertension (5.9%), dyspnea (4.5%), and cardiac failure (4.4%). Although patients receiving carfilzomib had a numeric increase in the rates of any-grade and grade ≥3 cardiac failure, dyspnea, and hypertension, the frequency of discontinuation or death due to these cardiac events was low and comparable between the carfilzomib and control arms. Serial echocardiography in a blinded cardiac substudy showed no objective evidence of cardiac dysfunction in the carfilzomib and control arms. Moreover, carfilzomib had no significant effect on cardiac repolarization. Our results, including the OS benefit, showed that the benefit of carfilzomib treatment in terms of reducing progression or death outweighed the risk for developing cardiac failure or hypertension in most patients. Appropriate carfilzomib administration and risk factor management are recommended for elderly patients and patients with underlying risk factors.

Apremilast reversed carfilzomib-induced cardiotoxicity through inhibition of oxidative stress, NF-κB and MAPK signaling in rats

Carfilzomib (CFZ), is a potent, selective second generation proteasome inhibitor, used for the treatment of multiple myeloma. The aim of the present study was to investigate the possible protective effect of apremilast (AP) on the CFZ -induced cardiotoxicity. Rats were randomly divided into four groups: Group 1, served as the control group, received normal saline. Group 2, served as the toxic group, received CFZ (4 mg/kg, intraperitoneally [i.p.]). Groups 3 and 4, served as treatment groups, and received CFZ with concomitant oral administration of AP in doses of 10 and 20 mg/kg/day, respectively. In the present study, administration of CFZ resulted in a significant increase in serum aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase-MB (CK-MB), which were reversed by treatment with AP. CFZ resulted in a significant increase in heart malondialdehyde (MDA) contents and decrease in cardiac glutathione (GSH) level and catalase (CAT) enzyme activity which were significantly reversed by treatment with AP. Induction of cardiotoxicity by CFZ significantly increased caspase-3 enzyme activity which were reversed by treatment with AP. RT-PCR analysis revealed an increased mRNA expression of NF-κB, ERK and JNK which were reversed by treatment with AP in cardiac tissues. Western blot analysis revealed an increased expression of caspase-3 and NF-κB p65 and a decrease expression of inhibitory kappa B-alpha (Iκbα) with CFZ, which were reversed by treatment with AP. In conclusion, apremilast showed protective effect against CFZ-induced cardiotoxicity.

A Phase I Study of Carfilzomib for Relapsed or Refractory Acute Myeloid and Acute Lymphoblastic Leukemia

Background: The outcome for patients with relapsed or refractory acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) remains extremely poor; new chemotherapy agents with activity against these leukemias are urgently needed. Proteasome inhibition is a promising therapeutic target in acute leukemias with established efficacy in several other hematologic malignancies. Several published studies have demonstrated the potent in vitro anti-leukemic activity of the selective proteasome inhibitor carfilzomib (CFZ) in leukemia cell lines as well as in primary human AML and ALL blasts. Given the favorable toxicity profile of CFZ, there was a strong rationale to begin the clinical study of this agent in the treatment of acute leukemias. We performed a phase I, single arm, single center, open label study of CFZ in adult patients with relapsed or refractory AML and ALL.Objectives: The primary objective was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of CFZ in adult patients with relapsed/refractory AML and ALL. Secondary objectives included: determination of disease response, time to response, remission duration, progression-free survival, event-free survival, and overall survival. The study was designed to determine the safety and tolerability of carfilzomib in this patient population.Patients/Methods: Patients with relapsed or refractory AML or ALL after ³ 1 line of therapy, with good performance status and organ function were eligible. CFZ was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in a 28-day cycle at escalating doses of 36, 45, and 56mg/m2. All dose levels included lead-in doses on days 1, 2, 8 and 9. Up to 6 cycles of treatment were allowed.Dose escalation was performed using a 3+3 design; MTD was defined as the highest dose level where DLT occurred in less than 1 of 3 or 2 of 6 patients. Disease response was determined using International Working Group (IWG) criteria for AML.Results: 18 patients were enrolled from Dec 2010-July 2014. Eight patients discontinued prior to completion of cycle 1 for reasons other than study-related toxicity and were replaced.The median age was 70 years (range 32-78). 12 of the 18 patients were male. 17 patients had AML while 1 patient had ALL. The median number of prior therapies was 2 (range 1-4). 2 patients had undergone prior allogeneic stem cell transplantation. The median time from diagnosis to start of protocol was 9.7 months (range 1.4-102.0).Median white blood cell (WBC) count at study start was 3.2x109/L (range 0.6-42.2), with median peripheral blood blasts of 18% (range 0-62), and bone marrow blasts 45.5% (range 11-92). 7 of the 17 patients with AML had complex cytogenetics.10 of the 18 patients were evaluable for disease response. Of the 10 evaluable patients, 2 patients achieved a partial response (PR), and 4 additional patients had stable disease (SD). The median duration on study was 21.5 days (range 1-64), with median overall survival (OS) of 1.9 months.CFZ was generally well tolerated; no DLTs were observed in any cohort. The most common grade 3/4 non-hematologic toxicities regardless of attribution were: dyspnea (17%), activated partial thromboplastin time prolongation (17%), intracranial hemorrhage or hematoma (11%), infection (11%), CHF exacerbation (11%), and hypophosphatemia (11%).Conclusions: Administration of CFZ was well tolerated, and a MTD was not established. The recommended dosage for further studies is 56mg/m2. In this limited phase 1 study of heavily pre-treated patients, we observed modest anti-leukemic activity. However, additional clinical trials incorporating CFZ in combination with other chemotherapeutic agents are now needed to assess the potential efficacy of CFZ in the treatment of AML and ALL.Abstract 5292. Table 1IDDose LevelDiagnosis# of Prior Lines of TherapyPrior SCT# of CyclesBest Response11 (36mg/m2)AML1N3SD21 (36mg/m2)AML3Y<1NA31 (36mg/m2)AML2N2PR41 (36mg/m2)AML2N2SD52 (45mg/m2)AML2N1PD62 (45mg/m2)AML2N<1NA72 (45mg/m2)AML3N<1NA82 (45mg/m2)AML2N<1NA92 (45mg/m2)AML2N2SD102 (45mg/m2)AML3N<1NA112 (45mg/m2)AML2N2SD122 (45mg/m2)AML2N1PD133 (56mg/m2)AML3N1PD143 (56mg/m2)AML4Y2PR153 (56mg/m2)AML1N1PD163 (56mg/m2)AML3N<1NA173 (56mg/m2)ALL1N<1NA183 (56mg/m2)AML2N<1NAAbbreviations: NA- Not Applicable; SD- Stable Disease; PR- Partial Response; PD- Progressive Disease DisclosuresOff Label Use: We performed a phase I, single arm, single center, open label study of the selective proteasome inhibitor carfilzomib (CFZ) in adult patients with relapsed or refractory AML and ALL. CFZ is approved for the treatment of patients with multiple myeloma who have already received at least two other treatments including bortezomib and an immunomodulatory agent (lenalidomide and/or thalidomide), and whose disease has progressed (got worse) on their last therapy or within 60 days of their last therapy.. Vij:Onyx Pharmaceuticals, Inc.: Honoraria, Research Funding.

Abstract LB-95: Estrogen receptor mRNA-directed therapy for triple-negative breast cancer

Abstract Introduction: A significant number of histologically triple negative breast cancer (TNBC) cells express substantial estrogen receptor (ER) mRNA but do not express ER protein as a result of rapid proteolytic degradation. Here we assessed whether proteasome inhibitors could sensitize such cells to tamoxifen-induced growth suppression. Methods: Data from the Katzenellenbogen laboratory elegantly demonstrate that in high ER mRNA MDA-MB-468 cells, ER protein is rapidly degraded via proteosomal degradation (Bhatt et al. MCB, 2012).Utilizing established human TNBC cell lines that express high ER mRNA (BT-20, MDA-MB-468, and newly established human TNBC cell lines from our laboratory MCJB2 and MCJB11), we defined a therapeutic strategy using the proteasome inhibitor carfilzomib in combination with the antiestrogen tamoxifen that demonstrates antitumor synergy. Results: We found that administration of carfilzomib in TNBC cell lines with high ER mRNA restored ER protein expression, and that combining this treatment with tamoxifen treatment led to enhanced growth suppression. We found that the TNBC MDA-MB-231 cells, which express no ER mRNA, show some growth suppression, but that tamoxifen provided no further growth suppression with these cells. We have previously shown that combined epigenetic therapy [methyltransferase inhibitor (decitabine) plus a histone deacetylase inhibitor (HDACi; romidepsin)] provided antitumor synergy in MDA-MB-231 cells via upregulation of the soluble Wnt suppressor, secreted frizzled protein 1 (sFRP1; Cooper et al. CCR, 2012). In addition, we show that this epigenetic therapy restores silenced ER mRNA and protein levels in MDA-MB-231 cells, and that combination of this epigenetic therapy with tamoxifen in MDA-MB-231 cells led to enhanced growth suppression by tamoxifen. We are currently testing these therapeutic strategies in vivo using established TNBC cell lines and our newly developed patient derived xenograft (PDX) mouse models that express either ERhigh or ERlow mRNA. Conclusions: If validated in animal models, we propose that ER mRNA expression level in TNBC patients could guide therapeutic choice, whereby, ERlow mRNA TNBC tumors could respond to epigenetic therapy followed by antiestrogen while ERhigh mRNA TNBC tumors could respond to a proteosome inhibitor followed by antiestrogen therapy. These results identify a novel epigenetic biomarker as predictive of therapeutic response. Citation Format: Christina A. von Roemeling, Laura A. Marlow, James Miller, Adam Mathias, Louis Dawson, Steadman Harrison, Beth A. Hollister, Derek C. Radisky, John Alton Copland. Estrogen receptor mRNA-directed therapy for triple-negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-95. doi:10.1158/1538-7445.AM2014-LB-95