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Cancer Therapies and Cardiac Dysfunction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Victoria Shklar, Katherine Godfrey, Michelle E. Bloom
Bortezomib is a reversible proteasome inhibitor which is overall felt to be relatively safe, with low rates of LV dysfunction and HF in over a decade of clinical use.85 The incidence of HF from bortezomib is in the range 2–5%. Meta-analysis rate of high-grade cardiac toxicity, including HF and sudden cardiac death, is estimated at 2.3%.86 Carfilzomib is an irreversible proteasome inhibitor used in reversed/relapsed multiple myeloma, with more potent activity than bortezomib. According to a pooled analysis of phase II studies on carfilzomib, 22% of patients experienced cardiac side effects, of which 7.2% exhibited HF and 2% developed cardiomyopathy. Among 60 myeloma patients treated with carfilzomib-based regimens, 12% experienced reversible LVEF reduction by 20%³ at 15 months.87 There was no dose-response association between carfilzomib and incidence of cardiac events. Carfilzomib toxicity is often reversible after drug cessation.87 In a trial of refractory multiple myeloma, there was a trend toward grade 3 or higher HF in the carfilzomib versus bortezemib arm, with grading defined by the Medical Dictionary for Regulatory Activities preferred terms.88
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The FDA approval of carfilzomib was based on multiple clinical trials, including one pivotal Phase II trial in patients with relapsed and refractory multiple myeloma. Carfilzomib as a single agent provided clinical benefit in 36% of the 266 patients evaluated, with an overall response rate of 22.9% and a median duration of response of 7.8 months. In another Phase II trial, carfilzomib had a 53% overall response rate in patients with relapsed and/or refractory multiple myeloma who had not previously received bortezomib. In another frontline Phase I/II study, a combination of carfilzomib, lenalidomide, and low-dose dexamethasone was highly active and well tolerated.
Overview of changes in cancer treatment strategies
Published in Susan F. Dent, Practical Cardio-Oncology, 2019
Grace Tang, Christine Brezden-Masley
At baseline, MM patients have a 54–74% risk of cardiovascular disease owing to advanced age at diagnosis (median 62 years), autologous stem cell transplantation, and disease-specific complications such as cardiac amyloidosis (72,79–82). Therefore, careful monitoring and a detailed history for cardiovascular risk factors and prior chemotherapy exposure (with particular attention to anthracyclines) are suggested (73). While there are no standard practice guidelines, Chari and Hajje published a set of recommendations for patients exposed to carfilzomib (83). In brief, screening echocardiograms should be obtained for all patients over the age of 60, with a history of amyloidosis, or other cardiovascular risk factors and repeated every two to three cycles (83). Carfilzomib should be administered slowly over 30 minutes instead of the 2–10 minutes indicated (83). In the event of suspected toxicity, carfilzomib should be withheld until complication resolves to below grade II and rechallenged at the last used or reduced dose (83).
A phase 1b dose-escalation study of carfilzomib in combination with thalidomide and dexamethasone in patients with relapsed/refractory systemic immunoglobulin light chain amyloidosis
Published in Amyloid, 2023
Sriram Ravichandran, Andrew Hall, Matthew Jenner, Mamta Garg, Bhuvan Kishore, Helen Lachmann, Julian Gillmore, Alexandra Pitchford, Jamie B. Oughton, Shameem Mahmood, Sajitha Sachchithantham, Philip Hawkins, Sarah Brown, Ashutosh Wechalekar
Carfilzomib is a distinct proteasome inhibitor that is licenced for the treatment of multiple myeloma. It is a tetrapeptide ketoepoxide-based inhibitor specific for the chymotrypsin-like active site of the 20S proteasome, structurally and mechanistically distinct from bortezomib. Autonomic and peripheral neuropathy are uncommon toxicities with carfilzomib [11]. There is extensive data using carfilzomib combined with immunomodulatory agents (IMiDs) in myeloma treatment. Therefore, it is very appealing to use this agent in AL amyloidosis. However, there are reported cardiac and renal toxicities with carfilzomib in a small number of patients. Hence, it cannot be adopted directly for AL amyloidosis without formal prospective studies. There is limited data on the use of carfilzomib in AL amyloidosis comprising only a single case series and a phase 1 dose-escalation study using Carfilzomib alone [12,13]. There is no data on the safety/efficacy of combination therapy using Carfilzomib.
Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group
Published in Amyloid, 2023
Ashutosh D. Wechalekar, M. Teresa Cibeira, Simon D. Gibbs, Arnaud Jaccard, Shaji Kumar, Giampaolo Merlini, Giovanni Palladini, Vaishali Sanchorawala, Stefan Schönland, Christopher Venner, Mario Boccadoro, Efstathios Kastritis
There is limited data on carfilzomib. Small studies have demonstrated efficacy. Cohen et al. reported their Phase I/II trial of carfilzomib in 28 patients with relapsed/refractory Mayo cardiac stage I or II disease. The 20/36 mg/m2 biweekly dosing was determined as the maximum tolerated dose (MTD). While the haematologic response rate of 63% is comparable to most other therapies for relapsed/refractory disease, the CR was low at 11%. 20 patients experienced Grade III/IV toxicity (according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0), many cardiac or pulmonary. It has also been reported to be useful with a once weekly schedule in combination with thalidomide and dexamethasone in a phase 1 study [37] with no substantial grade III/IV toxicity and good responses. Overall, there are significant safety concerns with carfilzomib, especially cardiac and renal disease, caution dosing and close monitoring is advised. It may have a role in patients with neuropathic presentation and should be used with once weekly protocol.
A comprehensive overview of daratumumab and carfilzomib and the recently approved daratumumab, carfilzomib and dexamethasone regimen in relapsed/refractory multiple myeloma
Published in Expert Review of Hematology, 2021
Shambavi Richard, Sundar Jagannath, Hearn Jay Cho, Samir Parekh, Deepu Madduri, Joshua Richter, Ajai Chari
Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. Carfilzomib inhibited proteasome activity and delayed tumor growth in animal models of multiple myeloma, as well as other hematologic and solid tumors. There was a greater inhibition of proteasome subunits at higher doses [48–50]. Toxicity studies were conducted in rats and monkeys using a 28-day schedule and bolus administration. Using this schedule, the dose-limiting toxicities (DLTs) were cardiovascular, hematologic, and gastrointestinal. At the maximum tolerated doses (MTDs) in all studies, transient cyclical thrombocytopenia without a loss of megakaryocytes was the most prominent hematological toxicity. Peripheral neuropathy (behavioral and histopathological) and myelosuppression (neutropenia and severe anemia) were not observed. Carfilzomib was found to be better tolerated when delivered as a 30-min infusion versus a bolus administration [48]. A rat myocyte model was used to study the cardiotoxic mechanisms and demonstrated that exposure to carfilzomib resulted in significant myocyte damage and apoptosis [44]. Cardiotoxicity timing and occurrence remain difficult to be predicted in humans.