Fatal pulmonary toxicity due to carfilzomib (Kyprolis™)

Lataifeh, Abdel Rahman; Nusair, Ahmad

doi:10.1177/1078155215588630

Cited by 17 publications

(17 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Pulmonary toxicity, albeit rare, has also been reported with PIs targeting the 20S proteasome subunit [14][15][16]. In a recent literature review of 35 reports of pulmonary toxicity attributed to bortezomib, most events were noted to occur after the first Fifteen patients were enrolled and 14 patients were treated.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma

Rowinsky¹,

Paner

Berdeja

et al. 2020

Invest New Drugs

View full text Add to dashboard Cite

This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570's formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.

show abstract

Section: Discussionmentioning

confidence: 99%

Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma

Rowinsky¹,

Paner

Berdeja

et al. 2020

Invest New Drugs

View full text Add to dashboard Cite

show abstract

“…11 There have been sporadic cases of more serious PAEs. Fatal pulmonary toxicity was reported to manifest as acute respiratory distress syndrome and diffuse alveolar hemorrhage within 1 week of receiving the first dose of carfilzomib, 12 and carfilzomib-related severe pneumonitis has been reported in the literature. 13 In addition to measuring the real-world incidence of CAEs and PAEs, it also is important to identify the underlying factors associated with the development of AEs.…”

Section: Discussionmentioning

confidence: 99%

Measuring cardiopulmonary complications of carfilzomib treatment and associated risk factors using the SEER‐Medicare database

Fakhri

Fiala

Shah

et al. 2019

Cancer

View full text Add to dashboard Cite

BACKGROUND: Carfilzomib improves survival in patients with recurrent myeloma. Given the strict eligibility criteria in clinical trials, the actual frequency of cardiac adverse events (CAEs) and pulmonary adverse events (PAEs) and the risk factors associated with these AEs in the general population need to be established. METHODS: The authors extracted myeloma cases in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database from 2000 through 2013 and corresponding claims through 2014. They then identified patients who received carfilzomib during their disease course. Subsequently, the International Classification of Diseases, Ninth Revision (ICD-9) was used to identify all the codes for CAEs, PAEs, and respiratory infections associated with carfilzomib use. Preexisting diagnoses corresponding to the CAEs and PAEs of interest were excluded to distinguish toxicity from comorbidity. Multivariate Cox regression was performed to determine those variables independently associated with the development of CAEs and PAEs. RESULTS: Of the 635 patients analyzed, the median age was 72 years (range, 36-94 years); 55% of the patients were male and 79% were white. The median duration of carfilzomib treatment was 58 days (range, 1-716 days). Overall, approximately 66% of the patients had codes for either CAEs or PAEs. In terms of CAEs, approximately 22% of patients developed hypertension, 15% developed peripheral edema, and 14% experienced heart failure. With regard to PAEs, approximately 28% of patients developed dyspnea, 15% developed cough, and 15% developed pneumonia. Only chronic obstructive pulmonary disease (COPD) was found to be independently associated with the development of CAEs. Patients with preexisting COPD were found to have a 40% increase in their hazard of developing CAEs (adjusted hazard ratio, 1.40; 95% CI, 1.03-1.90). CONCLUSIONS: In older adults with myeloma who are undergoing treatment with carfilzomib, new cardiac and pulmonary diagnoses were common. Patients with preexisting COPD were found to be at an increased risk of developing CAEs. Cancer 2020;126:808-813.

show abstract

“…Other pulmonary AEs that have been reported in this analysis include cough (26.0%), pleural effusion (4%), pulmonary hypertension (2%), pulmonary embolism (1%), hemoptysis (0.6%), and pneumonitis (0.4%). Fatalities associated with pulmonary toxicities have also been reported, including pulmonary hemorrhage in the presence of thrombocytopenia . Respiratory infections, mainly pneumonia (12.7%), were not uncommon.…”

Section: Toxicity and Adverse Events Managementmentioning

confidence: 99%

A practical review on carfilzomib in multiple myeloma

Muchtar

Gertz

Magen

2016

European J of Haematology

View full text Add to dashboard Cite

Carfilzomib, a second-generation proteasome inhibitor, has been increasingly used in relapsed/refractory multiple myeloma (MM) since its approval by the American food and drug administration (FDA) in the summer of 2012. The drug is active as a single agent and in combination with other antimyeloma agents. As a result of its efficacy and safety in the relapsed/refractory setting, carfilzomib is being evaluated in patients with newly diagnosed MM as well as in high-risk smoldering MM. This review will give a comprehensive summary of the drug, including its mechanism of action, the evaluated doses and schedules as well as a summary of the main clinical trials in the relapsed/refractory and newly diagnosed settings. A focus will be placed upon certain subgroups of interest as well as a description of the toxicity associated with carfilzomib use and a clinical perspective on toxicity management.

show abstract

Fatal pulmonary toxicity due to carfilzomib (Kyprolis™)

Cited by 17 publications

References 17 publications

Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma

Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma

Measuring cardiopulmonary complications of carfilzomib treatment and associated risk factors using the SEER‐Medicare database

A practical review on carfilzomib in multiple myeloma

Contact Info

Product

Resources

About