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

Chari, Ajai; Stewart, A. Keith; Russell, Stuart D.; Moreau, Philippe; Herrmann, Joerg; Banchs, José; Hájek, Roman; Groarke, John D.; Lyon, Alexander R.; Batty, G. N.; Ro, Sunhee Kwon; Huang, Mei; Iskander, Karim; Lenihan, Daniel J.

doi:10.1182/bloodadvances.2017015545

Cited by 66 publications

(57 citation statements)

References 48 publications

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“…[7][8][9][10][11] It is interesting to note that preexisting comorbidities with the same codes as the examined CAEs and PAEs could not be examined as risk factors because patients with these AEs were excluded. [7][8][9][10][11] It is interesting to note that preexisting comorbidities with the same codes as the examined CAEs and PAEs could not be examined as risk factors because patients with these AEs were excluded.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the literature review, we examined age, sex, and common comorbidities, including diabetes, dyslipidemia, and chronic obstructive pulmonary disease (COPD), as independent variables to identify the risk factors associated with developing toxicities. [7][8][9][10][11] It is interesting to note that preexisting comorbidities with the same codes as the examined CAEs and PAEs could not be examined as risk factors because patients with these AEs were excluded. Among all the examined variables, COPD was found to be independently associated with the development of AEs.…”

Section: Resultsmentioning

confidence: 99%

“…In the current study, the median duration of carfilzomib treatment was 58 days. 7 In non-trial-based studies, the rate of heart failure has been estimated to be 8% to 20%. That may have been because the drug was new at the time of data collection and physicians did not yet know how to support patients and manage toxicities, or it may have been due to early disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…However, it was noted that these AEs rarely led to treatment discontinuation or death. 7 In non-trial-based studies, the rate of heart failure has been estimated to be 8% to 20%. 8,9 As was observed with CAEs, the incidence of PAEs collected through the SEER-Medicare linked database was similar to the rates of clinical AEs gathered from clinical studies.…”

Section: Discussionmentioning

confidence: 99%

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

Fakhri

Fiala

Shah

et al. 2019

Cancer

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Fakhri

Fiala

Shah

et al. 2019

Cancer

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“…Carfilzomib treatment has been associated with cardiovascular AEs, including low rates of grade 3/4 cardiac failure, dyspnea, and hypertension. 32,33 However, in randomized phase 3 studies, the incidence of treatment discontinuation or death due to these cardiac events is low and comparable between treatment arms, highlighting the importance of control arms in elucidating treatment-related toxicities. 33 In this study, median LVEF remained stable, cardiac TEAEs were manageable and typically resolved, and no patient discontinued study treatment or died from cardiac TEAEs.…”

Section: Discussionmentioning

confidence: 99%

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Chari

Martínez‐López

Mateos

et al. 2019

Blood

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113

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K E Y P O I N T S l Daratumumab plus carfilzomib/ dexamethasone induced deep durable responses, regardless of prior treatment with lenalidomide. l Splitting the first dose of daratumumab was feasible, and the regimen was well tolerated.Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomiderefractory patients were eligible. Carfilzomib-and daratumumab-naïve patients (n 5 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m 2 initial dose, escalated to 70 mg/m 2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide.

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Plasma Cell Disorders

Yee¹,

Hideshima²,

Raje³

et al. 2022

Holland‐Frei Cancer Medicine

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Overview Plasma cell disorders have in common a proliferation of monoclonal plasma cells associated with the production of a monoclonal protein. These disorders range from the common, indolent condition of monoclonal gammopathy of undetermined significance to malignancies such as multiple myeloma characterized by the presence of hypercalcemia, anemia, renal dysfunction, and/or lytic bone lesions. Progress in the understanding of the molecular underpinnings of myeloma has led to remarkable advances in its treatment. High‐dose melphalan and autologous stem cell transplant have been a mainstay of treatment. Now, highly effective and well‐tolerated drug classes such as the proteasome inhibitors (e.g., bortezomib, carfilzomib), immunomodulatory drugs (e.g., lenalidomide, pomalidomide), and anti‐CD38 monoclonal antibodies (e.g., daratumumab, isatuximab) have rapidly transformed treatment and significantly improved overall survival. Newer therapies targeting B‐cell maturation antigen (BCMA) have the potential to further improve outcomes.

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

Cited by 66 publications

References 48 publications

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

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

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Plasma Cell Disorders

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