Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in ...patients with multiple myeloma (MM) receiving PIs.
Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide BNP, and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs.
Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib (
= .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8;
< .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0;
< .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank
= .01) and overall survival (log-rank
< .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications.
CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.
Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity ...and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy.
We conducted a genome-wide association study (GWAS) of change in LV function after anthracycline exposure in 385 patients identified from BioVU, a resource linking DNA samples to de-identified electronic medical record data. Variants with P values less than 1×10 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospective clinical trial. Pathway analysis was performed to assess combined effects of multiple genetic variants.
Both cohorts were middle-aged adults of predominantly European descent. Among 11 candidate loci identified in discovery GWAS, one single nucleotide polymorphism near PR domain containing 2, with ZNF domain (PRDM2), rs7542939, had a combined P value of 6.5×10 in meta-analysis. Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome. Identified pathways related to DNA repair, cellular metabolism, and cardiac remodeling.
Using genome-wide association we identified a novel candidate susceptibility locus near PRDM2. Variation in genes belonging to pathways related to DNA repair, metabolism, and cardiac remodeling may influence changes in LV function after anthracycline exposure.
Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has ...exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.
A unique resource for helping children and adults with hearing loss develop listening and spoken language as the foundation for cognition, literacy, and educational advancement Substantial ...neurobiological evidence indicates hearing is the most effective sensory modality for developing spoken language and cognition. From Listening to Language: Comprehensive Intervention to Maximize Learning for Children and Adults with Hearing Loss, edited by renowned clinicians Jane R. Madell and Joan G. Hewitt, features contributions from a distinguished group of experts. The text focuses on evidence-based practice to maximize the learning potential of children with hearing loss by nurturing the auditory brain development necessary to help them learn to listen and talk, as well as helping adults build stronger listening skills. Six sections and 22 chapters cover the spectrum of comprehensive listening and spoken language intervention for all age groups (including adults) and for the professionals working with them. Topics include literacy, executive function, bilingualism, dual diagnoses, educational support, changes in auditory access, red flags for auditory development, music therapy, telepractice, and intervention with adults. In-depth discussions of the stages of speech and language development for the diverse population of children with hearing loss assist new and experienced clinicians develop effective therapeutic and educational plans and encourage caregivers to become effective partners in their children's progress. Key Features * Reader-friendly chapters with summaries, key points, pearls, and pitfalls facilitate learning * Case studies assist clinicians in applying chapter information * A wealth of LSL resources, assessments, charts, suggested readings, websites, and more provide the opportunity to expand knowledge * Videos offer examples of hearing evaluation of infants and young children and speech perception testing, including demonstrations of the LMH (Ling-Madell-Hewitt) Test Battery. This is an essential textbook for graduate courses in audiology, speech- language pathology, early intervention, and deaf education, and an invaluable resource for new and experienced professionals and the caregivers with whom they work.
Introduction: Cardiovascular (CV) toxicity has been reported with use of proteasome inhibitors (PI) for multiple myeloma (MM). However, detailed descriptions of the frequency and severity of ...cardiovascular adverse events (CVAE) and risk factors associated with CVAEs are lacking. We conducted a prospective, observational, multi-institutional study to define CV risk factors and outcomes in MM patients receiving bortezomib or carfilzomib.
Methods: Patients with relapsed MM who were starting therapy with a regimen containing either carfilzomib (Car)- or bortezomib (Bor)- underwent a detailed baseline CV assessment including: assessment of traditional CV risk factors (CVRF; family history, hypertension (HTN), hyperlipidemia, diabetes and tobacco use), cardiac biomarkers troponin I and T, brain natriuretic peptide (BNP) and N-terminal proBNP (NTproBNP), electrocardiogram (ECG), transthoracic echocardiogram, and evaluation by a cardiologist. Patients with light chain amyloidosis were excluded.
CV assessments were performed at baseline and at the start of each chemotherapy cycle (i.e. every 3 or 4 weeks). Cardiac biomarkers were tested twice per cycle for up to 6 cycles. Patients were followed for development of CVAEs for a period of 18 months, defined according to the CTCAE v4.03: heart failure (HF), arrhythmia requiring treatment, acute coronary syndrome (ACS), grade III or IV HTN, angina, venous thromboembolic event (VTE) and pulmonary HTN (PH). All CVAEs were confirmed by a cardiologist.
Results: 97 patients were enrolled, with 65 receiving Car- and 32 Bor-therapy with a median follow-up of 14 months. Patients received a median of 2 prior lines of therapy in the Car group, and 1 prior line in the Bor group. There was no difference in baseline natriuretic peptide levels between cohorts (P=0.26). In total, 61 cardiac AEs occurred, with 54% being ≥ grade 3 (Table 1). Of evaluable patients, 50% (n=32) receiving Car and 15% (n=4) receiving Bor experienced at least one CVAE (P=.002). The median time to CVAE from start of treatment was 33 days, with the majority (86%) occurring within the first 3 months of treatment (Figure). Seventeen patients with CVAE (47%) experienced ≥2 CVAEs.
In patients receiving Car-therapy, a baseline BNP >100 pg/ml or NTproBNP >125 pg/ml was associated with an increased risk of CVAE (OR 11.7, 95% CI 3.3-41.5; P <.001). In patients with normal baseline natriuretic peptide levels, an increase during cycle 1 was associated with a higher risk of CVAE (OR of 35.1, 95% CI 4.3-289.5, P <.001).
In multivariate analysis (Table 2), Car-therapy was associated with a higher risk of CVAE (HR 5.4, 95% CI 1.6 to 18.4; P <.001) as compared to Bor-therapy. Elevated baseline natriuretic peptide levels were associated with higher risk of CVAE (HR 4.4, 95% CI 2.2 to 8.9; P <.001), and patients with ≤ 1 baseline CVRF had a lower risk of CVAE (HR 0.5, 95% CI 0.3 to 0.9, P=0.02). Other assessments evaluated and not found to be predictive of CVAEs included baseline troponins, ECG, left ventricular ejection fraction, intravenous fluid volume, chemotherapy duration, corticosteroid use and higher Car dose levels.
The majority (68%) of patients with CVAEs resumed PI-based therapy after CVAE without chemotherapy modification; another 30% who experienced a CVAE were able to resume PI-therapy with chemotherapy modifications. Only 2% required discontinuation of therapy due to CVAE. One grade 5 toxicity occurred during Car treatment from ACS leading to sudden cardiac death.
Summary and Conclusions: This is the first prospective study designed to systematically evaluate cardiac events in patients receiving carfilzomib or bortezomib. CVAEs were more common with Car than with Bor but usually did not require discontinuation of therapy with careful management. Additionally, prospective monitoring with natriuretic peptides and detailed cardiac history to determine risk factors are useful in identifying patients at high risk of CVAEs during treatment with PIs.
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Weiss:Alnylam: Honoraria; Prothena: Research Funding; Janssen: Honoraria; Prothena: Honoraria; Janssen: Research Funding. Cohen:Bristol Meyers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Jagasia:Janssen: Consultancy, Research Funding; Mallinckrodt: Consultancy; Therakos: Consultancy, Research Funding. Moslehi:Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy; Ariad: Consultancy; Acceleron: Consultancy; Incyte: Consultancy; Vertex: Consultancy; Regeneron: Consultancy; StemCentRx: Consultancy; Verastem: Consultancy; Heat Biologics: Consultancy; Rgenix: Consultancy. Savona:Sunesis: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Equity Ownership; Celgene: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vogl:Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Celgene: Consultancy; Teva: Consultancy; GSK: Research Funding; Calithera: Research Funding; Constellation: Research Funding.
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