Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): And randomised, phase 3, open-label, multicentre study

Background: Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods: In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m2; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. Findings: Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). Interpretation: For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. Funding: Onyx Pharmaceuticals, Inc., an Amgen subsidiary

Mitral and tricuspid annular abnormalities in hypereosinophilic syndrome – a three-dimensional speckle-tracking echocardiographic study

Abstract Introduction Peripheral eosinophilia with absolute eosinophil count more than 1.500 cells/uL and eosinophilic tissue and end-organ damage are typical features in hypereosinophilic syndrome. In the present study it was hypothesized that hypereosinophilic syndrome-related atrial and ventricular abnormalities are associated with changes in size and function of mitral and/or tricuspid annuli. Methods The study comprised 17 patients with hypereosinophilic syndrome who were recruited, prospectively, 2 patients had to be excluded due to suboptimal image quality (mean age: 61.7±11.2 years, 10 males). The control group consisted of 24 healthy volunteers (mean age: 55.2±7.9 years, 12 males). Complete two-dimensional Doppler echocardiography was performed, mitral and tricuspid annuli were measured by three-dimensional speckle-tracking echocardiography. Results Only interventricular septum proved to be significantly thickened in patients with hypereosinophilic syndrome, other parameters did not differ between the groups examined. Increased end-diastolic and end-systolic mitral annular diameter (2.6±0.3 cm vs. 2.4±0.3 cm, p&amp;lt;0.05 and 2.2±0.2 cm vs. 1.7±0.3 cm, p&amp;lt;0.05, respectively), area (9.5±2.3 cm2 vs. 7.5±1.9 cm2, p&amp;lt;0.05 and 6.7±2.0 cm2 vs. 3.8±1.1 cm2, p&amp;lt;0.05, respectively), and perimeter (11.6±1.7 cm vs. 10.4±1.3 cm, p&amp;lt;0.05 and 9.9±1.9 cm vs. 7.4±1.1 cm, p&amp;lt;0.05, respectively) together with reduced mitral annular fractional area change (29.6±13.0% vs. 47.7±15.8%, p&amp;lt;0.05) and fractional shortening (16.6±11.9% vs. 28.9±12.7%, p&amp;lt;0.05) could be detected in patients with hypereosinophilic syndrome as compared to that of matched controls. From tricuspid annular morphological parameters, only end-diastolic tricuspid annular area (9.1±2.4 cm2 vs. 7.5±1.9 cm2, p&amp;lt;0.05) and end-systolic tricuspid annular perimeter (9.9±1.2 cm vs. 9.3±1.4 cm, p&amp;lt;0.05) proved to be significantly increased in patients with hypereosinophilic syndrome as compared to controls with preserved tricuspid annular functional parameters. Conclusion Mitral annular dilation is more pronounced compared to that of tricuspid annulus in hypereosinophilic syndrome. Mitral annular functional impairment is present in hypereosinophilic syndrome. Funding Acknowledgement Type of funding sources: None. </jats:sec

The tricuspid annulus in cardiac amyloidosis – a three-dimensional speckle-tracking echocardiographic study

Abstract Introduction Amyloidosis is a rare condition due to extracellular deposition of excessive amount of protein in parenchymal tissues including the heart. The present study aimed to test whether cardiac amyloidosis (CA) is associated with morphological and functional abnormalities of the tricuspid annulus (TA). For this aim, the results of patients having CA were compared to age- and gender-matched healthy controls by three-dimensional speckle-tracking echocardiography (3DSTE). Moreover, differences in TA parameters between light-chain CA (AL-CA) and transthyretin CA (TTR-CA) were studied as well. Methods The study comprised 27 CA patients (mean age: 62.7±9.1 years, 21 males), their results were compared to those of 20 age- and gender-matched healthy volunteers (59.3±3.8 years, 13 males). Current consensus criteria were used for the definition of CA. Biopsy was carried out in all patients to confirm the diagnosis of CA. The first positive biopsy site was the myocardium in 7 cases, bone marrow in 6 cases, duodenum and rectum in 5 cases, salivary gland in 1 case, skin and subcutaneous tissue in 2 cases and kidney in 10 cases in the CA patients. In 5 CA patients, biopsy samples were collected from more than one organ. CA proved to be AL-CA in 21 subjects and TTR-CA in 6 patients. Complete two-dimensional Doppler echocardiography and 3DSTE were performed in all CA patients and controls. Results CA patients had significantly higher left atrial diameter, left ventricular (LV) end-diastolic diameter, thicker interventricular septum and LV posterior wall and increased E/A ratio compared to the results of healthy controls. None of the 27 CA patients and their matched controls had atrial fibrillation in their medical history. Dilated 3DSTE-derived end-diastolic and end-systolic TA diameter (3.0±0.6 cm vs. 2.1±0.2 cm, p&amp;lt;0.05 and 2.6±0.6 cm vs. 1.6±0.2 cm, p&amp;lt;0.05, respectively), area (10.7±3.5 cm2 vs. 6.1±1.1 cm2, p&amp;lt;0.05 and 8.0±3.2 cm2 vs. 4.1±1.0 cm2, p&amp;lt;0.05, respectively) and perimeter (12.5±2.0 cm vs. 9.8±1.0 cm, p&amp;lt;0.05 and 10.6±2.1 cm vs. 8.0±1.0 cm, p&amp;lt;0.05, respectively) could be detected in all CA patients and in the AL-CA and TTR-CA subgroups, as well. Although only a few TTR-CA patients were involved, morphologic TA parameters proved to be tendentiously higher as compared to those of AL-CA patients. Functional parameters of TA represented by TA fractional area change (TAFAC, 26.1±11.2% vs. 32.0±11.1%, p=0.07) and TA fractional shortening (TAFS, 12.8±10.3% vs. 21.6±7.4%, p&amp;lt;0.05) were found to be reduced in CA patients, which were more enhanced in TTR-CA patients (TAFAC for TTR-CA: 27.1±14.3% vs. TAFAC for AL-CA:25.7±10.5%, p=ns; TAFS for TTR-CA: 16.0±9.8% vs. TAFS for AL-CA: 11.9±10.4%, p=ns). Conclusions Dilated TA is associated with its functional deterioration in CA. Patients with TTR-CA have tendentiously more dilated TA with more enhanced TA functional parameters. Funding Acknowledgement Type of funding sources: None. </jats:sec