Grogan, M

Abstract Background AL amyloidosis and multiple myeloma are plasma cell dyscrasias characterized by excess light-chain production leading to cardiac amyloid deposition and organ dysfunction. While effective, proteasome inhibitor–based therapy and stem cell transplantation are often limited in advanced disease. Daratumumab provides durable and well-tolerated plasma cell suppression and enables assessment of long-term cardiac outcomes. Purpose To evaluate the long-term effects of daratumumab therapy on cardiac biomarkers and myocardial amyloid burden, assessed by artificial intelligence- based electrocardiographic (AI-ECG) and echocardiographic measures, in patients with AL amyloidosis and cardiac involvement. Methods Following IRB approval, we conducted a retrospective review of patients with AL amyloidosis and cardiac involvement treated with daratumumab at Mayo Clinic Rochester since 2015, with a minimum follow-up of 6 months. Demographic, clinical, cardiac biomarker, electrocardiographic, and echocardiographic data were collected at baseline and last follow-up. Paired comparisons were performed using the Wilcoxon signed-rank test. Results Overall, 67 patients with AL amyloidosis were included (mean age at diagnosis 59 ± 10 years; 47 [70%] male; concomitant multiple myeloma 13 (19%) patients, mean left ventricular ejection fraction 61 ± 7%), with a mean follow-up duration of 8.3 ± 5.4 years. At diagnosis, the most common organ involvements were renal and cardiac, affecting 78% and 67% of patients, respectively. Free light-chain isotype was λ in 52 patients (75%) and κ in 17 (25%) and immunoglobulin heavy-chain was identified in 26 patients. Among patients with available baseline staging data, Mayo Clinic revised cardiac staging (2012) classified 32% as stage I, 14% as stage II, 21% as stage III, and 32% as stage IV. Most patients were NYHA class II (62%), with 27% in class III–IV. Baseline creatinine clearance <60 ml/min was observed in 48% of patients. No significant changes were observed in conventional echocardiographic parameters during follow-up. In contrast, cardiac biomarkers improved significantly with high-sensitivity troponin T decreased from a baseline median of 59 [25, 104.5] ng/L to 30.5 [14.5, 58.75] ng/L at follow-up (p = 0.003), and NT-proBNP declined from 1,053 [423.5, 6,211.5] pg/mL to 729 [299, 2,328] pg/mL (p = 0.02). Interestingly, artificial intelligence–based electrocardiographic analysis demonstrated a marked reduction in the predicted likelihood of cardiac amyloidosis, decreasing from 55.8% [5.1, 99.6] at baseline to 19.3% [4.3, 68.4] at follow-up (p < 0.0001). Conclusions Long-term daratumumab therapy was associated with significant reductions in cardiac biomarkers and AI-ECG derived measures of myocardial amyloid burden. These findings support the hypothesis that sustained suppression of pathogenic light-chain production may permit gradual improvement in amyloid cardiomyopathy over time.

Abstract Background Tafamidis is a near-complete transthyretin kinetic stabiliser for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). It is administered orally, once daily, and has demonstrated a statistically significant reduction in mortality at 30 months vs placebo. Purpose Report findings from patients who received up to 7.5 years treatment with tafamidis in the phase 3 trial and its long-term extension (LTE) study. Methods In ATTR-ACT, patients were randomised (2:1:2) to blinded tafamidis meglumine 80 mg, 20 mg, or placebo for 30 months. Patients continued their blinded tafamidis dose into the up to 60-month LTE study, until commercial prescription availability, or study termination. Those who received placebo in ATTR-ACT were randomized (2:1) to blinded tafamidis meglumine 80 mg or 20 mg in the LTE study. All patients were subsequently switched to open label tafamidis free acid 61 mg (bioequivalent to meglumine 80 mg). Outcomes were assessed over the entire 90-month follow-up. Results Of the 264 patients randomised to tafamidis in ATTR-ACT, 173 completed the trial and 170 continued to receive tafamidis the LTE study (Taf/Taf group). Of 177 patients randomised to placebo in ATTR-ACT, 85 completed the trial and 82 initiated tafamidis in the LTE study (Pbo/Taf group). Over a median follow-up of 54.2 months in the Taf/Taf group and 30.5 months in the Pbo/Taf group, incidence of all-cause mortality (ACM) was 54.5% and 71.2%. Median time to ACM was 47.5 and 30.3 months, resulting in a hazard ratio of 0.62 (95% CI: 0.49-0.79; P=0.0001; Figure). Incidence of cardiovascular-related mortality (CVM) was 42.0% and 57.1% in the Taf/Taf and Pbo/Taf groups. Median time to CVM was 47.6 and 30.3 months, resulting in a hazard ratio of 0.61 (0.47-0.81; P=0.0005). The total annual rate of all-cause hospitalisation in the LTE study was 0.69 in the Taf/Taf group and 1.14 in the Pbo/Taf group, and the total annual rate of cardiovascular-related hospitalisation was 0.36 and 0.63. Among patients remaining at each LTE study visit and with available data, improvement in New York Heart Association functional classification was more commonly seen in the Taf/Taf vs Pbo/Taf group. Mean observed reduction from baseline in Kansas City Cardiomyopathy Questionnaire Overall Summary score was significantly smaller in the Taf/Taf vs Pbo/Taf group at most LTE study visits. Treatment-related adverse events occurred in 11.2% of the Taf/Taf and 23.2% of the Pbo/Taf groups during the LTE study and were consistent with the known safety profile of tafamidis. Conclusions With up to 7.5 years of follow-up data, this analysis of ATTR-ACT trial and its LTE study is the longest reported to date for an ATTR-CM population treated with disease-modifying therapy. Findings demonstrate better long-term outcomes including survival, hospitalisation rates, quality of life, and heart failure symptoms with long-term tafamidis treatment. For image description, please refer to the figure legend and surrounding text.

Abstract Background Age and sex influence the clinical expression of transthyretin (ATTR) amyloidosis, but limited evidence exists on their real-world impact across disease phenotypes. The prospective, multi-national MaesTTRo study, currently enrolling patients from the USA, Canada, the UK, Germany and Spain, provides a uniquely comprehensive opportunity to explore age- and sex-associated differences in routine practice. The aim of this analysis was to quantify the associations between these factors and diagnostic delay and cardiac findings. Methods Baseline data from 230 consecutively enrolled patients were analysed. Cohorts were stratified by age at diagnosis (<60 y, n = 45; ≥60 y, n = 185) and separately by sex (female n = 70; male n = 161). Clinical characteristics, laboratory values, echocardiographic parameters and Kansas City Cardiomyopathy Questionnaire (KCCQ-23) scores were compared descriptively. Additional data will be included in the presentation as enrollment continues. Results Younger patients exclusively expressed a hereditary genotype (100% vs 63%), and experienced a longer mean (+SD) diagnostic delay than older patients (48 ± 61.5 vs 40.9 ± 64.4 months). Cardiac involvement was markedly age-dependent: median NT-proBNP was 91.5 pg ml⁻¹ (IQR 48.5–307) in the <60 yrs group versus 1,393.5 pg ml⁻¹ (457–3,065) in the ≥60 yrs group. Older patients were more likely to experience New York Health Association (NYHA) class II–IV limitation than younger patients (88% vs 44%). Nonetheless, LV ejection fraction remained preserved in both cohorts (51 ± 14.8 vs 55.6 ± 9.3%). Older patients also reported a higher burden of cardiac symptoms (52% vs 33%). Patient-reported KCCQ scores were lower in the ≥60 yrs group vs <60 years (68.4 ± 22.3 vs 73.3 ± 27.4). Females were more often diagnosed with ATTRv (84% vs 63%) after longer delays (51.3 ± 80.9 vs 38.3 ± 54.6 months), despite a stronger family history (61% vs 34%), and had lower biomarkers (NT-proBNP: 589 pg ml⁻¹ [111–2,509] vs 1,220 pg ml⁻¹ [386–2,941]) and wall thickness (LV wall thickness >12 mm: 58% vs 73%), although there was no difference in LV mass index. Males reported better health status (KCCQ: 70.7 ± 22.2 vs 64.7 ± 24.4). Neurologic manifestations were common in both sexes (~70%), while musculoskeletal symptoms were more commonly reported in females (33% vs 23%). Conclusions Age and sex may independently modulate the diagnostic trajectory and cardiac presentation of ATTR amyloidosis. Advanced age and male sex are associated with more pronounced structural biomarker evidence of myocardial damage, whereas younger age and female sex are linked to delayed diagnosis of primarily hereditary ATTR amyloidosis with polyneuropathy and less cardiac involvement, especially when non-indexed echo measurements are used. These results underscore the need for age- and sex-specific approaches to prompt early clinical suspicion and diagnosis in order to enable treatment to mitigate disease progression.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.

Abstract Background 99mTc-labelled cardiac scintigraphy enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Guidelines recommend using planar semiquantitative (heart to contralateral ratio, H/CL) and single photon emission computed tomography (SPECT) qualitative visual grading for diagnostic interpretation. However, planar imaging has inherent limitations, and visual grading is prone to interobserver variability, underscoring the need for standardized quantitative assessment. We developed a 3D volumetric quantitative score (3D Score) and assessed its diagnostic performance compared to myocardial tissue, the gold standard for ATTR-CM diagnosis. Methods At a single, tertiary referral center, we retrospectively identified consecutive patients from 06/2017 to 06/2024 who underwent 3-hour 99mTc-pyrophosphate or 99mTc-hydroxymethylene diphosphonate planar and SPECT/CT for suspected ATTR-CM and had archived myocardial tissue (biopsy or myectomy). On planar imaging, H/CL was calculated. On SPECT/CT, volumes of interest were drawn around the entire left ventricle (LV), avoiding calcifications, and within the right atrium (RA) blood pool. Mean uptake values were used to calculate the 3D Score (LVmean:RAmean), Fig 1A. Myocardial tissue was stained via sulfated Alcian blue and/or Congo red histochemistry. Once histologically confirmed, amyloid deposits were subtyped by liquid chromatography tandem mass spectrometry. The diagnostic performance of H/CL and 3D Score was assessed using receiver operating characteristic (ROC) curve analysis and predictive characteristics were defined. ROC areas under the curve (AUC) were compared using Delong test. Optimal cutoffs were determined using Youden’s J statistic. Baseline characteristics (demographics, echocardiogram, biomarkers) and H/CL were compared between patients above and below 3D Score cutoff. Results 239 patients were identified (median age 72 [65-78], 78% male, 46% ATTR positive). Median time between cardiac scintigraphy and myocardial tissue collection was 22 (6-65) days. Distribution of the 3D Score stratified by ATTR-CM status is illustrated in Fig 1B-C. The discriminative ability of the 3D Score was excellent (AUC 0.92) and superior to H/CL (0.87, p =0.006, Fig 1D-E). The optimal 3D Score cutoff for identifying ATTR-CM was ≥1.0 with sensitivity of 86%, specificity of 92%, positive predictive value (PPV) 90%, and negative predictive value (NPV) 89%. The optimal H/CL ratio cutoff for identifying ATTR-CM was ≥1.4 with sensitivity of 72%, specificity of 86%, PPV 81%, NPV 78%. Baseline characteristics of the overall cohort stratified by 3D Score are displayed in Table 1. Conclusions The 3D Score demonstrated excellent diagnostic performance for detecting ATTR-CM and was superior to current quantitative metrics. Future studies are needed to externally validate its performance across diverse patient cohorts and imaging centers and to investigate correlation with myocardial amyloid burden. Figure 1

Abstract Background The National Amyloidosis Centre (NAC) staging system for transthyretin amyloid cardiomyopathy (ATTR-CM) is used to classify patients into prognostic categories based on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level and estimated glomerular filtration rate (eGFR). The NAC staging system has been shown to predict ongoing survival throughout the course of ATTR-CM, with survival progressively decreasing from stage I to stage III. Acoramidis, a highly selective, oral transthyretin stabilizer that achieves near-complete (≥90%) transthyretin stabilization, has recently been approved in Europe and the USA for the treatment of wild-type or variant ATTR-CM in adults. In the phase 3 ATTRibute-CM study, acoramidis treatment was well tolerated and led to a 42% relative risk reduction in the composite of all-cause mortality and recurrent cardiovascular hospitalizations over 30 months compared with placebo (p=0.0005). Purpose To evaluate the ability of acoramidis treatment, as compared with placebo, to stabilize or improve NAC stage after 30 months in participants with ATTR-CM from the ATTRibute-CM study. Methods Participants in ATTRibute-CM were randomized 2:1 to receive acoramidis or placebo for 30 months. Efficacy analyses were conducted in the modified intention-to-treat population, which consisted of all randomized participants who had received at least one dose of acoramidis or placebo, had at least one efficacy evaluation after baseline and had a baseline eGFR ≥30 mL/min/1.73 m2. NAC stage at baseline and Month 30 was assessed. Changes from baseline to Month 30 were categorized as "stable", "improved" or "worsened". The "stable" category comprised participants who stayed within the same NAC stage at baseline and Month 30. The "improved" category comprised participants who moved from a higher NAC stage at baseline to a lower stage at Month 30. The "worsened or missing" category comprised participants who moved from a lower NAC stage at baseline to a higher stage at Month 30 and participants whose Month 30 NAC stage was missing. The change in NAC stage was compared between treatment groups using a stratified Cochran-Mantel-Haenszel test with stratification factors of genotype, NT-proBNP level and eGFR as recorded in the interactive voice/web response system at randomization. Results Overall, 611 participants were analysed (acoramidis: n=409; placebo: n=202). Baseline characteristics were comparable between treatment groups. Most participants had NAC stage I at baseline (acoramidis: 58.9%; placebo: 59.4%; Table). At Month 30, NAC stage remained stable or improved in 52.1% of acoramidis participants compared with 43.1% of placebo participants (p=0.0351; Figure). Conclusions Acoramidis treatment resulted in a greater proportion of participants whose NAC stage improved or remained stable at Month 30 compared with placebo, indicating better stabilization of their disease.

Abstract Background The clinical efficacy of tafamidis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) was demonstrated during the phase 3, multinational, randomised, placebo-controlled Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT).(1) In ATTR-ACT, the risk of any cardiovascular (CV)-related hospitalisation was significantly reduced among patients who received tafamidis meglumine 80 mg (the approved dose) vs placebo (relative risk ratio 0.70 [95% CI 0.57, 0.85]; P=0.0005).(2) The benefit of tafamidis treatment was largest among patients with New York Heart Association (NYHA) class I/II vs III symptoms at baseline.(1,3,4) Purpose ATTR-CM is a progressive disease with a natural history that typically includes an increasing frequency of CV-related hospitalisation as the condition worsens. This post hoc analysis adds to current knowledge by evaluating the risk of recurrent (≥1) CV-related hospitalisation by baseline NYHA class in ATTR-ACT patients taking the approved dose of tafamidis or placebo. Methods Patients aged 18 to 90 years with biopsy-confirmed wild-type or variant ATTR-CM and NYHA class I-III symptoms took part in ATTR-ACT between 2013 and 2018. During the trial, the cause of hospitalisation was adjudicated by an independent committee. The hazard ratio (HR) for first CV-related hospitalisation was calculated using a Cox proportional hazards model. The HR for recurrent CV-related hospitalisation was calculated using the Liu-Wei-Yang-Ying (LWYY; also known as the modified Anderson-Gill) model. Models compared tafamidis meglumine 80 mg vs placebo and adjusted for transthyretin genotype (wild-type or variant). In the overall population, the LWYY model was also adjusted for baseline NYHA class. Results The frequency of adjudicated CV-related hospitalisations during ATTR-ACT by NYHA class are shown in the Figure. Across patients who were NYHA class I-III at baseline, the risk of recurrent CV-related hospitalisation was 37% lower in those who received tafamidis vs placebo treatment (HR 0.627 [95% CI 0.463, 0.848]; P=0.0025; Table). Among those who were NYHA class I/II at baseline, a lower proportion of tafamidis- vs placebo-treated patients (44% vs 61%) had ≥1 CV-related hospitalisation. The risks of first and recurrent CV-related hospitalisation were 40% (HR 0.601 [95% CI 0.420, 0.861]; P=0.0055) and 55% (HR 0.449 [95% CI 0.305, 0.661]; P<0.0001) lower with tafamidis vs placebo treatment. Consistent with the survivor bias previously observed in ATTR-ACT,(1-4) the risk of recurrent CV-related hospitalisation was statistically similar in tafamidis- and placebo-treated patients who were NYHA class III at baseline (HR 1.113 [95% CI 0.688, 1.799]; P=0.6624). Conclusions Building on previous findings, this analysis found the risk of recurrent CV-related hospitalisation to be reduced by tafamidis meglumine 80 mg treatment in patients with early stage ATTR-CM.