The International Society of amyloidosis Congress was a fantastic week-long conference on all aspects of amyloidosis held in Rochester, Minnesota, the home of the Mayo Clinic. There were over 1000 attendees and a huge Australian turnout of 20 + clinicians and nurses, strongly representing the Australian Amyloidosis Network. We enjoyed being in one large meeting room with delegates from across the world listening to updates from the pathophysiology of amyloidosis to advancements in treatment.
Below are some highlights from the meeting with commentary courtesy of Dr Niri Ranjit Anderson, Dr Natasha Gorrie, A/Prof Nikki Bart, A/Prof Peter Mollee and Ms Pat Neely.
Abstract 185. Efficacy and Safety of Daratumumab Monotherapy in Newly Diagnosed Patients with Stage 3B Light-Chain Amyloidosis: A Phase 2 Study by the European Myeloma Network
Author
Efstathios Kastritis1, Monique C. Minnema2, Meletios A. Dimopoulos1, Giampaolo Merlini3, Foteini Theodorakakou1, Despina Fotiou1, Antoine Huart4, Karim Belhadj5, Ioannis Ninos6, Giorgos Psarros6, Pieter Sonneveld7, Giovanni Palladini3
1.Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece,
2.Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands,
3.Amyloidosis Research and Treatment Center, University of Pavia, Pavia, Italy,
4.Department of Nephrology and Transplantation, Rangueil University Hospital, Toulouse,
5.Lymphoid Malignancies Unit, Henri Mondor Hospital, Créteil, France,
6.Health Data Specialists, Dublin, Ireland,
7.Erasmus MC Cancer Institute, Rotterdam, Netherlands
Main Body of the Abstract
EMN22 (NCT04131309), an ongoing, prospective, phase 2 study, primarily assesses the 6-month overall survival (OS) of patients with newly diagnosed AL amyloidosis (NDAL) and Mayo2004/European stage 3B, who are treated with daratumumab monotherapy. Daratumumab is administered at the standard dose and schedule (initially IV and since 02/2020 as SC) for a maximum of 2 years. Patients not achieving ≥hematological very good partial response by C4 can additionally receive bortezomib and dexamethasone (Vd). The planned accrual of 40 patients has been completed, and herein, we present updated study results (cutoff date 15/12/2023) (Table).
Four (10.0%) patients continue treatment, 26 (65.0%) discontinued, and 10 (25.0%) have completed the 2-year treatment. At a median (range) follow-up of 10.3 months (<0.1–50.1), the median number of daratumumab administrations was 18.0 (1.0–36.0). Ten (25.0%) patients received Vd. The 6-month OS rate (primary endpoint) was 65.0% (95% CI: 48.2–77.6); median OS was 10.3 (95% CI: 4.1-32.1) months. At 6 months, 31 (77.5%) patients have achieved hematologic response (50% hemVGPR or better), 13 (32.5%) any organ response, and 11 (27.5%) cardiac response. Overall cardiac response was 50% (10% carCR, 30% carVGPR and 10% carPR). All patients experienced ≥1 serious (SAE) or non-serious adverse event, and 17 (42.5%) had a fatal SAE, without new toxicity signals.
In patients with stage 3B NDAL, daratumumab monotherapy induced deep hematologic responses with a 6-month OS of 65.0%. No new safety signals were observed. Based on these outcomes, daratumumab monotherapy may be considered as a major treatment option for these patients.
Comment: Treatment and outcomes for patients with AL amyloidosis has meaningfully improved over the years, particularly since the pivotal ANDROMEDA trial; however, patients with stage 3B disease who were excluded from the study, remain a high-risk population due to early mortality. At ISA, the results of the EMN22 trial, a phase 2 prospective study evaluating daratumamab monotherapy in newly diagnosed stage 3B AL amyloidosis patients, were presented. The trial allowed for patients who had a suboptimal response after 3 cycles of monotherapy to initiate bortezomib and low dose dexamethasone for up to 6 cycles. The primary endpoint of the study was met with a 6-month overall survival rate of 65% and a median overall survival of 10.3 months, which is a significant improvement compared to historical controls in this group of 40-45% and 4-6 months, respectively. Disease response was rapid with an early haematological response in 77.5% and 50% of patients achieving a cardiac organ response by 6 months. The ongoing risk of early death was highlighted with a mortality rate of 10% at 1 month and 27.5% at 3 months. Daratumumab related adverse events were infection related and no new cardiac safety signals were observed in the monotherapy group. AL amyloidosis patients with stage 3B disease currently represent a cohort with an unmet need and future studies need to build on the daratumumab backbone with treatment combinations that can be tolerated in this group to establish an optimal treatment pathway for these complex patients.
Abstract 257. Impact of SGLT2 Inhibitors on the Incidence of Cardiac Arrythmias and Overall Outcomes in Transthyretin Cardiac Amyloidosis
Author
Stefano H Byer, MD; University of Iowa Hospitals and Clinics, Iowa City, IA
Main Body of the Abstract
Transthyretin cardiac amyloidosis (ATTR-CM) is the most common type of cardiac amyloidosis and an increasingly recognized cause of heart failure and cardiac arrythmias. Recent data suggest that sodium-glucose contransporter-2 inhibitors (SGLT2i) may attenuate development of cardiac arrythmias in selected patient populations. However, the impact of SGLT2i on the incidence of cardiac arrythmias in ATTR-CA has not been evaluated.
We used TriNetX database to identify cohorts with both wild-type and variant ATTR-CM and T2DM, and performed a propensity score matched analysis (based on age, race, sex and co-morbidities) between patients with ATTR-CA and DM on SGLT2i versus patients with ATTR-CA and DM not on SGLT2i. Outcomes over a 10-year period were analyzed.
After propensity score matching, 1,984 patients were included in each cohort. Overall mortality was significantly lower in the SGLT2i group [OR=0.476 (0.403, 0.561), p<0.0001]. The incidence of atrial fibrillation [OR= 0.679 (0.529, 0.872), p<0.0001] and ventricular tachycardia were lower in the SGLT2i group [OR = 0.649 (0.494, 0.854), p=0.0002]. We noted a reduced incidence of sudden cardiac arrest in the SGLT2i group [OR=0.705 (0.503, 0.988), p=0.042]. However, we observed no difference in cardiac device placement or need for cardiac ablation between sub-groups with specific cardiac arrythmias.
To our knowledge, this is the first report investigating the impact of SGLT2i on cardiac arrhythmias and outcomes in patients with ATTR-CA and DM. We demonstrate a significant reduction in the rates of all-cause mortality, atrial fibrillation, ventricular tachycardia, sudden cardiac arrest.
Abstract 409. SGLT2 Inhibitors for Transthyretin Amyloid Cardiomyopathy: A Propensity Score-Matched Analysis
Author
Frederick M. Lang
Clinical Cardiovascular Research Laboratory for the Elderly, NewYork-Presbyterian/Columbia University Irving Medical Center
New York, NY 10032
Main Body of the Abstract
Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce cardiovascular mortality in heart failure (HF), but few studies have assessed SGLT2i in HF secondary to transthyretin amyloid cardiomyopathy (ATTR-CM). We conducted a retrospective study to address this lack of data.
Methods: Through our institutional database, we identified 87 SGLT2i-treated patients and 95 contemporaneous untreated control patients. We matched 42 patients in each group using a propensity score based on age, NYHA class, and Columbia risk score. After matching, no significant baseline differences were observed between groups. Changes in disease markers were then compared across groups during follow-up.
Results: The mean age of the overall population was 78.6 (SD 8.5) years. 88% of patients were male, and 95% were on tafamidis or acoramidis. Median Columbia risk score was 4 (IQR 3). Compared with controls, SGLT2i treatment was associated with significantly greater reductions from baseline in loop diuretic dose, weight, uric acid, and troponin-T during follow-up (P<0.05) (Figure). SGLT2i treatment was also associated with a significantly greater reduction from baseline than controls in eGFR at 1 and 6 months (P<0.05) but not at final follow-up after 6 months. No significant between-group differences were observed in NTproBNP (P=0.424). Numerically less HF hospitalizations (0 versus 4) occurred in SGLT2i-treated patients versus controls over a median follow-up time of 5.0 and 8.6 months, respectively. Five (11.9%) patients discontinued SGLT2i, most commonly due to genitourinary symptoms.
Conclusions: SGLT2i treatment may combat diuretic resistance, decrease volume overload, and improve troponinemia in patients with ATTR-CM. Larger long-term studies are needed.
Comment: A clear take-home point for the supportive care of patients with transthyretin cardiac amyloidosis is the emerging, important role of SGLT-2 inhibitors. Patients with heart failure can now access both empagliflozin and dapagliflozin, regardless of ejection fraction, through the PBS but the utility in amyloid was unclear. Data from ISA demonstrated a likely mortality benefit for those on SGLT-2 inhibitors without any significant changes in renal function or blood pressure. Whilst these studies are not randomised controlled trials, follow up was demonstrated out past 4 years.
Abstract 99. AmyLite Assay Quantifies Kinetically Unstable Circulating Amyloidogenic Lambda FLC – Diagnostic and Prognostic Implications for Lambda AL Amyloidosis
Author
Xin Jiang et al, Protego Biopharma, San Diego, California
Main Body of the Abstract
Light chain amyloidosis (AL) is a rare, progressive, and often fatal protein misfolding disease. In AL, clonal plasma cells overproduce amyloidogenic free light chains (FLCs) that are kinetically unstable, leading to formation of misfolded soluble conformations, fragments, and amyloid fibrils that are toxic to organs such as the heart and kidney. Amongst all AL patients, involved lambda FLC accounts for around 80% of the cases.
Accurate diagnosis of AL has been hampered by factors such as heterogeneity of clinical symptoms and diversity of the FLC sequences. Delayed AL diagnosis is a main contributing factor to the high early mortality seen in the clinic. We developed the AmyLiteTM assay by leveraging the key distinction in varied thermodynamic and kinetic stabilities between amyloidogenic and non-amyloidogenic FLC proteins. The AmyLiteTM assay combines limited proteolysis and the specific detection of the resulting product, namely the dimeric LC constant domain (dLCCD), using a highly sensitive immunoassay. After applying limited proteolysis to plasma samples, the AmyLiteTM assay can specifically (p<0.0001) and sensitively (LLOQ ~4ng/L) detect dLCCD in treatment naïve monoclonal lambda AL patients (N=67), differentiating them from normal controls and patients with multiple myeloma or transthyretin amyloidosis (ATTR). In addition, baseline dLCCD levels from 50 treatment naïve lambda AL patients with known clinical outcome correlate strongly with overall survival (log-rank p=0.0018).
With additional testing and validation, the AmyLiteTM assay could provide a simple and accurate method for early diagnosis of lambda AL, including screening of monoclonal gammopathy patients and monitoring AL patient treatment response or relapse.
Comment: This abstract outlines the very exciting development of an assay that can determine if a lambda free light chain has amyloid forming potential. While more data is required, this new assay has important implications for screening MGUS to detect amyloidosis and for monitoring AL amyloidosis.
Abstract 296. Changes in Organ-Specific Amyloid Load Assessed by Serial PET/CT Imaging of Iodine (124I) Evuzamitide – Correlation with Serum Biomarkers
Author
Emily B. Martin
University of Tennessee Graduate School of Medicine
Knoxville, TN
Main Body of the Abstract
Background: Iodine-124-evuzamitide, is a novel radiotracer for the detection of systemic amyloidosis by PET/CT imaging, which is an inherently quantitative modality. Therefore, this technique can be used to monitor progression and regression of organ-specific amyloid load. Here we report a single site, open-label, repeat imaging study (NCT05968846) of nine AL (n=9) and ten ATTR (n=10) patients imaged 2.9±0.9 years apart. Changes in organ-specific radiotracer uptake were quantified and analyzed.
Methods: Patients received 1 or 2 mCi 124I-evuzamitide with PET/CT imaging at 5 h post injection. A manual 2D region of interest (ROI) analysis of the heart was performed and standard uptake value ratios (SUVRmean) calculated. Contemporaneous serum biomarkers including NTproBNP were collected at each imaging session. Correlation analyses were used to test for associations between variables.
Results: All patients with ATTR (n=10) received stabilizer or silencer therapy between imaging, whereas seven of the nine (7/9) AL patients were untreated during this time. In the whole population (N=19), there was a significant correlation between the change in cardiac SUVRmean (%) and the change in serum NTproBNP (%) (rS=0.57, p=0.011). Eight (n=8; 89%) AL patients and seven (n=7, 70%) ATTR patients had a decrease in cardiac SUVR. Cardiac uptake of 124I-evuzamitide (N=19) correlated significantly with contemporaneous serum NTproBNP (rP=0.64, p=0.0034).
Conclusion: 124I-evuzamitide uptake in the heart may be used to monitor changes in amyloid load (Fig. 1). These pilot data indicate that changes in radiotracer uptake correlate with changes in serum NTproBNP, a validated biomarker predictive of survival in AL amyloidosis.
Abstract 401. Comparative Analysis of Clinical and Echocardiographic Variations in Cardiac Amyloidosis Subtypes
Author
Faysal Massad1, Shriya Bavishi1, Hamza Izhan1, Viral Desai1, Christopher Scott2, Patricia Pellikka1. 1Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA. 2Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
Main Body of the Abstract
Background: Light chain cardiac amyloidosis (AL-CA), wild type-transthyretin cardiac amyloidosis (wATTR-CA) and hereditary type-transthyretin cardiac amyloidosis (hATTR-CA) can each have different presentations and clinical courses. Analysis of a large cohort of patients with cardiac amyloid (CA) may help inform machine learning algorithms to differentiate subtypes using echocardiography.
Methodology: This is a retrospective multi-site analysis of clinical, laboratory and imaging characteristics in patients with different CA subtypes who had transthoracic echocardiography between 2010-2020. Diagnosis was verified by manual chart review and included assessment by an amyloid expert in 1939 (99%); 493 (25%) had advanced cardiac imaging, and 491 (25%) had cardiac biopsy. Assessment also included bone marrow and other biopsies and genetic testing. Echo parameters were directly extracted from study reports. The Kruskal-Wallis test was used in the analysis of continuous data while the Chi-Square test was used for categorical data.
Results: Of 1968 unique CA patients, 1128 (57.3%) had AL-CA, 624 (31.7%) had wATTR-CA & 216 (11.0%) had hATTR-CA. Patients with wATTR-CA were older, more often male, and had more comorbidities. Patients with wATTR-CA also had the greatest left ventricular wall thickness, more valvular regurgitation, largest left atrial volume index, more right ventricular enlargement, and most impaired strain (Table).
Conclusion: Subtypes of CA differ not only in clinical characteristics, but also appear to have distinct features in echocardiographic imaging.
Comment: I found the following topics of particular interest- the role of different types of imaging used together to understand amyloid “load” (above abstracts), the role of oral diuretic intensification and biomarkers in demonstrating cardiac disease progression and clinical endpoints in amyloidosis.
Some thoughts from Ms Pat Neely, Chair of AAN Media and Communications Committee
Every two years the International Society of amyloidosis ISA offers one of the amyloidosis centres around the world the chance to run the ISA symposium. This time the meeting was organised by a group of well-known amyloidosis specialists at the Mayo Clinic in Rochester, a place steeped in medical history.
These symposia cover many aspects of amyloidosis care worldwide, through paper, posters and discussion groups delivered and listened to by scientists and physicians engaged in research, teaching, or practice in connection with amyloid and amyloidosis. There are now some sessions concentrating on living with amyloidosis and a half day devoted completely to educating and listening to the needs of patients.
I have attended these biennial symposia either face to face or virtually since 2004 and this year was a face-to-face year for me. Although the journey from Australia was long and a little frustrating with postponed flights, it was worth it just to be able to catch up with the many people from around the world who have supported our work in Australia over many years and become true friends and to be part of the discussions.
Attendance at these meetings continues to grow with well over 1000 registrants this year. The many papers and posters illustrated how amyloidosis care and knowledge is spreading around the world.
The discussion and papers overall have continued to deliver a more positive feeling than in some of the earlier meetings. This illustrates a greater understanding of how to treat many of the types of amyloidosis resulting in positive results with patients now living long, productive lives.
Far more research projects and trials are being carried around the world. But listening to the papers also illustrated how much is not known about why some people develop amyloidosis and the amyloid protein itself and how to stop it completely from depositing in organs of the body, especially the heart and nerves. For some types of hereditary amyloidosis there is still very little or no treatment available to stop the production of the amyloid.
And in spite of a growing amyloidosis awareness patients continue to be diagnosed late.
This excellent meeting illustrated to me how important face to face discussion is and how young researchers, in fact all researchers must be encouraged and supported. And that those interested and involved in all types of amyloidosis care around the world must continue to work closely together to pooling ideas and results.
A/Prof Nikki Bart: “A fantastic conference all round demonstrating the interest and advancements in amyloidosis. From the St Vincent’s Hospital and Victor Chang Cardiac Research Institute perspective, I was proud to see our own neurologist Dr Antonia Carroll win a President’s prize for her work, as well as Dr Natasha Gorrie and Dr Elyn Montgomery present their work in amyloidosis imaging and frailty respectively.”
A/Prof Peter Mollee: “It was great to see the growing AAN presence at the world’s premiere amyloidosis scientific meeting. I was proud to see the AAN’s three travel grant winners, Dr Natasha Gorrie from the Victor Chang Cardiac Research Institute and St Vincent’s Hospital Sydney, Dr Niri Ranjit Anderson from the Queensland Amyloidosis Centre at the Princess Alexandra Hospital in Brisbane and Dr Dr Thanh Huyen Phan from the Westmead Institute for Medical Research, present their research in the poster sessions. AAN members had a busy meeting networking with international colleagues, meeting with Pharmaceutical companies to develop and conduct new clinical trials and advocate for registration and reimbursement of new therapies in Australia. The cardiology committee members were actively trying to progress the AAN’s plans for an ATTR amyloidosis registry. AAN members also met with colleagues to investigate better ways to provide support to Australian patients and their families. The next Congress in 2025 will be in Montevideo, Uruguay. We hope to see even more of you at that meeting.”