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PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

ABSTRACT Systemic AL amyloidosis is a clonal plasma cell dyscrasia, where toxic free light chains (FLCs) lead to vital organ damage, with risk of early mortality despite effective therapies. Notably, there is a paucity of data on the incidence and predictors of early mortality in the daratumumab (Dara) era. We conducted a multi‐center retrospective cohort study to develop and validate a risk‐prediction model for early mortality (all‐cause death within 6 months) in patients treated with Dara‐based frontline regimens. We used univariate analysis to identify covariates for a logistic regression model predictive of 6‐month mortality and generated a clinical risk score. Among 339 patients across eight centers, 36 (10.6%) experienced early mortality. Multivariate analysis identified four independent predictors: NT‐proBN P > 5300 pg/mL (odds ratio [OR] 3.83, p = 0.006), A ge > 75 years (OR 2.96, p = 0.073), absence of t(11;14) on C ytogenetics (OR 3.0, p = 0.022), and E COG performance status (OR 1.72 per unit increase, p = 0.044). The resulting PACE score stratified patients into three risk groups with a 6‐month mortality of 1.2% (low‐risk), 11.7% (intermediate‐risk), and 50.0% (high‐risk). The PACE score demonstrated superior discrimination (C‐index 0.78) for early mortality compared to Mayo 2004 (0.69) and Mayo 2012 (0.55) staging systems. External validation confirmed robust discrimination (C‐index 0.73) with corresponding 6‐month mortality rates of 4.2%, 15.25%, and 37.04% across respective risk groups. The PACE score provides a clinically applicable tool for early mortality risk stratification in AL amyloidosis patients receiving Dara‐based therapy, and will enable improved patient counseling, clinical trial design, and identification of ultra‐high‐risk patients requiring intensive monitoring and novel therapies.

Abstract Rapid and profound reduction of free light chains (FLCs) improves outcomes in AL amyloidosis; however, early FLC kinetics with daratumumab‐based frontline therapy remain undefined. We retrospectively analyzed 315 patients treated with daratumumab–bortezomib–cyclophosphamide–dexamethasone (Dara–VCd) or Dara–Vd at eight centers. Involved FLC (iFLC), the difference between iFLC and uninvolved FLC (dFLC), and hematologic response (≥very good partial response [VGPR]) were assessed at baseline and at 1, 3, and 6 months, and correlated with light chain isotype, disease burden (bone‐marrow plasma‐cell percentage [%BMPC], baseline dFLC), and cytogenetics. Hematological ≥VGPR increased from 49.8% at 1 month to 66.0% at 3 months. The kappa isotype showed slower responses, with higher iFLC/dFLC and lower ≥VGPR at each time point compared to lambda. Higher %BMPC or baseline dFLC predicted persistently elevated iFLC/dFLC and reduced ≥VGPR. The t(11;14) translocation was associated with lower baseline FLC but similar subsequent kinetics. BMPC < 10% and dFLC < 18 mg/dL independently predicted early ≥VGPR (in ≤1 month). Early ≥VGPR conferred superior hematologic event‐free survival (heme‐EFS) and overall survival (OS) versus later responders (P < 0.001). At a 3‐month landmark, achieving dFLC < 1 mg/dL further stratified prognosis, conferring longer heme‐EFS and OS (P < 0.01). Frontline Dara‐based therapy elicits rapid, deep responses in AL amyloidosis; early ≥VGPR (within 1 month) and dFLC < 1 mg/dL by 3 months predict durable EFS and OS, whereas higher baseline disease burden delays hematologic response.

PURPOSE Outcomes in systemic light chain (AL) amyloidosis have improved with modern therapy limiting utility of existing risk stratification models. We validate a new staging system, incorporating longitudinal strain (LS) to the biomarker-based (NT-proBNP and Troponin-T) staging system in the contemporary treatment era (2015-2024). METHODS AL International Staging System (AL-ISS) was derived from a cohort of patients with AL amyloidosis from the UK National Amyloidosis Centre (2015-2019). The model was validated in patient cohorts from Europe (Greece, Italy, the Netherlands, and Switzerland), the United States (2015-2024), and the United Kingdom (2020-2024). RESULTS In total, 2,493 patients were included (derivation, n = 573; validation n = 1,920). In a multivariable model for the derivation cohort, LS ≥ –9% and cardiac biomarkers at previously validated thresholds (NT-proBNP 332 ng/L and 8,500 ng/L and high-sensitivity troponin T ≥ 50 ng/L) were independent poor prognostic factors stratifying patients into stages I, II, IIIA, IIIB, and IIIC. In the validation cohort, the patient stages were stage I: 317 (17%), II: 782 (41%), IIIA: 551 (29%), IIIB: 174 (9%), and IIIC: 96 (5%), respectively (first-line daratumumab treated: 826; 43%). With a median follow-up of 34 months, median overall survival (OS) was not reached (NR); estimated 1-year, 2-year, and 3-year OS was 82%, 74%, and 70% respectively. The median survival for stages I to II, IIIA, IIIB, and IIIC were NR, 67, 26, and 7 months (1-year OS IIIC 53% v 68% for IIIB in the daratumumab-treated patients), respectively ( P < .001). External validation exhibited good predictive performance: 12-month calibration slope was 1.09, Harrell C 0.69, Royston D 1.19, and R 2 D 0.25. Stage IIIC independently discriminated the poorest outcome across all cohorts. CONCLUSION This defines and validates a new staging system from systemic AL amyloidosis with robust identification of an ultra-poor risk stage (IIIC) in contemporarily treated patients.

Abstract Background B-cell maturation antigen (BCMA)-targeting immunotherapies represent a promising class of treatment for the management of immunoglobulin light chain (AL) amyloidosis, a disease that is related to clonal plasma cells. Etentamig is a 2nd generation, off-the-shelf, fully human BMCA X CD3 bispecific antibody with bivalent BCMA domain and low CD3 affinity that targets both BCMA-expressing plasma cells and CD3-expressing T cells. Etentamig monotherapy is being studied in multiple myeloma (MM) in an ongoing phase 3 study (NCT06158841). Here, we report the first safety and efficacy results from M24-209, an open-label phase 1/2 study evaluating etentamig monotherapy in patients (pts) with relapsed/refractory (RR) AL amyloidosis from dose level 1 (DL1). Methods The phase 1 dose escalation (ESC) portion of the study (NCT06158854) with etentamig enrolled pts with RR AL amyloidosis with ≥1 prior lines of therapy (LOT), including a proteasome inhibitor and an anti-CD38 monoclonal antibody with no prior BCMA exposure. Eligible pts were required to have a difference in involved and uninvolved serum free light chain (dFLC) of ≥50 mg/L, and pts with Mayo Clinic 2004 cardiac risk stage IIIb with NT-proBNP ≥8500 pg/ml were excluded. Three dose groups were explored in dose ESC (etentamig dose levels [DL] 1, 2, and 3). In all cohorts, pts will receive up to 24 cycles of treatment and will be followed until disease progression. In dose ESC, the primary objectives are to determine safety/tolerability, pharmacokinetic/pharmacodynamic, and recommended phase 2 dose. The secondary objectives include evaluation of efficacy as measured by hematologic response and organ response. Responses are investigator assessed per consensus guidelines (Comenzo, et al. Leukemia. 2012. 26[11]:2317-25; Palladini G, et al. Amyloid. 2021 [Epub];28[1]:1-2). Results As of 17 July 2025, all DLs in dose ESC have been fully enrolled, and 12 pts have been treated with etentamig at DL1. Due to short follow-up, this initial report only includes data from DL1, with further follow-up data from ESC to be included at the time of presentation. Median duration of follow up in DL1 was 9.4 months (8.3–13.8) with 83% of pts continuing treatment. Median age for pts was 72 years (range, 56–85 years). Median number of prior LOT was 2 (range, 1–6), and median time from initial diagnosis was 3.6 years. Thirty-three percent have received a prior stem cell transplant and 50% previously received the regimen of daratumumab with cyclophosphamide, bortezomib, and dexamethasone in combination. Median dFLC at study baseline was 110. 5 mg/L (range, 56.6–617.5). At baseline, 83% of pts had cardiac involvement, 25% had renal involvement, and 8% had hepatic involvement. Eighty-three percent of pts had lambda AL amyloidosis. Treatment-emergent adverse events were reported in 100% (42% Grade ≥3) of pts at DL1. Cytokine release syndrome (CRS) occurred in 2 pts (17%, all Grade 1), with no instances of any grade immune effector cell-associated neurotoxicity syndrome (ICANS). CRS occurring after the first dose had median time to onset of 6.8 hours (range, 6.7–6.9). Grade ≥3 infections occurred in 1 pt (8%, all Grade 3). Grade ≥3 neutropenia also occurred in 1 pt (8%, all Grade 3), and no Grade ≥3 events of thrombocytopenia or anemia occurred. No Grade 5 events have occurred. Within the dose ESC DL1 cohort, the overall hematologic response rate was 100%, with all pts achieving ≥VGPR and 83% of pts achieving complete response (CR). The median time to CR was 0.9 months (0.3–9.3). The median duration of response has not yet been reached and 100% of pts remain in their best overall response by investigator assessment. To date, no pts have experienced hematologic progression on study. Cardiac response was observed in 30% of evaluable pts. Renal response was seen in 67% of evaluable pts. Conclusions In the DL1 cohort, etentamig showed a manageable safety profile in AL amyloidosis with low incidence and severity of CRS, no ICANS, and limited Grade ≥3 cytopenia events. Deep and rapid hematologic responses were observed with 100% ≥VGPR rate and 83% hematologic CR rate. Additional dose-level data will be presented at the time of the meeting. All pts remain in ongoing follow-up and evaluation, and the study will begin the dose expansion (EXP) portion after dose selection.

Abstract Background: Systemic AL amyloidosis is an incurable disorder caused by misfolded light chain fibrils. Survival is determined by the extent of cardiac involvement and response to therapy. Mayo 2012 (stage I-IV) and European modified Mayo 2004 (stage I-IIIB) prognostic scores were developed in a historic treatment era, prior to widespread bortezomib and daratumumab use. These no longer discriminate those with the poorest outcomes. We presented a new model sub-stratifying IIIB into a high risk, ‘IIIC’ group, incorporating longitudinal strain (LS) to the European modified score (IIIC: LS &gt;-9% + NT-proBNP &gt;8500ng/L + high-sensitivity troponin T [hs-TnT] &gt;50ng/L) in the bortezomib-era (2015-2019) last year (Khwaja et al, ASH 2024). Here, we present an independent external validation of the IIIC model in the modern treatment era. Methods: The ‘IIIC model’ was derived from a large real-world cohort of adults from the UK National Amyloidosis Centre (2015-2019). Performance was externally validated across Europe (Greece, Italy, Netherlands, Switzerland), USA (2015-2024) and UK (2020-2024). Survival estimates were generated from diagnosis to death or last follow-up using the Kaplan-Meier method and groups compared using Cox regression (using Stata v18). Stage IIIB and IIIC were defined as follows IIIB: LS &lt;-9%, NT-proBNP &gt;8500ng/L, hs-TnT &gt;50ng/L and IIIC: LS &gt;-9%, NT-proBNP &gt;8500ng/L, hs-TnT &gt;50ng/L, respectively. Stage I, II and IIIa were defined as previously described in the European modification of Mayo 2004 staging system. Results: 2493 patients were analysed from 2015-2024 (derivation, n=573; validation: Europe, n=374, USA n=458, UK, n=1088). In the derivation cohort, LS ≥-9% and standard cardiac biomarkers (NT-proBNP 332ng/L and 8500ng/L and hs-TnT&gt;50ng/L) were selected as independent prognostic factors in a multivariable model. In the European and UK validation cohort (n=1462), median age at diagnosis was 67 years (range 35-95) with 1014 (69%) cardiac and 869 (60%) renal involvement. Median difference in involved and uninvolved free light chain (dFLC) was 181 mg/L (range 0-24933), NT-proBNP 1911ng/L (range 42-70000), hs-TnT 45ng/L (range 3-1221) and LS -14.7% (range -3- -28). In the US cohort median NT-proBNP was 1764 (range 13-71000) and hs-TnT 44 (6-687). Applying the new model staging, the patient stages were across Europe and UK were stage I: 224 (15%), II: 627 (43%), IIIA: 396 (27%), IIIB: 139 (10%) and IIIC: 76 (5%), respectively. 592 (41%) were treated with first-line daratumumab-based regimens. In the US dataset stage I: 103 (22%), II: 176 (38%), IIIA: 131 (29%), IIIB: 48 (10%) and IIIC: 16 (3%), respectively. 234 (51%) were treated with first-line daratumumab-based regimens. At a median follow-up of 30 months (95% CI 28-32) in the European and UK validation cohort, estimated median overall survival (OS) was not reached and 2-year OS was 74% (95% CI 72-77). Median survival for stages I-II, IIIA, IIIB and IIIC were not reached (NR), 67, 31 and 10 months, respectively (p&lt;0.001). Hazard ratios for stage II, IIIA, IIIB, IIIC were 2.01 (95% CI 1.32-3.07), 3.51 (95% CI 2.31-5.35), 5.67 (95% CI 3.60-8.91) and 11.12 (95% CI 6.93-17.87), respectively (p&lt;0.001). This was confirmed in the US cohort with a median survival for respective stages were NR, NR, NR, 8 and 2 months (p&lt;0.001). External validation in the European and UK cohorts exhibited good predictive performance: 12-month calibration slope was 1.00 (95% CI 0.81-1.20, p=0.98), Harrel's C was 0.90 (95% CI 0.76-1.00), Royston's D 1.07, R2D 0.21 (95% CI 0.15-0.28). In 1462 patients with dataset available, stage IIIC discriminated the poorest outcome despite a greater proportion treated with first-line daratumumab v IIIB in the validation cohort (59% v 40%, p=0.008). 12-month OS for IIIC v IIIB was 44% (95% CI 32-55) v 69% (95% CI 60-76), specificity for 12-month OS 97% v 92% and diagnostic odds ratio 6.62 v 2.36. Conclusions: This study validates the new staging system from stage I-IIIC with robust identification of an ultra-poor prognostic group (Stage IIIC) in a contemporarily treated patient cohort. Despite novel therapies, the OS remains &lt;12 month in the IIIC group and also poor in stage IIIB with median OS 31 months compared to a median of &gt;5 years for all other stages. This staging system can be considered as a new standard of care for risk stratification of AL amyloidosis. Novel approaches are required for patients with advanced risk.

BACKGROUND: Thresholds to define prognosis with hs-cTnI (high-sensitivity cardiac troponin I) have not been systematically addressed in wild-type transthyretin amyloid cardiomyopathy, in part because of the multiplicity of hs-cTnI assays. The aims of this study were: first, to assess the prognostic performance of hs-cTnI measured with different assays in patients with wild-type transthyretin amyloid cardiomyopathy and, second, to identify assay-specific hs-cTnI thresholds for prognosis that could be integrated into staging systems for risk stratification. METHODS: Observational multicenter study of stable wild-type transthyretin amyloid cardiomyopathy patients from different cohorts using the Abbott Architect Stat hs-cTnI assay and the Beckman Coulter Access hs-cTnI assay (testing cohorts) and the Siemens Centaur XPT hs-cTnI assay (validation cohort). Outcome was all-cause mortality. RESULTS: In the Abbott cohort (n=136; median follow-up 22 [13–41] months; 31 [23%] deaths) and Beckman cohort (n=98; median follow-up 19 [12–28] months; 16 [16%] deaths), natural log-transformed hs-cTnI was an independent predictor of mortality (age- and sex-adjusted hazard ratio, 1.62 [95% CI, 1.11–2.35]; P =0.012 and 2.47 [95% CI, 1.48–4.14]; P <0.001, respectively). The best hs-cTnI threshold for 18-month mortality of the combined Abbott/Beckman cohorts (n=234) was 81 ng/L, rounded to 80 ng/L for simplicity of clinical use. A 2-variable staging system (based on the Mayo Clinic system) using hs-cTnI (>80 ng/L) and NPs (natriuretic peptides; NT-proBNP [N-terminal pro-B-type natriuretic peptide] >3000 ng/L or BNP [B-type natriuretic peptide] >250 ng/L) identified 3 groups with progressively worse prognosis. The staging system (using hs-cTnI >80 ng/L and NT-proBNP>3000 ng/L) was then applied to an independent cohort evaluated with the hs-cTnI Siemens assay (n=345, median follow-up 32 [24-42] months, 119 [34%] deaths). The significant differences between the groups were maintained. CONCLUSIONS: In patients with wild-type transthyretin amyloid cardiomyopathy, hs-cTnI is a strong and independent predictor of mortality. A threshold of hs-cTnI of 80 ng/L for these 3 assays provides effective risk stratification alone and in a staging system with NP.

Background: Despite substantial improvements in early mortality (EM) for patients with systemic light chain amyloidosis (AL), rates remained high in the bortezomib-era, at approximately 25% (Muchtar et al. Blood. 2017). However, the therapeutic landscape in AL amyloidosis has changed with the ANDROMEDA trial, which led to the approval of daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone (Dara-VCd) in the frontline setting. The incidence and predictors of EM in the context of daratumumab-based frontline therapy have not been studied. Methods: We performed an international multicenter retrospective cohort study of all consecutive patients with newly diagnosed AL treated with frontline Dara-VCd or Dara-Vd, and followed until 12/31/2023. EM was defined as death from any cause within 6 months of treatment initiation. Our primary objective was to identify the rate and significant predictors of EM. Univariate logistic regression was used to identify significant predictors of EM, which were then included in a multivariate logistic regression model. The receiver operator characteristic (ROC) analysis was used to determine the best threshold values that discriminated EM rates for the following continuous variables: age, dFLC (involved-uninvolved), eGFR, NT-proBNP, albumin, and high-sensitivity Troponin-T (hs-TnT). Other variables tested in univariate analysis were the following: ECOG performance status, NYHA functional class, sex, race, light chain isotype, percent bone marrow plasma cells, status of the following cytogenetic abnormalities-t(11;14), +1q, hyperdiploidy, del(13q), high-risk translocations, and del(17p), and the number of organs involved (2 vs 1). To build the clinical prediction score, each variable was weighted according to the β coefficient (natural logarithm of odds ratio) obtained from the multivariable regression. The β coefficients were rounded to the nearest 0.5 and multiplied by 2 to obtain an even number. Results The study cohort included 335 AL patients treated with daratumumab-based frontline therapy (92.2% Dara-VCd, 7.8% Dara-Vd), with all surviving patients having at least 6 months of follow-up. The median age at diagnosis was 66.5 years (range, 59.4 - 71.3), and 6.7% (n = 22) were Non-Hispanic blacks. Median dFLC at diagnosis was 22.91 mg/dL (range, 0.2-1093.4), and median NT-proBNP was 2415 pg/mL (range, 13-70,000). Mayo 2004 stages IIIA/IIIB represented 44% of the total cohort, with 17% having ECOG ≥ 2 and 25.4% having NYHA Class III/IV symptoms. The cumulative incidence of EM was 10.7%, with the incidence in patients with Mayo 2004 stage I, II, IIIA, and IIIB being 0%, 8%, 12.5%, and 25% respectively. On univariate analysis with unadjusted odds ratio (OR), the following variables significantly predicted EM: Age ≥ 75 (OR=2.8, p=0.013) ECOG ≥ 2, (OR 4.9, p&lt;0.001), NYHA Class ≥ III (OR=4.95, p&lt;0.001), dFLC ≥9 mg/dL (OR, 10.18, p=0.023), eGFR &lt;33 mL/min/1.73 m2 (OR=2.7, p=0.026), NT-proBNP &gt;5276 pg/mL (OR=7.69, p &lt;0.001), hs-TnT &gt;70 ng/L (OR=5.88, p&lt;0.001), and absence of t(11; 14) (OR=2.33, p=0.041). These variables were entered into multivariate regression, except for ECOG and NYHA, which were combined to create a single variable (values ranging from 0-8), and hs-TnT was dropped due to substantial missing data as centers used different troponin assays. NT-proBNP was rounded to 5300 pg/ml for ease of clinical application. Based on the multivariate analysis, the following scores were assigned to each variable: Age ≥75 (2.0), ECOG+NYHA (1.0 x combined score), NT-proBNP &gt;5,300 pg/ml (2.0), and absence of t(11;14) (3.0). This led to a score ranging from 1-15, and two risk-groups: low-risk (score &lt;9; 87.5%) and high-risk (score ≥9; 12.5%). The respective cumulative incidence of EM was 6.1% versus 50% (p&lt;0.001). The c-index of the model was 0.725 (95% CI, 0.676-0.774). Conclusion: Using variables that are readily available in the clinic, we have developed a two-tiered risk-prediction model for EM in AL amyloidosis in the context of daratumumab-based frontline therapy. The model needs to be externally validated in an independent dataset.