Prognostic factors and progression biomarkers in AL amyloidosis: mapping current knowledge and critical gaps

Blood · 2026-03-04

ABSTRACT: The therapeutic landscape for systemic immunoglobulin light chain (AL) amyloidosis has been revolutionized by daratumumab-based regimens, achieving 76% 5-year overall survival in the landmark ANDROMEDA trial. However, the current prognostic models were developed using patient populations treated with now-suboptimal therapies, creating a critical gap between risk stratification models and contemporary outcomes. This comprehensive review analyzes prognostic factors and progression biomarkers in AL, categorizing them into disease-specific (clone-related and organ-related) and patient-specific factors. Notably, traditional baseline biomarkers including difference between involved and uninvolved free light chains and bone marrow plasma cell burden are losing prognostic significance with effective clone-directed therapies. Emerging approaches show promise, including dynamic markers such as minimal residual disease by free light chain mass spectrometry, cardiac imaging parameters such as global longitudinal strain, and functional measures. There is an urgent need for validation studies and prognostic model refinement to identify patients at high risk who may benefit from interventions beyond anti-plasma cell therapy.

A plain language review of the ATTRibute-CM study: efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy

Future Cardiology · 2025-09-10 · 1 citations

Plain Language Summary: What is this plain language review about? This plain language review describes the results of a study called ATTRibute-CM. This study looked at how well a drug called acoramidis worked to treat people with transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is a type of heart disease that occurs when a protein called transthyretin (TTR) breaks down, changes shape (misfolds), and forms harmful amyloid fibrils (clumps of misfolded proteins). These amyloid fibrils then accumulate in the heart muscle, leading to thickening and stiffening of the heart walls, thereby reducing its ability to pump blood effectively. Symptoms of ATTR-CM include shortness of breath, swelling in the lower legs, and irregular heart beat. What is ATTRibute-CM? ATTRibute-CM is a study that recruited 632 participants with ATTR-CM who either took acoramidis HCl (the salt form of acoramidis) 800 mg or a placebo (a pill that looked like acoramidis, but did not contain any medicine) twice a day by mouth for 30 months. What were the results and what do they mean? Compared to participants in the placebo group, participants in the acoramidis group had better results on efficacy measures (measures of how well a treatment works) that included death due to any cause, being admitted to a hospital for a heart problem, change in NT-proBNP level (a type of protein that indicates worsening heart failure), and change in 6-minute walking distance. Common side effects included diarrhea and gout. Acoramidis showed clinical benefit in people with ATTR-CM compared with placebo. Clinical trial number: NCT03860935.

Correction to: The N400 component reflecting semantic and repetition priming of visual scenes is suppressed during the attentional blink

Attention Perception & Psychophysics · 2025-01-17

Linvoseltamab in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) in the LINKER-MM1 Study: Longer Follow-up and Subgroup Analyses

Clinical Lymphoma Myeloma & Leukemia · 2025-09-01 · 1 citations

Phase 1/2 dose escalation and expansion study of etentamig in patients with relapsed or refractory light chain amyloidosis

Blood · 2025-11-03

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.

Indirect comparison of linvoseltamab versus elranatamab for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM).

Journal of Clinical Oncology · 2025-05-28 · 2 citations

7531 Background: In the absence of head-to-head trials comparing anti-BCMA×CD3 bispecific antibodies in TCE RRMM, this study used an unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy of linvoseltamab and elranatamab. Methods: Patient (pt)-level data from LINKER-MM1 (117 pts receiving linvoseltamab 200 mg, data cut-off [DCO] 7/2024, median follow-up [mFU] 21.3 months [mos]) and published data from MagnetisMM-3 Cohort A (123 elranatamab pts, DCO 9/2024, mFU 33.9 mos) were analyzed. Ten LINKER-MM1 pts with prior BCMA antibody–drug conjugate exposure were excluded to align with MagnetisMM-3. LINKER-MM1 pts were weighted to match MagnetisMM-3 pts on prespecified prognostic factors deemed most important by an international expert panel: cytogenetic risk, age, refractory status, R-ISS stage, ECOG PS, extramedullary and/or paramedullary disease. Objective response rate (ORR), very good partial response or better (≥VGPR) and complete response or better (≥CR) rates, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were compared. DOR and PFS in LINKER-MM1 were recalculated to match MagnetisMM-3 censoring rules. Additional MAICs matched all available prespecified prognostic factors, included all 117 LINKER-MM1 pts, or matched to a MagnetisMM-3 subgroup with ECOG PS 0/1. Results: After matching, linvoseltamab effective sample size (ESS) was 71.3 (range of patient weights: 0.04–2.90). Linvoseltamab demonstrated statistically significantly higher ORR and ≥CR rate, a numerically higher ≥VGPR rate, and longer DOR, PFS, and OS vs elranatamab (Table). The additional MAICs yielded directionally consistent findings. Conclusions: Linvoseltamab demonstrated significantly higher ORR and ≥CR rate, numerically better ≥ VGPR rate, DOR, PFS, and OS compared with elranatamab, though the follow-up was shorter. These results highlight the potential of linvoseltamab as a highly effective treatment option for TCE RRMM. Elranatamab Linvoseltamab Linvoseltamab Linvoseltamab vs elranatamab Linvoseltamab vs elranatamab N=123 Unadjusted N=107 Adjusted ESS= 71.3 Unadjusted Adjusted % % % OR (CI) OR (CI) ORR 61 71 71 1.57 (1.04–2.37)* 1.60 (1.00–2.57)* ≥VGPR 56 64 65 1.36 (0.93–2.00) 1.45 (0.94–2.24) ≥CR 37 52 50 1.84 (1.26–2.68)* 1.71 (1.12–2.61)* Median, mos (CI); 12-mo landmark % Median, mos (CI); 12-mo landmark % Median, mos (CI); 12-mo landmark % HR (CI) HR (CI) DOR NR (29.4–NE); 73.9 NR (NE–NE); 82.8 NR (NE–NE); 84.4 0.93 (0.53–1.66) 0.82 (0.43–1.55) PFS 17.2 (9.8–NE); 56.4 NR (15.7–NE); 65.5 NR (16.2–NE); 64.7 0.86 (0.59–1.27) 0.86 (0.55–1.34) OS 24.6 (13.4–NE); 62.3 31.4 (27.8–NE); 75.5 NR (27.8–NE); 74.6 0.70 (0.47–1.04) 0.67 (0.42–1.05) OR >1 or HR <1 favor linvoseltamab. *Statistically significant at p<0.05. CI: 95% confidence interval, HR: hazard ratio, NE: not estimable, NR: not reached, OR: odds ratio.

PRIMARY ENDPOINT EFFICACY RESULTS IN THE ATTRIBUTE-CM STUDY: PRE-SPECIFIED SENSITIVITY ANALYSES ADDRESSED TAFAMIDIS USE

Journal of the American College of Cardiology · 2025-03-29 · 2 citations

ROBUSTNESS OF PRIMARY ENDPOINT EFFICACY RESULTS WITH ACORAMIDIS IN ATTR-CM IN THE ATTRIBUTE-CM STUDY: PRE-SPECIFIED NT-PROBNP SENSITIVITY ANALYSES

Journal of the American College of Cardiology · 2025-03-29

Indirect Comparison of Linvoseltamab Versus Teclistamab for the Treatment of Triple-Class Exposed Relapsed/Refractory Multiple Myeloma

Clinical Lymphoma Myeloma & Leukemia · 2025-06-22 · 5 citations

Indirect comparison of linvoseltamab versus teclistamab for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM).

Journal of Clinical Oncology · 2024-06-01 · 1 citations

7560 Background: No head-to-head clinical trials have compared effectiveness of anti-BCMA×CD3 bispecific antibodies for TCE RRMM. This analysis compared efficacy of linvoseltamab vs teclistamab via an unanchored matching-adjusted indirect comparison (MAIC). Methods: A MAIC was deemed feasible after excluding 10 patients (pts) with prior BCMA antibody–drug conjugate exposure from LINKER-MM1 (linvoseltamab) to match MajesTEC-1 (teclistamab) criteria. Pt-level data from LINKER-MM1 (107 pts receiving 200 mg in Phase 1/2, data cut-off [DCO] 9/2023, median follow-up 11.1 months [mos]) and published data from MajesTEC-1’s efficacy population (150 pts, DCO 11/2021, median follow-up 9.8 mos) were analyzed. LINKER-MM1 pts were weighted to match key baseline characteristics in MajesTEC-1 (cytogenetic risk, age, refractory status, ISS stage, ECOG score, extramedullary disease/plasmacytoma status) selected via a prespecified algorithm (Kumar et al., 2023). Objective response rate (ORR), very good partial response or better (≥VGPR), complete response or better (≥CR), and minimal residual disease (MRD) negativity (- [at 10-5 threshold]) rates, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were compared. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were reported before and after matching; a sensitivity analysis included all LINKER-MM1 200 mg pts (n=117). Results: Effective sample size for linvoseltamab was 82 after matching and baseline characteristics were balanced with MajesTEC-1. Before and after matching, linvoseltamab exhibited higher ORR, ≥VGPR, ≥CR, and MRD(-) rates, with significant differences in ≥CR. Linvoseltamab had significantly longer PFS and a trend toward longer OS and DOR (Table). Sensitivity analysis results were similar. Conclusions: The results suggest potentially greater efficacy for linvoseltamab vs teclistamab for all outcomes, highlighting its potential as a highly effective treatment option for TCE RRMM. [Table: see text]