Vaishali Sanchorawala

B-cell maturation antigen (BCMA)–targeted therapies have emerged as promising treatment options for patients with relapsed/refractory immunoglobulin light-chain (AL) amyloidosis. However, comprehensive data on their efficacy and safety remain limited. We conducted a systematic descriptive pooled analysis of published studies reporting outcomes of BCMA-directed therapies including chimeric antigen receptor T-cell (CAR-T) therapies, bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). The analysis included 256 patients. CAR-T therapy was administered to 89 patients (35%), BsAbs to 82 patients (32%), and ADCs to 85 patients (33%). The pooled overall response rate (ORR) was 83%, with CAR-T demonstrating 92% ORR; BsAbs, 89%; and ADCs, 68%. Deep hematologic responses (≥very good partial response) were achieved in ∼70% of CAR-T and BsAb recipients and 64% of ADC recipients. Minimal residual disease negativity was documented in 75% of evaluable CAR-T patients and in 86% of evaluable BsAb patients with reported data. Organ responses were observed in 30% of evaluable patients, with cardiac responses in 41%. Cytokine release syndrome (CRS) occurred in 74% of CAR-T and 49% of BsAb patients, predominantly grade 1 to 2. Grade ≥3 CRS was rare (9% in CAR-T and 1% in BsAb). Ocular toxicity was the predominant adverse event in ADC recipients (84% with any grade and 29% with grade ≥3). Grade ≥3 infections occurred in 13% of CAR-T, 20% of BsAb, and 6% of ADC patients. BCMA-targeted therapies result in high response rates with manageable safety profiles among patients with heavily pretreated AL amyloidosis, supporting continued investigation and clinical application of these approaches.

In this systematic review, we aimed to assess the diagnostic test accuracy (DTA) of abdominal fat pad sampling and bone marrow biopsy for immunoglobulin light-chain (AL) amyloidosis using organ biopsy as the reference standard. We searched the literature using PubMed, Embase, and CENTRAL databases from inception through March 2024. We used QUADAS-2 to assess the risk of bias and the GRADE approach to assess the certainty of evidence (COE). After deduplication, 29,237 records were screened, and 31 studies were included. Twenty-five studies (n=4,649) reported on fat pad sampling, with a pooled sensitivity of 0.77 (95%CI 0.72-0.81), while twenty studies (n=2,771) reported on bone marrow biopsy, with a pooled sensitivity of 0.55 (0.46-0.63). All studies enrolled patients with confirmed disease, specificity was not reported in the included studies. Fat pad aspiration (15 studies, n=1,590) and surgical or punch biopsy (4 studies, n=222) showed similar sensitivities of 0.80 (0.76-0.83) and 0.77 (0.61-0.88), respectively. In a single study (n=612), performing both tests together yielded a sensitivity of 0.89. COE was judged to be Moderate for fat pad sampling and Low for bone marrow biopsy.

Immunoglobulin light chain (LC) amyloidosis is a debilitating multiorgan disease with limited treatment options. Sequence and structural variability make LC amyloids particularly challenging for therapeutic targeting. We report four cryo-EM structures of λ6-LC amyloid fibrils from four organs of two patients. Fibrils from different patients show different N-terminal conformations expanding known repertoire of λ6-LC amyloid folds. These folds contain a planar β-arch with a flexible linker containing the complementarity-determining region 2, flanked by N- and C-terminal segments in variable patient-specific conformations. The surface location of the structurally frustrated charged segment may contribute to the overrepresentation of the λ6-LC family in amyloidosis. These and other λ6-LC amyloid structures from different patients show different side chain packing. Conversely, cardiac, renal and splenic amyloids from the same patient exhibit similar structures with small peripheral organ-specific variations. Moreover, they show similar “orphan” densities, suggesting collagen-like triple helices bound to a tyrosine ladder along the fibril spine. Mass spectrometry detects collagen type-VI in tissue-extracted amyloids. Molecular dynamics simulations suggest amyloid binds collagen-VI triple helices via mixed interactions facilitated by the geometric complementarity between the layered amyloid structure and the triple helix. Similar interactions may drive formation of other amyloid-collagen complexes, influencing biological properties of amyloids.

Light chain (AL) amyloidosis is a fatal plasma cell dyscrasia characterized by the overproduction of misfolded l or k immunoglobulin light chains (LCs) produced by clonal plasma cells, which aggregate into amyloid fibrils that deposit in tissues and cause progressive organ damage. While current anti-plasma cell therapies reduce the production of new amyloidogenic LCs, pre-existing fibrils persist and continue to drive organ damage. Amyloid-targeting monoclonal antibodies birtamimab and anselamimab were developed and tested for active AL amyloid clearance; however, they failed to meet the primary endpoint in Phase 3 trials, presumably due to insufficient binding affinity for l LC amyloid, which occurs in ~80% of patients. Here, we reported the development of 1F10, a novel high-affinity l subtype-specific amyloid-binding monoclonal antibody that does not cross-react with soluble native l or k LCs. 1F10 exhibits superior binding affinity to l AL amyloid fibrils and significantly enhances antibody-dependent phagocytosis (ADP) of l AL amyloid compared with birtamimab and anselamimab. Specific binding of 1F10 to l amyloid is confirmed by immunohistochemical staining of patient-derived tissue biopsies. Importantly, 1F10 demonstrates robust in vivo activity, significantly accelerating the resolution of l amyloid fibrils in an AL amyloidoma mouse model. Together, these findings establish 1F10 antibody as a promising subtype-specific immunotherapeutic candidate for targeting l LC amyloid, addressing a critical unmet need for the majority of patients with AL amyloidosis.

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.

The role of autologous stem cell transplantation (ASCT) is central in AL amyloidosis and continues to be defined in the era of newer therapies. To evaluate contemporary patient selection, practice patterns, and outcomes, we conducted a retrospective, multicenter study across nine tertiary referral centers, including 1047 patients with AL amyloidosis who underwent ASCT between 2010 and 2020. Most patients (67.9%) received full-dose melphalan conditioning, and 66.5% received pre-ASCT induction therapy, predominantly proteasome inhibitor-based regimens. Day-100 all-cause mortality was 3.0%, representing a substantial improvement compared with historical cohorts. Post-ASCT hematological responses were satisfactory in 75.4% of patients. Among patients with paired assessments, ASCT deepened responses in 56.3% who had not achieved a complete response with induction therapy. With a median follow-up of 5.1 years, the median overall survival was 6.3 years. Independent predictors of inferior survival included age ≥60 years, bone marrow plasma cells ≥20%, pre-ASCT dFLC ≥40 mg/L, elevated cardiac biomarkers, lambda-restricted disease, reduced eGFR and reduced-dose conditioning. In this contemporary cohort, ASCT for AL amyloidosis demonstrated low early mortality, high rates of deep hematologic response, and durable survival in carefully selected patients. These findings support its role as an effective consolidative strategy, while its optimal positioning alongside emerging therapies requires further study.

In the primary analysis of ANDROMEDA, addition of subcutaneous daratumumab to bortezomib/cyclophosphamide/dexamethasone (D-VCd) significantly improved hematologic complete response (CR) rate versus VCd, establishing D-VCd as the only approved therapy for light-chain (AL) amyloidosis. We present results from the preplanned final analysis. In this phase 3 trial, we randomly assigned 388 patients with newly diagnosed AL amyloidosis to six cycles of VCd alone (control group) or with subcutaneous daratumumab (D-VCd) followed by single-agent daratumumab every 4 weeks for up to 24 total cycles. The primary endpoint was hematologic CR. The updated hematologic CR rate was 59.5% for D-VCd versus 19.2% for VCd (odds ratio, 6.03; 95% confidence interval [CI], 3.80-9.58; P<0.0001). Median time to hematologic CR was shorter with D-VCd (67.5 days [range, 8.0-879.0]) versus VCd (85.0 days [range, 14.0-617.0]). With a median follow-up of 61.4 months, significant improvement was observed with D-VCd versus VCd in major organ deterioration-progression-free survival (hazard ratio, 0.44; 95% CI, 0.31-0.63; P<0.0001) and overall survival (hazard ratio, 0.62; 95% CI, 0.42-0.90; P=0.0121). Cardiac and renal response rates were 2-3 times higher with D-VCd versus VCd. Achieving hematologic or cardiac CR was associated with improved major organ deterioration-progression-free survival and overall survival. Adverse events were consistent with the known safety profiles for VCd and daratumumab. Adding daratumumab to VCd resulted in deeper and more rapid hematologic responses and recovery of organ function, translating to statistically significant improvement in both overall survival and major organ deterioration-progression-free survival in newly diagnosed AL amyloidosis. ClinicalTrials.gov NCT03201965.