Renal amyloidosis — most often from immunoglobulin light-chain (AL) amyloidosis — results from deposition of misfolded light chains as amyloid fibrils, causing proteinuria, nephrotic syndrome, and progressive renal decline. Treatment now targets the underlying plasma-cell clone rapidly and deeply, with a fibril-clearing frontier that has proved harder to conquer.
Daratumumab-based therapy: the standard of care
The ANDROMEDA trial established daratumumab added to bortezomib, cyclophosphamide, and dexamethasone (DARA-VCd) as frontline therapy: hematologic complete response rose to 59.5% (versus 19.2% with VCd alone), with markedly improved major-organ-deterioration progression-free survival, higher renal and cardiac response rates, and better overall survival. It is generally well tolerated, and DARA-VCd is now the standard of care for newly diagnosed AL amyloidosis.
Venetoclax and the fibril-clearing frontier
Venetoclax is particularly promising for patients with the t(11;14) translocation, inducing hematologic and organ responses in relapsed or refractory disease. The major unmet goal has been to clear amyloid fibrils that are already deposited — but this frontier has met setbacks. The anti-fibril antibody anselamimab (CAEL-101) did not meet the primary endpoint of its Phase 3 CARES program in advanced (Mayo stage III) disease in 2025, and birtamimab — which showed a survival signal only in advanced cardiac disease in an earlier trial — is being reassessed in a confirmatory Phase 3 study. As of now, no fibril-directed therapy is approved, so the mainstay remains rapid, deep suppression of the light-chain clone.
Supportive care
Management of nephrotic syndrome (RAAS blockade, diuretics, anticoagulation where risk is high) and early, multidisciplinary care substantially improve kidney and overall outcomes.
| Therapy | Setting | Key result |
|---|---|---|
| DARA-VCd | First-line | CR 59.5% vs 19.2% (ANDROMEDA); improved organ response and survival |
| Venetoclax | Relapsed / t(11;14) | Responses in selected cytogenetics |
| Anti-fibril antibodies | Fibril clearance | CAEL-101 Phase 3 missed endpoint; birtamimab under reassessment |
Further reading: ANDROMEDA daratumumab (Kastritis et al., NEJM 2021); venetoclax in t(11;14) AL amyloidosis; CAEL-101 (anselamimab) CARES program and birtamimab AFFIRM-AL (2025).