Systemic amyloidosis: From “untreatable” disease to a new era of targeted therapies For decades, systemic amyloidoses were considered rare, devastating diseases with limited treatment options and often fatal outcomes. Today, advances in molecular biology and immunotherapy have transformed amyloidosis into a highly treatable group of disorders, highlighting how understanding disease mechanisms can directly translate into life-changing therapies. Amyloidosis occurs when misfolded proteins aggregate and deposit in tissues, causing progressive organ dysfunction. Two major forms dominate clinical practice: 🔹 Transthyretin (ATTR) amyloidosis 🔹 Light chain (AL) amyloidosis For ATTR amyloidosis, decades of research into transthyretin misfolding and aggregation led to the development of therapies targeting different stages of disease biology. Since 2018, six novel therapies have been approved, including approaches that stabilize transthyretin or reduce production of the pathogenic protein. In AL amyloidosis, treatment has been transformed by plasma cell–directed therapy. The combination of: 💊 Daratumumab + cyclophosphamide + bortezomib + dexamethasone (Dara-CyBorD) became a major advance after FDA approval in 2021, improving hematologic responses and organ outcomes. The field is now entering another phase with the emergence of immune-based therapies, including: 🧬 Bispecific T-cell engagers (BiTEs) 🧬 Other next-generation immunotherapies targeting the pathogenic plasma cell clone Early clinical trials in relapsed AL amyloidosis have shown remarkable activity, raising the possibility that deeper and more durable disease control may be achievable. However, successful treatment depends on early recognition. The key clinical message is: Think amyloidosis early → confirm the diagnosis quickly → accurately type the amyloid protein → start disease-directed therapy without delay. This shift represents one of the most remarkable stories in modern hematology: a group of diseases once considered rare, mysterious, and almost uniformly fatal are now becoming examples of precision medicine in action. Future challenges remain — particularly achieving true cures for AL and ATTR amyloidosis — but advances in protein biology, targeted therapies, and immune-based approaches have fundamentally changed the outlook for patients. thelancet.com/journals/lance…