AL amyloidosis is a rare disorder of the plasma cells, a type of white blood cell found in the bone marrow. Abnormal plasma cells produce excessive misfolded light chain proteins that aggregate into toxic amyloid fibrils. These fibrils deposit in vital organs, most commonly the heart and kidneys, causing organ dysfunction and failure. Historically, treatment was challenging due to patient frailty and the need for rapid suppression of the protein source to prevent irreversible organ damage. The treatment landscape is currently undergoing a rapid evolution, incorporating highly specific, targeted therapies.
The Established Baseline
For decades, treatment focused on eliminating the plasma cell clone responsible for producing toxic light chains. High-dose chemotherapy using melphalan followed by Autologous Stem Cell Transplantation (ASCT) was the most potent approach for eligible patients. This regimen involves collecting a patient’s healthy stem cells, administering high-dose melphalan to eradicate abnormal plasma cells, and then re-infusing the collected stem cells to restore the blood-forming system.
ASCT is only suitable for a minority of physically fit patients with minimal organ involvement, especially without advanced cardiac damage. For those ineligible for transplantation, a less intensive oral regimen of melphalan and dexamethasone (MDex) was the standard. The later introduction of the proteasome inhibitor bortezomib, combined with cyclophosphamide and dexamethasone (CyBorD or VCD), offered a highly effective chemotherapy alternative. This combination became a widely accepted front-line therapy, significantly improving hematologic response rates compared to older regimens.
Targeted Therapies Using Monoclonal Antibodies
The most significant recent advance is the incorporation of monoclonal antibodies (MABs), adopted from multiple myeloma treatment. Daratumumab (DARA) has fundamentally shifted the standard of care for newly diagnosed patients. Daratumumab is an antibody that targets the CD38 protein, which is highly expressed on the surface of the abnormal plasma cells producing the light chains.
By binding to CD38, daratumumab triggers immune-mediated mechanisms to destroy the plasma cell clone, including inducing cell death and flagging abnormal cells for destruction by the immune system. The Phase III ANDROMEDA trial demonstrated the benefit of adding daratumumab to the established CyBorD regimen, creating the Dara-CyBorD quadruplet therapy. This combination was highly effective, leading to a significantly higher rate of deep hematologic responses compared to CyBorD alone.
Achieving a rapid and deep hematologic response is important in AL amyloidosis because it stops the production of new light chains, allowing organs a chance to recover. Daratumumab-based regimens provide this rapid suppression, benefiting patients with life-threatening organ involvement. The drug is typically administered intravenously or subcutaneously until the disease progresses and has demonstrated a manageable safety profile.
Novel Combination and Oral Agents
Beyond monoclonal antibodies, other novel agents, primarily small-molecule drugs, have expanded the treatment toolkit for combination use or relapsed disease. These agents eliminate the plasma cell clone but operate through distinct biochemical pathways. The class of Proteasome Inhibitors (PIs) includes newer options like carfilzomib and the oral agent ixazomib.
PIs disrupt the cell’s protein waste disposal system, causing misfolded proteins to build up within abnormal plasma cells, leading to cell death. Carfilzomib, an injectable PI, shows strong efficacy but requires careful consideration due to potential cardiotoxicity, especially in patients with existing heart damage. Ixazomib provides a convenient, entirely oral treatment option being tested in combination regimens. Its oral nature is an advantage for patients needing long-term maintenance or avoiding frequent clinic visits.
Immunomodulatory Drugs (IMiDs), such as pomalidomide, modulate the immune system and exert direct anti-plasma cell effects. Pomalidomide is often reserved for patients with relapsed or refractory AL amyloidosis who have stopped responding to initial therapies. Patients with AL amyloidosis may have reduced tolerance for IMiDs at the high doses used in multiple myeloma, requiring careful dose adjustments. These agents provide flexibility for physicians to tailor combination therapy based on the patient’s specific organ involvement.
Emerging Strategies in Clinical Trials
Current research is moving toward strategies that not only eliminate the source of the amyloid protein but also actively remove the toxic deposits already present in the organs. This fibril-targeting approach uses specialized monoclonal antibodies, such as CAEL-101. CAEL-101 is an investigational antibody designed to bind directly to the amyloid fibrils in the tissues.
By coating the deposits, CAEL-101 is thought to promote their clearance by the immune cells, potentially leading to organ function recovery even if the plasma cell clone is not fully eliminated. This agent is currently being tested in Phase 3 trials in combination with chemotherapy to restore damaged organ function. Chimeric Antigen Receptor (CAR) T-cell therapy is also being adapted for AL amyloidosis. This therapy involves genetically engineering a patient’s T-cells to target proteins, such as BCMA, present on the amyloid-producing plasma cells. Early trials show that BCMA CAR T-cells can induce rapid and deep hematologic responses in patients with difficult-to-treat relapsed or refractory disease.