Amyloidosis is a group of disorders characterized by the accumulation of an abnormal, misfolded protein called amyloid in various organs and tissues. Multiple myeloma is a cancer of the plasma cells, a type of white blood cell housed primarily in the bone marrow. The two conditions are intimately linked because multiple myeloma, or a related plasma cell disorder, is the underlying cause of the most common form in the Western world: Amyloid Light-chain (AL) amyloidosis. This dual diagnosis is a serious systemic illness where the underlying blood cancer creates toxic protein deposits that cause widespread organ damage. Simultaneous treatment of both conditions is necessary for a positive patient outcome.
The Plasma Cell Mechanism
The process connecting multiple myeloma to AL amyloidosis begins with a clonal expansion of abnormal plasma cells within the bone marrow. Plasma cells normally produce antibodies, which are Y-shaped proteins composed of two heavy chains and two light chains. In this disease state, the abnormal clone of plasma cells produces an excessive amount of a single type of misfolded immunoglobulin light chain.
These light chains, often referred to as monoclonal free light chains (FLCs), are unstable and prone to aggregation outside of the bone marrow. The protein structure is fundamentally flawed, causing the chains to spontaneously misfold into an insoluble, rigid beta-sheet structure. This structural change transforms the soluble protein into the toxic substance known as amyloid.
The misfolded proteins then stack together to form microscopic, rope-like structures called amyloid fibrils. These fibrils accumulate and deposit extracellularly in the interstitial spaces of organs and soft tissues throughout the body. The “AL” designation specifically refers to these amyloid deposits being derived from the immunoglobulin Amyloid Light chain precursor protein. This mechanism explains why treatment must target the source of the problem: eliminating the plasma cell clone responsible for the light chain overproduction.
Recognizing Signs of Organ Damage
The clinical presentation of AL amyloidosis is highly varied, as the disease is systemic and often affects multiple organ systems simultaneously. Symptoms depend on which organs receive the highest burden of amyloid deposits.
The heart is frequently and dangerously involved, as amyloid fibrils infiltrate the muscle, causing the walls to thicken and stiffen. This leads to restrictive cardiomyopathy, preventing the heart chambers from properly relaxing and filling with blood. Patients often experience significant shortness of breath, fluid retention, and edema in the legs due to heart failure. Deposits can also disrupt the electrical system, causing serious arrhythmias.
Kidney involvement is common, often presenting as nephrotic syndrome. Amyloid deposits damage the filtering units, leading to a massive loss of protein into the urine, known as proteinuria. This protein loss causes severe systemic swelling and edema. If left unchecked, the progressive damage can lead to end-stage kidney failure requiring dialysis.
The nervous system is frequently affected, manifesting as peripheral and autonomic neuropathy. Peripheral neuropathy causes numbness, tingling, or pain, typically in the hands and feet. Autonomic neuropathy affects involuntary bodily functions, leading to symptoms like dizziness upon standing (orthostatic hypotension) or debilitating gastrointestinal issues. Other telltale signs include macroglossia (unusual enlargement of the tongue) and periorbital purpura (bruising around the eyes due to fragile blood vessels).
Diagnostic Procedures and Testing
Confirming a diagnosis of AL amyloidosis requires a multi-step process to identify both the amyloid deposits and the underlying clonal plasma cell disorder. The first step involves blood and urine tests to identify the abnormal monoclonal protein. A serum free light chain (FLC) assay measures the levels of unbound kappa and lambda light chains, revealing a skewed ratio that signals the presence of an abnormal clone.
Once a monoclonal protein is identified, the presence of amyloid must be confirmed via a tissue biopsy. A sample is typically taken from an easily accessible site, such as the abdominal fat pad or bone marrow, and stained with Congo red dye, which fluoresces under polarized light to reveal the characteristic deposits. If initial sites are negative, a biopsy of a symptomatic organ may be necessary.
Crucially, the amyloid type must be definitively identified as AL, and not another form like AA or ATTR. This is accomplished using mass spectrometry, which analyzes the protein composition of the amyloid fibrils to confirm their immunoglobulin light chain derivation. Diagnostic workup is completed with imaging and functional tests, such as an echocardiogram and renal function tests, to provide a baseline for organ involvement.
Therapeutic Approaches
The treatment strategy for AL amyloidosis is twofold, focusing on eradicating the plasma cell clone and providing support for damaged organs. The primary goal is to rapidly suppress the production of the amyloid-forming light chains, as controlling the underlying plasma cell disorder is the only way to halt further amyloid deposition.
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an intensive treatment option for younger, fitter patients with less severe organ damage, aiming for a deep and durable response. For the majority of patients, treatment relies on systemic chemotherapy regimens adapted from those used for multiple myeloma. Bortezomib-based combinations, often including cyclophosphamide and dexamethasone, are widely used and have improved outcomes. These agents are effective at targeting and eliminating abnormal plasma cells, quickly reducing the level of circulating free light chains.
While anti-plasma cell therapy works to stop the source, aggressive supportive care is simultaneously administered to manage organ dysfunction. This can involve the use of diuretics to control fluid retention from heart or kidney failure and specific medications to manage arrhythmias or neuropathy. In rare cases of severe, irreversible organ damage, a heart or kidney transplant may be considered, though the underlying plasma cell disorder must first be controlled.
A newer area of investigation involves therapies that actively target and remove the amyloid deposits already present in the organs. Monoclonal antibodies, such as birtamimab, are being developed to bind to the deposited amyloid fibrils, flagging them for clearance by the body’s immune system. These novel approaches aim to facilitate the regression of existing amyloid, offering the potential for organ function to improve over time.