Systemic amyloidoses are a group of rare, related diseases in which an abnormally folded protein forms a substance called amyloid. This substance can build up in one or more organs — such as the kidney, heart, or liver — or in tissues in the nervous system. The most common type of amyloid is made of immunoglobulin produced by plasma cells in your bone marrow.
As amyloid accumulates, it can disrupt the functioning of your affected organs and eventually cause them to fail.
There are four major forms of systemic amyloidoses — AL amyloidosis (or primary systemic amyloidosis), familial amyloidosis, senile systemic amyloidosis, and secondary amyloidosis. Treatment for any of the systemic amyloidoses is usually aimed at limiting amyloid production.
Symptoms of Systemic Amyloidoses
Symptoms of systemic amyloidoses can include:
- Weakness or fatigue
- Weight loss
- Heart damage (congestive heart failure) or irregular heart rhythm
- Shortness of breath
- Swelling of your feet and legs due to accumulation of fluid
- Stomach discomfort on your right side
- Abdominal swelling
- Early fullness with eating
- Gastrointestinal bleeding
- Chest pains
- Lightheadedness (due to lowering of blood pressure during sudden position changes)
- Numbness and tingling in the lower extremities (called peripheral neuropathy)
AL Amyloidosis (Primary Systemic Amyloidosis)
The most common form of systemic amyloidoses is systemic light chain amyloidosis — also called AL amyloidosis or primary systemic amyloidosis. AL amyloidosis is diagnosed in approximately 3,000 people in the United States each year, although many experts think it is underdiagnosed because primary care physicians may not recognize when and how to test for it.
In patients with AL amyloidosis, abnormal plasma cells produce an immunoglobulin light-chain protein that forms the amyloid. Over time, these light-chain proteins come together to create amyloid deposits in different organs, preventing the organs from working normally and potentially causing serious damage.
Although AL amyloidosis is rare, our doctors care for numerous patients with the disease. This extensive experience enables our physicians to make accurate diagnoses and to select the optimal course of treatment based on the needs of each individual patient.
To diagnose AL amyloidosis, our physicians use a number of tests, including blood and urine tests to look for the presence of abnormal immunoglobulin light-chain protein, a bone marrow biopsy, a biopsy taken from an affected organ or a site rich in blood vessels (such as abdominal fat or the rectum), and imaging tests to detect damage to your heart and other organs that may be affected.
Current therapies for AL amyloidosis are aimed at eliminating the abnormal plasma cells and removing the immunoglobulin light-chain proteins — and resulting amyloid — that these cells produce. Our physicians plan treatment for individual patients with AL amyloidosis based on a variety of factors, including the risk of side effects.
While there are no drugs approved by the US Food and Drug Administration specifically for the treatment of AL amyloidosis, therapies used against multiple myeloma can be effective against the disease. One limitation is that, due to disrupted organ function, patients with AL amyloidosis often cannot tolerate the same dosage of these drugs as patients with multiple myeloma.
To treat AL amyloidosis, our physicians usually use a combination of traditional chemotherapy drugs such as melphalan and dexamethasone as well as novel agents such as bortezomib, a new type of drug called a proteasome inhibitor.
Proteasome inhibitors block the activity of the proteasome, which is responsible for the removal of defective proteins. Because AL amyloidosis is a disorder of abnormal proteins, plasma cells in AL amyloidosis are often very sensitive to proteasome inhibitors.
Doctors at Memorial Sloan Kettering may also recommend autologous stem cell transplantation for the treatment of AL amyloidosis. In autologous stem cell transplantation — also called bone marrow transplantation — your own blood-forming stem cells are isolated and frozen. After you have received high-dose chemotherapy, the stem cells are re-infused into your bloodstream.
Before undergoing stem cell transplantation, you will be thoroughly tested to ensure that your heart, liver, and lungs are healthy enough to withstand the rigors of this procedure, as you will need to receive very high doses of chemotherapy before the transplantation to kill your plasma cells.
If you are not healthy enough for stem cell transplantation, you will likely receive chemotherapy as a primary treatment.
If AL amyloidosis has progressed enough to cause organ failure, an organ transplant may sometimes be considered. In this case, our doctors will refer you to appropriate transplant centers for specialized care.
New Approaches for Treating AL Amyloidosis
Recently our physicians began achieving excellent results by giving a second chemotherapy dose — called “consolidation chemotherapy” — after stem cell transplantation in patients whose AL amyloidosis persists. For patients who are good candidates for stem cell transplantation, this has proven to be a safe and effective treatment.
With this approach, patients first receive a high dose of the chemotherapy drug melphalan and then undergo autologous stem cell transplantation. Following the transplantation, a combination of the proteasome inhibitor bortezomib and the traditional chemotherapy drug dexamethasone are used. With this course of treatment, our experts have been able to safely achieve a response rate in nearly 80 percent of patients. This includes a complete response (total removal of the abnormal plasma cells and immunoglobulin light-chain proteins) in nearly 60 percent of patients — one of the highest complete response rates ever reported in treatment of AL amyloidosis.(1)
Our investigators are also conducting clinical trials to investigate new treatment approaches for AL amyloidosis. Three clinical trials will test the effectiveness of newer proteasome inhibitors in patients whose AL amyloidosis has returned after initial treatment.
One trial will test the proteasome inhibitor carfilzomib given along with dexamethasone; a second trial will test bendamustine (a form of chemotherapy) and dexamethasone; while the third will test an oral proteasome inhibitor called MLN9708 given with dexamethasone. These novel drugs have already shown promise in clinical trials for multiple myeloma.
In addition, our investigators are developing and testing strategies to remove amyloid that remains in tissues after chemotherapy treatment, in an effort to speed the return of normal organ function. A monoclonal antibody called NEOD001 targets the protein believed to be involved in AL amyloidosis and has shown some effectiveness in laboratory testing.
Other Forms of Amyloidosis
The three other major forms of amyloidosis — familial amyloidosis, senile systemic amyloidosis, and secondary amyloidosis — are even rarer than AL amyloidosis. Our doctors are experienced at diagnosing these disorders, but do not routinely treat these forms of amyloidosis. Instead, they refer patients to appropriate specialists for supportive management, organ transplantation, or treatment of the underlying condition causing the disease.
Familial amyloidosis (AF), or hereditary amyloidosis, develops among people who inherit a specific genetic mutation. Familial amyloidosis is inherited autosomal dominant, which means that if you have the disease, your child has a 50 percent chance of inheriting the mutation for it as well.
In the most common type of AF, the liver produces an abnormal form of a protein called transthyretin, which forms amyloid deposits. Although the mutated gene makes the abnormal transthyretin from birth, the amyloid deposits do not begin until midlife.
The only treatment for familial amyloidosis is liver transplantation, and we refer patients to appropriate transplantation centers for this specialized care.
Senile systemic amyloidosis (SSA) is an age-related amyloidosis that is not inherited. It is most commonly diagnosed in men over age 60. SSA involves accumulation of a non-mutated form of transthyretin, often resulting in heart dysfunction.
It is important for patients to receive an accurate diagnosis of SSA in order to avoid treatment with chemotherapy and to gain access to clinical trials testing novel treatments. Our doctors can diagnose SSA and refer patients to appropriate centers where new drugs are being tested.
Secondary amyloidosis (AA) is caused by inflammation resulting from either a chronic infectious disease – such as tuberculosis or osteomyelitis (a bone infection) – or a chronic inflammatory disease, such as rheumatoid arthritis.
This disease is rare in the developed world, where the underlying chronic infectious diseases are much less prevalent than in other areas. The goal of treatment is to address the underlying condition — the infectious or inflammatory disease. Sometimes the underlying condition can be treated at Memorial Sloan Kettering, but more often patients are referred to appropriate specialists elsewhere.