AL Amyloidosis
In the United States, AL amyloidosis is the most common type, with approximately 4,500 new cases diagnosed every year. It usually affects people from ages 50-80, although there are a few cases of people being diagnosed as early as their late 20s. About two-thirds of the patients are male.
AL amyloidosis is caused by a bone marrow disorder. The bone marrow in the center of bones produces cells in the blood system, including “plasma cells.” These plasma cells are the part of the immune system that makes antibodies for fighting infections. The term “immunoglobulin” refers to the class of proteins that function as antibodies. Immunoglobulins are composed of four protein chains: two light chains, either kappa or lambda light chains, and two heavy chains, of which there are several types.
These proteins are produced by the plasma cells in the bone marrow. In AL patients, these plasma cells produce an abnormal antibody (immunoglobulin) protein. For AL amyloidosis, it is the “light chains” that become misfolded, and the abnormal, misfolded result is the forming of amyloid. With AL amyloidosis, the “A” is for amyloid and the “L” is for light chain.
These misfolded amyloid proteins are deposited in and around tissues, nerves and organs. As the amyloid builds up in an organ, nerve or tissue, it gradually causes damage and affects their function. Each amyloidosis patient has a different pattern of amyloid deposition in their body. It often affects more than one organ. AL amyloidosis does not affect the brain.
AL amyloidosis is caused by a bone marrow disorder. The bone marrow in the center of bones produces cells in the blood system, including “plasma cells.” These plasma cells are the part of the immune system that makes antibodies for fighting infections. The term “immunoglobulin” refers to the class of proteins that function as antibodies. Immunoglobulins are composed of four protein chains: two light chains, either kappa or lambda light chains, and two heavy chains, of which there are several types.
These proteins are produced by the plasma cells in the bone marrow. In AL patients, these plasma cells produce an abnormal antibody (immunoglobulin) protein. For AL amyloidosis, it is the “light chains” that become misfolded, and the abnormal, misfolded result is the forming of amyloid. With AL amyloidosis, the “A” is for amyloid and the “L” is for light chain.
These misfolded amyloid proteins are deposited in and around tissues, nerves and organs. As the amyloid builds up in an organ, nerve or tissue, it gradually causes damage and affects their function. Each amyloidosis patient has a different pattern of amyloid deposition in their body. It often affects more than one organ. AL amyloidosis does not affect the brain.
Symptoms
The symptoms of AL amyloidosis vary by patient. Initially, the symptoms can be minor or similar to those of many other conditions or systemic diseases. Some symptoms can announce themselves quickly and be very noticeable. For each patient, the symptoms will depend on which organs are affected by the amyloid deposits. It also depends on the degree that the organ function is impaired. Fatigue, weight loss and swelling are the most common symptoms.
Impairment of many organs, nerves and soft tissues can cause symptoms, among them the kidneys, heart, the GI tract (the digestive system) and the nervous system.
Impairment of many organs, nerves and soft tissues can cause symptoms, among them the kidneys, heart, the GI tract (the digestive system) and the nervous system.
The Kidneys
Chronic kidney disease is common in patients with AL amyloidosis. Amyloid deposits in the kidneys can affect how they filter toxins and proteins in the blood. This may result in a condition called nephrotic syndrome, where there is excess protein in the urine and the lower legs can become swollen (also called “edema”). Swelling can affect the belly, arms, and lungs as well. In some cases, the amyloid deposits will cause the kidneys to lose the ability to purify the blood, which can lead to kidney failure; also known as “renal” failure. These patients may need dialysis to replace the function of the kidneys.
The Heart
Amyloid deposits in the heart can cause it to become unusually thickened and stiff, making it unable to function efficiently. This results in shortness of breath, which may occur with only minor activity. Amyloid can also affect the electrical system of the heart, causing the normal heartbeat to speed up or slow down. This is known as arrhythmia.
The Digestive System
The digestive system is also called the gastrointestinal tract (or GI tract). Amyloid deposits in the digestive system can cause nausea, diarrhea or constipation, weight loss, loss of appetite, or a feeling of fullness in the stomach after eating small amounts.
The Nervous System
Amyloid deposits can affect the nerves of the hands, feet and lower legs and may cause pain, numbness and tingling. A loss of sensitivity to temperature may also occur. This is called peripheral neuropathy. Nerves that control blood pressure, heart rate, bowel motility, erectile function, and other body functions can also be affected, causing a variety of symptoms including dizziness when standing too quickly, nausea and diarrhea. This is called autonomic neuropathy.
Other Symptoms
There are other symptoms that are common and may have been present for some time before diagnosis, such as chronic fatigue and weakness. Some patients with AL amyloidosis experience purpura, which is bruising around the eyes or other skin areas.
Swelling may develop and cause symptoms as a result of the amyloid deposits. For example, patients may have carpal tunnel syndrome, where amyloid deposits in the wrist area can squeeze and irritate the nerve, causing tingling and numbness in the fingers and thumb. Deposits in the tongue may lead to a swollen and enlarged tongue, called “macroglossia.” In addition, some patients experience the “shoulder pad” symptom; where the patient notices an enlargement of the shoulders, causing restriction in the joint due to swelling and/or amyloid deposits in the surrounding tissues.
One significant, but less common, symptom is that some patients can develop bleeding or clotting problems.
Swelling may develop and cause symptoms as a result of the amyloid deposits. For example, patients may have carpal tunnel syndrome, where amyloid deposits in the wrist area can squeeze and irritate the nerve, causing tingling and numbness in the fingers and thumb. Deposits in the tongue may lead to a swollen and enlarged tongue, called “macroglossia.” In addition, some patients experience the “shoulder pad” symptom; where the patient notices an enlargement of the shoulders, causing restriction in the joint due to swelling and/or amyloid deposits in the surrounding tissues.
One significant, but less common, symptom is that some patients can develop bleeding or clotting problems.
Diagnosis
Diagnostic testing for AL amyloidosis involves blood tests, urine tests and biopsies. Blood and/or urine tests can indicate signs of the amyloid protein, but only bone marrow tests or other small biopsy samples of tissue or organs can positively confirm the diagnosis of amyloidosis. Some tests are only done once to establish a diagnosis of AL amyloidosis, while others will be repeated to monitor disease progression and response to therapy.
Blood and Urine Tests
Blood and urine tests should be performed to help verify the diagnosis. They can also aid in discovering which organs are involved and how much they are compromised. These tests may include:
A 24-hour urine collection to look at the level of protein in your urine sample. Excess protein in the urine may be an indication of kidney involvement. The level of ALP (an enzyme called “alkaline phosphatase”) in your regular blood workup. Blood tests to look for stress and strain on the heart are useful in many forms of heart disease, including AL amyloidosis. The cardiac biomarkers that are used include troponin T or troponin I, and NT-proBNP (which stands for N-terminal pro-brain natriuretic peptide) or BNP (brain natriuretic peptide). Different laboratories use one versus the other. Tests for abnormal antibody (immunoglobulin) proteins in the blood include the Freelite Assay, which shows the level of kappa and lambda light chains in a separate blood test. The Freelite Assay test is often referred to as FLC, which is an abbreviation for free light chains. Another test for abnormal immunoglobulin can be done with blood and/or urine. It is called “immunofixation electrophoresis.”
These blood and urine tests can help with the diagnosis and used often while monitoring response to treatment.
A 24-hour urine collection to look at the level of protein in your urine sample. Excess protein in the urine may be an indication of kidney involvement. The level of ALP (an enzyme called “alkaline phosphatase”) in your regular blood workup. Blood tests to look for stress and strain on the heart are useful in many forms of heart disease, including AL amyloidosis. The cardiac biomarkers that are used include troponin T or troponin I, and NT-proBNP (which stands for N-terminal pro-brain natriuretic peptide) or BNP (brain natriuretic peptide). Different laboratories use one versus the other. Tests for abnormal antibody (immunoglobulin) proteins in the blood include the Freelite Assay, which shows the level of kappa and lambda light chains in a separate blood test. The Freelite Assay test is often referred to as FLC, which is an abbreviation for free light chains. Another test for abnormal immunoglobulin can be done with blood and/or urine. It is called “immunofixation electrophoresis.”
These blood and urine tests can help with the diagnosis and used often while monitoring response to treatment.
Echocardiogram and Imaging
The echocardiogram (also called “echo”) is an ultrasound of the heart. A doctor can look for amyloid deposits in the heart, while viewing the size and shape of it and the location and extent of any impact of amyloid.
Recently, other imaging tests for the heart have also shown to be useful. One test is the MRI (magnetic resonance imaging), and, in this instance, is also referred to as CMR (for cardiac magnetic resonance). Pyrophosphate scanning, a nuclear medicine test, is also used to evaluate whether an unusual type of abnormality of heart muscle function (“cardiomyopathy”) is present. Current data suggests this scan may be useful in distinguishing different types of amyloid heart disease.
Recently, other imaging tests for the heart have also shown to be useful. One test is the MRI (magnetic resonance imaging), and, in this instance, is also referred to as CMR (for cardiac magnetic resonance). Pyrophosphate scanning, a nuclear medicine test, is also used to evaluate whether an unusual type of abnormality of heart muscle function (“cardiomyopathy”) is present. Current data suggests this scan may be useful in distinguishing different types of amyloid heart disease.
Tissue Biopsy
A tissue biopsy involves the removal of a small sample of tissue to find evidence of amyloid deposits. Any kind of tissue or organ biopsy must be sent to a lab for microscopic examination, where the tissue is stained with a dye called “Congo-red stain.” After putting it under a microscope, amyloid protein is discovered if it turns an apple-green color, resulting in a diagnosis of amyloidosis. Possible areas for less invasive biopsies include:
A fat pad biopsy (from under the skin in the abdomen); Labial salivary gland biopsy (the inner lip); and, Skin or bone marrow.
With combinations of these blood and urine tests and tissue biopsies, a positive diagnosis can be confirmed in a high percentage of patients.
A fat pad biopsy (from under the skin in the abdomen); Labial salivary gland biopsy (the inner lip); and, Skin or bone marrow.
With combinations of these blood and urine tests and tissue biopsies, a positive diagnosis can be confirmed in a high percentage of patients.
Bone Marrow Aspirate and Biopsy
There are two types of bone marrow tests that may be performed. These involve the removal of some liquid bone marrow (a bone marrow aspirate) and/or the removal of a 1 – 2 cm core of bone marrow tissue in one piece (a bone marrow biopsy). These samples can help to determine the percentage of amyloid producing plasma cells, and when tested in the lab they can assist in identifying whether the abnormal plasma cells are producing kappa or lambda light chains.
Organ Biopsy
If amyloidosis is still suspected but biopsies of the bone marrow, fat pad, lip or skin sites turn up negative, then a surgical biopsy of the organ that is indicating symptoms should be performed and sent to a lab. Biopsy samples may be taken from the:
Liver Kidney Nerve Heart Gut (stomach or intestines).
If any biopsy result shows a positive diagnosis for amyloidosis, then it is essential to also determine the accurate type of amyloid protein that is involved. In this case, the type of AL amyloidosis must be confirmed, showing a bone marrow disorder with light chain involvement, also known as a “plasma cell dyscrasia.”
Liver Kidney Nerve Heart Gut (stomach or intestines).
If any biopsy result shows a positive diagnosis for amyloidosis, then it is essential to also determine the accurate type of amyloid protein that is involved. In this case, the type of AL amyloidosis must be confirmed, showing a bone marrow disorder with light chain involvement, also known as a “plasma cell dyscrasia.”
Treatment
Treatment for AL amyloidosis is tailored to the patient with their individual health in mind. The type of treatment is based upon disease progression and seriousness of the patient’s organ, tissue, and nerve involvement.
Today’s treatment plans are two-fold:
Supportive treatment – treating your symptoms and organ damage; and, Source treatment – slowing down, or stopping, the overproduction of amyloid at the source of the disease.
The doctor will need to prescribe the supportive treatment that the patient needs as well as source treatment for the disease itself.
Today’s treatment plans are two-fold:
Supportive treatment – treating your symptoms and organ damage; and, Source treatment – slowing down, or stopping, the overproduction of amyloid at the source of the disease.
The doctor will need to prescribe the supportive treatment that the patient needs as well as source treatment for the disease itself.
Supportive Treatment
Supportive treatment is helpful for various symptoms, including cardiac and kidney problems, and can change the quality of life for many people.
For example, gastrointestinal dysfunction may require treatment for symptoms that include poor nutritional health, diarrhea or constipation, and nausea or vomiting. Doctors can prescribe medications to help with these symptoms to lessen the pain and the symptom itself.
Management of heart problems, heart failure, and kidney dialysis can make a significant improvement in a patient’s quality of life. Treatment for heart and kidney failure in amyloidosis is different from organ problems due to other diseases. It is important for a patient to consult with specialists that are aware of what medications are, and are not, safe for amyloidosis patients.
Reversing any damage to the organs and other parts of the body is difficult to achieve. If treatment begins during the early onset of clinical symptoms, the overall success rate is higher, so early detection is essential.
For example, gastrointestinal dysfunction may require treatment for symptoms that include poor nutritional health, diarrhea or constipation, and nausea or vomiting. Doctors can prescribe medications to help with these symptoms to lessen the pain and the symptom itself.
Management of heart problems, heart failure, and kidney dialysis can make a significant improvement in a patient’s quality of life. Treatment for heart and kidney failure in amyloidosis is different from organ problems due to other diseases. It is important for a patient to consult with specialists that are aware of what medications are, and are not, safe for amyloidosis patients.
Reversing any damage to the organs and other parts of the body is difficult to achieve. If treatment begins during the early onset of clinical symptoms, the overall success rate is higher, so early detection is essential.
Source Treatment
The U.S. Food and Drug Administration (FDA) has approved the use of DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj), a subcutaneous formulation of daratumumab, in combination with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis.
Stem Cell Transplant
In the United States, a stem cell transplant (SCT) is often the preferred therapy, as it can provide long-term control of the underlying disease. However, only a minority of AL patients are eligible for this. For the majority of AL amyloidosis patients, and in many other countries outside the U.S., other chemotherapy-based treatments are considered. These treatment regimens are tailored for each patient and based upon the patients’ organ function, symptoms, and preferences.
Combination Therapy
Patients with AL amyloidosis have benefited from the recent development of new drugs for myeloma, many of which work effectively on the plasma cells that cause AL amyloidosis. Many drug combinations are more effective than single drugs in attacking the abnormal plasma cells and the dosage is tailored to each individual patient, to enable the best course of treatment and possible outcome. Categories of drugs that may be useful include:
Traditional Chemotherapy Drugs:
- Melphalan, Cyclophosphamide (Cytoxan™), Bendamustine (Treanda™)
- Drugs called “proteasome inhibitors”: Bortezomib (Velcade™), MLN9708 (Ixazomib™), Carfilzomib (Kyprolis™)
- Drugs called “immunomodulators”: Thalidomide (Thalidomid™), Lenalidomide (Revlimid™), Pomalidomide (Pomalyst™)
Note that some of these drugs are still considered investigational for AL amyloidosis, and should not be used outside of a sponsored clinical trial. Also, most of them are given with a steroid such as dexamethasone, which seems to increase their effectiveness.