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From OncoLog, May 2014, Vol. 59, No. 5

New Treatments May Improve Outcomes for AL Amyloidosis Patients

By Bryan Tutt 

Image: Fluorescence microscopy image of pancreatic tissue specimen
Fluorescence microscopy with Congo red stain reveals amyloid fibrils, which appear bright green, in a pancreatic tissue specimen. Image courtesy of Dr. Gregg Staerkel.
AL amyloidosis—a rare, potentially fatal disease—has no approved treatments. The “standard” treatments are prescribed off-label, and few clinical trials have compared their effectiveness.

Recently, however, researchers at The University of Texas MD Anderson Cancer Center opened clinical trials of new drug combinations and even a new agent to treat this disease. If successful, this new agent would be the first drug approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of AL amyloidosis.

Cause and symptoms


AL amyloidosis occurs when clonal plasma cells in the bone marrow produce abnormal κ or λ light chains. These light chain proteins form amyloid fibrils, which accumulate in one or more organs and cause damage. The organs most often affected are the kidneys and the heart, but amyloid fibrils have been known to accumulate in all types of tissue except brain tissue.

A common cause of death for patients with AL amyloidosis is heart disease. “The amyloid deposits can cause thickening of the walls of the heart,” said Robert Orlowski, M.D., Ph.D., a professor in the Department of Lymphoma and Myeloma. “This thickening impairs heart function and causes an irregular heart rhythm.”

Unfortunately, symptoms of heart failure may be the first signs of AL amyloidosis. Indications of kidney damage such as fluid retention, anemia, increased serum creatinine levels, or proteinuria also may be the first signs of AL amyloidosis.

“It’s important to recognize AL amyloidosis early in the disease process—before organ damage has occurred, which makes the disease more difficult to treat,” said Jatin Shah, M.D., an assistant professor in the Department of Lymphoma and Myeloma. Suggestive of AL amyloidosis are indications of organ damage on routine physical examination, such as fluid retention because of kidney or heart failure, or laboratory findings such as increased serum creatinine levels or proteinuria.

AL amyloidosis should also be suspected in patients with multiple myeloma. Although most patients with AL amyloidosis do not have myeloma, AL amyloidosis occurs in 10%–15% of myeloma patients. For this reason, Dr. Shah recommends that all patients with multiple myeloma and symptoms of potential organ damage be screened for AL amyloidosis.

AL amyloidosis is typically diagnosed by the presence of clonal plasma in bone marrow aspirate and amyloid fibrils in a tissue biopsy. The tissue can be obtained by needle aspiration of the abdominal fat pad or of an organ suspected to be involved.

Standard treatments

Because AL amyloidosis and myeloma both arise from abnormal plasma cells in the bone marrow, treatments that are effective against myeloma are also used to treat AL amyloidosis. These treatments include stem cell transplantation, the proteasome inhibitor bortezomib, the corticosteroid dexamethasone, immunomodulatory drugs like thalidomide and its analogues lenalidomide and pomalidomide, and alkylating agents like melphalan or cyclophosphamide.

The standard treatments for newly diagnosed AL amyloidosis are melphalan plus dexamethasone and/or autologous stem cell transplantation. However, Dr. Orlowski said, “It’s not known whether stem cell transplantation or a nontransplant approach is more effective, because AL amyloidosis is not common.”

Because of the small number of patients with the disease, few randomized clinical studies have been done in patients with AL amyloidosis. However, a randomized study in France comparing stem cell transplantation with low-dose melphalan and dexamethasone found that transplantation did not offer an advantage in survival or response rates. Nevertheless, Dr. Orlowski said, patients with certain disease characteristics, such as kidney involvement, seem to benefit from stem cell transplantation. “In general, the approach is to consider using stem cell transplantation with or without preceding chemotherapy to reduce the disease burden,” he said.

The main goal of AL amyloidosis treatment is to kill the abnormal plasma cells in the bone marrow that produce the amyloid proteins. Once these proteins are no longer being produced, the body can absorb some of the amyloid fibrils that have accumulated in the affected organ(s).

Photo: Dr. Robert Orlowski Photo: Dr. Jatin Shah
Dr. Robert Orlowski

Dr. Jatin Shah

Complete remission is defined as the absence of amyloid proteins in the serum, also called a complete hematologic response. This occurs in about 60% of patients who receive standard treatment. However, Dr. Orlowski said, “Although the disease will stay in remission for prolonged periods of time, standard treatments don’t cure the majority of patients with AL amyloidosis.”

Another important measure of a treatment’s effectiveness is organ function. Although organ function improves in 30%–40% of patients who receive standard treatment for AL amyloidosis, organ recovery is slow and depends on which organs are affected and how long the damage has been occurring. Dr. Shah said it can take as long as 2 years for the affected organs to heal.

Multidisciplinary care

“Patients with AL amyloidosis are often very sick and can be difficult to treat,” Dr. Shah said. “Many do not tolerate chemotherapy well and encounter many complications.” He added that because of the various organs that can be damaged, the care of amyloidosis patients requires a multidisciplinary approach.

Dr. Orlowski agreed, suggesting that patients with AL amyloidosis be referred to a large center where the myeloma specialists who treat amyloidosis work closely with nephrologists, cardiologists, and other specialists who may be required to treat the affected organs. He said, “Input from all these people is important to ensure our patients get the best care.”

Clinical trials

New treatments for AL amyloidosis are being investigated in two clinical trials at MD Anderson.

In the first trial, a phase I/II study available only at MD Anderson, patients with newly diagnosed AL amyloidosis receive melphalan and dexamethasone on days 1–4 and pomalidomide on days 1–21 of a 28-day cycle. Dr. Orlowski, the trial’s principal investigator, said, “Pomalidomide with dexamethasone has been shown to work for people with relapsed amyloidosis, so combining pomalidomide with the standard of care for newly diagnosed patients, melphalan and dexamethasone, is likely to be effective in people with newly diagnosed disease.”

The study’s drug combination does not interfere with stem cell transplantation. Patients who are eligible for transplantation receive two cycles of the drug combination and then undergo a transplant; patients who are not eligible for transplantation but for whom the drugs are effective and well tolerated receive prolonged therapy and eventually move to a maintenance dose.

In the second trial, an international phase III study, patients are randomly assigned to receive the experimental oral proteasome inhibitor ixazomib (also called MLN9708) plus dexamethasone or the physician’s choice of dexamethasone alone or dexamethasone plus melphalan, cyclophosphamide, thalidomide, or lenalidomide. Dr. Shah, MD Anderson’s principal investigator for the trial, said that the study could lead to the FDA’s approval of ixazomib for AL amyloidosis.

“AL amyloidosis affects a small number of patients, so it takes a major effort and commitment by multiple academic centers to complete a trial,” Dr. Shah said. The difficulty of organizing large trials for a small patient population is a major reason why no drugs have yet been approved for the treatment of AL amyloidosis.

In both studies, it is hoped that the experimental drug combinations will prolong patients’ remissions. Another potential benefit for patients is the convenience of taking oral medications. “Both these studies offer all-oral regimens,” Dr. Orlowski said, “so patients don’t have to schlep back and forth to the clinic for intravenous or subcutaneous injections.”

For more information, contact Dr. Robert Orlowski at 713-792-2860 or Dr. Jatin Shah at 713-745-6130.

Other articles in OncoLog, May 2014 issue:

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