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Bortezomib and Chemotherapy for Systemic Light-Chain Amyloidosis

Name of the Trial

Phase III Randomized Study of Melphalan and Dexamethasone with Versus without Bortezomib in Patients with Previously Untreated Systemic Light-Chain Amyloidosis (ECOG-E4A08). See the protocol summary.

Principal Investigator

Dr. Angela Dispenzieri, Eastern Cooperative Oncology Group

Dr. Angela Dispenzieri

Dr. Angela Dispenzieri Principal Investigator

Why This Trial Is Important

Systemic amyloidosis refers to a group of diseases in which certain proteins fold into an abnormal conformation known as “amyloid.” The build-up of these abnormally folded proteins in organs and/or tissues can cause serious health problems.

The most common form of systemic amyloidosis in the United States is amyloid light-chain, or AL, amyloidosis. It is a rare disease in which abnormal plasma cells produce an abundance of improperly folded immunoglobulin (Ig) light-chain proteins. These misfolded Ig proteins accumulate in organs throughout the body and may impair organ function, ultimately leading to organ failure. Without treatment, patients diagnosed with AL amyloidosis typically die from organ failure within a year.

The treatment of AL amyloidosis focuses on the killing of plasma cells to reduce the production of misfolded Ig light-chain proteins. In patients who can tolerate it, high-dose chemotherapy with melphalan followed by transplantation of stem cells from the patient’s own blood (autologous stem cell transplantation) is one treatment option. In a phase II trial, this therapy reduced the number of misfolded light chains in the blood in 64 percent of patients. Such a hematologic response in patients with AL amyloidosis has been shown to predict longer survival. Unfortunately, about two-thirds of patients with this disease are unable to tolerate autologous stem cell transplantation because of advanced age and/or poor organ function caused by their disease or other health problems.

Patients who are ineligible for or who are concerned about the risk and logistics of autologous stem cell transplantation are usually treated with combination chemotherapy consisting of melphalan and a steroid, such as dexamethasone. However, only about two-thirds of the patients treated with melphalan and dexamethasone achieve a hematologic response, so new treatments are needed for patients with AL amyloidosis.

AL amyloidosis is related to a cancer of plasma cells called multiple myeloma. Adding the drug bortezomib to chemotherapy for multiple myeloma has helped improve survival in patients with that disease. The improvements seen in myeloma patients have spurred an interest in evaluating bortezomib in combination with chemotherapy for AL amyloidosis. In an early clinical trial, patients with relapsed AL amyloidosis experienced encouraging hematologic response rates when treated with bortezomib alone.

In the current clinical trial, patients with previously untreated AL amyloidosis will be randomly assigned to receive melphalan and dexamethasone with or without bortezomib. Doctors will assess the overall hematologic response rates to these chemotherapy regimens, as well as organ responses (improvements in the function of affected organs). In addition, they will monitor patients for toxicity, progression-free survival, overall survival, and quality of life.

“In patients with myeloma, the triplet regimen of bortezomib, melphalan, and dexamethasone appears to be better than the doublet of melphalan and dexamethasone, so it may well be that the triplet will perform better in AL amyloidosis as well,” said Dr. Dispenzieri.

“The caveat for AL patients, however, is that while drugs that work well in myeloma can also work well in AL patients, they tend to be a lot more toxic in these patients. So, even though the three-drug combination might turn out to be better at killing the plasma cells, patients might have so many more complications that they may not do any better, or may even do worse. We simply don’t know and that’s why we’re conducting the randomized trial,” she explained.

For More Information

See the lists of entry criteria and trial contact information or call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

  • Posted: October 18, 2011