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Amyloidosis: High Hematologic Response Rates with Bortezomib

Carlson, Robert H.

doi: 10.1097/01.COT.0000387942.00866.a8

CHICAGO—Amyloidosis is gaining researchers’ attention as more effective treatments become available and the disease is diagnosed more often and treated earlier.

A poster discussion session here at the ASCO Annual Meeting featured five presentations on amyloidosis, including three of bortezomib in amyloid light chain (AL) amyloidosis.

Giampaolo Merlini, MD, PhD, Professor of Clinical Biochemistry at the University of Pavia, Italy, discussing these papers, said that survival for patients with AL amyloidosis and heart involvement has improved significantly in recent years, particularly after 1999.

He said that based on data from several studies, cumulative survival in the first year after treatment was approximately 80% for patients treated in 1986-1996 as well as those treated after 1999.

But at seven years, cumulative survival was less than 20% for patients treated in 1986-1996, versus more than 40% for those treated after 1999.

“We are making progress in treating AL amyloidosis,” Dr. Merlini said.

But there is much more to be done, he said, particularly for patients with heart involvement at high risk for sudden death. “Early diagnosis is vital, and correct typing of amyloid deposits is essential.”

Treatment strategies today can take advantage of new rapid-acting agents, new biomarkers for patient stratification and monitoring, physical removal of cardiotoxic light chains by dialysis, and cardiac transplantation in selected patients, he said.

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Speaking of bortezomib, a study from the Karmanos Institute in Detroit showed the MD-Bz regimen (melphalan-dexamethasone-bortezomib) to be highly effective against AL amyloidosis and light chain deposition disease (LCDD), with an overall 88% hematologic response rate, a 49% partial response (IMWG criteria), and 38% hematologic complete response.

Principal investigator Jeffrey A. Zonder, MD, Associate Professor in the Division of Hematology/Oncology, reported on 33 patients evaluable for response.

“Unlike multiple myeloma, amyloidosis patients, because of the amyloid deposition in different organs, are much more fragile, often present at a much more frail state and are less able to tolerate therapy,” Dr. Zonder explained in an interview. “Certain therapies we routinely use in myeloma, like high-dose chemotherapy, aren’t available to as many amyloid patients because they don’t tolerate it as well.”

Plans for this study came after the Phase III VISTA multiple myeloma study, reported by Jesús F. San Miguel, MD, and colleagues, that compared melphalan-prednisone with melphalan-prednisone-bortezomib (Velcade) (NEJM 2008;359:906-917).



“That study was stopped early because of a variety of positive endpoints favoring the Velcade-containing arm, all of which we felt were important in amyloid,” Dr. Zonder said. “We felt the frequency and quality of responses in that regimen made it something attractive to look at [in amyloidosis].”

Patient response was measured by proton electrophoresis with immuno-fixation, urine proton electrophoresis with protein fixation, and serum-free light chain assays.

“No patient had hematologic progression on this study,” Dr. Zonder said. “Some 12% had stable disease but the rest were responding.” Response was defined as a reduction of at least 50%.

Dr. Zonder said organ response sometimes occurs early, but characterizing it is extremely difficult—”The best response often occurs in two to three months, but some patients need six months or more for best response.”

Patients with Stage III disease did far worse, and some sudden cardiac deaths occurred even in patients who were responding to treatment.

Dr. Zonder said dose adjustments are frequently needed, at baseline and subsequently.

Neuropathy is a predictable side effect and is manageable, Dr. Zonder said, “but even risk-adapted dexamethasone dosing can be difficult.”

There were six deaths on the study, one an infectious complication of the therapy, the rest amyloid-related. Two were caused by progressive organ deterioration, one in the heart and one in the kidney.

“The other three were sudden deaths, arrhythmias, presumably,” Dr. Zonder said.

He noted that two randomized studies are now planned comparing melphalan-dexamethasone with melphalan-dexamethasone-bortezomib, one by the Eastern Cooperative Oncology Group and the other in Europe, running parallel with very similar designs. These should be opening by the end of the year, he said.

“We’re extremely happy with the responses [in our trial], and gratified to see that Stage 2 patients are doing as well as Stage 1 patients in our study. It’s early but we have seen some organ improvements, heart improvements, and kidney function improvements.”



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Response Higher with Bortezomib, But Also Toxicity

In another presentation, Daniel J. Landsburg, MD, a resident physician in the Department of Medicine at the University of Pennsylvania, reported that the use of both bortezomib- and lenalidomide-based regimens in patients with primary amyloidosis resulted in hematologic and end-organ responses, as well as survival rates comparable to published studies.

In this retrospective study, patients receiving bortezomib had a higher rate of hematologic and organ response than those treated with lenalidomide, he said. But they also had a higher incidence of toxicity, particularly neuropathy.

Statistical significance was not achieved for these results, possibly due to small sample size, he noted. Of the 23 patients evaluable, 10 received lenalidomide and 13, bortezomib. Patients had a median of two organs involved, primarily cardiac and renal, and a median of one previous treatment.

He said about 60% of study patients had multiple myeloma as well.

“We see a large number of amyloidosis patients at Penn, and we took a look at the patients treated with two novel agents that are really popular in multiple myeloma, Revlimid [lenalidomide] and [bortezomib] Velcade,” he said. “We were curious to see how our population fared with these agents.”

The overall hematologic response rate was 54% with bortezomib vs 40% with lenalidomide; complete response was 15% vs 10%, respectively; and organ response rates were 38% and 20%, respectively. Time to hematologic and organ response was similar among both groups.

The toxicity rate was higher with bor-tezomib compared with lenalidomide, 77% vs 40%, respectively, resulting in more frequent dose-reduction or discontinuation—54% vs 40%. The primary toxicities reported were neuropathy (54%) in patients receiving bortezomib, and neuropathy and cytopenias (20% each) in patients receiving lenalidomide.

The estimated one-year survival rates were similar between patients in the bor-tezomib and lenalidomide groups, 74% and 80%, respectively.

Dr. Landsburg said lenalidomide and especially the proteosome inhibitor bor-tezomib appear to break down the amyloid protein itself, regulating production of the protein, similar to the way they work in multiple myeloma.

Dr. Merlini, the abstract’s Discussant, noted that although the retrospective study was limited by the small number of patients and the results did not reach statistical significance, the trial did show that time to hematologic response and organ responses were shorter with bortezomib.

“Bortezomib may be more indicated as upfront therapy, keeping lenalidomide for later maintenance ‘consolidation’ therapy,’” he said.

© 2010 Lippincott Williams & Wilkins, Inc.
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