Read this article on Medscape's
free mobile app. Download Now
free mobile app. Download Now
February 16, 2012 — A combination of drugs, one of which is the targeted agent bortezomib (Velcade), which is successful in the treatment of multiple myeloma, has shown striking activity in patients with light-chain amyloidosis.
Two unrelated groups of researchers have written brief reports on the use of the combination in amyloidosis; both were published online February 13 in Blood.
Joseph Mikhael, MD, MEd, FRCPC, FACP, from the Mayo Clinic Scottsdale, Arizona, and colleagues reportresults from a retrospective series of 17 patients with a median follow-up of 21 months. Christopher Venner, MD, from the National Amyloidosis Center at University College London, United Kingdom, and colleagues reportresults from 43 patients with a median follow-up of 14 months.
Both groups used bortezomib in combination with cyclophosphamide and dexamethasone, and report seeing rapid, deep, and durable responses, better than anything that has been seen previously with any other combination.
This combination should be studied further, but already "the data we have so far are strong enough to justify the use of this combination in clinical practice in patients with amyloidosis," Dr. Mikhael told Medscape Medical News.
Some of the results, such as the 94% response rate and the 71% complete response rate, are unprecedented, Dr. Mikhael said in an interview. "Although I am cognizant that these are preliminary results from small studies, I am excited.... These results will have to be corroborated in larger studies, but this combination holds great promise."
"In view of the rapidity and the depth of the responses, as well as the tolerability of the regimen, I think this combination is the best choice for patients," he said.
Considered a Type of Cancer
Amyloidosis shares some characteristics with multiple myeloma. Both conditions involve defects in the bone marrow production of plasma cells. Multiple myeloma is a "frank cancer of the plasma cells," where the body produces a high proportion of these cells; with amyloidosis, there are fewer of these plasma cells, but they produce proteins that undergo a conformational change and are then deposited in organs, Dr. Mikhael explained.
"Although we do consider amyloidosis to be a type of cancer," he continued, this is the hallmark of the disease — these deposits of light-chain-derived proteins in various organs, typically in the kidney and heart, but also in nerves, in the gastrointestinal tract and, in fact, potentially every organ of the body, he said. Median overall survival after diagnosis is typically 3 years, but when the heart is already damaged on diagnosis, it can be only 1 year.
To date, the standard of care has been conventional chemotherapy. This has had limited success; some patients go on to stem cells transplantation, which can achieve remission for a period of time, Dr. Mikhael explained. However, many patients are not eligible for this treatment option because of the organ damage from the amyloid deposits, he added.
Other drugs that have proven successful in the treatment of multiple myeloma, such as thalidomide (Thalomid, Celgene) and lenalidomide (Revlimid, Celgene), have also shown some benefit in amyloidosis, Dr. Mikhael said. However, thalidomide is not well tolerated by amyloid patients; they seem to be more sensitive to the sedative effects and complain about fatigue. Also problematic is the neuropathy associated with this drug; the disease itself is already damaging to the nerves. In addition, the responses are slow.
The related drug, lenalidomide, produces results that are somewhat better than thalidomide, he said, but this new combination of bortezomib, cyclophosphamide, and dexamethasone has produced the best results seen so far in these patients.
In the Mayo series of 17 patients, 12 achieved a complete response in a median of 2 months; all 12 remained alive at a median follow-up of 21 months. Nine (75%) of these patients remain in complete remission, with a mean duration of response of 22 months (range, 5 to 30 months).
Three patients, considered ineligible for stem cell transplantation at the beginning of the study because of low cardiac function, improved to such an extent that they became eligible. "This is seen rarely, and very intermittently, and never before in this proportion of patients," Dr. Mikhael said.
The improvement seems to be related to the speed of the response, he said. "If we can suppress the production of amyloid, it seems that the body tries to remove the deposits, but time is critical.... It's like a ship that is sinking; the faster you can bail out the water...the more likely you are to get the ship back above the water, but if you do it slowly, the more likely the ship is to continue sinking."
"Unfortunately, that's often all we can do — just slow the progression. Now we feel that if we can shut off the production rapidly, we have a chance of seeing parameters improve," he said.
The hope for the future is that the improved responses seen with this bortezomib combination will translate to an improvement in survival, as has already been seen in multiple myeloma. Longer follow-up is needed to see if this will be the case.
Good Results From the United Kingdom
Similarly good results were reported in the British series of patients. Compared to what we have seen in the past with various treatment regimens, the results with the 3-drug combination of cyclophosphamide, bortezomib, and dexamethasone appear to be better, especially in terms of response rates, Dr. Venner reported.
"The response rates are higher and deeper... [and] there is a higher rate of complete responses," he said. In the British series of 43 patients, the overall response rate was 81.54%, and 39.50% of those were complete responses. In responding patients, the time to response was 4.1 months.
At a median follow-up of 14 months, only 2 patients had died. Median progression-free survival has not yet been reached, but for the whole cohort, median progression-free survival at 1 year was 70% and at 2 years was 53.1%.
Dr. Venner highlighted the fact that in a subgroup of high-risk patients (Mayo stage 3), 1-year progression-free survival was 74% and 2-year overall survival was 94.4%. This is "compelling...and strikingly different" from the outcomes described in a recent European collaborative trial of similar patients, where overall survival was 7 months. This is a "first hint that bortezomib-induced deep hematological responses may overcome prognostic features of stage 3 disease," Dr. Venner and colleagues write.
"We anticipate that this will eventually show a survival advantage," Dr. Venner said in an interview. One of the common findings in older studies with different treatment regimens is that a deeper response — that is, a higher proportion of complete responses — translates into improved progression-free survival, and then into improved overall survival, he said. "The fact that we have seen such decent progression-free survival already is quite encouraging," he added.
Dr. Venner said that further studies are planned, and the data so far are encouraging enough to include high-risk patients, who are often left out of clinical trials.
In the United Kingdom, bortezomib is not indicated for upfront use in amyloidosis; the standard of care is currently cyclophosphamide, thalidomide, and dexamethasone, Dr. Venner explained. However, for patients who are unable to tolerate thalidomide, and for those in whom a rapid response is needed, the use of bortezomib can be justified, he said.
Most Promising Regimen
Medscape Medical News approached an expert in the field who was not involved in either of these studies to comment on the data.
"These are very encouraging results in a rare plasma cell dyscrasia," said David Vesole, MD, cochief and director of research in the multiple myeloma division at the John Theurer Cancer Center, in Hackensack, New Jersey.
"Response rates are almost double those observed with the 'gold standard' of melphalan and dexamethasone. These outcomes appear to be superior to doublet regimens of bortezomib and dexamethasone or lenalidomide and dexamethasone. Further, these results are comparable to some of the transplant data," he said.
"This is the most promising nontransplant combination regimen that has been used to treat amyloidosis," he added. "We have already incorporated this regimen into treatment approaches for our amyloid patients. We are using a modification of this regimen as induction therapy for many of our amyloid patients, transplant eligible or ineligible."
Although these are small studies, amyloidosis is a rare disease and it is quite difficult to conduct large studies in a timely fashion, Dr. Vesole explained. "The information in these 2 studies can be applied to the larger amyloidosis patient population. This has been the case in the more common plasma cell dyscrasia, where modest phase 2 data have been used to advance treatment for multiple myeloma."
Dr. Mikhael has disclosed no relevant financial relationships, but several of his coauthors report consulting arrangements with pharmaceutical companies, including Janssen-Ortho, Celgene, Onyx, Millennium, Genzyme, Medtronic, Bristol-Myers Squibb, Amgen, Otsuka, Intellikine, and Cylene. Dr. Venner has disclosed no relevant financial relationships, but one of his coauthors reports receiving honoraria from Janssen-Cilag. Dr. Vesole has disclosed no relevant financial relationships.
- Author: Anita Basu, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
Updated: Jun 3, 2010
Background
Beta-2-microglobulin amyloidosis is a disabling condition that affects patients undergoing long-term hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD).[1, 2] Case reports involving patients with near end-stage renal disease also exist. It does not affect individuals with normal or mildly reduced renal function or patients with a functioning renal transplant.
Beta-2-microglobulin is a major constituent of amyloid fibrils.[3] Its accumulation has been shown to invade synovial membranes and osteoarticular sites, causing destructive osteoarthropathies, such as carpal tunnel syndrome, flexor tenosynovitis, subchondral bone cysts, and erosions, as well as pathologic fractures.
Visceral involvement has been found in different organs, such as the gastrointestinal tract, heart, and tongue, but overt manifestations are rare.
No comments:
Post a Comment