Bortezomib (Velcade®) Delays Progression of Advanced Multiple Myeloma Longer than Standard Therapy: Results of the APEX Trial
Early results from an international phase III trial in patients with relapsed multiple myeloma show that the new targeted drug bortezomib (Velcade®) is more effective than a standard treatment of high-dose dexamethasone at delaying disease progression. Though certain serious side effects were worse for patients taking bortezomib, more of them were alive after one year than patients receiving the standard treatment.
New England Journal of Medicine, June 16, 2005 (see the journal abstract).
About 15,980 people are expected to develop multiple myeloma in the United States in 2005, and 11,300 to die from the disease. Though treatments for the disease are effective at first, the long-term prognosis is generally poor. About 29 percent of patients are alive five years after diagnosis.
Patients with multiple myeloma suffer from an impaired immune system. A type of white blood cell called a plasma cell, which produces infection-fighting antibodies, starts reproducing uncontrollably. This flood of abnormal plasma (myeloma) cells crowds out healthy blood cells in the bone marrow (the spongy tissue inside large bones) and can lead to fatigue, bone pain, anemia, kidney failure, and/or recurrent infections.
Chemotherapy often succeeds in lowering the number of myeloma cells, which puts many patients into remission for two years or longer. However, most therapies for multiple myeloma eventually lose their effectiveness. When the number of myeloma cells begins to rise again, patients have developed relapsed or recurrent multiple myeloma.
No single therapy has been shown to be most effective in this group of patients, but high doses of steroids such as prednisone or dexamethasone are commonly used, often followed by bone marrow transplant.
Proteasome inhibitors are a new class of targeted therapies that may be more effective in patients with relapsed or refractory (treatment-resistant) blood-cell cancers like multiple myeloma. The first such therapy to show real promise in phase II studies is bortezomib (Velcade®). By targeting a protein that is active in some cancers, bortezomib delays tumor growth and enhances the cell-killing effects of radiation and chemotherapy.
The U.S. Food and Drug Administration (FDA) gave bortezomib “fast-track” approval for the treatment of patients whose multiple myeloma has progressed after at least two courses of treatment. The phase III trial described here – called the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial – was conducted to provide more definitive evidence.
The study enrolled 669 patients with relapsed or refractory multiple myeloma at 94 centers in the United States, Canada, Europe, and Israel. All patients had previously received between one and three therapy treatments, but not bortezomib. They were randomly assigned to receive either bortezomib or a standard high-dose treatment of dexamethasone, with the primary aim being to find out which treatment would better prevent the disease from progressing. APEX was the first large randomized controlled trial (considered the “gold standard” in cancer research) of bortezomib, after smaller trials indicated it was safe and effective.
Early results dramatically favored bortezomib, and thus a companion study was launched where patients in the dexamethasone group were switched to bortezomib as soon as their disease began to progress. Forty-four percent of the dexamethasone group ultimately crossed over to the bortezomib group.
The study’s principal investigator was Paul G. Richardson of the Dana-Farber Cancer Institute in Boston, Mass. (See the protocol summary.)
The patients taking bortezomib went nearly twice as long before disease began to progress, 6.22 months compared to 3.49 months for the dexamethasone group. Patients in both groups responded to their treatments in about the same amount of time (a median of 43 days), but the response lasted longer for those taking bortezomib (a median of 8 months) than for those taking dexamethasone (a median of 5.6 months).
In the end, 38 percent of patients had a complete or partial response to bortezomib, compared to 18 percent for dexamethasone. Both groups saw higher response rates among those patients who had received only one prior treatment before joining the trial.
In terms of overall survival, patients in the bortezomib group did significantly better, even after factoring in the number of dexamethasone patients who crossed over to the other group. Those taking bortezomib reduced their risk of dying by 43 percent, with a one-year survival rate of 80 percent compared to 66 percent for those taking dexamethasone.
Side effects were a greater problem in the bortezomib group, forcing 121 (37 percent) of them to withdraw from the study compared to 96 (29 percent) who had to withdraw from the dexamethasone group.
While the rates of the most serious (grade 4) side effects were similar in both arms, less serious but still severe grade 3 events were reported by 61 percent of the bortezomib group, compared to 44 percent of the dexamethasone group. Though the grade 3 toxicities to the patients’ blood and nerves were significantly greater with bortezomib, these effects were treatable. Rash, insomnia, pain in bones and limbs, and muscle cramps were all significantly worse with dexamethasone.
(Note: Results from the APEX trial were originally presented at the 2004 meeting of the American Society of Clinical Oncology. An updated analysis with longer follow-up was published online Aug. 9, 2007, by Blood; see the journal abstract.)
The APEX trial results support the FDA’s decision to approve bortezomib, said Angela Dispenzieri, M.D., from Rochester, Minnesota’s Mayo Clinic, in an accompanying editorial. Noting that no new multiple myeloma treatments have been developed for a generation, she now believes “the future is bright.” Preliminary reports from other studies, she wrote, show high rates of response to bortezomib, especially in combination with other agents.
Indeed, said Thomas Davis, M.D., of the National Cancer Institute’s (NCI) Cancer Therapy Evaluation Program, bortezomib “is becoming widely used in the relapsed setting, especially in combination with other therapies like dexamethasone.” The toxicity problem is reduced with that combination because, he added, “as APEX illustrates, their side effects are very different.”
Because few drugs have shown significant activity in relapsed myeloma, explained Davis, “this is new, and anything that looks promising will get a lot of attention. This level of cellular activity is really quite exciting. The drug is the first to be fully developed in this new class of proteasome inhibitors, and its effectiveness as a single agent in that setting gives us hope it may be even more active when used to treat the disease initially.”
While statistically significant data showed that one-year overall survival rates were higher in the bortezomib group, the trial was primarily designed to reliably determine whether bortezomib did a better job at keeping the disease at bay (by improving “time to progression”).
What’s more, said Wyndham Wilson, M.D., Ph.D., of the NCI’s Center for Cancer Research, because the trial was stopped early and the ethical decision was made to allow patients on dexamethasone to switch to bortezomib, it will be difficult for the APEX trial to definitively determine, even with longer follow-up, whether bortezomib extends patients’ long-term survival and, if so, by how much.
Davis agreed, but pointed out that no clinical trial of relapsed multiple myeloma patients is likely to collect this kind of long-term survival data. As APEX illustrates, he said, when a new treatment provides striking benefits, patients will be switched to the experimental treatment, thereby compromising researchers’ ability to calculate a survival benefit. Nonetheless, he said, “what we know about bortezomib’s activity suggests these patients are receiving a significant benefit long-term.”
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