NEW ORLEANSBortezomib (Velcade), a first-in-class
proteasome inhibitor, provides significant benefit when used as a single agent
in the treatment of relapsed or refractory multiple myeloma. This was the
principal finding of an interim analysis of the phase III APEX trial comparing
bortezomib with high-dose dexamethasone, one of the standard therapies used in
treating this disease. Paul Richardson, MD, of the Dana-Farber Cancer
Institute, presented the data at the American Society of Clinical Oncology 40th
Annual Meeting (abstract 6511).
The clinical application of bortezomib follows more than a
decade of preclinical investigations showing that a variety of cancer cell
types are more sensitive than normal cells to inhibition of the proteasome, the
organelle responsible for the physiological degradation and recycling of
cellular proteins. In the specific case of multiple myeloma, it is believed
that bortezomib inhibits a variety of cellular processes, including growth,
survival, and adhesion, while promoting apoptosis (Nat Rev Cancer
Following favorable phase I results (J Clin Oncol
20:4420-4427, 2002) and the pivotal phase II SUMMIT trial showing survival
benefit and an overall 35% response rate in patients with relapsed and
refractory disease (N Engl J Med 348:2609-2617, 2003), bortezomib
was FDA approved for multiple myeloma patients whose disease progressed after
at least two prior therapies.
The confirmatory APEX trial was an international,
multicenter, open-label phase III study that extended the earlier work to less
intensively treated patients, including those who suffer from relapsed or
refractory disease after one to three lines of prior therapy.
The investigators randomized 669 patients to eight 3-week
cycles of intravenous bortezomib (327 patients) or four 5-week cycles of 40 mg
oral dexamethasone (330 patients); both arms also included subsequent
maintenance cycles, for a total treatment duration of approximately 9 months. A
companion crossover study provided bortezomib to patients who progressed on
The primary endpoint of the study was time to disease
progression. Secondary endpoints included survival, response rate, response
duration, time to skeletal events, incidence of grade 3 or higher infection,
and overall safety.
Dr. Richardson reported that at the interim analysis, the
principal endpoint, time to disease progression, was 5.7 months for bortezomib,
and 3.6 months for dexamethasone, an improvement of 58% (P < .0001).
This difference was sufficient to prompt the independent monitoring committee
to order a halt to the trial, 1 year early, he said, so that all patients on
the dexamethasone arm could be offered bortezomib.
At the time of the interim analysis, 110 patients on
dexamethasone had discontinued the drug due to progressive disease vs only 61
on bortezomib; there was no significant difference between the number of
patients discontinuing prior to disease progression (59 on dexamethasone vs 65
Overall survival at the time of interim analysis and prior
to crossover was longer with bortezomib, with 13 deaths (2 possibly drug
related) in the bortezomib group vs 24 (9 possibly drug related) in the
dexamethasone arm (P = .038).
Overall safety was essentially balanced between the study
arms, Dr. Richardson said, with grade 3 or higher adverse events occurring in
66% of patients in the bortezomib group vs 56% in the dexamethasone group.
Grade 4 events occurred in only 11% and 13%, respectively.
With respect to the two specific safety categories
considered to be of particular interest, there were very few skeletal events
and, consequently, no discernible treatment differences in their time of onset.
As to the incidence of grade 3 or higher infections, the data tended to favor
bortezomib, although the difference did not reach statistical significance
(6.7% vs 10.6%; P = .096).
Bortezomib as expected was associated with a higher
incidence of grade 3-4 gastrointestinal, hematologic, and nervous system
adverse events, compared with dexamethasone, while the latter was associated
with more psychiatric, infectious, and metabolic events, Dr. Richardson said.
Each of the bortezomib 21-day treatment cycles resulted in
an initial depression of the mean platelet count, Dr. Richardson said, but this
effect was completely reversible during the same cycle, and there were no
differences in the number of bleeding events between the two treatment arms.
In the final data analysis, he said, survival statistics will include those
patients who crossed over to bortezomib from dexamethasone. He cited
encouraging preliminary data including these patients (median follow-up, 8
months) showing significantly improved overall survival at 1 year in the