Bortezomib Superior to High-Dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

NEW ORLEANS—Bortezomib (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 4:349-360, 2004).

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 JMed 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 dexamethasone.

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.

Study Results

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 on bortezomib).

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).

Adverse Events

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 bortezomib group.