ASCO 2009-A BORTEZOMIB SCHEDULE FOR ELEDRLY PATIENTS WITH LESS NEURITIS

June 18, 2009 (Orlando, Florida) — A change in the administration schedule for elderly patients with myeloma significantly reduces the likelihood of serious neuropathy, according to presenters here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting

By reducing the infusion of bortezomib (Velcade) in these patients from twice weekly to once weekly, the risk for grade 3/4 neuropathy dropped to "practically nothing," said S. Vincent Rajkumar, MD, from the Mayo Clinic in Rochester, Minnesota.

Dr. Rajkumar was commenting on the interim results of a new clinical trial comparing 2 different treatment combinations, both of which contained bortezomib, in newly diagnosed elderly myeloma patients who are not candidates for surgery. He was a discussant at a session on myeloma at ASCO during which the study was presented.

The findings about neuropathy are important because of the seriousness of this adverse effects and the expected longevity of many of the patients in this setting, Dr. Rajkumar explained.

I don't want my front-line patients, who are going to live 5 to 7 years, to have a 10% risk of grade 3/4 neuropathy," he said, highlighting the fact that the risk is at least 10% for a twice-weekly schedule of bortezomib, which is standard myeloma therapy.

Grade 3/4 neuropathy is the type that matters most clinically, Dr. Rajkumar reminded the audience.

"We have to be very careful about how we describe neuropathy," he said, noting that there is a vast difference between a grade 1 "tingling sensation" in the extremities and a grade 3 "foot drop" that prevents patients from carrying on with activities of daily living.
"Practice changing" was how Dr. Rajkumar described the news that serious neuropathy diminishes when bortezomib therapy is cut from twice to once weekly in elderly patients. "It will impact clinical practice immediately," he said.

Clinicians do not need to fear that the change in schedule will significantly affect the benefit of bortezomib, said Dr. Rajkumar. "You are probably going to be able deliver the full planned schedule of bortezomib and get the maximum benefit," he said.

Safety Improvement: Major Aim of Study

The study that Dr. Rajkumar highlighted is a multicenter Italian phase 3 clinical trial in elderly (65 years and older) myeloma patients. Evaluating the potential safety improvement of once-weekly bortezomib was 1 of 2 main aims of the study, said lead author Antonio Palumbo, MD, from the University of Turin in Italy.

The other main objective was to compare the efficacy of 2 bortezomib-containing treatment combinations; the combinations were identical, except that 1 had an additional drug, thalidomide.

In the study, patients were randomized to receive either the VMPT combination (bortezomib 1.3 mg/m² on days 1, 8, 15, 22; melphalan 9 mg/m² on days 1 to 4; prednisone 60 mg/m² on days 1 to 4; and thalidomide 50 mg on days 1 to 35) or the VMP combination (bortezomib, melphalan, and prednisone at the same doses and schedules). Patients were treated with nine 5-week cycles.

For this interim analysis of the 5-year study, 177 evaluable patients were randomized to each combination. The complete response rate for the VMPT combination was 35% and for the VMP combination was 21%. The difference was highly significant (P < .0001), said Dr. Palumbo.

However, progression-free survival and overall survival at 3 years were not statistically significantly different, he added.

Progression-free survival was 71% for the VMPT combination and 56% for the VMP combination (P = .13). Overall survival was 90% for the VMPT combination and 89% for the VMP combination (P = .81).

Dr. Palumbo reminded the audience that conclusions about progression-free and overall survival should not be made from the interim 3-year data.

"VMPT is not ready for primetime," said Dr. Rajkumar, observing that the overall survival rates were basically the same and that final results were needed.

Neuropathy and Discontinuation: Twice- vs Once-Weekly Bortezomib

In each group, the majority of patients received bortezomib once weekly, but some received it twice weekly so that questions about safety could be examined.

For patients taking the VMPT combination, the rate of grade 3/4 neuropathy was 18% for the twice-weekly group (n = 71) and 2% for the once-weekly group (n = 150).

For patients taking the VMP combination, the rate of grade 3/4 neuropathy was 14% for the twice-weekly group (n = 64) and 2% for the once-weekly group (n = 165).

"The weekly infusion is dramatically reducing the risk of peripheral neuropathy in elderly patients," summarized Dr. Palumbo.

Patients receiving a once-weekly infusion of bortezomib also had lower rates of discontinuation due to peripheral neuropathy, noted Dr. Palumbo.

For patients taking the VMPT combination, the rate of discontinuation was 10% for the twice-weekly group and 3% for the once-weekly group. For patients taking the VMP combination, the rate of discontinuation was 15% for the twice-weekly group and 4% for the once-weekly group.

Dr. Palumbo is a consultant to and has received honoraria from Celgene and Janssen-Cilag. Dr. Rajkumar has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract 8515. Presented June 1, 2009