Bortezomib Improves Outcomes in Initial Treatment of Myeloma

Zosia Chustecka

August 28, 2008

August 28, 2008 — Bortezomib (Velcade, Millennium Pharmaceuticals) significantly improved outcomes when added to a standard regimen of melphalan plus prednisone for the initial treatment of myeloma in patients who were not candidates for hematopoietic stem-cell transplantation. These results, from a large phase 3 manufacturer-sponsored study, are reported in the August 28 issue of the New England Journal of Medicine, but they have already led to US Food and Drug Administration approval for first-line use of the drug.

These are important results, but they must be considered in the larger context of other emerging treatments and other recent trials in myeloma, Brian G.M. Durie, MD, from the Cedars–Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, in Los Angeles, California, comments in an accompanying editorial. Thalidomide and lenalidomide (Revlimid, Celgene) with various combinations have shown similar results, they point out.

The bortezomib results were first presented at the American Society of Hematology meeting in December 2007, as reported by Medscape Oncology. The study involved 682 patients and was known as the Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone (VISTA) trial. The first author is Jesus San Miguel, MD, PhD, from Hospital Universitario de Salamanca, in Spain.

The addition of bortezomib to the standard therapy of melphalan plus prednisone resulted in significantly better time to progression (24 months vs 16 months; P < .001), the main end point of the trial, and the responses were significantly more complete (30% vs 4%; P < .001). In addition, there was a survival benefit despite crossover from the control group after disease progression. At a median follow-up of 16.3 months, 45 patients in the bortezomib group and 76 in the control group had died (hazard ratio, 0.61; P = .008).

The addition of bortezomib increased adverse effects characterized as grade 3 (reported by 53% vs 44% of patients; P = .02), but not those characterized as grade 4. There was no increase in treatment-related deaths, and the rate of death was low, compared with historic controls, the researchers comment.

"Our findings suggest that bortezomib plus melphalan–prednisone is a valuable front-line treatment for patients with myeloma who are 65 years of age or older and cannot receive more aggressive treatment," Dr. San Miguel and colleagues conclude. "Melphalan and prednisone alone can no longer be considered the standard of care in patients who are 65 years of age older," they add.

Other Combinations Also Appear Promising

Four combination therapies appear to be promising in myeloma, comments Dr. Durie. Although the data all come from different trials, the results obtained with bortezomib and melphalan plus prednisone are similar to those seen previously with lenalidomide plus dexamethasone, with lenalidomide and melphalan–prednisone, and with thalidomide and melphalan–prednisone.

Another particularly exciting combination, comments Dr. Durie, is bortezomib plus lenalidomide and low-dose dexamethasone, which is currently being compared with lenalidomide and low-dose dexamethasone alone in the Southwest Oncology Group Trial.

However, no data are available yet from randomized trials that compare these regimens against one another in a way that can be used to determine the best choice of therapy, Dr. Durie comments.

"We are fortunate to have so many options both in the clinic and in development," Dr. Durie writes. "Our challenge will be to assess each patient on an individual basis and to identify and customize therapy for maximum long-term benefit."

Dr. San Miguel reports receiving consulting and lecture fees from Ortho Biotech, Millennium Pharmaceuticals, Celgene, and Pharmion. Other authors also report ties with several different pharmaceutical companies: 1 of the authors is an employee of Millennium, and 3 are employees of Johnson & Johnson. Dr. Durie reports serving on advisory boards for Millennium Pharmaceutics and Celgene.

N Engl J Med. 2008;359:909-917, 964.

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