Bortezomib Improves Survival of Newly Diagnosed Patients with Multiple Myeloma
The targeted drug bortezomib, when added to standard therapy (melphalan and prednisone), significantly improves time to progression and overall survival in patients with newly diagnosed multiple myeloma, according to the results of VISTA, an international randomized phase III trial. Bortezomib was approved for use in the U.S. on the basis of the initial results from this trial.
New England Journal of Medicine, August 28, 2008 (see the journal abstract). Updated results subsequently published online April 19, 2010, in the Journal of Clinical Oncology (see the journal abstract).
Multiple myeloma arises when abnormal plasma cells (a type of white blood cell) reproduce uncontrollably in the bone marrow. Although the disease is rarely curable, it is highly treatable. Chemotherapy often succeeds in lowering the number of myeloma cells and is the first choice for patients who are not physically able to undergo stem cell transplantation. That population includes most patients over 65, who are the most likely to be diagnosed with the disease.
The standard chemotherapy treatment for several years has been melphalan plus prednisone, but several other agents have shown promising results. These include dexamethasone, thalidomide, and lenalidomide in various combinations. Another promising new agent is bortezomib (Velcade®), a targeted therapy that interferes with the action of a large cellular structure, the proteasome, that controls protein degradation.
Based on initial results from the trial described here, the U.S. Food and Drug Administration (FDA) approved bortezomib for the initial treatment of multiple myeloma on June 20, 2008.
The StudyIn the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial, newly diagnosed patients with multiple myeloma who had not yet been treated and were not candidates for stem cell transplantation were randomly assigned to receive bortezomib in addition to melphalan and prednisone (344 patients) or or melphalan plus prednisone alone (338 patients). The median age of participants was 71, and 30 percent were older than 74.
The patients, recruited from 151 centers in 22 countries in Europe, Asia, and North and South America between December 2004 and September 2006, knew which drug combination they were receiving. All patients were scheduled to receive nine 6-week cycles of the standard therapy, and the patients in the bortezomib group also got intravenous injections of bortezomib. Blood and urine samples were taken from the patients every three weeks during treatment to check for disease progression, and adverse events were monitored continuously. After treatment, patients were seen for follow-up evaluation at least every 12 weeks.
The study's lead author is Jesús F. San Miguel, M.D., Ph.D., from the Hospital Universitario de Salamanca, Spain.
In June 2007, the data safety and monitoring committee stopped the study because the superiority of the bortezomib combination had become clear. After that date, the researchers did not collect additional data on response rates, time to disease progression, and survival without progression of disease. However, overall survival, use of subsequent therapies, and responses to subsequent therapies were tracked through March 2009.
Patients who received bortezomib had a 35 percent reduction in the risk of death at any time. At three years after treatment, overall survival was 68.5 percent for the bortezomib group compared to 54 percent for patients who received mephalan and prednisone alone.
The majority of patients in both groups eventually received additional treatment. The time until the next treatment was needed was longer for patients who received bortezomib—a median of 28.1 months, compared with 19.2 months for patients who received mephalan and prednisone alone as their initial treatment.
Importantly, initial treatment with bortezomib did not cause the disease to be more resistant to additional therapies upon recurrence. Response rates to the drugs thalidomide and lenalidomide given after disease recurrence were similar between the two groups. Patients who received bortezomib as part of their initial treatment lived longer overall than patients who received it upon relapse.
Rates of treatment side effects differed between the two groups. Serious (grade 3 or 4) nerve problems or pain occurred in 13 percent of patients in the bortezomib group and none of the patients in the standard therapy group. However, most of these nerve problems improved or resolved completely within a few months. Altogether, 53 percent of bortezomib patients experienced a serious adverse events of some sort, compared to 44 percent of those receiving standard therapy.
Recent trials have also demonstrated comparable results with lenalidomide plus low-dose dexamethasone, and either thalidomide or lenalidomide plus the standard melphalan¬prednisone therapy. In an editorial accompanying the publication of the initial results from the trial, Brian Durie, M.D., of the Samuel Oschin Comprehensive Cancer Institute in Los Angeles, wrote that "all four [of these] combination therapies appear promising, but no data are available from randomized trials that compare these regimens against one another in a way that can be used to determine the best choice of therapy."
“For 40 years we made very little progress in treating multiple myeloma,” said Ola Landgren, M.D., Ph.D., of the Medical Oncology Branch in the National Cancer Institute’s Center for Cancer Research. “So it is heartening to see the emerging advances made in the past years. Clearly, there is more we can do for our patients,” he said, including the use of bortezomib added to standard therapy as shown in this trial.
In the general population, the average age of onset for persons affected with multiple myeloma is around 70 years. Thus, many multiple myeloma patients are older, he explained, and typically do not tolerate the rigors of a stem-cell transplant.
“For them - and their numbers are growing as the population lives longer - the growing menu of novel therapeutic agents presents exciting choices for the future,” said Landgren, and many of these drugs appear to have better adverse event profiles. Though not a cure at this time, he cautioned, this is a very promising research trajectory in a disease where people were previously unlikely to live much more than three to four years on average.