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    Posted: 09/11/2008
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Bortezomib for Initial Therapy in Multiple Myeloma

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Bortezomib Approved for First-Line Treatment of Multiple Myeloma

Key Words

Multiple myeloma, bortezomib (Velcade®), melphalan, prednisone. (Definitions of many terms related to cancer can be found in the Dictionary.)


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 phase III trial. Bortezomib was approved for use in the U.S. on the basis of these results.


New England Journal of Medicine, August 28, 2008 (see the journal abstract).


Patients with multiple myeloma suffer from an impaired immune system. A type of white blood cell called a plasma cell starts reproducing uncontrollably in the bone marrow. Chemotherapy often succeeds in lowering the number of these myeloma cells, and is the first choice for patients who are not physically able to undergo autologous 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 new agents have shown promising results. One of these is bortezomib (Velcade®), which targets a protein active in some cancers and thereby delays tumor growth while enhancing the cancer-killing effects of radiation and chemotherapy.

Based on 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. Other promising drugs are also being tested for newly diagnosed patients, including dexamethasone, thalidomide and lenalidomide in various combinations. Multiple myeloma remains incurable, but these new treatments developed in the last decade have increased how long patients live.

The Study

In the VISTA trial (Velcade as Initial Standard Therapy in Multiple Myeloma), newly diagnosed, untreated multiple myeloma patients who were not candidates for high-dose therapy plus stem-cell transplantation were randomly assigned to one of two groups: 344 patients received bortezomib, in addition to melphalan and prednisone, while the control group of 338 received melphalan plus prednisone alone. Only 7 percent of patients were younger than 65, while 61 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 six-week cycles of the standard therapy, while the bortezomib group also got intravenous injections. Every three weeks their blood and urine samples were taken to check disease progression, and adverse events were monitored continuously.

The study's lead author is Jesứs F. San Miguel, M.D., Ph.D., from the Hospital Universitario de Salamanca, Spain.


Data were collected until June 2007, when the data safety and monitoring committee stopped the study because the superiority of the bortezomib combination was clear. At that point, 337 patients in the bortezomib group could be evaluated and 47 were still receiving therapy. Overall, the bortezomib group had completed an average of eight cycles of treatment.

In the standard therapy group, 331 could be evaluated at the time the study was stopped, 33 were still receiving therapy, and overall the group had completed an average of 7 cycles.

The bortezomib group’s median time to progression was 24 months, 52 percent better than the 16.6 months for the control group. Responses in the bortezomib group lasted a median of 19.9 months, compared to 13.1 months in the control group.

Twice as many bortezomib patients had a partial response or better. Only 4 percent of control group patients had a complete response, compared to 30 percent of bortezomib patients. After a median follow-up of 16.3 months, 45 patients taking bortezomib had died, compared to 76 in the control group, a 39 percent reduction in risk.

Rates of treatment side effects differed somewhat between the two groups. Nerve problems or pain occurred in 43 bortezomib patients, compared to 16 receiving standard therapy. All grade 3 or 4 gastrointestinal problems were more frequent in the control group. Altogether, 46 percent of bortezomib patients experienced serious adverse events of some sort, compared to 36 percent for 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 results, 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.”

While Durie accepts the clear-cut advantage of the bortezomib combination over standard therapy, he is cautious about interpreting some of the data, especially on complete response. In multiple myeloma patients, complete response is not “a consistent surrogate for overall survival,” he writes, and is also “a fragile end point” because it relies on a subjective laboratory test.


“For 40 years we made very little progress in treating multiple myeloma,” said Ola Landgren, M.D., Ph.D., of the National Cancer Institute’s Division of Cancer Epidemiology and Genetics. “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.

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