Related Pages Multiple Myeloma/Other Plasma Cell Neoplasms 1 NCI's gateway for information about multiple myeloma and other plasma cell neoplasms. Search for Clinical Trials 2 NCI's PDQ® registry of cancer clinical trials.

Key Words

Multiple myeloma, bortezomib ³ (Velcade®), melphalan, prednisone. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ⁴.)

Summary

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.

Source

New England Journal of Medicine, August 28, 2008 (see the journal abstract ⁵).

Background

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.

Results

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.

Limitations

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.

Comments

“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.

Glossary Terms

The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete remission.

In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works.

A synthetic steroid (similar to steroid hormones produced naturally in the adrenal gland). Dexamethasone is used to treat leukemia and lymphoma and may be used to treat some of the problems caused by other cancers and their treatment.

Into or within a vein. Intravenous usually refers to a way of giving a drug or other substance through a needle or tube inserted into a vein. Also called I.V.

A drug that is similar to thalidomide, and is used to treat multiple myeloma and certain types of anemia. It is also being studied in the treatment of other types of cancer. Lenalidomide belongs to the family of drugs called angiogenesis inhibitors. Also called CC-5013 and Revlimid.

A statistics term. The middle value in a set of measurements.

A drug that is used to treat multiple myeloma and ovarian epithelial cancer and is being studied in the treatment of other types of cancer. It belongs to the family of drugs called alkylating agents. Also called Alkeran.

A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

A type of white blood cell that produces antibodies.

A drug that is used to treat several types of cancer and other disorders. Prednisone also inhibits the body's immune response. It is a type of steroid.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

In medicine, treatment that experts agree is appropriate, accepted, and widely used. Health care providers are obligated to provide patients with standard therapy. Also called standard of care or best practice.

A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells.

A drug that is used to treat multiple myeloma in patients who have just been diagnosed, and a painful skin disease related to leprosy. It is also being studied in the treatment of other types of cancer. Thalidomide belongs to the family of drugs called angiogenesis inhibitors. Also called Thalomid.

A measure of time after a disease is diagnosed (or treated) until the disease starts to get worse.