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Summary: The usual drug treatment for multiple myeloma is a combination of melphalan and prednisone. Adding another drug to the mix, however, shows promise for helping older patients, according to 2 recent studies. One found that people older than 65 who got thalidomide (Thalomid) along with melphalan and prednisone lived longer than a matched set of patients who received only the standard therapy. The second study reported better outcomes for older patients who added the drug bortezomib (Velcade) to the melphalan and prednisone combination.

Why it's important: Multiple myeloma is a cancer of bone marrow cells that will be diagnosed in an estimated 16,500 people in 2006. It is generally a fatal disease and in people older than 65, only one-fourth will live longer than 5 years. For younger people, the standard treatment is high-dose chemotherapy followed by stem cell transplant. But older patients are often unable to tolerate this demanding treatment, particularly since many have other medical problems. Thalidomide and bortezomib may provide important treatment alternatives for people in this situation.

"Approximately half of patients with multiple myeloma are elderly and not eligible for transplantation," said Jesus San Miguel, professor of medicine at the University of Salamanca, Spain, and lead researcher on the bortezomib study. "New treatments … are desperately needed."

What's already known: For patients who cannot tolerate stem cell transplant, the standard treatment for multiple myeloma has been a combination of the drugs melphalan and prednisone. These are easy to take and have few side effects. But they are only moderately effective in stopping or shrinking the myeloma. Within a year or two, most patients will see their myeloma begin to grow again. Drugs such as thalidomide, which is given as a pill, and bortezomib, which is given intravenously, have been effective in treating people after they relapse. Because of this, the investigators decided to add the drugs to melphalan and prednisone as the first treatment for older patients who weren't eligible for high-dose chemotherapy.

How these studies were done: In the thalidomide study, Italian researchers treated 331 patients with myeloma who were older than 65. Half received melphalan and prednisone only, while the other half were also given thalidomide. In the bortezomib study, Spanish researchers treated 60 myeloma patients over age 65 with that drug along with melphalan and prednisone. Both studies looked at the toxicities of the drugs along with the benefits, such as shrinkage of the myeloma, how long it took for the myeloma to start growing again, and how long the patients lived. The thalidomide study had a control group, patients who did not get thalidomide, for comparison. The bortezomib study used a less scientifically acceptable approach by comparing their results with those of patients treated in the past with only melphalan and prednisone.

What was found: Both studies found the 3-drug combination to be better than melphalan and prednisone alone. In the thalidomide study, patients who got all 3 drugs had a higher remission rate and slower regrowth of the myeloma. After 3 years, 80% of patients who took thalidomide were still alive, compared to 64% in the group that did not get thalidomide.

Adding bortezomib to melphalan and prednisone likewise led to a higher remission rate and better survival compared to patients in the past who were treated with only melphalan and prednisone. Just how much better this 3-drug combination might be can't be known because there are always problems in comparing patients treated now and those treated in the past. Because of this, a randomized controlled study comparing bortezomib, melphalan, and prednisone with melphalan and prednisone alone (the VISTA study) is now in progress.

Both thalidomide and bortezomib added toxicity to the treatment. People taking thalidomide were more likely to develop blood clots. In fact, once that became clear, all patients receiving the drug were given blood thinners. These patients also had problems with severe constipation, fatigue, nerve damage (peripheral neuropathy), and infections. Patients receiving bortezomib also experienced peripheral neuropathy, and had nausea and diarrhea. Bortezomib also lowered their blood counts.

The bottom line: Both these drugs, when added to melphalan and prednisone, look like they will improve outcomes for older patients with myeloma who are not able to tolerate high-dose chemotherapy and stem cell transplant. The thalidomide study was a "gold standard" randomized trial that had a control group of patients who received the older treatment. That makes its results more scientifically valid than the bortezomib study, and may make it the preferred treatment choice.

If the VISTA trial finds that bortezomib along with melphalan and prednisone is truly superior to melphalan and prednisone alone, then both 3-drug combinations will need to be compared. There is also a third drug, lenalidomide, that has recently been approved for multiple myeloma patients. It works like thalidomide but has fewer side effects. Studies are being done to compare those 2 drugs to see which is better.

All of these clinical trials will likely take several years to complete. People with myeloma should consider entering a clinical trial since the best treatment is still not known.

Citation: "Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomized controlled trial." Published in the March 11, 2006, Lancet (Vol.367, No. 9513: 825-831). First author: Antonio Palumbo, MD, University of Torino, Torino, Italy.

"Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase I/II study." Published online June 13, 2006, in Blood. First author: Maria-Victoria Mateos, Hematology Division, Grupo Español de MM (GEM/PETHEMA), Spain.