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Key Words

Multiple myleloma, high-dose chemotherapy, autologous stem-cell transplantation. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

In this randomized trial, multiple myeloma patients treated with high-dose chemotherapy and radiation therapy (HDT) followed by stem-cell transplantation fared no better than those treated with standard chemotherapy in terms of progression-free survival or overall survival. These findings conflict with earlier trials; further studies are required to clarify the issue.

Source

Journal of Clinical Oncology, published online Jan. 23, 2006; in print February 20, 2006 (see the journal abstract).
(J Clin Oncol. 2006 Jan 23; [Epub ahead of print])

Background

Multiple myeloma is a cancer of the plasma cells, a type of white blood cell. Abnormal plasma cells build up in the bone marrow and form tumors in many bones of the body. These tumors can prevent the bone marrow from making enough healthy blood cells.

The bone marrow is very sensitive to chemotherapy and radiation therapy. Therefore, high doses cannot be given without destroying the bone marrow and its capacity to make new blood cells. Performing a transplant of healthy bone-marrow stem cells after chemotherapy or radiation therapy allows higher doses to be used in treatment. The stem cells can be collected before treatment either from the patient (autologous stem cells) or taken from a donor.

Other clinical trials have indicated that HDT regimens followed by autologous stem-cell transplantation increase response to treatment and extend both progression-free and overall survival compared to standard chemotherapy regimens without a transplant. The trial described here was an attempt to confirm these findings.

The Study

All patients enrolled in this randomized phase III trial (called S9321) first received induction (first-step) therapy consisting of the chemotherapy drugs vincristine and doxorubicin plus the steroid dexamethasone. Researchers then treated every patient with high-dose cyclophosphamide, which stimulates the bone marrow to release stem cells into the blood stream so that researchers can collect the cells for later transplantion back into the patient.

Patients were then randomly assigned to receive one of two treatments: either a standard five-drug regimen or HDT followed by stem-cell transplantation. The HDT regimen included total-body irradiation and the chemotherapy drug melphalan.

Those patients in either group who responded to therapy were then randomly assigned to one of two follow-up plans: either to four years of maintenance therapy with the drug interferon or to observation. The investigators measured response to treatment, progression-free survival, and overall survival for each step of the trial.

The study’s lead author is Bart Barlogie, M.D., Ph.D., from the University of Arkansas for Medical Science in Little Rock.

Results

After induction therapy, 255 patients were randomly assigned to receive standard therapy and 261 to receive HDT plus stem-cell transplantation. Patients’ response in both groups was “virtually identical,” state the authors, and no difference was seen either in progression-free or overall survival. Eight treatment-related deaths occurred in the HDT group, and one in the SDT group.

In addition, no difference in survival was observed between the groups receiving either interferon or observation as follow-up care. Toxicity took its toll in the interferon group. One patient died, and after a median of four months researchers stopped administering the drug because of serious side-effects in 32 percent of the group.

Limitations

The study included total-body irradiation in the high-dose therapy regimen, an approach that was later showed to harm patients without helping them to live longer.

Comments

Why did this study fail to find a survival advantage for HDT plus stem-cell transplantation, in contrast to earlier studies? One reason, say the authors, may be that all patients in their trial received high-dose cyclophosphamide to help with stem-cell collection. The authors suggest that the combination of cyclophosphamide and the five-drug standard chemotherapy regimen used in this trial “may be more effective than the standard regimens used in the other trials.”

“This study re-opens the role of transplantation in the management of multiple myeloma,” stated Michael Bishop, M.D., a physician with the National Cancer Institute’s Experimental Transplantation and Immunology Branch. Future trials will re-evaluate the use of HDT with autologous stem-cell transplantation in the initial treatment of multiple myeloma, he explained, especially as experimental targeted therapies for multiple myeloma, such as thalidomide and bortezomib, move to the forefront of research.

The authors also propose abandoning the use of interferon in the follow-up care of patients with multiple myeloma, due to the drug’s “considerable toxicity and subsequent discontinuation in a high fraction of patients.”

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