Researchers at the Myeloma Institute for Research and Therapy have developed analytical methods and tools for identifying patients whose myeloma cells have characteristics consistent with high risk for early disease-related death. Based on a study of more than 500 newly diagnosed patients treated for multiple myeloma at the Myeloma Institute, our researchers found that measuring the activities of just 17 genes (out of the 25,000 genes in a human cell) revealed whether a patient had this high-risk form of myeloma.* Gene array analysis is now used to examine the expression levels of those 17 genes for each of our patients, providing as a powerful predictor of response to therapy.
Analysis of results from the Total Therapy 3 clinical trial revealed that separating patients according to the molecular signature for low- or high-risk myeloma revealed very different outcomes for the two groups. For patients with low-risk myeloma, survival and duration of complete response were very good, but patients with high-risk myeloma did not fare nearly as well.
These results clearly indicate that no single approach to treatment is appropriate for all patients with myeloma —a personalized approach will lead to better outcomes. This provided the impetus for incorporating molecular risk-based therapy into the next generation of Total Therapy clinical trials. Total Therapy 4 and Total Therapy 5 were the first clinical trials ever to use this state-of-the-art molecular tool for personalized treatment of myeloma.
Total Therapy 4 for Low-Risk Myeloma
Only patients with low-risk myeloma are enrolled in the Total Therapy 4 phase III clinical trial.** For this group of patients, the superior results achieved with Total Therapy 3 are difficult to improve upon. Therefore, the goal of Total Therapy 4 is to minimize the side-effects of treatment while maintaining therapeutic effectiveness. The trial is designed to determine whether this goal can be achieved by modifying the chemotherapy regimens before, during, and after the stem-cell transplants.
Total Therapy 5 for High-Risk Myeloma
A separate phase II clinical trial,** Total Therapy 5, was designed specifically for patients with high-risk myeloma. The overall goal of Total Therapy 5 is to improve survival for this group, which is about 20% of patients. The clinical trial investigates whether sustained effective anti-myeloma therapy can be achieved by:
- using multi-agent combination chemotherapy in more frequent but lower doses; the change in dosing is designed to be well tolerated and to not compromise a patient’s ability to complete the full therapeutic regimen
- applying treatment between transplants in an attempt to prevent high-risk myeloma from regrowing during the intervening time
A similar clinical trial, Total Therapy 6, is also underway for patients who have high-risk myeloma but who have already undergone previous therapy.
*Complete findings are reported in a plenary paper published in Blood (2007 Mar 15;109(6):2276-84;).
**From Clinical Trials.gov, http://clinicaltrials.gov/ct2/info/glossary:
Phase III trials: Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug(s) has been obtained; intended to gather additional information to evaluate overall benefit-risk relationship of the drug(s) and provide an adequate basis for physician labeling.
Phase II trials: Controlled clinical studies conducted to evaluate the effectiveness of the drug(s) for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks.