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The first results from a multicenter phase III trial by the Eastern Cooperative Oncology Group (ECOG 4A03) indicate low-dose dexamethasone combined with lenalidomide confers a survival benefit over the higher, standard dose of dexamethasone in newly diagnosed multiple myeloma patients.
The potential impact of these findings led the Data and Safety Monitoring Committee to recommend early release of the findings. "The high [96%] 1-year survival rate of low-dose dexamethasone and lenalidomide is striking." said Dr. S. Vincent Rajkumar a professor of medicine at the Mayo Clinic, Rochester, Minn., where the regimen is now front-line therapy in transplant candidates.
ECOG 4A03 included 445 patients with untreated symptomatic multiple myeloma. All patients received 25 mg of lenalidomide (Revlimid) orally per day on days 1-21 of a 28-day cycle. In addition, 223 patients also received 40 mg of high-dose dexamethasone on days 1-4, 9-12, and 17-20. The remaining 222 patients received 40 mg of low-dose dexamethasone on days 1, 8, 15, and 22.
The first interim analysis included all patients. After 15 months of follow-up, 1-year overall survival was 96% in the low-dose dexamethasone arm, compared with 87% in the high-dose dexamethasone arm (P < .0001). Overall survival differences in favor of the low-dose arm were seen in patients under the age of 65—98% versus 91% (P = .01)—and in those aged 65 and older—94% versus 83%, respectively (P = .004). Survival was already superior with the low dose at 4 months, and remained in excess of 90% even at 2 years.
The final efficacy data, including the other outcome measures, are expected to be announced at the American Society of Hematology meeting in December.
The low-dose arm was also less toxic. Major grade 3 or higher nonhematologic toxicities, included thromboembolism (24% in the high-dose vs. 9% in the low-dose dexamethasone arm), infection/pneumonia (15% vs. 5%), and hyperglycemia (10% vs. 6%). In terms of major hematologic toxicities, only neutropenia was higher with the low-dose treatment (19% vs. 10%).
Dr. Rajkumar said that he believes the survival benefit is a consequence of improved safety and "possibly improved efficacy," and should be consistent over time. "We don't expect the survival curves to change. I think this is definite," he added in an interview.
In addition, he said the findings have implications for other regimens. He advises not only switching to lower doses of dexamethasone in combination with lenalidomide, but also considering the termination of the routine use of high-dose dexamethasone in general.
Discussant Dr. Paul Richardson of Harvard University, Boston, applauded ECOG for performing this research in "what will be a landmark study." Dr. Richardson, clinical director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute in Boston, said, "The estimated 1-year survival of 96% is remarkable, and I would argue this is potentially a new standard for upfront therapy."
Rajkumar S.V. et al. Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group. Abstract LBA8025.
Commentary |
The findings from ECOG 4A03 may change our frontline treatment of multiple myeloma patients. The estimated 1-year survival of 96% with low-dose dexamethasone is fairly remarkable, especially considering that we are using a much less toxic regimen to achieve survival rates that are better than those we have seen in a number of phase III studies of higher doses. It is particularly encouraging that patients over the age of 65 enjoy the same benefit as younger patients. One-year survival in this age group was still robust at 95%, a 12% improvement over the high-dose regimen. There are, however, a few caveats to these exciting results. We need longer follow-up, and we need to know the response rates in order to fully analyze the results critically. In addition, the morbidity associated with high-dose dexamethasone appeared to be greater than that witnessed in individual institutions with significant experience treating multiple myeloma. There may be select patients who continue to benefit from high doses of dexamethasone. We should also realize that thromboembolism remains a concern. While rates with the low dose were significantly lower than with the higher dose, the low-dose rates were still 9%. The optimal approach to deep vein thrombosis prophylaxis needs to be determined. That being said, ECOG provided convincing data that low-dose dexamethasone may be a reasonable alternative to the previously used high-dose regimens. — Steven T. Rosen, M.D.
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