Low-Dose Dexamethasone Better Than High Dose With Lenalidomide in Multiple Myeloma

Zosia Chustecka

July 26, 2007

July 26, 2007 -- Low-dose dexamethasone combined with lenalidomide ( Revlimid, Celgene) gave results superior to those seen with the standard high dose currently used in multiple myeloma in a phase 3 trial reported at the recent American Society for Clinical Oncology 43rd Annual Meeting, in Chicago, Illinois.

These results may lead to a change in clinical practice, commented Nikhil Munshi, MD, from the Dana-Farber Cancer Institute, in Boston, Massachusetts, speaking at a "highlights-of-the-day" session during the meeting. The trial was stopped early because of the clear difference between 2 doses, he noted: the low-dose-dexamethasone/lenalidomide group had significantly superior survival and lower toxicity than the high-dose dexamethasone group.

The results from the study were presented in a late-breaking abstract session by S Vincent Rajkumar, MD, from the Mayo Clinic in Rochester, Minnesota. "This study has major implications for future use of high-dose dexamethasone in the treatment of multiple myeloma," he said at the meeting. In an interview with Medscape, Dr. Rajkumar said the trial showed clearly that "more is not better." He explained that the high-dose dexamethasone regimen is not supported by trial data; it was "really something that was picked out of a hat and has been used ever since," he commented, "but we have shown that patients pay a price for the high dose in terms of side effects, and there is no proof that they will live longer."

Dexamethasone should now be used at the low dose in all newly diagnosed multiple myeloma patients, Dr. Rajkumar commented. That the low dose is preferable in combination with lenalidomide is the conclusion from the phase 3 trial, he commented, but he said that he would extrapolate further to other combinations, adding that, in his opinion, low-dose dexamethasone should also be used instead of the high-dose regimen with all other drugs in this patient population. He would even go further and suggest that it should be used in relapsed multiple myeloma, even though this is a different set of patients, adding that "you can always start with the low dose and then escalate if necessary."

Better Results With Lower Dose

The trial was conducted in patients with untreated symptomatic multiple myeloma; 445 patients were accrued, with a median age of 65 years. All patients received lenalidomide 25 mg/day on days 1 through 21 for 28 days and were randomized to also receive dexamethasone, either at the standard high dose of 40 mg on days 1 through 4, 9 through 12, and 17 through 20 every 28 days or at the low dose of 40 mg given on days 1, 8, 15, and 22 every 28 days.

At the first interim analysis, overall survival was significantly superior in the low-dose group: 1-year survival was 96.5%, vs 86% in the high-dose group ( P < .001). The difference in overall survival was seen both in patients younger than 65 years (1-year rate was 98% with low-dose vs 90% with high dose; P = .015) as well as in patients who were 65 years or older (1-year rate 95% vs 83%; P = .004).

In addition, patients in the low-dose group experienced less toxicity. Major grade 3 or higher toxicities included thromboembolism (22.1% with the high dose vs 6.1% in the low dose), infection/pneumonia (15.7% vs 7.5%), and hyperglycemia (9.7% vs 6.6%). Grade 3 or higher nonhematologic toxicities were seen in 65% of the high-dose group vs 54.9% in the low-dose group, and corresponding grade 4 or higher rates were 20.3% vs 13.1%, respectively.

After the interim analysis, the trial data monitoring committee recommended releasing the survival data and switching all patients to low-dose dexamethasone, Dr. Rajkumar told the meeting.

In the interview, Dr. Rajkumar said that at the Mayo Clinic, the combination of low-dose dexamethasone with lenalidomide is the preferred first-line treatment for newly diagnosed multiple myeloma patients who are candidates for stem-cell transplants. For patients who are not candidates for transplants, the preferred first-line treatment is melphalan ( Alkeran , Celgene) with prednisone and thalidomide. A detailed discussion of the data supporting these decisions, with a treatment algorithm, can be found in a recent paper by Dr. Rajkumar and colleagues in the Mayo Clinic Proceedings (Dispenzieri A et al. Mayo Clin Proc. 2007;82:323-341). Dr. Rajkumar is also the author of a recent review of chemotherapy in multiple myeloma on UptoDate.

American Society for Clinical Oncology in Chicago 43rd Annual Meeting. Late-breaking abstract LBA8025. Presented June 3, 2007.

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