October 22, 2009 — The trial showing that low-dose dexamethasone is superior to high-dose dexamethasone when added to lenalinomide (Revlimid, Celgene) for initial therapy of myeloma was published online October 22 in the Lancet Oncology.
This trial was stopped early when overall survival at 1 year was shown to be significantly better with the low-dose dexamethasone regimen; not surprisingly, the lower dose of this steroid was also associated with less toxicity.
When these results were first presented in 2007, principal investigator Vincent Rajkumar, MD, from the Mayo Clinic in Rochester, Minnesota, called for clinical practice to be changed and for low-dose dexamethasone to replace the use of the high-dose dexamethasone, which had been the standard.
This trial shows clearly that more is not better, Dr. Rajkumar noted. The use of the high dose is not supported by trial data; "it was really something that was picked out of a hat and has been used ever since," he explained.
Other experts in the field concurred, as reported by Medscape Oncology at the time. "This is a landmark trial," said Jean-Luc Harousseau, MD, founding member of the Intergroupe Francophone du Myeloma, who was not involved in the study. "We are seeing long-term results with fewer side effects in patients of all ages. These are the best survival data we have seen in newly diagnosed multiple myeloma."
Now, in the paper detailing the results, Dr. Rajkumar and colleagues state that "the results of this trial show that the use of high-dose dexamethasone is not needed for the most part in the context of new active agents for myeloma and, as a result, almost all current phase 3 trials have adopted low-dose dexamethasone as the standard in combination regimens."
In an accompanying editorial, Antonio Palumbo, MD, and Francesca Gay, MD, from the University of Turin in Italy, write that low-dose dexamethasone plus lenalidomide has "thus been established" as initial therapy for myeloma.
"A prolonged gentle treatment approach with low-dose dexamethasone seems an effective and well tolerated front-line regimen, particularly in elderly patients with myeloma," they write.
However, they add that more randomized phase 3 trials are needed to verify whether low-dose dexamethasone plus lenalinomide can become a new standard of care for patients with myeloma. It needs to be establish whether the optimal therapeutic strategy should be long-term treatment with lenalidomide and steroids or short-term treatment followed by consolidation with autologous transplantation.
Better Short-Term Survival, Less Toxicity
The trial involved 445 patients with untreated symptomatic myeloma, all of whom received lenalidomide 25 mg for 21 days. They also received dexamethasone, but were randomized to either a low dose (40 mg on days 1, 8, 15, and 22 of a 28-day cycle) or high dose (40 mg on days 1–4, 9–12, and 17–20 of a 28-day cycle). Treatment continued for 4 cycles, after which patients could continue or choose to pursue stem-cell transplantation.
The primary end point of the trial was response at 4 months, and this was significantly better in the high-dose group — 79% had a complete or partial response, compared with 68.3% of the low-dose group (P = .008).
However, an interim analysis after 1 year showed significantly better overall survival in the low-dose group, with 96% still alive, compared with 87% in the high-dose group (P = .0002).
As a result of this survival difference, the trial was stopped, and patients on the high-dose regimen were crossed over to the low-dose regimen. The data monitoring committee recommended that the data be made public, and Dr. Rajkumar reported the findings in 2007 at the annual meetings of the American Society of Clinical Oncology and the American Society of Hematology.
"The lack of correlation between response and overall survival has been previously reported in myeloma," the researchers note.
Not surprisingly, lower doses of the steroid had less toxicity. During the first 4 months, 1 of the 220 patients in the low-dose group died, compared with 12 of the 222 patients in the high-dose group (P = .003).
Grade 3 or worse toxic effects were reported by 35% of patients in the low-dose group and by 52% of those in the high-dose group (P = .0001). The most common of these were deep vein thrombosis (26% in the low-dose group vs 12% in the high-dose group; P = .0003), infections, including pneumonia (16% vs 9%; P = .04), and fatigue (15% vs 9%; P = .08).
What Happens Next?
The editorial points out that at 3 years, there was no difference in survival between the 2 groups.
However, when patients completed 4 months of the trial, they could opt for 1 of several different treatment options, and each of these was associated with a different survival rate. When the researchers conducted a landmark analysis at 4 months on the 431 patients who were still alive, they found that:
- Patients who stopped treatment at 4 months and underwent stem cell transplantation, as recommended by the trial protocol (n = 90), had a 3-year overall survival rate of 92%;
- Patients who continued on primary therapy beyond 4 months (n = 248) had a 3-year survival rate of 79%;
- Patients who discontinued treatment at 4 months and did not pursue transplantation (n = 93) had a 3-year survival rate of 55%.
"Results of the landmark analysis suggest that short-term treatment cannot be considered an optimal option unless followed by autologous transplantation," the editorialists write. These results emphasize "the importance of transplantation as a therapeutic strategy, even in the era of new agents," they add.
The funding for this study came from the US National Cancer Institute. Dr. Rajkumar has disclosed no relevant financial relationships, but some of his coauthors reported links with Celgene (the manufacturer of lenalidomide) and other companies; full details can be found in the paper. Dr. Palumbo reports receiving honoraria from Celgene, Jansen-Cilag, and Pharmion. Dr. Gay has disclosed no relevant financial relationships.
Lancet Oncol. Published online October 22, 2009.
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