Study spells end for high-dose dex in first-line myeloma pts

ATLANTA—In newly diagnosed multiple myeloma patients, lenalidomide (Revlimid) plus low-dose dexamethasone led to superior overall survival, compared with the standard regimen of lenalidomide plus high-dose dexamethasone. Vincent Rajkumar, MD, of the Mayo Clinic, reported the 2-year results of the phase III ECOG trial at ASH 2007 (abstract 74).

A total of 445 patients were randomized to receive either four cycles of lenalidomide 25 mg/d orally on days 1-21 every 28 days plus standard high-dose (HD) dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 (480 mg total) every 28 days, or the same dose of lenalidomide plus low-dose (LD) dexamethasone 40 mg on days 1, 8, 15, and 22 (160 mg total) every 28 days. The median follow-up time was 21 months.

The best overall response rate within four cycles was 82% for the HD arm vs 71% for the LD arm. The rates of complete response/very good partial response were 52% and 42%, respectively. Median duration of response has not yet been achieved in either arm at this time point.

At 2 years, overall survival was significantly superior in the LD arm (87% vs 75% for the HD arm , P = .009). These values compare to the 1-year survival rates of 96% and 88%, respectively, that were reported at ASCO 2007 (LBA-8025).

For patients who continued on treatment past 6 months, 1-year overall survival was 99% for LD and 97% for HD.

The survival advantage was independent of age, although in patients less than 65 years, the 2-year survival advantage with LD was not as large (91% vs 85% for HD).

Major nonhematologic toxicities of grade 3 or higher were significantly lower in the LD arm, compared with HD, including deep vein thrombosis/pulmonary embolism (9% vs 25%, P < .001) and non-neuropathic weakness (4% vs 10%, P = .008). Neutropenia (grade 3 or higher) was greater on the LD arm (19% vs 12%), but the rate of infections was lower with the LD treatment (7% vs 14%, P = .03).

Notably, the mortality rate within the first 4 months was substantially lower on the LD arm (0.5% vs 5%; P = .01). The increased death rate in the HD arm was due to disease progression as well as increased toxicity associated with the higher dexamethasone dose.

Dr. Rajkumar concluded that while both regimens are highly active as induction therapy in newly diagnosed myeloma, the LD regimen is associated with superior overall survival and improved safety, compared with HD. Time to progression and progression-free survival were not statistically inferior with LD.

"This study has major implications for the continued use of high-dose dexamethasone in multiple myeloma, including regimens that use high-dose dexamethasone combinations with other chemotherapeutic drugs," he said.

Adding bortezomib

Paul Richardson, MD, of the Dana-Farber Cancer Institute, noted that the significant survival difference in favor of the lower-dose dexamethasone-containing arm "likely reflects not only excess toxicity with high-dose dexamethasone but also a loss of disease control, because of the need to dose reduce both lenalidomide and dexamethasone for patients on the higher-dose arm."

Based on these results and other data showing high response rates using bortezomib (Velcade), he suggested that lenalidomide, bortezomib, and low-dose dexamethasone combined could be a very exciting regimen for further study.

Preliminary data presented by Dr. Richardson's group at ASH (abstract 187) support the significant activity of this regimen, with a response rate of 98% observed in the front-line setting, together with a high rate of complete response and manageable side effects, with no significant peripheral neuropathy and a low rate of deep vein thrombosis reported.