Less Toxicity With Revlimid/Lower-Dose Dex for Myeloma

ORLANDO—Induction therapy with lenalidomide (Revlimid) and low-dose dexamethasone substantially reduces the risk of adverse events, compared with a high-dose steroid regimen, in patients with newly diagnosed multiple myeloma, S. Vincent Rajkumar, MD, of Mayo Graduate School of Medicine, Rochester, Minnesota, reported at the 48th Annual Meeting of the American Society of Hematology (abstract 799).

Early mortality (within 4 months) and the risk of venous thromboembolism (VTE) were significantly lower in patients who received low-dose dexamethasone plus standard-dose lenalidomide. Additionally, patients who received the low-dose steroid regimen had a significantly lower incidence of grade 3+ nonhematologic toxicity and significantly less grade 4+ toxicity of any type.

"Lenalidomide plus high-dose dexamethasone is associated with greater toxicity, including increased thrombotic events," Dr. Rajkumar said. "The risk of deep-vein thrombosis is high with lenalidomide/dexamethasone, and all patients should receive some form of prophylaxis."

The combination of thalidomide (Thalomid) and dexamethasone, currently the only approved induction therapy in the United States, achieves response rates of 60% to 70% but has substantial toxic effects. Dr. Rajkumar and his colleagues recently reported a 91% overall response rate in a small clinical evaluation of lenalidomide and dexamethasone (Blood 105:4050-4053, 2005). However, grade 3+ toxicity occurred in almost half of the patients. "We wanted to see whether we could improve the efficacy and reduce the toxicity of induction therapy with lenalidomide and dexamethasone," Dr. Rajkumar said.

Investigators in the multicenter clinical study randomized 445 newly diagnosed multiple myeloma patients to oral lenalidomide 25 mg/d plus either high-dose dexamethasone (40 mg on days 1-4, 9-12, and 17-20) or low-dose dexamethasone (40 mg on days 1, 8, 15, and 22). After 4 months, patients who had a major response or stable disease could proceed to transplant or continue treatment with lenalidomide/dexamethasone at the investigator's discretion.

Initially, the protocol recommended thromboprophylaxis with aspirin. After investigators noted a high rate of early VTE, the protocol was amended to mandate aspirin, and prophylactic use of warfarin or low-molecular weight heparin was strongly recommended.

Serious (grade 3+) hematologic adverse events during the first 4 months of treatment were uncommon and occurred in a similar proportion of patients in both treatment groups. However, serious nonhematologic adverse events occurred substantially more often with high-dose dexamethasone; these included infection/pneumonia (16.1% vs 9%, P = .031) and fatigue (11.7% vs 4.1%, P = .004).

Early (≤ 4 months) VTE occurred in 18.4% of patients receiving high-dose dexamethasone vs 6.3% of the low-dose group (P < .001). The overall VTE incidence was 22.4% with high-dose steroids and 6.8% with low-dose steroids. Grade 4+ VTE occurred in 8% of the high-dose group and 3.2% of the low-dose group. Grade 3+ atrial fibrillation/flutter occurred significantly more often (P = .015) with high-dose dexamethasone.

Overall, early serious adverse events occurred in 54.3% of patients who received high-dose dexamethasone vs 39.6% of the low-dose group (P = .002). Early mortality with high-dose dexamethasone was almost 10 times greater (4.9% vs 0.5%, P = .006).