American Society of Hematology
Dexamethasone and Lenalidomide (Revlimid) Effects in Multiple Myeloma
Presenter: S. Vincent Rajkumar, MD, Professor of Medicine, Mayo Graduate School of Medicine, Rochester, Minnesota
In patients with newly diagnosed multiple myeloma (MM) who received combination induction therapy with lenalido-mide (Revlimid, Celgene) and dexamethasone, a lower dose of was found to reduce the risk of adverse drug events (ADEs).
Dr. Rajkumar and colleagues recently reported a 91% overall response rate in a small clinical evaluation of lenalidomide and dexamethasone. However, grade 3 or greater (grade 3+) toxicity occurred in almost 50% of the patients.
In an effort to assess the effects on toxicity of a lower dexamethasone dose, the investigators randomly assigned 445 patients with newly diagnosed MM to receive one of these two regimens:
- oral lenalidomide 25 mg/day plus either high-dose dexamethasone (40 mg on days one to four, nine to 12, and 17 to 20)
- low-dose dexamethasone (40 mg on days one, eight, 15, and 22).
Serious hematological ADEs of grade 3+ were uncommon during the first four months of treatment. These ADEs occurred in a similar proportion of patients in both treatment groups. However, serious non-hematological ADEs occurred much more often with high-dose dexamethasone, including infection and pneumonia (in 16.1% of patients vs. 9%; P = 0.031) and fatigue (in 11.7% of patients vs. 4.1%; P = 0.004).
After the investigators noted a high rate of early venous thromboembolism (VTE), the protocol was amended to mandate aspirin, and they also strongly recommended the prophylactic use of warfarin (Coumadin, Bristol-Myers Squibb) or low-molecular-weight heparin.
VTE occurred early (at four months or less) in 18.4% of patients receiving high-dose , in contrast to 6.3% of patients receiving the low dose (P < 0.001). The overall incidence of VTE was 22.4% with high-dose steroids and 6.8% with low-dose steroids.
Grade 4+ VTE occurred in 8% of patients in the high-dose dexamethasone group and in 3.2% of those in the low-dose group. Grade 3+ atrial fibrillation with flutter occurred significantly more often (P= 0.015) with the high dose.
Overall, early serious ADEs affected 54.3% of patients who received high-dose dexamethasone versus 39.6% of patients receiving the low dose (P = 0.002). Early mortality was almost 10 times greater with high-dose dexamethasone (in 4.9%), compared with the low-dose formulation (in 0.5%) (P= 0.006).
In conclusion, lenalidomide plus high-dose dexamethasone was associated with greater toxicity, including an increased number of thrombotic events.