Lenalidomide after stem-cell transplantation for multiple myeloma

Abstract

Background: Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma.

Methods: Between April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to lenalidomide or placebo, which was administered until disease progression. The starting dose of lenalidomide was 10 mg per day (range, 5 to 15).

Results: The study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P<0.001); of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients who received lenalidomide (37%) and 132 of 229 patients who received placebo (58%) had disease progression or had died. The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). A total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) died (P=0.03). More grade 3 or 4 hematologic adverse events and grade 3 nonhematologic adverse events occurred in patients who received lenalidomide (P<0.001 for both comparisons). Second primary cancers occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%).

Conclusions: Lenalidomide maintenance therapy, initiated at day 100 after hematopoietic stem-cell transplantation, was associated with more toxicity and second cancers but a significantly longer time to disease progression and significantly improved overall survival among patients with myeloma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00114101.).

Figure 1. Kaplan–Meier Estimates of Progression-free and Overall Survival

HSCT denotes hematopoietic stem-cell transplantation.

Figure 2. Forest Plot of Time to Progression and Overall Survival

Hazard ratios from subgroup analyses of time to disease progression and overall survival in the randomized population are shown (on a natural-log scale). The radii of the circles are proportional to the inverse of the square of the standard error.

Figure 3. Cumulative Incidence of Second Primary Cancers, Disease Progression, and Death in the Lenalidomide and Placebo Groups after Randomization

The cumulative incidence risk of second primary cancers was greater in the lenalidomide group than in the placebo group (P = 0.0008). The cumulative incidence risks of progressive disease and death were greater in the placebo group (P<0.001 for progression and P = 0.002 for death). All P values are two-sided.