By Will Boggs MD
NEW YORK (Reuters Health) - Lenalidomide maintenance therapy after autologous stem-cell transplantation (ASCT) prolongs the time to remission in patients with multiple myeloma (MM), according to an updated analysis of the CALGB 100104 phase 3 trial.
"Lenalidomide maintenance can be considered a standard of care following ASCT for MM,” Dr. Philip L. McCarthy from Roswell Park Cancer Institute, in Buffalo, New York, told Reuters Health by email.
The first publication from CALGB 100104 showed that lenalidomide maintenance was associated with significantly longer time to disease progression and a significant improvement in overall survival at a median follow-up of 34 months, compared with placebo. And a later meta-analysis that included the study found that lenalidomide maintenance therapy significantly improved overall survival.
In the current report, Dr. McCarthy and colleagues present a post hoc analysis of CALGB 100104, analyzing long-term follow-up data regarding time to progression, overall survival, and incidence of second primary malignancies.
The original study was unblinded at a median follow-up of 18 months after three interim analyses, at which point 67% of patients originally assigned to placebo chose to cross over to the lenalidomide group.
During the median follow-up of 91 months for the updated survival analysis, the median time to disease progression was 57.3 months for the lenalidomide group, significantly more than the 28.9 months for the placebo group. The median overall survival was 113.8 months for the lenalidomide group and 84.1 months for the placebo group (P=0.0004).
Overall survival at five years was 76% for lenalidomide recipients and 64% for placebo recipients, the researchers report in The Lancet Haematology, online August 17.
The hazard ratios for time to progression and overall survival were similar for the original lenalidomide group and for the lenalidomide group that included placebo recipients who had crossed over to lenalidomide within six or 12 months after randomization.
Lenalidomide maintenance benefited overall survival whether or not patients had received previous lenalidomide induction.
Adverse events were more common with lenalidomide than with placebo, and almost all hematological adverse events in the placebo group occurred in patients who had crossed over to receive lenalidomide.
Among the 231 lenalidomide patients, there were 18 hematological, 14 solid-tumor and 11 noninvasive second primary malignancies, compared to three hematological, nine solid-tumor and six noninvasive second primary malignancies among the 229 placebo patients. Most of the second malignancies in the placebo group were in the subgroup that crossed over to lenalidomide maintenance.
The cumulative incidence risk (CIR) of progressive disease or death was 43% lower with lenalidomide than with placebo (P<0.0001), whereas the CIR of second primary malignancy was 2.34-fold higher (P=0.0073).
These translated into a lower CIR of death from myeloma but a higher CIR of death from a second primary malignancy in the lenalidomide group.
These findings "reinforce the continued value of lenalidomide maintenance after ASCT," Dr. McCarthy said. "This study continued lenalidomide until progressive disease and not for a fixed time. Patients received benefit from lenalidomide maintenance whether in complete remission or not."
“We need to better understand the risk of developing a second primary cancer/malignancy (SPM),” Dr. McCarthy said. “The risk of a SPM is less than the risk of dying from MM; however, it is important to understand the risk and predict who is at risk for a SPM.”
“Despite this sound analysis (large number of patients, almost 10-year follow-up) and the positive patient outcomes, several uncertainties remain regarding maintenance treatment,” writes Dr. Mario Boccadoro from the University of Turin, Italy, in a related editorial. “First, we need to define which patient subgroup might actually benefit from maintenance therapy.”
“Second, the optimum duration of maintenance treatment to maximize effectiveness and reduce toxic effects is unknown,” he adds.
Dr. Aya Nakaya from Kansai Medical University in Hirakata, Japan, who recently described a lenalidomide dose-adjustment strategy for elderly patients with multiple myeloma, told Reuters Health by email, "Maintenance therapy after transplant has already been established, but there had been no positive phase 3 study of lenalidomide maintenance.”
"This study establishes the proof of effectiveness," said Dr. Nakaya, who was not involved in the research.
SOURCE: http://bit.ly/2euIu8y and http://bit.ly/2euT7YV
Lancet Haematol 2017.
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