New results from the large phase III Myeloma XI trial confirm that maintenance therapy with lenalidomide improves progressionfree survival (PFS) over observation alone in patients with newly diagnosed multiple myeloma (MM). However, in the intentionto-treat analysis, lenalidomide maintenance was not associated with improvement in overall survival (OS), according to findings published in Lancet Oncology.
“These data are from the largest study ever conducted on maintenance therapy in MM,” lead study investigator Graham H. Jackson, MD, of Newcastle University in the U.K., told ASH Clinical News. “The outcomes mirror previously published meta-analysis data, confirming that, in a transplant-eligible population of patients with MM, lenalidomide maintenance prolongs the PFS by more than three years.”
The Myeloma XI trial enrolled 4,420 patients with newly diagnosed symptomatic MM or non-secretory MM from more than 100 centers. The study had three potential randomization arms: induction treatment (allocation by transplantationeligibility status), intensification treatment (allocation by response to induction therapy), and maintenance treatment.
A total of 1,971 patients were assigned to receive maintenance therapy with either lenalidomide (10 mg on days 1-21 of a 28-day cycle; n=1,137) or observation (n=834). All patients had completed their assigned induction therapy per study protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide.
After a median follow-up of 31 months (interquartile range = 18-50 months), median PFS (co-primary endpoint) from the time to randomization was 39 months (range = 36-42 months) in the lenalidomide group and 20 months in the observationalone group. This translated to a significantly lower risk of disease progression or death in the lenalidomide group (hazard ratio [HR] = 0.46; 95% CI 0.41-0.53; p<0.0001).
However, there was no significant difference in the other co-primary endpoint of three-year OS: 78.6 percent in the lenalidomide group and 75.8 percent in the observation group (HR=0.87; 95% CI 0.73-1.05; p=0.15).
In subgroup analysis of transplant-eligible patients, however, lenalidomide was associated with improved OS (3-year OS: 87.5%vs. 80.2%; HR=0.69 [95% CI 0.52-0.93]; p=0.014). OS differences also were noted for patients with higher-risk cytogenetic profiles:
- standard risk: 86.4% vs. 81.3%
- high risk: 74.9% vs. 63.7%
- ultra-high risk: 62.9% vs. 43.5% (p values not reported)
Lenalidomide maintenance also was associated with an acceptable toxicity profile, the authors commented, although a greater proportion of patients receiving lenalidomide experienced serious adverse events (AEs) compared with patients on observation (45% vs. 17%; p value not reported). In patients who received lenalidomide during the study, the most common grade 3 or 4 AEs included:
- neutropenia (33%)
- thrombocytopenia (7%)
- anemia (4%)
Infections represented the most common serious AEs in both groups. More deaths occurred in the observation group (27%) versus the lenalidomide group (21%), yet the deaths that occurred in the lenalidomide group were not deemed attributable to the maintenance therapy.
Taken together, “the manageable safety profile of this drug and the encouraging results in subgroup analyses of patients [including those eligible for transplant and with high-risk cytogenetics], support further investigation of maintenance lenalidomide in this setting,” the authors concluded.
“The main area of continued argument in the field of myeloma is whether patients with high-risk cytogenetics benefit from lenalidomide maintenance,” Dr. Jackson said. “These data suggest that patients with high-risk cytogenetics do indeed benefit from lenalidomide maintenance.”
He also noted the differences in survival according to age. “In older, transplant-ineligible patients, the data demonstrate an impact on PFS and time to second disease progression, but they do not demonstrate an OS advantage for patients who are maintained on lenalidomide after induction therapy.”
The lack of powered subgroup analyses, missing cytogenetic data for some patients, and the lack of prospectively collected data on quality of life represent potential limitations of this study, the researchers concluded.
The authors report relationships with Celgene, the manufacturer of lenalidomide.
Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:57-73.