Survival Benefit in Multiple Myeloma With Continuous Therapy

Continuous treatment with combined lenalidomide plus low-dose dexamethasone given until disease progression improved progression-free survival and overall survival in patients with multiple myeloma who were ineligible for transplant compared with the alkylator-based standard therapy of melphalan/prednisone/thalidomide (MPT), according to the results of a large phase III analysis published in the New England Journal of Medicine.

“Although additional follow-up is needed to fully assess the survival benefit with continuous lenalidomide/dexamethasone, this trial provides substantial evidence that among patients with newly diagnosed multiple myeloma, those who are elderly or are ineligible for stem-cell transplantation may benefit from continuous therapy,” wrote Lotfi Benboubker, MD, of Hôpital Bretonneau, Centre Hospitalier Régional Universitaire, and colleagues from the FIRST Trial Team.

Lenalidomide is currently FDA-approved in combination with dexamethasone for patients with multiple myeloma who have received at least one prior therapy. However, studies have been lacking in older patients or those patients who are ineligible for transplant.

In the FIRST (Frontline Investigation of Revlimid and Dexamethasone vs Standard Thalidomide) study, Benboubker and colleagues enrolled and randomly assigned 1,623 patients to lenalidomide/dexamethasone in 28-day cycles until disease progression (n = 535), lenalidomide and dexamethasone for 72 cycles (n = 541), or MPT for 72 weeks (n = 547).

The median duration of treatment was 18.4 months for continuous lenalidomide/dexamethasone, 16.6 months for 18 cycles of lenalidomide/dexamethasone, and 15.4 months for MPT. The median duration of follow-up of surviving patients was 37 months.

Treatment with continuous lenalidomide/dexamethasone resulted in significant improvements in progression-free survival compared with MPT (HR for progression or death = 0.72; P < .0001). Continuous treatment also decreased risk for progression or death compared with 18 cycles of lenalidomide/dexamethasone (HR = 0.70; P < .0001). The median progression-free survival was 25.5 months with continuous lenalidomide/dexamethasone, 20.7 months with 18 cycles of lenalidomide/dexamethasone, and 21.2 months with MPT.

An interim analysis of overall survival, showed a 59% survival rate for patients assigned continuous lenalidomide/dexamethasone at 4 years compared with 56% for those assigned 18 cycles of lenalidomide/dexamethasone, and 51% for those assigned MPT.

“Although the difference in overall survival did not cross the prespecified superiority boundary (P < .0096), continuous lenalidomide/dexamethasone reduced the risk of death, as compared with MPT (HR = 0.78; 95% CI, 0.64-0.96; P = .02),” the researchers wrote.

Superiority of continuous lenalidomide/dexamethasone was found in both younger patients and those aged 75 years and older.

Data showed that lenalidomide/dexamethasone was associated with fewer hematologic and neurologic toxic events compared with MPT. In addition, grade 3 or 4 adverse events were reported in 70% of patients on continuous lenalidomide/dexamethasone compared with 78% of those assigned MPT.

In an editorial published with the study, David Avigan, MD, and Jacalyn Rosenblatt, MD, of Beth Israel Deaconess Medical Center, Boston, pointed out that although response rates were higher with both lenalidomide regimens only continuous therapy resulted in improved outcomes. Therefore, “the study suggests that treatment until disease progression is preferable to suspending treatment after achieving a maximal response.”