Impact of maintenance therapy on subsequent treatment in patients with newly diagnosed multiple myeloma: use of “progression-free survival 2” as a clinical trial end-point

摘要

Maintenance therapy has generally been shown to improve outcomes in newly diagnosed multiple myeloma (NDMM).~(~(1)~(8)) Increases in progression-free survival (PFS) and overall survival (OS) have been demonstrated in some trials of maintenance therapy,~(~(4)~(6)) but others have reported improved PFS with no corresponding improvement in OS.~(~(1)~(3)) The lack of OS benefit may be due to crossover and insufficient follow-up, as well as the fact that these trials were not powered to detect differences in OS between treatment groups. Theoretically, an experimental treatment may negatively affect OS (despite improving PFS) by increasing long-term toxicity or altering the tumor population or microenvironment to induce drug resistance or evolution of an aggressive clone.~(~(9)~(11)) To account for these possibilities, the European Medicines Agency (EMA) has recently recommended using progression-free survival 2 (PFS2) as a clinical end-point to evaluate the efficacy of maintenance therapy in hematology/oncology trials.~(~(10)) To rule out possible negative effects of treatment on the efficacy of next-line therapy, PFS2 in the experimental arm should be sufficiently superior to that in the control arm.~(~(10)) In this article, we explore the concept of PFS2 and apply it to a trial in NDMM patients to determine whether lenalidomide maintenance therapy influenced the efficacy of subsequent treatment.The design of this multicenter, double-blind, placebo-controlled, phase III MM-015 trial has been published previously.~(~(1)) In brief, 459 transplant-ineligible NDMM patients aged 65 years were randomized (1:1:1) to: melphalan, prednisone, lenalidomide (MPR) followed by lenalidomide maintenance (MPR-R) (nine 4-week cycles); MPR (nine 4-week cycles followed by placebo maintenance therapy); or melphalan and prednisone (MP) (nine 4-week cycles followed by placebo maintenance therapy). Maintenance therapy continued until disease progression or unacceptable toxicity. Patients who progressed could either enroll in an open-label extension phase to receive lenalidomide with or without dexamethasone, or be offered any other second-line therapy during the follow-up phase of the protocol. All patients were followed for survival and subsequent therapy for 5 years from randomization or until death.