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

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.