Lenalidomide maintenance compared to observation in patients with newly diagnosed multiple myeloma: sub-group results from the Myeloma XI trial

The substrates targeted for E3 ubiquitin ligase proteasomal degradation by lenalidomide can result in a wide array of downstream effects, including a direct tumoricidal effect on myeloma cells and the activation of an immunomodulatory effect.¹ Lenalidomide maintenance therapy has previously been shown to improve outcomes in high-risk multiple myeloma (MM) patients through the control of residual disease clones.²

Lenalidomide has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a maintenance therapy in MM patients. Results from the randomization to maintenance treatment in the adaptive design trial with three randomization stages, open-label, randomized Myeloma XI trial (NCT01554852) for patients with MM were reported in Lancet Oncology.³ The primary endpoints were progression-free survival (PFS) and overall survival (OS), with a data cut-off of October 23, 2017.

In this study, 1,971 patients in the intention-to-treat population were randomly assigned to maintenance treatment with patients assigned to the lenalidomide group (n = 1,137) or the observation group (n = 834). In the safety population, 1,931 patients received their allocated intervention (1,097/1,137 received lenalidomide; 834/834 received observation). For maintenance therapy, 100 days after autologous stem-cell transplantation or once a maximum response was achieved for transplantation-ineligible patients from induction, patients received lenalidomide 25 mg per day (orally on days 1–21 of each 28–day cycle) or were observed without lenalidomide therapy.

Key findings

All data shown is stated as lenalidomide group vs observation group

Efficacy

• Median follow-up after randomization: 31 months (IQR, 18–50)
• Patients who had disease progression or died during study duration: 40% (456/1,137) vs 64% (533/834)
  • Patients who died during study duration: 21% (234/1137) vs 27% (226/834)
• Median PFS: 39 months (95% CI, 36–42) vs 20 months (95% CI, 18–22), HR = 0.46 (95% CI, 0.41–0.53), P < 0.0001
• Median OS: not reached (NR) (95% CI, 66–NR) vs NR (95% CI, 61–NR), HR = 0.87 (95% CI, 0.73–1.05), P = 0.15
  • Five-year OS: 61.3% (95% CI, 56.6–66.1) vs6% (95% CI, 51.5–61.7)
• Median PFS in transplantation-eligible patients: 57 months (95% CI, 50–NR) vs 30 months (95% CI, 25–32), HR = 0.48 (95% CI, 0.40–0.58), P < 0.0001
• Median PFS in transplantation-ineligible patients: 26 months (95% CI, 22–31) vs 11 months (95% CI, 5–23), HR = 0.44 (95% CI, 0.37–0.53), P < 0.0001

Safety

• Median duration of lenalidomide maintenance therapy was 18 cycles (IQR, 6–30)
  • Dose modifications applied to 69% (781/1,137) patients allocated to lenalidomide maintenance
• The most common serious adverse events (AEs) in both groups were infections
  • Four-hundred and sixty deaths occurred during maintenance treatment: 21% (234/460) vs 27% (226/460), no deaths were reported as treatment-related in the lenalidomide group

In conclusion, Professor Graham Jackson and colleagues concluded that lenalidomide maintenance significantly improved PFS compared with observation in adult patients with newly diagnosed MM. Moreover, a significant improvement in OS was seen in transplantation-eligible patients but not transplantation-ineligible patients treated with lenalidomide maintenance compared with those assigned to observation.