Lenalidomide maintenance therapy for newly diagnosed MM patients

In September 2014 the results from a double-blind, multi-center, phase 3 trial (MM-015), comparing melphalan–prednisone–lenalidomide induction therapy, followed by lenalidomide maintenance therapy (MPR-R), with melphalan–prednisone–lenalidomide (MPR) or melphalan–prednisone (MP) followed by placebo, were published in the New England Journal of Medicine. Patients who were 65 years of age or older with Newly Diagnosed Multiple Myeloma (NDMM) and ineligible for stem-cell transplantation, were recruited from February 2007 to September 2008. The primary endpoint was progression-free survival (PFS) and the primary comparison was between MPR and MP; secondary endpoints included overall survival (OS) (although the study was not specifically empowered to assess OS), as well as response rate, time to response, duration of response and safety profile.

Treatment

• Patients (pts) were randomly assigned (1:1:1) to receive: oral MPR-R (n = 152), MPR (n = 154) or MP (n = 154) and stratified according to age: 65-75 yrs or >75 yrs
• MPR-R regimen: Nine 28-day cycles of melphalan (0.18 mg/kg body weight on days 1-4), prednisone (2 mg/kg on days 1-4), and lenalidomide (10 mg on days 1- 21), followed by lenalidomide maintenance (10 mg on days 1-21 of each 28-day cycle) until disease progression or the development of unacceptable rates of adverse effects
• MPR group: same MPR induction, followed by placebo maintenance (n = 152)
• MP group received MP induction (at the same dose and schedule as MPR regimen), with placebo during induction and maintenance (n = 153
• Pts with progressive disease during induction therapy could discontinue and enroll in an open-label extension phase to receive lenalidomide alone or with dexamethasone (n = 154)

Key Findings

• Median age = 71 years; 111 patients (24%) were > 75 years of age
• Pts with International Staging System stage III disease = 48-51% across all treatment groups
• Median duration of follow-up = 30 months (range, 1-47)
• Median PFS:
  • MPR-R = 31 months
  • MPR = 14 months; HR = 0.49; P<0.001
  • MP = 13 months; HR = 0.40; P<0.001
• Lenalidomide maintenance therapy extended PFS from the start of maintenance therapy (median, 26 months) vs placebo (median, 7 months)
• HR for MPR-R vs MPR group = 0.34; P<0.001
• PFS benefit with MPR-R was consistent across all subgroups, except > 75 year
• Significant treatment-by-age interaction (P=0.001) was observed for median PFS:
  • Pts 65-75 years of age: MPR-R vs MPR = 31 vs 15 months; HR = 0.48; P<0.001 and MP = 12 months; HR = 0.30; P<0.001
  • MPR vs MP HR = 0.62; P=0.006
  • Pts > 75 years: MPR-R = 19, MPR =12, MP= 15 months
• Very good partial response or better: MPR-R = 33%, MPR = 33%, MP = 12%
• Median time to response: MPR-R and MPR = 2 months; MP = 3 months (P<0.001 for both comparisons with MP)
• Median duration of a complete or partial response:  MPR-R = 29 months, MPR = 13 months, MP = 13 months (P<0.001 for comparisons of MPR-R with MPR, and MPR-R with MP)
• Deaths: MPR-R = 28%, MPR = 34%, MP = 29%
• OS rate (3 year): MPR-R = 70%, MPR = 62%, MP = 66%

Safety 

• Most frequent adverse events (AEs) were hematologic:
  • Grade 4 neutropenia: MPR-R = 35%, MPR = 32%, MP = 8%
  • Grade 4 thrombocytopenia: MPR-R = 11%, MPR = 12%, MP = 4%
• Non-hematologic AEs were minimal with infections being the most common
• AEs causing discontinuation: MPR-R = 16%, MPR = 14%, MP = 5%
• Rate of invasive second primary tumors (3-year): MPR-R = 7%, MPR = 7%, MP = 3%
• Rate of progression or death (3-year): MPR-R = 58%, MPR = 91%, and MP = 94%
• Lenalidomide-related deaths MPR-R =4 and MPR = 4
• Discontinuation due to AEs: pts age 65-75 = 13% and pts >75 = 22%

This study indicated that the use of lenalidomide in both the induction treatment phase, as well as the maintenance phase, was highly effective; in particular, lenalidomide maintenance was associated with higher PFS regardless of age, and had a favourable safety profile. However, the use of lenalidomide in the induction phase only conferred benefits to patients aged 65-75. Consequently, lenalidomide maintenance therapy was approved for use in patients with NDMM ineligible for transplantation by both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), following this trial.