Updated results from the FIRST clinical trial to compare lenalidomide-dexamethasone with MPT

In June 2016, Cyrille Hulin and colleagues published an updated analysis of the FIRST clinical trial to compare lenalidomide plus low-dose dexamethasone with the standard regimen of Melphalan, Prednisone, and Thalidomide (MPT), in transplant ineligible patients with Multiple Myeloma (MM).  The data was presented in the Journal of Clinical Oncology. Details of the study design and results from the interim analysis can be found in a previous MMHub article. Patients were stratified according to age (≤75 yrs, n= and ≥75 yrs, n=567).

Key Findings

Results are presented as: continuous lenalidomide plus dexamethasone (Rd), 18 cycles of lenalidomide plus dexamethasone (Rd18) and MPT:

• Median follow-up for surviving patients = 45.5 months
• Len-Dex: pts ≤75 yrs were still receiving treatment (19.8%) compared with ≥75 yrs (11.9%)
• All pts in Rd18 and MPT arms had completed or discontinued treatment
• Longer PFS was achieved with Rd continuous vs MPT, independent of age 
• ITT population, risk of progression or death:
  • Rd continuous vs MPT: HR = 0.69; 95% CI, 0.59 to 0.80; P < .001 and age:
  • Pts ≥ 75 years: HR = 0.80; 95% CI, 0.62 to 1.03; P = .084
  • Pts ≤75 years: HR = 0.64; 95% CI, 0.53 to 0.77; P < .001
• Four-year PFS more than doubled with Rd vs MPT, regardless of age
• PFS with Rd18 was similar to MPT, regardless of age
• OS:
  • Rd continuous vs MPT = 58.9 vs 48.5 months; HR =0.75; 95% CI, 0.62 to 0.90 (10-month survival benefit)
  • Pts ≥ 75 yrs = 52.3 vs 37.8 months; HR = 0.72; 95% CI, 0.54 to 0.96
  • Pts ≤75 yrs = 60.9 vs 55.3 months HR = 0.76; 95% CI, 0.60 to 0.96
• OS rate at 4 yrs with Rd18 was marginally lower than with Rd continuous: pts ≤75 yrs = 3% lower and pts ≥75 yrs = 4% lower
• Rd continuous resulted in higher ORR (≥ PR), including high-quality responses (≥ very good partial response [VGPR]), and prolonged DoR in the ITT population and both age groups compared with MPT:
• Rd continuous vs MPT:
  • ORR = 81% vs 67% (OR = 2.04; 95% CI, 1.54 to 2.70)
  • Median DoR = 32 vs 22 months (HR = 0.60; 95% CI, 0.51 to 0.72)
  • Pts ≤75 yrs: 82% vs 71%; OR = 1.91; 95% CI, 1.34 to 2.73
  • Pts ≥75 yrs: 78% v 61%; OR, 2.30; 95% CI, 1.46 to 3.61)
• Median DoR via age:
  • Pts ≤75 yrs:  37 vs 22 months (HR, 0.55; 95% CI, 0.44 to 0.69)
  • Pts ≥75 yrs: 27 vs 22 months (HR, 0.73; 95% CI, 0.54 to 1.00)
• VGPR or better were higher with Rd continuous vs MPT overall and in both age groups
• Median time to response Rd continuous vs MPT = 2 vs 3 months
• Rd continuous extended the time to second antimyeloma therapy
• Mean treatment duration:
  • Rd continuous = 24 months Pts ≤75 yrs and 20 months Pts ≤75 yrs
  • MPT = 12 months Pts ≤75 yrs and 11 months Pts ≤75 yrs
•  Discontinuation rates (72 weeks):
  • Rd18 vs MPT = 14% vs 26% for pts ≤75 yrs and 23% vs 29% for pts ≥75 yrs
  • Rd continuous vs MPT = age ≤ 75 years: 21% v 26%; age > 75 years: 26% v 30%
• Grade 3-4 TEAEs (hematologic and nonhematologic) were similar across age groups
• Most common Grade 3-4 TEAEs: neutropenia and anemia
• Rate of grade 3-4 neutropenia higher with MPT vs Rd continuous or Rd18, regardless of age
• Most common grade 3- 4 non-hematologic TEAEs: infections

Treatment options for elderly patients with MM are dependent upon general physical and mental health of individual patients. In addition, elderly patients are under-represented in many clinical trials. This study was able to assess age-related effects and concluded that for NDMM patients that are ineligible for transplant, continuous lenalidomide plus low-dose dexamethasone treatment was more effective than MPT, regardless of age. Similar safety profiles were also observed across both age ranges.

Abstract

Purpose

This analysis of the FIRST trial in patients with newly diagnosed multiple myeloma (MM) ineligible for stem-cell transplantation examined updated outcomes and impact of patient age.

Patients and Methods

Patients with untreated symptomatic MM were randomly assigned at a one-to-one-to-one ratio to lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks), stratified by age (≤ 75 v > 75 years), disease stage (International Staging System stage I/II v III), and country. The primary end point was progression-free survival. Rd continuous and MPT were primary comparators.

Results

Between August 21, 2008, and March 7, 2011, 1,623 patients were enrolled (Rd continuous, n = 535; Rd18, n = 541; MPT, n = 547), including 567 (35%) age older than 75 years. Higher rates of advanced-stage disease and renal impairment were observed in patients older than 75 versus 75 years of age or younger. Rd continuous reduced the risk of progression or death compared with MPT by 31% (hazard ratio [HR], 0.69; 95% CI, 0.59 to 0.80; P < .001) overall, 36% (HR, 0.64; 95% CI, 0.53 to 0.77; P < .001) in patients age 75 years or younger, and 20% (HR, 0.80; 95% CI, 0.62 to 1.03; P = .084) in those age older than 75 years. Median overall survival was longer with Rd continuous than with MPT, including a 14-month difference in patients age older than 75 years. Progression-free survival with Rd18 was similar to that with MPT, and overall survival with Rd18 was marginally inferior to that with Rd continuous. Rates of grade 3 to 4 treatment-emergent adverse events were similar for Rd continuous-treated patients age 75 years or older and those age older than 75 years; however, older patients had more frequent lenalidomide dose reductions.

Conclusion

Results support Rd continuous treatment as a new standard of care for stem-cell transplantation-ineligible patients with newly diagnosed MM of all ages.