Patients non-eligible for transplant

The FIRST clinical trial to assess lenalidomide and dexamethasone in transplant-ineligible MM patients 

Patients with multiple myeloma (MM) that are ineligible for transplant are currently treated with a triple-drug regimen of melphalan, prednisone and thalidomide (MPT). In September 2014, the results of the open-label, phase 3 clinical trial FIRST (MM-020/IFM 07-01) were published in the New England Journal of Medicine, in which the MPT regimen was compared with the combined therapy of lenalidomide plus low-dose dexamethasone. The primary end point was progression-free survival (PFS) with continuous lenalidomide–dexamethasone versus MPT; overall survival (OS) was a secondary endpoint, along with response rate, duration of response, time to response, safety and time to second line therapy.

Treatment

  • A large cohort of 1,623 patients were enrolled (August 2008- March 2011)
  • Patients were randomly assigned into the three treatment groups:
    • Continuous treatment of lenalidomide plus dexamethasone - 28-day cycles until disease progression (535 pts)
    • Lenalidomide plus dexamethasone – 18 cycles, 72 weeks (541 pts)
    • MPT – 42-day cycles, 72 weeks (547 pts)
  • Dosing:
    • Lenalidomide - 25 mg/day on days 1 to 21 of each 28-day cycle
    • Dexamethasone - 40 mg on days 1, 8, 15, and 22
    • Melphalan (0.25 mg/kg body weight per day on days 1-4), prednisone (2 mg/kg per day on days 1-4), and thalidomide (200 mg per day) were administered in 42-day cycles

Key Findings:

All data is listed in the order: continuous lenalidomide–dexamethasone (Len-DEX), 18 cycles of lenalidomide–dexamethasone (Len-DEX18), and MPT, respectively:

  • Median duration of treatment: 18.4, 16.6, 15.4 months
  • Median duration of follow-up among surviving patients (at data cut-off, May 2013) = 37.0 months (range, 0 to 56.7 months)
  • Median PFS: 25.5, 20.7, 21.2 months
  • Len-DEX vs MPT: HR = 0.72; 95% CI, 0.61 to 0.85; P<0.001)
  • Len-DEX vs Len-DEX18: HR = 0.70; 95% CI, 0.60 to 0.82; P<0.001)
  • Len-DEX18 vs MPT: HR = 1.03 (95% CI, 0.89 to 1.20; P=0.70)
  • Deaths at the interim analysis: 173 pts, 192 pts, and, 209 pts
  • OS (at 3 years):70%, 66%, 62%; OS (at 4 years): 59%, 56%, 51%
  • Continuous dexamethasone reduced the risk of death as compared to MPT:                                     HR = 0.78 (95% CI, 0.64-0.96; P=0.02)
  • PFS benefit was observed across subgroups, but was questionable in patients with poor prognostic features such as high-risk cytogenetic profile
  • RR: 75%, 73%, 62%
  • PR: 44%, 43%, 28%
  • CR: 15%, 14%, 9%
  • Median duration of response: 35, 22.1, and 22.3 months
  • Pts receiving second-line therapy: 43% (231 of 535 pts), 55% (299 of 541 pts), 56% (309 of 547 pts)
  • Time to second-line anti-myeloma therapy: 39.1, 28.5, 26.7 months (P<0.001)
  • Survival benefit of continuous lenalidomide-dexamethasone treatment was maintained with the next line of therapy, as observed by the median PFS 2: 42.9 months vs. 36.3 months, HR = 0.78; P=0.005

Safety

  • AEs ≥ grade 3 or 4: 85%, 80%, 89%
  • Grade 3 or 4 neutropenia: 28%, 26%, 45%
  • Febrile neutropenia: 1%, 3%, 3%
  • Infection of grade 3 or 4: 29%, 22%, 17%
  • Deep-vein thrombosis, pulmonary embolism, or both: 8%, 6%, 5%
  • Cardiac events of grade 3 or 4: 12%, 7%, and 9%
  • Peripheral sensory neuropathy: 1% 1%, 9%
  • Invasive second primary cancers: 3%, 6%, 5%
  • Hematologic cancers: <1% (2 cases), <1% (2 cases), 2% (12 cases)
  • Solid tumors: 3%, 5%, 3%

Updated results (June 12th 2015):

  • PFS: Continuous = 26 months, MPT = 21.9 months HR = 0.69 (95% CI, 0.59-0.80) p=0.00031        PFS: 18 cycles = 21 months
  • Continuous treatment with lenalidomide vs MPT: HR = 0.75 (95% CI, 0.62-0.90)
  • Median OS; Continuous = 10.4 months (range, 48.5-58.9); 18 cycles = 56.7 months
  • Median follow-up = 45.5 months
  • Safety data for most AEs was comparable with that above
  • Updated results:
    • Invasive second primary malignancies = 3.9%, 6.1%, 5.5%
    • Incidence of solid tumors = 3.4%, 5.9%, 3.3%

This pivotal study demonstrated that continuous treatment of patients with newly diagnosed multiple myeloma who are ineligible for stem-cell transplantation, with lenalidomide plus low-dose dexamethasone, conferred a significant improvement in PFS and an OS benefit. Lenalidomide is currently approved by both the US FDA and the EMA for the treatment of multiple myeloma.

 

References
  1. Benboubker L. et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. DOI: 10.1056/NEJMoa1402551.
  2. Updated Results from MM-020/IFM 07-01 (First) Study of REVLIMID® Presented at European Hematology Annual Congress
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