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 12^th 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.