Publication Only: Myeloma and other monoclonal gammopathies - Clinical
The pivotal FIRST trial, the largest study conducted in transplant-ineligible (TNE) patients (pts) with newly diagnosed multiple myeloma (NDMM), examined lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous), Rd for 18 cycles (Rd18), and melphalan, prednisone, and thalidomide (MPT). The study, conducted in 18 countries in Europe, North America, and Asia Pacific, demonstrated that Rd continuous significantly improved progression-free survival (PFS) vs MPT (median 26.0 vs 21.9 mos; HR, 0.69; 95% CI, 0.59-0.79; P < .00001). PFS was similarly extended for Rd continuous vs Rd18 (median 21.0 mos; HR, 0.70; 95% CI, 0.60-0.81). Furthermore, median overall survival (OS) was significantly longer with Rd continuous vs MPT (median 59.1 vs 49.1 mos; HR, 0.78; 95% CI, 0.67-0.92; P = .0023). These results support the use of frontline oral, alkylator-free continuous therapy for TNE NDMM pts and established Rd continuous as a standard of care as reflected by clinical guidelines in Canada, the US, and Europe.
To report outcomes in the subset of patients from Canada and the US.
Pts with TNE NDMM were randomized 1:1:1 to Rd continuous (with lenalidomide given on days 1-21 of 28-day cycles until disease progression), Rd18 (with lenalidomide given on days 1-21 of eighteen 28-day cycles), or MPT (twelve 42-day cycles). Rd18 and MPT were both 72 weeks in duration. Stratification factors included country and Rd continuous vs MPT was the primary comparison. The primary endpoint was PFS and secondary endpoints included OS, time to next therapy (TTNT) and safety. Time from randomization to second progression or death (PFS2) was an exploratory analysis. Response assessment used for PFS and PFS2 analysis was determined by investigators based on International Myeloma Working Group criteria. Data is presented as of the January 21, 2016 cutoff used for the final OS analysis.
A total of 312 pts from Canada (n = 252) and the US (n = 60) were enrolled (104 in each arm). Consistent with results from the intent-to-treat (ITT) analysis, the Canada/US subgroup also demonstrated a significant improvement in PFS with Rd continuous vs MPT (median 29.3 vs 20.2 mos; HR, 0.69; 95% CI, 0.49-0.97; P = .03326) and an improvement vs Rd18 (median 21.9 mos; HR, 0.72; 95% CI, 0.51-1.02; Table). Median OS was 56.9 vs 46.8 mos for Rd continuous vs MPT (HR, 0.77; 95% CI, 0.53-1.11; P = .15346). Median PFS2 was longer for Rd continuous vs MPT (median 39.3 vs 35.1 mos; HR, 0.69; 95% CI 0.50-0.95) as was TTNT (median 39.1 vs 24.6 mos; HR, 0.54; 95% CI, 0.37-0.78). Additional details, including safety data, will be presented at the meeting.
In the Canada/US subpopulation of pts from FIRST, Rd continuous extended median PFS by 9 mos vs MPT and > 7 mos vs Rd18. Rd continuous also delayed median TTNT > 14 mos and resulted in a longer PFS2 vs MPT, suggesting that the benefit from frontline Rd continuous is maintained at relapse. These results are consistent with that from the ITT population confirming the advantage of Rd continuous vs MPT in the Canada/US subgroup and supporting the role of Rd continuous as a standard of care for TNE pts with NDMM. The efficacy observed with Rd continuous raises the question on the role of immunostimulatory effects by the immunomodulatory agents in NDMM.