Background
Randomized phase 3 trial of 1,623 patients with newly diagnosed multiple myeloma ineligible for transplant. Final analysis of the FIRST (Frontline Investigation of Revlimid Plus Dexamethasone Versus Standard Thalidomide) trial; original report Benboubker et al, NEJM, 2014, PMID: 25184863.
Interventions and follow up
Arm A: Lenalidomide + dexamethasone (Rd) continuous until progression
Arm B: Rd x18 months (72 weeks)
Arm C: Melphalan + prednisone + thalidomide (MPT) x12 cycles
Dosing: Lenalidomide 25 mg (dose-adjusted for age/CrCl) D1-21 + dexamethasone 40/20 mg D1,8,15,22 Q28D; MPT melphalan + prednisone D1-4 with thalidomide 200 mg daily Q42D
Primary endpoint: PFS (Arm A vs C)
Median follow-up: 67 months
Arm B: Rd x18 months (72 weeks)
Arm C: Melphalan + prednisone + thalidomide (MPT) x12 cycles
Dosing: Lenalidomide 25 mg (dose-adjusted for age/CrCl) D1-21 + dexamethasone 40/20 mg D1,8,15,22 Q28D; MPT melphalan + prednisone D1-4 with thalidomide 200 mg daily Q42D
Primary endpoint: PFS (Arm A vs C)
Median follow-up: 67 months
Results
Median PFS: 26 months (continuous Rd) vs 21 months (Rd x18mo) vs 21.9 months (MPT)
HR (Rd continuous vs Rd18): 0.70, 95% CI 0.60-0.81
HR (Rd continuous vs MPT): 0.69, 95% CI 0.59-0.79, P<.001
HR (Rd continuous vs Rd18): 0.70, 95% CI 0.60-0.81
HR (Rd continuous vs MPT): 0.69, 95% CI 0.59-0.79, P<.001
Adverse events
Hematologic (grade ≥3): Neutropenia 30% (Rd cont) vs 26% (Rd18) vs 45% (MPT)
Non-hematologic: Infections 32% vs 22% vs 17%; second primary malignancy 1% vs <1% vs 3%, respectively
Non-hematologic: Infections 32% vs 22% vs 17%; second primary malignancy 1% vs <1% vs 3%, respectively
Conclusions
In transplant-ineligible newly diagnosed multiple myeloma, continuous lenalidomide plus dexamethasone significantly improved PFS compared with fixed-duration Rd and with MPT, with a lower rate of second primary malignancy than MPT.
Key Limitations
MPT comparator is no longer a frontline standard, and the trial predates triplet/quadruplet regimens (e.g., daratumumab-Rd) now preferred for transplant-ineligible patients. Continuous therapy entails cumulative toxicity and indefinite treatment burden.
Clinical Context
FIRST established continuous Rd as a frontline standard for transplant-ineligible multiple myeloma and supported FDA/EMA approval of lenalidomide in this setting. Rd remains a backbone onto which CD38 antibodies are now added (e.g., MAIA) per ASCO and ESMO guidance.
References