Background
Phase 3, randomized, double-blind, placebo-controlled trial. 205 RBC transfusion-dependent patients with IPSS Low/Intermediate-1-risk del5q31 MDS. Crossover to lenalidomide or higher dose was permitted after 16 weeks of placebo or lower-dose assignment.
Interventions and follow up
Arm A: Lenalidomide 10 mg/day orally on days 1–21 of 28-day cycles (n=69)
Arm B: Lenalidomide 5 mg/day orally on days 1–28 of 28-day cycles (n=69)
Arm C: Placebo (n=67)
Primary endpoint: RBC transfusion independence ≥26 consecutive weeks
mFollow up: Median 1.55 years
Arm B: Lenalidomide 5 mg/day orally on days 1–28 of 28-day cycles (n=69)
Arm C: Placebo (n=67)
Primary endpoint: RBC transfusion independence ≥26 consecutive weeks
mFollow up: Median 1.55 years
Results
RBC-TI ≥26 weeks (Len 10 mg): 56.1%
RBC-TI ≥26 weeks (Len 5 mg): 42.6%
RBC-TI ≥26 weeks (Placebo): 5.9% (both lenalidomide arms P<.001 vs placebo)
Median duration of RBC-TI: Not reached; 60–67% of responses ongoing at data cutoff
Cytogenetic response (Len 10 mg): 50%
Cytogenetic response (Len 5 mg): 25% (P=.066 vs 10 mg)
3-year OS (combined len arms): 56.5%
3-year AML risk (combined len arms): 25.1%
RBC-TI ≥8 weeks associated with: 47% reduction in risk of death (P=.021) and 42% reduction in AML progression/death (P=.048)
RBC-TI ≥26 weeks (Len 5 mg): 42.6%
RBC-TI ≥26 weeks (Placebo): 5.9% (both lenalidomide arms P<.001 vs placebo)
Median duration of RBC-TI: Not reached; 60–67% of responses ongoing at data cutoff
Cytogenetic response (Len 10 mg): 50%
Cytogenetic response (Len 5 mg): 25% (P=.066 vs 10 mg)
3-year OS (combined len arms): 56.5%
3-year AML risk (combined len arms): 25.1%
RBC-TI ≥8 weeks associated with: 47% reduction in risk of death (P=.021) and 42% reduction in AML progression/death (P=.048)
Adverse events
Hematologic: Grade 3–4 neutropenia and thrombocytopenia were the most common AEs (consistent with MDS-003), managed with dose interruption or reduction
Other: No new safety signals identified
Other: No new safety signals identified
Conclusions
Both lenalidomide doses produced significantly superior transfusion independence vs placebo in del5q LR-MDS. The 10 mg dose achieved higher cytogenetic response rates. Achievement of transfusion independence was associated with meaningful reductions in mortality and AML transformation risk.
Key Limitations
Crossover design after 16 weeks limits OS interpretation; the placebo arm was not followed long-term without active therapy. AML transformation risk at 3 years was 25%, raising concern about whether lenalidomide accelerates clonal evolution (later addressed in retrospective analyses but not definitively resolved). Open-label crossover may have diluted efficacy endpoints. The trial was enriched for del5q; applicability to non-del5q MDS remains absent.
Clinical Context
MDS-004 confirmed the phase 3 efficacy of lenalidomide in del5q LR-MDS and informed European registration. Lenalidomide 10 mg is standard first- or second-line therapy in del5q LR-MDS per ELN guidance. Concern about AML risk in TP53-mutated del5q patients has prompted molecular screening recommendations prior to initiation.