Background
DETERMINATION (ECOG-ACRIN E1A11) was a phase III randomized open-label US trial (n=722) comparing early (upfront) ASCT to initial VRd consolidation in transplant-eligible NDMM, using indefinite lenalidomide maintenance in both arms — unlike IFM 2009, which used only 1 year of lenalidomide.
Interventions and follow up
Arm A (no ASCT): VRd (bortezomib 1.3 mg/m² SC + lenalidomide 25 mg PO days 1–14 + dex 40 mg weekly) × 3 induction → stem cell collection → VRd × 5 additional cycles → lenalidomide 10 mg/day indefinite maintenance until progression
Arm B (ASCT): VRd × 3 induction → stem cell collection → melphalan 200 mg/m² ASCT → VRd × 2 consolidation → lenalidomide 10 mg/day indefinite maintenance until progression
Primary endpoint: PFS
Secondary: OS, response rates, MRD, quality of life
mFollow-up: 76 months
Arm B (ASCT): VRd × 3 induction → stem cell collection → melphalan 200 mg/m² ASCT → VRd × 2 consolidation → lenalidomide 10 mg/day indefinite maintenance until progression
Primary endpoint: PFS
Secondary: OS, response rates, MRD, quality of life
mFollow-up: 76 months
Results
mPFS: 67.5mo (ASCT) vs 46.2mo (no ASCT) (HR 0.53, 95% CI 0.45–0.63; P<.001)
5-yr OS: 80.7% vs 82.1% (HR 1.10, 95% CI 0.73–1.65; P=.64 — not significant)
≥CR: 68.0% vs 58.1% (P=.009)
High-risk cytogenetics: ASCT PFS benefit maintained (HR ~0.56)
5-yr OS: 80.7% vs 82.1% (HR 1.10, 95% CI 0.73–1.65; P=.64 — not significant)
≥CR: 68.0% vs 58.1% (P=.009)
High-risk cytogenetics: ASCT PFS benefit maintained (HR ~0.56)
Adverse events
Overall: Grade ≥3 AEs 94.1% (ASCT) vs 78.5% (no ASCT) — higher with ASCT predominantly due to melphalan; second primary malignancies 6.5% vs 4.5%
Hematologic: hematologic toxicity markedly higher in ASCT arm
Neurologic: peripheral neuropathy Grade ≥3 4.7% vs 5.8%
QoL: transient worsening post-ASCT with recovery by 12 months
Hematologic: hematologic toxicity markedly higher in ASCT arm
Neurologic: peripheral neuropathy Grade ≥3 4.7% vs 5.8%
QoL: transient worsening post-ASCT with recovery by 12 months
Conclusions
Early ASCT significantly prolonged PFS by 21 months (HR 0.53) compared with VRd + indefinite lenalidomide maintenance in transplant-eligible NDMM, reaffirming upfront ASCT as standard of care; 5-yr OS was not significantly different, likely reflecting effective salvage strategies including delayed ASCT.
Key Limitations
OS not improved — 27% of control arm received salvage ASCT, diluting any OS signal; VRd triplet induction without daratumumab (pre-quadruplet era) may underestimate current induction efficacy; second primary malignancy rate numerically higher with ASCT + indefinite lenalidomide; open-label design; QoL impact of ASCT relevant for shared decision-making.
Clinical Context
DETERMINATION confirmed IFM 2009 findings in a US population with modern indefinite lenalidomide maintenance: early ASCT prolongs PFS but OS is equivalent. Together these trials are the cornerstone of the recommendation for early ASCT in eligible patients per ASCO/ESMO guidance. The quadruplet D-VRd era (PERSEUS, 2024) sets up the next debate — SWOG S1803/DRAMMATIC will be the definitive modern answer.