The OPTIMUM/MUKnine phase 2 trial evaluated intensified induction (daratumumab + cyclophosphamide + bortezomib + lenalidomide + dexamethasone), extended consolidation, and maintenance after ASCT in 107 newly diagnosed high-risk multiple myeloma patients (≥2 HRCAs, high-risk GEP, or plasma cell leukaemia) at 22 UK centres, compared against 120 molecularly matched external controls from the Myeloma XI trial over a median 71-month follow-up.
At 5-year follow-up, median PFS was not reached (NR) in OPTIMUM vs 24.4 months in controls (HR 0.32, 95% CI 0.22–0.45; p<0.0001); median OS was NR vs 57.4 months (HR 0.43, 95% CI 0.28–0.65; p<0.0001); median PFS2 was NR vs 43.9 months (HR 0.26, 95% CI 0.17–0.41; p<0.0001). Benefit was consistent across high-risk subgroups **except** patients with ≥3 HRCAs.
- External control design (Myeloma XI) introduces potential confounding; groups were molecularly matched but not randomised. - Subgroup analyses (≥2 HRCAs, high-risk GEP, plasma cell leukaemia) were selected post-hoc. - No survival benefit demonstrated in the ≥3 HRCAs subgroup, suggesting a ceiling for this regimen in the highest-risk patients.
For newly diagnosed high-risk myeloma defined by ≥2 cytogenetic abnormalities, high-risk GEP, or plasma cell leukaemia, an intensified daratumumab-based quadruplet regimen with extended consolidation and maintenance can more than double PFS and meaningfully extend OS. Molecular risk stratification at diagnosis is key to selecting patients most likely to benefit.
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