Intensified therapy for high-risk myeloma is still ahead at five years

Design

multicentre, externally controlled, phase 2 trial with Bayesian design, 5-year follow-up

Population

107 patients with newly diagnosed high-risk myeloma or plasma cell leukaemia at 22 UK centres; 120 matched Myeloma XI controls

Primary outcome

progression-free survival, progression-free survival 2 and overall survival at 5 years

Effect

PFS not reached vs 24.4 months (HR 0.32, 95% CI 0.22–0.45); OS not reached vs 57.4 months (HR 0.43, 0.28–0.65)

High-risk multiple myeloma — two or more high-risk cytogenetic abnormalities, high-risk gene expression profiling, or plasma cell leukaemia — has continued to do badly despite quadruplet induction. OPTIMUM/MUKnine tested intensified induction with daratumumab, cyclophosphamide, bortezomib, lenalidomide and dexamethasone, melphalan-bortezomib conditioning, two phases of consolidation and maintenance with lenalidomide and daratumumab, in 107 patients across 22 UK centres, against 120 genetically matched controls from Myeloma XI.

At a median 71.1 months of follow-up, median progression-free survival had not been reached in OPTIMUM against 24.4 months in the control cohort (hazard ratio 0.32, 95% CI 0.22 to 0.45, p < 0.0001). Median overall survival was also not reached against 57.4 months (HR 0.43, 0.28 to 0.65). Progression-free survival 2, which counts through to a second progression and so partly accounts for what happens at relapse, was not reached against 43.9 months (HR 0.26, 0.17 to 0.41). Benefit was consistent across high-risk subgroups except in patients with three or more high-risk cytogenetic abnormalities.

The design is the caveat that has to be stated: this is a phase 2 trial with an external control cohort, genetically matched but treated in a different trial at a different time, with more than twice the follow-up. That comparison cannot exclude the effect of improvements in supportive care and salvage therapy over the intervening years. What it does establish is that molecular risk stratification at diagnosis changes what should be offered — which requires the cytogenetics and gene expression profiling to have been done in the first place, and that is the part most likely to be missing in routine Indian practice.

• Obtain full cytogenetics at myeloma diagnosis before treatment decisions are made
• Identify the two-or-more high-risk abnormality group specifically — that is the group this applies to
• Plan for extended consolidation and maintenance rather than fixed-duration therapy in high-risk disease
• Note that patients with three or more high-risk abnormalities did not show consistent benefit

Why it matters

It makes molecular risk stratification at diagnosis a decision that changes treatment, not a prognostic label.

Don't overread it

This is a phase 2 trial against an external control cohort from a different trial and era — not a randomised comparison.

The statistics, in plain English

A median not reached at 71 months against 24.4 months is a large difference, and the hazard ratio interval of 0.22 to 0.45 keeps it large throughout. The design is the weakness: an external control from a different trial era is not a randomised comparator, and control patients were followed for 117.8 months against 71.1, so the two cohorts are not observed over the same calendar period. Subgroups were selected post hoc, so the exception in patients with three or more abnormalities is a signal rather than a finding.

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