According to results published in The Lancet Oncology, a risk-adapted, extended quadruplet regimen significantly extended progression-free survival and overall survival compared with conventional therapy in patients with high-risk multiple myeloma. At a median follow-up of 71.1 months for the phase 2 OPTIMUM/MUKnine trial and 117.8 months for the Myeloma XI external control, the median progression-free survival was not reached in the OPTIMUM arm, compared with 24.4 months in the control group, based on findings released by the trial investigators.
Trial Design and Extended Quadruplet Regimen
The multicenter OPTIMUM trial enrolled 108 participants aged 18 years or older across 22 sites in the United Kingdom, with 107 patients included in the final analysis. High-risk disease was defined by central trial genetics as possessing two or more high-risk cytogenetic abnormalities, a high-risk gene expression profiling signature via the SKY92 test, or plasma cell leukemia.
Participants received an intensive treatment schedule. This regimen featured extended induction using daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone. Patients then underwent autologous stem-cell transplantation with melphalan-bortezomib, followed by a two-part consolidation phase consisting of daratumumab, bortezomib, lenalidomide, and dexamethasone. Maintenance therapy comprised lenalidomide plus daratumumab until disease progression, unacceptable toxicity, or patient withdrawal.
OPTIMUM Regimen Components:
- Daratumumab (Darzalex)
- Cyclophosphamide
- Bortezomib (Velcade)
- Lenalidomide (Revlimid)
- Dexamethasone
Control Comparison:
Outcomes were benchmarked against a molecularly matched external control cohort of 120 patients from the Myeloma XI trial. Those patients received standard proteasome inhibitor- and immunomodulatory drug-based induction, autologous stem-cell transplantation, and lenalidomide maintenance.
Survival Outcomes and Subgroup Analysis
The trial demonstrated a hazard ratio of 0.32 for progression-free survival favoring the OPTIMUM regimen over the Myeloma XI external control. A secondary time-to-event endpoint, PFS2, which measures time to second disease progression or death, was also not reached in the OPTIMUM cohort, compared with 43.9 months in the Myeloma XI cohort, yielding a hazard ratio of 0.26.
Martin F. Kaiser, MD, professor of molecular hematology at The Institute of Cancer Research in London and consultant hematologist at The Royal Marsden NHS Foundation Trust, noted in a news release that high-risk myeloma remains a severe clinical challenge. “These long-term results show that when we adapt treatment to the biology of the disease, we can significantly extend survival for many patients who previously had very limited options,” Kaiser stated.
The survival advantage remained consistent across most high-risk subgroups. However, patients presenting with three or more high-risk cytogenetic abnormalities showed no clear progression-free or overall survival benefit over the external control cohort. Study authors noted that this specific group experiences poor outcomes regardless of regimen and should preferentially be directed toward clinical trials featuring innovative approaches.
Role of Molecular Testing and Gene Expression Profiling
Gene expression profiling identified a subset of patients who would not traditionally be classified as high-risk under standard clinical parameters. According to the research data, these patients experienced markedly better outcomes when treated with the personalized quadruplet approach, with 62.3% remaining progression-free at six years, compared to 20.3% of similar patients receiving standard care.
Because gene expression profiling is not currently performed as standard practice within the United Kingdom’s National Health Service, investigators warn that real-world patients with aggressive disease features are frequently missed. Kaiser emphasized that identifying these individuals earlier allows clinicians to tailor therapy from the start.
“This study also shows that some patients with aggressive disease are currently being missed because the necessary molecular tests are not routinely available,” Kaiser stated in the news release.
Study Limitations and Trial Design Context
The study authors acknowledged several limitations in their published findings. The OPTIMUM trial used an enrichment design where every enrolled participant carried specific high-risk features defined by entry criteria, which can limit broader generalizability. Additionally, because the trial predated the 2025 International Myeloma Society-International Myeloma Working Group high-risk classification updates, post hoc recategorization remains difficult to interpret.
Investigators also noted that the trial relied on a prespecified external comparator rather than prospective randomization. Study authors stated that in 2016, when the trial was designed and no established standard of care existed for this high-risk population, an externally controlled phase 2 design was the only feasible and ethically acceptable approach.
Frequently Asked Questions
What is the OPTIMUM/MUKnine trial?
The OPTIMUM/MUKnine trial is a multicenter, externally controlled phase 2 clinical study evaluating a risk-adapted, extended quadruplet regimen for patients with newly diagnosed high-risk multiple myeloma or plasma cell leukemia.
Which drugs make up the quadruplet induction regimen?
The regimen includes daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone, alongside stem-cell transplantation, consolidation phases, and ongoing maintenance therapy.
Why is gene expression profiling important in high-risk myeloma?
Gene expression profiling identifies high-risk molecular signatures that standard clinical testing may miss, allowing doctors to select targeted, personalized treatments that improve long-term progression-free survival.
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