TOPLINE

Extended risk-adapted therapy with daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone improved progression-free and overall survival among patients with newly diagnosed high-risk multiple myeloma compared with conventional treatment. The benefit persisted across most molecular subgroups. Safety data were not reported in this analysis.

METHODOLOGY

• Researchers conducted a 5-year follow-up analysis of a multicentre, externally controlled, phase 2 trial (OPTIMUM) that enrolled 108 adults (median age, 60 years; 60% men) with newly diagnosed plasma cell leukaemia or high-risk multiple myeloma (defined as two or more high-risk cytogenetic abnormalities or a high-risk gene expression signature) at 22 UK centres; of these, 107 received treatment and were included in this analysis.
• Participants received induction with daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone before and after autologous stem cell transplant, followed by extended consolidation. Patients then received maintenance therapy with lenalidomide and daratumumab until disease progression, unacceptable toxicity, or withdrawal, whichever occurred first.
• Patients in the treatment group were compared with 120 molecularly matched patients from the Myeloma XI trial (the external control group) who received conventional induction therapy, an autologous stem cell transplant, and maintenance therapy with lenalidomide.
• The primary endpoint, 18-month progression-free survival, was reported previously; outcomes of this analysis were progression-free survival, progression-free survival 2 (defined as the time to second progression or death), and overall survival. Safety data were not reported in this analysis.
• The median follow-up duration was 71.1 months for patients in the OPTIMUM group vs 117.8 months for those in the external control group.

TAKEAWAY

• Median progression-free survival was not reached in the extended therapy group vs 24.4 months in the Myeloma XI group (hazard ratio [HR], 0.32; P < .0001); at 72 months, 53.8% vs 17.6% of patients remained progression free.
• Median overall survival was not reached in the extended therapy group vs 57.4 months in the Myeloma XI group (HR, 0.43; P < .0001); at 72 months, 69.1% and 42.5% of patients in the respective groups were alive.
• Median progression-free survival 2 was not reached in the OPTIMUM group vs 43.9 months in the external control group (HR, 0.26; P < .0001).
• The survival benefit was consistent across patients with two or more high-risk cytogenetic abnormalities, high-risk gene expression, or both; however, no discernible benefit was seen among seven patients with three or more abnormalities in the OPTIMUM group vs 10 patients in the Myeloma XI group. Among nine patients with plasma cell leukaemia, median progression-free and overall survival were 20.9 and 30.9 months, respectively.

IN PRACTICE

"[The study] findings show that risk-stratified continuous combination treatment should be considered for patients with high-risk multiple myeloma and support access to diagnostic testing to identify transplant-eligible patients with newly diagnosed multiple myeloma who would benefit from risk-stratified treatment," the authors wrote.

SOURCE

The study was led by Martin F. Kaiser, MD, Institute of Cancer Research, London, UK. It was published online on September 07, 2026, in The Lancet Oncology.

LIMITATIONS

The study was limited by the enrichment design, which may have limited generalisability; exploratory post hoc subgroup analyses; and post hoc recategorisation under the 2025 International Myeloma Working Group risk criteria. The external comparator was not randomly assigned; extramedullary disease status was unknown or missing for 39% of participants; and long-term safety outcomes were not reported in this analysis and will be published separately.

DISCLOSURES

The study was funded by Myeloma UK, Bristol Myers Squibb, and Johnson & Johnson. Kaiser reported receiving funding from Janssen and Bristol-Myers Squibb (Celgene) and consultancy fees and honoraria from several pharmaceutical companies, including Johnson & Johnson, GSK, Pfizer, Sanofi, and Takeda. Full disclosures are reported in the original source article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.