The 5-year follow-up of the phase II OPTIMUM/MUKnine trial found sustained improvements in progression-free and overall survival with an intensive, risk-adapted treatment strategy for patients with newly diagnosed high-risk multiple myeloma. The findings, reported by Kaiser et al in The Lancet Oncology, address the continued poor long-term outcomes observed among patients with molecularly defined high-risk disease despite advances in induction therapy.
Study Details
The multicenter, externally controlled OPTIMUM trial enrolled adults with newly diagnosed high-risk multiple myeloma or plasma cell leukemia at 22 centers in the United Kingdom. High-risk disease was defined by two or more high-risk cytogenetic abnormalities, high-risk gene-expression profiling, or plasma cell leukemia. Treatment activity was compared with a molecularly matched external control cohort from the phase III Myeloma XI trial.
Patients in OPTIMUM received induction with daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone, followed by autologous stem-cell transplantation incorporating melphalan and bortezomib. Post–autologous stem-cell transplantation therapy included 6 cycles (28 days/cycle) of daratumumab, bortezomib, lenalidomide, and dexamethasone consolidation (consolidation part 1), followed by 12 cycles of daratumumab, bortezomib, and lenalidomide (consolidation part 2). Maintenance with daratumumab and lenalidomide continued until disease progression, unacceptable toxicity, or withdrawal.
The analysis included 107 patients in OPTIMUM and 120 molecularly matched patients from Myeloma XI. Median follow-up was 71.1 months (interquartile range [IQR] = 66.9–77.7 months) in OPTIMUM and 117.8 months (IQR = 98.3–128.6 months) in Myeloma XI. Outcomes in the 5-year analysis included progression-free survival, progression-free survival 2 (defined as time from registration to second disease progression or death), and overall survival.
Key Results
Median progression-free survival was not reached in OPTIMUM (95% confidence interval [CI] = 70.6 months–not reached) compared with 24.4 months (95% CI = 19.7–30.4 months) in Myeloma XI (hazard ratio [HR] = 0.32, 95% CI = 0.22–0.45; P < .0001). At 72 months, progression-free survival rates were 53.8% and 17.6%, respectively. Median overall survival was also not reached with OPTIMUM vs 57.4 months with Myeloma XI (HR = 0.43, 95% CI = 0.28–0.65; P < .0001); 72-month overall survival rates were 69.1% and 42.5%, respectively.
Median progression-free survival 2 was not reached with OPTIMUM compared with 43.9 months with Myeloma XI (HR = 0.26, 95% CI = 0.17–0.41; P < .0001); corresponding 72-month rates were 75.0% and 31.3%. Exploratory subgroup analyses indicated a progression-free and overall survival benefit with OPTIMUM across molecular high-risk subgroups defined by cytogenetic abnormalities, gene-expression profiling, or a combination of these features.
Patients with three or more high-risk cytogenetic abnormalities continued to have poor outcomes. Among seven such patients in OPTIMUM, six had experienced disease progression by 72 months, and the investigators observed no discernible progression-free or overall survival benefit compared with Myeloma XI.
The authors concluded: “OPTIMUM shows sustained progression-free survival and overall survival improvement with risk-stratified extended therapy, supporting implementation of molecular diagnostics and tailored treatment in patients with newly diagnosed high-risk multiple myeloma.”
Martin F. Kaiser, MD(Res), of Division of Genetics and Epidemiology, Institute of Cancer Research, London and Royal Marsden Hospital, London, is the corresponding author for the Lancet Oncology article.
DISCLOSURE: The study was funded by Myeloma UK, BMS, and Johnson & Johnson. For full disclosures of the study authors, visit thelancet.com.
