Induction and extended consolidation with daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone in patients with high-risk multiple myeloma (OPTIMUM/MUKnine): 5-year follow-up of a multicentre, externally controlled, phase 2 trial.

BACKGROUND: High-risk multiple myeloma, defined by two or more high-risk cytogenetic abnormalities (HRCAs), high-risk gene expression profiling (GEP), or plasma cell leukaemia, remains associated with poor long-term outcomes despite quadruplet induction therapy. OPTIMUM showed that intensified induction, extended consolidation, and maintenance therapy after autologous stem-cell transplantation (ASCT) improved progression-free survival for patients with high-risk multiple myeloma. Here we report the 5-year follow-up of survival outcomes across molecular subgroups. METHODS: The multicentre, externally controlled, phase 2 OPTIMUM trial was conducted at 22 centres in the UK and enrolled patients aged 18 or older with newly diagnosed high-risk multiple myeloma or plasma cell leukaemia, measurable disease according to IMWG criteria, up to two previous induction cycles, and an Eastern Cooperative Oncology Group Performance Status of 2 or less. Participants received intravenous or subcutaneous daratumumab, oral cyclophosphamide, subcutaneous bortezomib, oral lenalidomide, and oral or intravenous dexamethasone induction at protocol specified doses before and after ASCT; melphalan-bortezomib during ASCT; consolidation part 1: daratumumab, bortezomib, lenalidomide, and dexamethasone; consolidation part 2: bortezomib, lenalidomide, and daratumumab; and maintenance lenalidomide and daratumumab until disease progression, unacceptable toxicity, or withdrawal. The trial used a Bayesian design and activity of treatment was compared with a molecularly matched external control cohort from the Myeloma XI trial. The primary endpoint was 18-month progression-free survival and has been previously reported. In this analysis, we report progression-free survival, progression-free survival 2 (time from registration until second disease progression or death, whichever occurred first), and overall survival at 5 years follow-up; and subgroup analyses by high-risk multiple myeloma features at entry (≥2 HRCAs, high-risk GEP, ≥2 HRCAs and high-risk GEP; and plasma cell leukaemia; subgroups selected post-hoc). OPTIMUM was registered with ClinicalTrials.gov (NCT03188172; active [not recruiting], with ongoing follow-up and maintenance). FINDINGS: Between Sept 29, 2017, and Sept 24, 2019, 108 participants with high-risk multiple myeloma were recruited to OPTIMUM and 107 were included in the analysis, with 120 genetically matched patients from the Myeloma XI trial (external control). Median follow-up was 71·1 months (IQR 66·9-77·7) for OPTIMUM and 117·8 months (98·3-128·6) for Myeloma XI. Progression-free survival (not reached [NR; 70·6-NR] vs 24·4 months [19·7-30·4]; HR 0·32 [95% CI 0·22-0·45]; p<0·0001) and overall survival (NR [NR-NR] vs 57·4 months [47·3-74·2]; HR 0·43 [95% CI 0·28-0·65]; p<0·0001) was longer in OPTIMUM than in Myeloma XI. Median progression-free survival 2 was NR (NR-NR) in OPTIMUM and 43·9 months (38·3-51·5) in Myeloma XI (HR 0·26 [95% CI 0·17-0·41]; p<0·0001). The survival benefit was consistent across high-risk multiple myeloma subgroups, except for patients with three or more HRCAs. INTERPRETATION: 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. FUNDING: Myeloma UK, BMS, and Johnson & Johnson.