Risk-Adapted Quadruplet Therapy Sustains 5-Year Survival Benefit in High-Risk Myeloma

A risk-adapted, extended quadruplet regimen led to significantly longer progression-free survival (PFS) and overall survival (OS) compared with conventional therapy in patients with high-risk multiple myeloma, according to 5-year follow-up results from the phase 2 OPTIMUM/MUKnine trial (NCT03188172) published in The Lancet Oncology.¹

At a median follow-up of 71.1 months (IQR, 66.9-77.7) for OPTIMUM and 117.8 months (IQR, 98.3-128.6) for the Myeloma XI external control, median PFS was not reached (95% CI, 70.6-not reached) in OPTIMUM vs 24.4 months (95% CI, 19.7-30.4) in Myeloma XI (HR, 0.32; 95% CI, 0.22-0.45; P < .0001). Median OS was also not reached in OPTIMUM vs 57.4 months (95% CI, 47.3-74.2) in Myeloma XI (HR, 0.43; 95% CI, 0.28-0.65; P < .0001). At 72 months, PFS was 53.8% (95% CI, 43.5-64.1) with OPTIMUM vs 17.6% (95% CI, 10.7-24.6) with conventional therapy, and OS was 69.1% (95% CI, 59.9-78.2) vs 42.5% (95% CI, 33.5-51.4).

“High-risk myeloma has traditionally been one of the toughest challenges we face, with patients often relapsing early despite the best available treatments,” Martin F. Kaiser, MD, professor of molecular hematology at The Institute of Cancer Research (ICR), London, and consultant hematologist at The Royal Marsden NHS Foundation Trust, stated in a news release from the ICR.² “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.”

Trial Design

OPTIMUM is a multicenter, externally controlled phase 2 trial conducted at 22 centers in the United Kingdom that enrolled 108 patients aged 18 years or older with newly diagnosed high-risk multiple myeloma or plasma cell leukemia, of whom 107 were included in the analysis. High-risk disease was defined by central trial genetics as 2 or more high-risk cytogenetic abnormalities (HRCAs), a high-risk gene expression profiling (GEP) signature by the MMProfiler SKY92 test, or plasma cell leukemia.¹

Participants received extended induction with daratumumab (Darzalex), cyclophosphamide, bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone; melphalan-bortezomib during autologous stem-cell transplantation (ASCT); 2-part consolidation with daratumumab, bortezomib, lenalidomide, and dexamethasone regimens; and maintenance lenalidomide plus daratumumab until disease progression, unacceptable toxicity, or withdrawal.

Outcomes were compared against a molecularly matched external control cohort of 120 patients from the Myeloma XI trial who received conventional proteasome inhibitor- and immunomodulatory drug-based induction, ASCT, and lenalidomide maintenance. A second time-to-event end point, PFS2 (time to second disease progression or death), was not reached in OPTIMUM vs 43.9 months (95% CI, 38.3-51.5) in Myeloma XI (HR, 0.26; 95% CI, 0.17-0.41; P < .0001).

Subgroup Findings

The survival benefit with OPTIMUM was consistent across high-risk subgroups defined by 2 or more HRCAs and high-risk GEP, but not in patients with 3 or more HRCAs, who showed no clear PFS or OS benefit over the external control.

Among patients with 2 or more HRCAs, PFS at 72 months was 74.6% (95% CI, 54.5%-94.8%) with OPTIMUM vs an HR of 0.16 (95% CI, 0.06-0.42) against Myeloma XI; among those with high-risk GEP, the HR for PFS was 0.23 (95% CI, 0.13-0.44).

Patients with both high-risk GEP and 2 or more HRCAs had the poorest outcomes among the high-risk diagnostic subgroups, with median PFS of 52.3 months (95% CI, 20.0-not estimable) in OPTIMUM, though this still favored OPTIMUM over Myeloma XI (HR, 0.32; 95% CI, 0.18-0.58).

The study authors noted that patients with 3 or more HRCAs, though a small subgroup, “should preferentially be considered for clinical trials with innovative approaches,” given their poor outcomes in both cohorts.

Identifying Higher-Risk Patients via Molecular Testing

According to the ICR news release, a subgroup of patients identified as high-risk only through GEP, and who would not otherwise have been classified as high-risk, showed markedly better outcomes with the personalized approach: 62.3% remained progression-free at 6 years, compared with 20.3% of similar patients who received standard treatment.² Because GEP is not done as a standard practice in the UK’s National Health Service, real-world patients who would be high-risk by GEP may not receive risk-adapted treatment.

“This study also shows that some patients with aggressive disease are currently being missed because the necessary molecular tests are not routinely available,” Kaiser said in the news release. “Identifying these patients earlier could allow us to tailor treatment from the start and change the course of their disease.”

Study Limitations

The study authors noted that OPTIMUM used an enrichment design in which all treated patients carried the specific high-risk features defined by trial entry criteria, which can limit generalizability and the interpretation of further subgroup analyses.¹ Because the trial predated the 2025 International Myeloma Society-International Myeloma Working Group high-risk classification update, post hoc recategorization using newer criteria is difficult to interpret. The trial also used a prespecified external comparator rather than prospective randomization, an approach the study authors stated was the only feasible and ethically acceptable design in 2016, when no established standard of care existed for this high-risk patient population.

REFERENCES

1. Kaiser MF, Phillip RH, Brown SR, et al. 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. Lancet Oncol. Published online September 7, 2026. doi:10.1016/S1470-2045(26)00286-X

2. Precision treatment helps high risk blood cancer patients live longer, research shows. News release. The Institute of Cancer Research, London. September 7, 2026. Accessed September 11, 2026. https://tinyurl.com/3bekrd2z