Extended Intensified Consolidation and Maintenance Improve Ultra High-Risk Multiple Myeloma Patient Outcome - Long-Term Follow-up of the Ukmra Optimum/Muknine Trial
Authors: Kaiser Martin F , Hall Andrew , Phillip Rachel , Holroyd Amy , Ferris Elsa , Roberts Sadie , Clayton Laura , Bowles Kristian , Garg Mamta , Lokare Anand , de Tute Ruth M , Drayson Mark , Messiou Christina , Owen Roger G , Houlston Richard S , Jackson Graham , Cook Gordon , Pratt Guy , Brown Sarah R , Jenner Matthew W. 
Published: December 2024

Background: Outcome for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (MM) remains unsatisfactory. Recently, we showed promising early results with stratified treatment for UHiR MM; however, maintaining responses is most challenging in UHiR, but also most relevant for patients, and efficacy beyond the initial 36 months has not yet been reported for any of the novel risk-stratified MM trials. We present here the 5-year PFS and OS follow-up for the risk stratified OPTIMUM/MUKnine trial (NCT03188172), in which treatment was specifically tailored to address UHiR MM relapse patterns.
Methods: In OPTIMUM, NDMM patients with UHiR by ≥2 HRCA: t(4;14), t(14;16), t(14;20), del(1p), gain(1q), del(17p) or gene expression risk (GEP; SKY92 signature), identified through central genomic screening of all-comers, or with PCL, received up to 6 cycles of Dara-CVRd induction, V-ASCT, 6 cycles Dara-VRd (Cons1) and 12 cycles Dara-VR (Cons2), before moving to monthly Dara-R maintenance until progression.
OPTIMUM recruited 107 UHiR participants, including 9 PCL, from 472 all-comer patients screened at 39 UK NHS hospitals between Sep 2017 and Jul 2019. We report here results of the pre-planned 5-year PFS and OS analysis for the overall group, and for pre-defined sub-groups by genetics and GEP. Results are contextualised with UHiR patient outcomes from the digital comparator Myeloma XI (MyXI) trial, in which patients received carfilzomib/cyclophosphamide-Rd (KCRd) or CRd induction, ASCT and lenalidomide maintenance or observation. Median follow-up for OPTIMUM was 61.2 months, and 60.3 months for MyXI.
Results:
With more than 5 years of follow-up, the median PFS and OS for OPTIMUM UHiR patients were not reached. A continuous improvement in PFS outcomes was noted over the digital MyXI UHiR comparator, with a hazard ratio (HR) of 0.325 (95% CI: 0.220, 0.480; p&lt;0.0001). PFS estimates for OPTIMUM at 36, 48 and 60 months were 75.2% (95% CI: 66.9, 83.4), 70.1% (95% CI: 61.3, 78.9) and 61.4% (95% CI: 51.8, 71.0), compared to MyXI with 32.1% (95% CI: 23.1, 41), 25.3% (95% CI: 16.4, 34.2) and 23% (95% CI: 13.9, 32.1), respectively. PFS estimates for patients who received KCRd in MyXI were 40.8% (95% CI: 23.1, 58.5), 23.8% (95% CI: 1.3, 46.3) and 23.8% (95% CI: 1.3, 46.3), respectively. Importantly, a continuous improvement in OS for OPTIMUM compared to MyXI also emerged with longer follow-up, with a hazard ratio of 0.467 (95% CI: 0.302, 0.723; p=0.0006). OS estimates at 60 months were 71.1% (95% CI: 62.1, 80) for OPTIMUM, versus 43.5% (95% CI: 33.4, 53.6) for MyXI.
We further analyzed outcome of clinical and molecular sub-groups of interest. OPTIMUM included 9 PCL patients, who experienced inferior outcome compared to UHiR MM (HR 4.01), with PFS at 36, 48 and 60 months of 44.4%, 33.3% and 16.7%, respectively, highlighting an ongoing unmet need of this population.
We found a strong association between genetic characteristics and outcome for the remaining 98 UHiR MM patients (excluding PCL), who were included in the trial based on ≥2 HRCA, ≥2 HRCA+GEP risk, or GEP risk alone. Patients with 3 HRCA (n=7) had markedly shorter 60 mo PFS with 14.3% (95% CI: 0, 40.2) than patients with 2 HRCA (n=50) with 66.9% (95% CI: 53.6, 80.3). Of the 50 patients with 2 HRCA, 21 had no GEP risk signature, and nearly all were still progression free and alive at 60 mo with a PFS of 95% (95% CI: 85.4, 100), suggesting exceptional benefit from OPTIMUM treatment, versus PFS 46.9% (95% CI: 28.4, 65.5) for those with 2 HRCA+GEP risk. Furthermore, UHiR MM patients identified by GEP only (n=49) had 60 mo PFS of 64.2% (95% CI: 49.9, 78.4) with OPTIMUM treatment, confirming their need for intensified treatment. Further sub-group analyses are underway and will be presented at the meeting.
Conclusions:
Our results demonstrate extended PFS beyond 5 years for the majority of UHiR MM treated with OPTIMUM treatment, and markedly improved overall survival over the MyXI UHiR digital comparator. Results exceed recently reported outcomes for patients with ≥2 HRCA, even from quadruplet induction trials, supporting OPTIMUM tailored treatment for UHiR with quintuplet induction, extended 18 mo Dara-VR consolidation, with permissive bortezomib dose reduction, and ongoing Dara-R maintenance. Furthermore, results reveal exceptional responders and ongoing unmet need groups and highlight, like for other lymphoid malignancies, the strength of integrating GEP with genetic testing in MM.