Double hit ultra-high risk myeloma treated with isatuximab, bortezomib, lenalidomide, dexamethasone and cyclophosphamide (Isa-VRDc) induction and isa-VRD consolidation: Initial results of the UK myeloma research alliance (UKMRA)  RADAR trial in newly

Abstract Background: Clinical outcomes in transplant eligible (TE) newly diagnosed myeloma (NDMM) patients continue to improve, which highlight the persistent unmet need in patients with genetically high-risk disease. Recently published IMS/IMWG high risk criteria confirms poor outcomes in double-hit [2 high risk cytogenetic abnormalities (HRCA)] disease in comparison to patients with single HRCA (Avet-Loiseau JCO 2025). RADAR aimed to evaluate Isa-VRDc induction followed by single autologous stem cell transplant (ASCT), Isa-VRD consolidation and IsaR maintenance, in patients with ultra-high-risk disease. Study design/ Methods: UK-MRA RADAR is a prospective, national, multi-centre, risk-adapted, response-guided multi-arm, multi-stage (MAMS) phase II/III trial which aims to recruit 1400 patients with NDMM eligible for ASCT. Participants enter a high-risk pathway based on the presence of ≥2 HRCA (t(4;14), t(14;16), t(14:20), del(17p), del1p and gain(1q)) defined by standard-of-care cytogenetic (FISH/MLPA) testing. Participants with high-risk disease in v4 of the protocol (HRv4) received 4 x 21 day cycles of Isa-VRDc (Isa: Weekly C2, D1 and D8 C3, D1 and D15 C4; V: Weekly; R:D1-14; D:Weekly; c: D1 and D8). Participants received an ASCT followed by 4 x 21 day cycles of Isa-VRD consolidation (Isa: Weekly C1, D1 and D8 C2, D1 and D15 C3+; V: Weekly; R:D1-14; D:Weekly) and 28 day cycles of IsaR maintenance (Isa: Weekly C1, D1 and D15 C2; R: D1 – D21) until progression. Flow MRD testing (sensitivity 10-5) was done post-induction, post-transplant and 3, 6,12 and 18 months after starting consolidation. Primary endpoint was the proportion of patients alive and progression-free at 18 months. HRv4 followed a Sargent three-outcome phase II design. It was designed to test the null hypothesis (Ho) that the proportion of patients alive and progression-free at 18 months post-registration was ≤65.9% (based on data from Myeloma XI) against the alternative hypothesis of ≥81.7% (OPTIMUM, Kaiser Blood 2021). 70 patients were required for at least 80% power, testing at the 1-sided maximum 5% significance level with a 5% drop-out rate. Results: 70 participants were registered to HRv4 between 1Sept22 and 4Sept23. Median age was 60 yrs (range, 40-74). 84.3% of individuals were of white ethnicity. R-ISS staging proportions at diagnosis I/II/III/missing was 18.6%/67.1%/10.0%/4.3% respectively. All participants had 2 HRCA and 8/70 had ≥3 HRCA. Median follow up was 24 months (IQR, 21-26). 69/70 participants started induction treatment. 68/69 completed all four cycles. Adequate stem cell harvest was obtained in all eligible patients (62/68), and 61 proceeded to ASCT. 56 participants commenced post-ASCT treatment. Dose delivery was as per the protocol in >90% of all treatment cycles across the entire treatment pathway (induction, consolidation and maintenance). 67/70 participants were evaluable for primary endpoint. The cut-offs for the three-outcome design were: Red (do not reject Ho) ≤47 / 67, Amber (neither accept or reject Ho) 48 - 51 / 67, Green (reject Ho) ≥52 / 67. In total 59/67 participants were alive and progression-free at 18 months (88.1% (95%CI: 77.8-94.7)). ≥VGPR rates increased from 82.9% post induction to 87.5% post-transplant and were 96.2% and 85.7% at 6 and 12 months after starting consolidation. MRD negativity was 26.2% post-induction, 69.5% post-transplant and 69.6% and 59.5% at 6 and 12 months after starting consolidation. Of MRD negative participants post-ASCT with a sample available, 66.7% remained MRD negative 12 months after starting consolidation. A grade 3-4 adverse reaction was reported in 63.8% of participants. No treatment-related deaths have been reported. 47/69 (68.1%) participants had an SAE. Infections were the commonest SAE; 36/85 (42.4%) with 31/36 ≥G3 (86.1%).Conclusions: RADAR HRv4 pathway is the largest analysis of ultra-high risk (double hit) patients reported to date. All participants meet the new IMS/IMWG HR criteria. Isa-VRDc induction, followed by Isa-VRD consolidation post-ASCT and IsaR maintenance met the primary endpoint, with the study crossing the Green design threshold, with 88% (59/67) alive and progression-free at 18 months. These results compare favourably to the TE NDMM GMMG HD-7 trial which included standard and high-risk patients, and high-risk CONCEPT and OPTIMUM NDMM trials with extended consolidation