Isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) for high-risk (HR) newly diagnosed multiple myeloma (NDMM): First-time report of the full cohort of transplant-eligible (TE) patients in the GMMG-CONCEPT trial.
Authors: Lisa B. Leypoldt, Varun Raj Ginde, Britta Besemer, Marc S. Raab, Mathias Haenel, Christoph Mann, Christian Michel, Hans Christian Reinhardt, Yon-Dschun Ko, Igor W. Blau, Christof Scheid, Maike de Wit, Martin Görner, Peter Staib, Hermann Einsele, Michael Hundemer, Axel Benner, Carsten Bokemeyer, Hartmut Goldschmidt, Katja C. Weisel
Journal: Journal of Clinical Oncology (2025)

7509 Background: Patients (pts) with HR NDMM have shown impaired survival outcomes even in the era of modern combination therapies. Establishing Isa-KRd in an intensified first-line regimen, the Phase II CONCEPT trial (NCT03104842) aimed at improving outcomes for HR NDMM pts for whom clinical trials had long been missing. Methods: The prospective, multicenter, academic Phase II CONCEPT trial has 2 parallel treatment arms according to transplant-eligibility. Adult NDMM pts with HR disease, defined as ≥1 HR cytogenetic aberration (CA) (del(17p), t(4;14), t(14;16), ≥3 copies 1q21) in combination with ISS stage II/III were included. All pts received Isa-KRd induction (6 cycles), intensification (HD-MEL+ASCT [TE pts; arm A] or 2 cycles Isa-KRd [non-TE pts; arm B]), 4 cycles Isa-KRd consolidation and 2 years Isa-KR maintenance. Primary endpoint is minimal residual disease (MRD) negativity (NGF, 10 -5 ) at the end of consolidation, tested against the null hypothesis MRD-neg rate ≤50% (TE pts); key secondary endpoints include survival times (PFS, OS). The trial recruited in 2 phases: 2017-2020 (TE+TNE; 1 st cohort) and 2021-2022 (TE only; 2 nd cohort), with a switch in carfilzomib application implemented in 2021 (1x weekly instead of 2x weekly). Interim results of the 1 st cohort have been shown before. Here, we report for the first time the final analysis on the primary endpoint from the full cohort of TE pts. Results: 219 TE pts (and 26 TNE pts) were included and dosed. At data cut-off (9 Jan 2025), 66 pts were still on treatment. Median age of TE pts was 60 years (range, 31-73) with 119 and 100 showing ISS II and III. Del(17p) and gain1q were the most common HRCA (40.6% and 46.6%) and 35.6% had ≥2 HRCA. The trial met its primary endpoint with an MRD-neg rate after consolidation of 73.2% in the MRD-analysis population (153/209; 10 not assessable). Further analyses confirmed the benefit across different CA subgroups. Overall, 58.4% reached MRD-neg ≥CR, 86.8% reached MRD-neg at any time. 64.8% and 40.6% retained ≥1-year- and ≥2-year-sustained MRD-neg. With a median follow-up (mFU) of 42 mo (0-85.5 mo), mPFS for TE pts was 69.7 mo, while mOS has not been reached. For TNE pts (mFU 60 mo), mPFS and mOS have not been reached. Reaching and remaining in MRD-neg state led to a significant PFS benefit ( hr 0.16 [0.08;0.32], time-dependent Cox regression). Carfilzomib 1x weekly resulted in fewer K discontinuations than 2x weekly dosing (0.6% and 4.8%, TE pts), with more dose reductions in the 1x weekly dosing (9.5% and 5.5%, TE pts). Conclusions: The full CONCEPT cohort represents the largest prospective trial cohort of purely HR NDMM pts reported so far. Isa-KRd resulted in unprecedented rates of MRD-neg., sustained MRD-neg. and survival supporting the use of Isa-KRd as a standard-of-care regime in this hard-to-treat population. Clinical trial information: NCT03104842 .