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    Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

    (OA-49) Insights from Cytogenetic Subgroup Analyses in the GMMG-CONCEPT trial with Isa-KRd in High-Risk Newly Diagnosed Multiple Myeloma

    Wednesday, September 17, 2025
    16:40 - 16:50 East Coast USA Time
    Location: Room 718
    Introduction: High-risk (HR) multiple myeloma (MM) patients (pts) continue to show impaired survival compared to standard risk pts with newly diagnosed (ND) disease and are therefore in need of novel effective treatment options. The academic, multi-center phase II GMMG-CONCEPT trial (NCT03104842) investigates the quadruplet isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in ND HR MM both transplant-eligible (TE) and ineligible (TNE) pts and is the largest prospective HR trial. We have previously shown high rates of minimal residual disease (MRD) negativity with overall MRD-negativity rates of 86.8% [TE] and 69.2% [TNE] (Leypoldt et al.). Here, we report detailed outcomes from the different HR cytogenetic subgroups of the whole cohort.


    Methods: HR MM was defined by ISS stage 2 or 3 and any of del17p, t(4;14), t(14;16), or ≥3 copies 1q21 (gain1q). Isa-KRd induction (6 cycles), high-dose therapy (for TE pts; 2 cycles Isa-KRd for TNE pts) and consolidation (4 cycles) are followed by 2 years of Isa-KR maintenance. MRD is centrally assessed by next-generation flow with a sensitivity level of 10-5. Clinical data cutoff was 28.04.2025.


    Results:

    The trial included 245 HR NDMM pts (219 TE, 26 TNE) with a median age of 59.6 (TE) and 74.9 years (TNE); del17p (40.8%) and gain1q (47.3%) were the most common HR cytogenetic aberrations, followed by t(4;14) and t(14;16) (35.1% and 15.5%, respectively). Eighty-five pts (34.7%) had ≥ 2 HRCA; of these, the most frequent double-hit combinations were del(17p) + gain1q (26 pts, 10.6%) and t(4;14) + gain1q (36 pts, 14.7%).


    As reported, the primary endpoint of MRD-negativity at the end of consolidation was achieved in 74.8% (TE) and 69.2% (TNE) of pts. With regards to HRCA subgroups (in TE pts only due to sample size), the majority demonstrated a similar distribution, including pts with del(17p) and ≥2 HRCA with only slightly lower rates (65.5% [57/87] and 68% [51/75], respectively). Lowest MRD-negativity rates, however, were observed in pts with del(17p) + gain1q (54.2%; 13/24), del(17p) + t(4;14) (46.7%; 7/15), and del(17p) + t(14;16) (37.5%, 3/8), strikingly all marking del(17p) double-hit. In contrast, highest rates of MRD-negativity were seen in pts with t(4;14) only (82.8%, 24/29), pts without del(17p) (81.1%, 99/122), or pts with gain1q + t(14;16) (80%, 12/15). Detailed MRD kinetics (incl. induction, intensification, maintenance) will be presented.


    Conclusions: These data from our CONCEPT trial underline the high potency of Isa-KRd to induce high rates of MRD-negative remissions across different cytogenetic subgroups in HR NDMM pts. An unmet need still remains for patients with double-hit HRCA including del(17p) whereas e.g. pts with gain1q seem to be adequately addressed by this isatuximab-containing regimen.


    Sponsor: University Medical Center Hamburg-Eppendorf. Funding and IMP: Sanofi, Amgen, BMS/Celgene.