Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (Isa-KRd) in Patients with High-Risk Newly Diagnosed Multiple Myeloma: Planned Interim Analysis of the GMMG-Concept Trial

Background: High-risk (HR) multiple myeloma (MM) patients (pts) have a significantly disadvantageous prognosis. Emerging data show that achievement of minimal residual disease (MRD) negativity is associated with better outcome in HR pts. Most recently, several clinical trials demonstrated that addition of monoclonal anti CD38 antibodies (i.e. isatuximab) significantly improve MRD negativity, response rate and survival when added to standard of care regimens. Carfilzomib (K), lenalidomide (R) and dexamethasone (d) is one of the most effective and tolerable regimens in newly diagnosed multiple myeloma (NDMM). The phase II CONCEPT trial (NCT03104842) investigates the quadruplet regimen isatuximab plus KRd (Isa-KRd) in HR NDMM in induction and consolidation including high-dose melphalan (HDM) for pts being transplant-eligible (TE). Here, we report for the first time the planned interim analysis (IA) of the primary endpoint MRD negativity after consolidation for TE-patients and the corresponding final analysis of transplant non-eligible (TNE) pts.

Methods: 153 pts with HR NDMM were included into the open-label, academic, multicentre phase II clinical trial, an extension cohort of TE pts is currently recruiting. According to the trial design, 99 of 127 TE pts in study arm A (TE-ITT) were included in the intention-to-treat population (ITT) of the planned IA (TE-ITT-IA); results of the 26 TNE pts in study arm B (TNE-ITT) are finally reported. HR MM was defined by the presence of del17p or t(4;14) or t(14;16) or > 3 copies 1q21 in combination with ISS 2 or 3 stage disease. Pts could be included after a maximum of 1 cycle of MM treatment. Pts received 6 cycles of Isa-KRd induction, followed by HDM for TE pts or 2 Isa-KRd cycles for TNE pts, 4 cycles Isa-KRd consolidation and Isa-KR maintenance. Primary endpoint is MRD negativity at end of consolidation measured by next-generation flow at the minimum sensitivity threshold of 10^-5 (H0: MRD-neg-rate ≤ 50% (TE) and ≤ 30% (TNE), tested by one-sided binomial test), this planned IA reports on. Secondary endpoint is progression-free survival (PFS), tertiary endpoints include overall response rate (ORR) and safety.

Results: 125 pts (99 TE-ITT-IA, 26 TNE-ITT) were included from August 2017 to April 2020 in the IA population in 17 German Centres. No bias arose in the reduction of the TE-ITT population to the TE-ITT-IA population. Based on inclusion criteria, all pts had cytogenetic HR disease including del17p in 55 pts (44.0%), t(4;14) in 48 (38.4%), t(14;16) in 19 (15.2%) and > 3 copies 1q21 in 45 pts (36.0%). 38 pts (30.4%) had ≥ 2 HR aberrations. 66 pts (52.8%) had ISS 2 and 58 (46.4%) ISS 3 disease. Median age (range) was 58 (35-73) years in the TE-ITT-IA and 74 (64-87) years in the TNE-ITT. The design of the study provides for the MRD-analysis to be performed on 93 patients in the TE-ITT-IA and 24 patients in the TNE-IA. At the end of consolidation, in the TE-ITT-IA population 67.7% (n=63) of pts were MRD negative, 3.2% (n=3) MRD positive, 24.7% (n=23) timepoint not reached, 4.3% (n=4) missing (4 pts not assessable, 2 did not start). In the TNE-ITT population 54.2% (n=13) of pts were MRD negative, 0% MRD positive, 45.8% (n=11) timepoint not reached. The primary endpoint was significantly reached in both study arms (p = 0.0004 for TE-ITT-IA and p=0.012 for TNE-ITT). ORR (best response to treatment) in the TE-ITT-IA was 94.9% (n=94) with 72.7% showing complete remission (CR) or better (n=72), 18.2% (n=18) very good partial remission (VGPR), 4% (n=4) partial remission (PR), 1% (n=1) progressive disease (PD) and 4% (n=4) timepoint not reached. In the TNE-ITT, 57.7% (n=15) showed CR or better 30.8% (n=8) VGPR, 3.8% (n=1) were unknown and 7.7% (n=2) timepoint not reached. Updated PFS data will be shown. Safety-population consists of 122 pts. In total, 85.2% (n=104) developed ≥ grade 3 treatment-emergent adverse events (TEAEs). Serious TEAEs occurred in 64.8% (n=79) of pts. TEAEs leading to discontinuation of study treatment occurred in 5 pts.

Conclusions: The CONCEPT trial is the first trial investigating Isa-KRd for HR NDMM in TE and TNE patients. Isa-KRd in induction and consolidation leads to high MRD negativity rates after consolidation in this difficult-to-treat population. Toxicity was consistent with expectations and no new safety signals occurred in this IA. In our view, our data underline the importance of optimized quadruplet treatment in NDMM, especially in HR disease.