The ongoing GMMG-Concept trial is a phase 2, multicenter, investigator-initiated, open-label trial examining the induction, consolidation, and maintenance treatment of the 4-drug combination of isatuximab plus carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in patients newly diagnosed with high-risk multiple myeloma (MM); this includes both transplant-eligible and non–transplant-eligible patients.
High-risk criteria for inclusion are based on the fluorescence in situ hybridization analysis criteria of the presence of ≥1 of the genetic abnormalities of del(17p), t(4;14), or t(14;16), or >3 copies of 1q21 and International Staging System stage 2 or 3 disease. The study’s primary outcome measure is minimal residual disease (MRD)-negativity measured by flow cytometry.
At initiation, the trial planned to include 153 patients with high-risk MM to assess the overall response rate of induction, consolidation, and maintenance treatments. Patients enrolled in the study were stratified into 2 arms by transplant eligibility. Patients in arm A were those eligible for stem-cell transplantation (N = 117), and patients in arm B were those not eligible for transplantation (N = 36). For patients in arm A, the treatment regimen involved a 6-cycle induction treatment of Isa-KRd, a 4-cycle induction period of Isa-KRd, and an Isa-KR maintenance regimen. Patients in arm B received 2 additional cycles of Isa-KRd induction. The study included a safety run-in phase with the first 10 patients in arm A; this showed that the regimen was well-tolerated.
The study’s interim results focused on the interim analysis population of 50 patients; 46 in arm A and 4 in arm B. High-risk cytogenetics, including del(17p), t(14;4), t(14;16), and >3 copies of 1q21, were present in 52%, 38%, 12%, and 42% of patients, respectively. Overall response rate was 100%; 10% of patients showed partial remission, 44% of patients had a very good partial response (VGPR), and 46% of patients had complete remission in arm A. VGPR was achieved in the 4 patients in arm B. During induction, MRD assessment was completed for 33 patients from arm A: 20 patients were positive for MRD, 11 patients were negative for MRD, and 2 patients were not assessable. All 46 patients in arm A underwent stem-cell transplantation with median stem-cell yield of 6.0 × 106 CD34+ cells/kg.
The safety profile was examined in all 50 patients. Regarding grade 3/4 adverse events with the Isa-KRd regimen, 34% of patients experienced neutropenia, 26% had leukopenia, 28% had lymphopenia, 10% had anemia, and 14% had thrombocytopenia. The nonhematologic grade 3/4 toxicities included hypertension in 12% of patients and infection in 8% of patients.
In newly diagnosed patients with high-risk MM, the interim results of the GMMG-Concept trial investigating the quadruple regimen of Isa-KRd for the first time resulted in very positive results. Adverse events and toxicity reports are consistent with previous safety results for these agents. The study is continuing to enroll patients; results are ongoing.
Reference
Abstract and Presentation S204. EHA 2020. June 12, 2020. Depth of response to isatuximab, carfilzomib, lenalidomide and dexamethasone (ISA-KRD) in frontline treatment of high-risk multiple myeloma: interim analysis of the GMMG-Concept trial.