GMMG-Concept Trial: Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone in Treatment of High-Risk Multiple Myeloma

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) for newly diagnosed high-risk patients with multiple myeloma (HRMM), including both transplant-eligible and non–transplant-eligible patients. The 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 Stage System stage 2 or 3 disease. The primary outcome measure for the study is minimal residual disease (MRD) negativity measured by flow cytometry.

At initiation, the trial planned to include 153 HRMM patients with the goal of assessing the overall response rate of induction, consolidation, and maintenance treatments. Patients enrolled in the study were stratified by transplant eligibility into 2 arms. Arm A includes those eligible for stem-cell transplantation (n = 117), and arm B includes those who are not eligible for transplant (n = 36). The treatment regimen involves a 6-cycle induction treatment of Isa-KRd, a 4-cycle induction period of Isa-KRd, and an Isa-KR maintenance regimen for patients in arm A, and patients in arm B receive 2 additional cycles of Isa-KRd induction. The study included a safety run-in phase with the first 10 patients in arm A, showing the regimen is well tolerated.

The interim results of the study focus 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. The overall response rate was 100%, with 10% of patients showing partial remission, 44% of patients had a very good partial response (VGPR), and 46% of patients had complete remission in arm A. The 4 patients in arm B achieved VGPR. MRD assessment was completed for 33 patients from arm A during induction; 20 patients were MRD negative, 11 patients were MRD positive, and 2 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. In terms of grade 3/4 adverse events with the Isa-KRd regimen, 34% of patients experienced neutropenia, 26% experienced leukopenia, 28% experienced lymphopenia, 10% experienced anemia, and 14% experienced thrombocytopenia. The nonhematologic grade 3/4 toxicities included hypertension (12% of patients) and infection (8% of patients).

The interim results of the GMMG-Concept trial investigating the quadruple regimen of Isa-KRd for the first time resulted in very positive results in newly diagnosed HRMM patients, and adverse events and toxicity reports that are consistent with previous safety results for these agents. The study is continuing to enroll patients, with ongoing results.


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.

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