Special Issue: Multiple Myeloma Year in Review

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone Induction in High-Risk Multiple Myeloma Patients: Interim Analysis of the GMMG-CONCEPT Trial

2022 Year in Review - Multiple Myeloma

In the first trial with this treatment regimen, quadruplet induction with Isa-KRd in patients with high-risk MM demonstrated promising activity and a tolerable safety profile.

Although novel agents have led to significant improvement in outcomes in patients with multiple myeloma (MM), treatment of high-risk MM (HRMM) remains a challenge with limited survival benefit seen even with aggressive approaches. GMMG-CONCEPT is a phase 2, multicenter trial evaluating induction, consolidation, and maintenance with quadruplet regimen isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in primary diagnosed HRMM patients. Leypoldt and colleagues reported findings from an interim analysis focused on best response during induction and progression-free survival (PFS) data.

Planned recruitment for the trial consists of 246 patients; however, data from the first 50 patients are reported in this analysis. Eligible patients presented with high-risk features defined by presence of del17p (≥10% of purified cells), t(4;14), t(14;16), or >3 copies of 1q21. All patients had International Staging System stage II or III disease. A maximum of 1 cycle of any MM first-line treatment was allowed as emergency treatment. Arm A consisted of patients ≤70 years of age who were eligible for high-dose therapy, and arm B consisted of patients >70 years old. The primary end point was minimal residual disease (MRD) negativity. A total of 40 (80%) patients completed induction treatment with Isa-KRd. Seven patients discontinued treatment due to progressive disease, death, or patient request.

The overall response rate (ORR) was 100%; 90% had a very good partial response (VGPR) or better, 40% had a complete response, and 6% had a stringent complete response. All 4 patients in arm B completed induction and had a VGPR. A total of 95.8% achieved at least a partial response after the first induction cycle. MRD negativity assessment during induction was recommended in patients with at least a VGPR and was completed in 33 patients. A total of 20 patients achieved MRD negativity, and 2 were not able to be assessed. Median PFS was not reached after a median follow-up of 24.9 months; median 12-month PFS was 79.6%, and median 24-month PFS was 75.5%.

Adverse events occurring in more than 10% of patients included neutropenia, lymphopenia, leukopenia, anemia, thrombocytopenia, upper respiratory tract infections, pyrexia, rash, peripheral sensory neuropathy, arterial hypertension, and nasopharyngitis. The most common grade 3/4 adverse events in more than 10% of patients were neutropenia, lymphopenia, leukopenia, thrombocytopenia, anemia, infections, and arterial hypertension. Isatuximab-related infusion reactions occurred in 32% of patients, all of which were grade 1/2.

Trials for patients with HRMM are rare, and this population is often underrepresented in clinical trials. GMMG-CONCEPT is the first trial investigating the quadruplet Isa-KRd regimen, and the interim analysis showed promising results with an ORR of 100% and a tolerable safety profile. Rapid and deep responses with Isa-KRd induction may translate into durable responses, which will be reported in further results of this ongoing trial.


  1. Leypoldt LB, Besemer B, Asemissen AM, et al. Isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: interim analysis of the GMMG-CONCEPT trial. Leukemia. 2022;36:885-888.

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