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.
Reference
- 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.