The addition of isatuximab to standard carfilzomib-lenalidomide-dexamethasone (KRd) therapy has demonstrated significant improvements in achieving minimal residual disease (MRD) negativity in patients with newly diagnosed multiple myeloma, according to results from two major clinical trials presented at recent hematology conferences.
Phase 3 IsKia Trial Shows Superior MRD Outcomes
The randomized phase 3 IsKia trial (NCT04483739) met its primary endpoint, demonstrating that isatuximab-carfilzomib-lenalidomide-dexamethasone (Isa-KRd) significantly increased MRD negativity rates compared to KRd alone in transplant-eligible patients with newly diagnosed multiple myeloma.
At a median follow-up of 21 months, the MRD negativity rates at the 10-5 cutoff post-consolidation were 77% in the Isa-KRd arm (n = 151) versus 67% in the KRd arm (n = 151; OR, 1.67; P = .049). The difference was even more pronounced at the more stringent 10-6 cutoff, with rates of 67% versus 48% respectively (OR, 2.29; P < .001).
"The primary end point of the study was met," said Francesca Gay, MD, PhD, associate professor in the Department of Molecular Biotechnology and Health Sciences at the University of Torino. "The rate of MRD negativity by intention to treat analysis was significantly higher with Isa-KRd vs KRd."
Progressive Improvement Throughout Treatment
MRD negativity rates improved consistently throughout the treatment course. At the 10-5 cutoff, rates were 45% versus 26% (OR, 2.34; P < .001) post-induction, 64% versus 49% (OR, 1.93; P = .006) post-autologous stem cell transplant (ASCT), and 77% versus 67% (OR, 1.67; P = .049) post-consolidation in the Isa-KRd versus KRd arms, respectively.
At the 10-6 cutoff, MRD negativity rates were 27% versus 14% (OR, 2.36; P = .004) post-induction, 52% versus 27% (OR, 3.01; P < .001) post-ASCT, and 67% versus 48% (OR, 2.29; P < .001) post-consolidation.
High-Risk Patients Benefit from Isatuximab Addition
The GMMG-CONCEPT trial (NCT03104842) specifically evaluated Isa-KRd in high-risk multiple myeloma patients, providing additional evidence of the regimen's efficacy in challenging patient populations.
Among evaluable transplant-eligible patients (n = 93), 67.7% achieved MRD negativity at 10-5 sensitivity at the end of consolidation (95% CI, 0.589-1; P = .0004). In transplant-ineligible patients (n = 24), the MRD-negativity rate was 54.2% (95% CI, 0.358-1; P = .012).
"Isa-KRd induces high rates of MRD-negative remissions in these [patients with] high-risk, newly diagnosed myeloma, [including those who are] transplant eligible and ineligible," said Lisa Leypoldt, MD, clinician scientist at University Medical Center Hamburg-Eppendorf.
Sustained MRD Negativity
The durability of response was notable, with 81.8% of transplant-eligible patients and 69.2% of transplant-ineligible patients achieving MRD negativity at any point. MRD negativity was sustained for at least one year in 62.6% and 46.2% of transplant-eligible and -ineligible patients, respectively.
Efficacy Across Risk Groups
Subgroup analyses from the IsKia trial revealed consistent benefits across patient populations. "The increase in [the] MRD negativity rate in the Isa-KRd arm was seen in all the subgroups of patients analyzed at the 10-5 and 10-6 cutoff. Interestingly, this was true for standard risk, high-risk, and very high-risk patients," Gay noted.
In patients with very high-risk disease, post-consolidation MRD negativity rates at the 10-5 cutoff were 77% in the Isa-KRd arm versus 53% in the KRd arm. At the 10-6 cutoff, these rates were 77% versus 27%, respectively.
Safety Profile Remains Manageable
Treatment-related adverse events were manageable in both studies. In the IsKia trial, patients experienced at least one any-grade hematologic toxicity in 55% of the Isa-KRd arm versus 44% of the KRd arm, with neutropenia (41% vs 26%), thrombocytopenia (34% vs 25%), and anemia (21% vs 19%) being most common.
Any-grade non-hematologic toxicities occurred in 90% of Isa-KRd patients and 85% of KRd patients, with grade 3 or 4 toxicities in 41% versus 37% of patients, respectively.
Prognostic Significance of MRD Negativity
Analysis from the GMMG-CONCEPT trial demonstrated that achieving MRD negativity conferred significant prognostic benefits. A univariate time-varying Cox-regression model showed a prognostic progression-free survival benefit for MRD negativity (HR, 0.118; 95% CI, 0.049-0.289; P = .0027).
"We could clearly see that the achievement of MRD negativity did confer a significant prognostic PFS benefit," Leypoldt concluded.
The median progression-free survival and overall survival were not reached in either arm of the GMMG-CONCEPT trial, with 3-year progression-free survival rates of 68.8% in transplant-eligible patients and 58.4% in transplant-ineligible patients.
