For the treatment of newly diagnosed multiple myeloma with high-risk features, a quadruplet regimen of the anti-CD38 antibody isatuximab plus carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) induced high rates of measurable residual disease (MRD) negativity, both in transplant-eligible and transplant-ineligible patients, in the phase II GMMG-CONCEPT trial.1 These remissions were durable, with 1-year sustained MRD negativity in 62.6% and 46.2% of these cohorts, respectively, and median progression-free survival not reached after more than 3 years, according to Lisa B. Leypoldt, MD, clinician and researcher in the Department of Oncology, Hematology, and Bone Marrow Transplantation at University Medical Center Hamburg-Eppendorf, Germany, and a postdoctoral research fellow at Dana-Farber Cancer Institute, Boston.
Lisa B. Leypoldt, MD
Dr. Leypoldt presented the results at the International Myeloma Society 2023 Annual Meeting in Athens.1 The study was concurrently published in the Journal of Clinical Oncology.2
“Patients with high-risk multiple myeloma continue to show significantly poorer survival outcomes than patients without high-risk disease, even in the current era of novel agents and immunotherapy. To date, achievement of MRD negativity is the strongest predictor of outcomes. That’s why our academic phase II investigator-initiated GMMG-CONCEPT trial examined the MRD negativity rate in high-risk newly diagnosed patients with myeloma, both transplant-eligible and transplant-ineligible, who were treated with Isa-KRd,” said Dr. Leypoldt.
An earlier analysis showed the MRD negativity rates to be 67.7% in transplant-eligible patients and 54.2% in transplant-ineligible patients, thus meeting the study’s primary endpoint.3 A very good partial response or better was achieved by 90.9% and 88.5% of patients in these two groups, respectively. Dr. Leypoldt presented additional data, with a focus on sustained MRD negativity, subgroup analyses, progression-free survival, and overall survival.
About GMMG-CONCEPT
The phase II study reported on 125 newly diagnosed patients considered at high risk for the following reasons: International Staging System (ISS) stage II or III disease plus at least one cytogenetic alteration—including del(17p), t(4;14), or t(14;16)—and/or more than three copies of 1q21(amp1q21). Approximately 30% of patients had at least two cytogenetic alterations. The 99 transplant-eligible patients received 6 cycles of Isa-KRd as induction followed by autologous stem cell transplantation and 4 cycles of consolidation Isa-KRd, then 26 cycles of maintenance Isa-KR (no dexamethasone). The 26 transplant-ineligible patients underwent 8 cycles of Isa-KRd, followed by an additional 4 cycles, then 26 cycles of maintenance.
As reported in the earlier analysis, the rate of MRD negativity at the end of consolidation was 67.7% in the transplant-eligible cohort and 54.2% in the transplant-ineligible cohort. Dr. Leypoldt noted these initial responses deepened over time, with complete responses or better achieved by 72.7% and 57.7%, respectively. At any point during the study, 81.8% and 69.2% of patients, respectively, achieved MRD negativity, and 62.6% and 46.2%, respectively, demonstrated MRD negativity for at least 1 year, she reported.
KEY POINTS
- The GMMG-CONCEPT trial evaluated isatuximab plus carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in patients with high-risk newly diagnosed multiple myeloma.
- After consolidation with this quadruplet, more than two-thirds of transplant-eligible patients and more than half of transplant-ineligible patients achieved MRD negativity.
- Responses deepened over time, and MRD negativity was sustained for at least 1 year in 62.6% and 46.2%, respectively.
- Median progression-free survival was not reached after more than 3 years in either cohort.
“Next, we asked whether these high rates translate into survival. We saw that in high-risk transplant-eligible patients, with close to 4 years of follow-up, the median progression-free survival was not yet reached,” she noted. In both cohorts, the secondary endpoint of progression-free survival was met. In transplant-eligible patients, medians for progression-free and overall survival were not reached after a median follow-up of 44 months. The progression-free survival rates were 84.5% at 1 year, 77.2% at 2 years, and 68.8% at 3 years. Overall survival rates were 90.7%, 84.4%, and 72.8%, respectively, Dr. Leypoldt reported.
Similarly, in the transplant-ineligible cohort, after a median follow-up of 33 months for progression-free survival and 35 months for overall survival, the medians were not reached. Progression-free survival rates were 75.1% at 1 year, 62.6% at 2 years, and 58.4% at 3 years. Overall survival rates were 83.5%, 71.0%, and 71.0%, respectively.
The investigators found three markers to be associated with worse overall survival: elevated lactate dehydrogenase, the presence of at least two high-risk cytogenetic alterations, and the occurrence of del(17p). The analysis also showed that MRD negativity clearly conferred a significant prognostic progression-free survival benefit.
DISCLOSURE: Dr. Leypoldt has served as an advisor and/or received honoraria from GSK, Sanofi, Janssen, Bristol Myers Squibb, and Celgene; institutional research support from AbbVie and GSK; and training and/or travel support from GSK, Sanofi, and AbbVie.
REFERENCES
1. Leypoldt LB et al: Analysis of sustained MRD negativity and progression-free survival of isa-KRd in high-risk newly diagnosed multiple myeloma. International Myeloma Society Annual Meeting. Abstract OA-43. Presented September 27, 2023.
2. Leypoldt LB et al: Isatuximab, carfilzomib, lenalidomide, and dexamethasone for the treatment of high-risk newly diagnosed multiple myeloma. J Clin Oncol. September 27, 2023 (early release online).
3. Weisel K et al: Isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in patients with high-risk newly diagnosed multiple myeloma. Blood 140(suppl 1):1836-1838, 2022.
