Isa-KRd Quadruplet Yields “Unprecedented” MRD Negativity in Newly Diagnosed High-Risk MM

Treatment with the quadruplet isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) as induction and consolidation, with an Isa-KR maintenance achieved not only high rates of remission but also long-lasting, deep measurable residual disease (MRD)-negative remissions for patients with high-risk multiple myeloma (MM), according to data from the GMMG-CONCEPT trial published in The Journal of Clinical Oncology.¹

Katja C. Weisel, MD, of University Medical Center Hamburg-Eppendorf in Hamburg, Germany, and colleagues reported results from this interim analysis of the phase II GMMG-CONCEPT trial, which included 99 transplant-eligible and 26 transplant-ineligible patients with high-risk newly diagnosed MM. Patients were treated with Isa-KRd induction and consolidation and 26 cycles of Isa-KR maintenance. Transplant-eligible patients received high-dose melphalan (HDT) prior to autologous hematopoietic cell transplant (AHCT). Transplant-ineligible patients had two additional cycles of Isa-KRd instead of HDT-AHCT.

The trial’s primary endpoint was MRD negativity measured to 10^-5 at the end of consolidation. MRD negativity was achieved in about two-thirds (67.7%) of transplant-eligible and more than half (54.2%) of transplant-ineligible patients.

Among transplant-eligible patients, 81.8% achieved MRD negativity at any time point. About two-thirds (62.6%) of all patients sustained MRD negativity for one year or longer.

“Treatment with the quadruplet Isa-KRd in induction, consolidation, and with an Isa-KR maintenance is able to achieve not only high rates but also long-lasting, deep MRD-negative remissions for roughly two-thirds of patients, and this achievement translates into survival prognosis,” Dr. Weisel said.

With a median follow-up of 44 months for transplant-eligible patients and 33 months for transplant-ineligible patients, median progression-free survival was not reached in either arm.

“We believe that these data are really important for our patients [with MM] and their caregivers,” Dr. Weisel said.

In addition to the Isa-KRd regimen tested in CONCEPT, the KRd backbone has also been tested with daratumumab, a CD38-directed antibody, in the MASTER trial,² which had enrichment for high-risk cytogenetic abnormalities. A KRd backbone was also tested in IFM-2018-04³ using daratumumab, carfilzomib, lenalidomide, and dexamethasone. Another trial, OPTIMUM,⁴ tested the quintuplet daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone.

“Albeit inclusion criteria and definition for high-risk disease and exact treatment schedules differed, high rates of MRD negativity were achieved with either treatment combination,” Dr. Weisel said. “To date, the rates of one-year-sustained MRD negativity reported in CONCEPT are so far unprecedented and indicate long-lasting, deep remissions in these hard-to-treat patients.”

Because none of the trials was randomized, there are no direct comparisons of the CONCEPT data to standard-of-care regimens.

“However, when we look on the results of the CONCEPT trial and in line with what was reported from OPTIMUM and MASTER trials, and recently also IFM 2018-04, we are convinced that the standard for newly diagnosed high-risk MM should nowadays be a prolonged four- or five drug-induction including a CD38-directed antibody, followed by a quadruplet consolidation and a multiagent maintenance,” Dr. Weisel said. “We have to put our efforts into making these treatments broadly available for any patient [with high-risk MM] at need, and we are working on improving outcomes even further.”

This study was limited by comparisons with similar but “never completely equal” studies.

Any conflicts of interest declared by the authors can be found in the original article.

References

1. Leypoldt LB, Tichy D, Besemer B, et al. Isatuximab, carfilzomib, lenalidomide, and dexamethasone for the treatment of high-risk newly diagnosed multiple myeloma [published online ahead of print, 2023 Sep 27]. J Clin Oncol. doi: 10.1200/JCO.23.01696.
2. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. 2022;40(25):2901-2912.
3. Touzeau C, Perrot A, Hulin C, et al. Daratumumab carfilzomib lenalidomide and dexamethasone as induction therapy in high-risk, transplant-eligible patients with newly diagnosed myeloma: results of the phase 2 study IFM 2018-04. J Clin Oncol. 2022;40(16_suppl):8002-8002.
4. Kaiser MF, Hall A, Walker K, et al. Daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone as induction and extended consolidation improves outcome in ultra-high-risk multiple myeloma. J Clin Oncol. 2023;41(23):3945-3955.