For newly diagnosed patients with multiple myeloma participating in the international phase III ATLAS trial, use of carfilzomib, lenalidomide, and dexamethasone (KRd) as maintenance therapy after induction and autologous stem cell transplantation (ASCT) significantly reduced the risk of disease progression by 44%, compared with standard lenalidomide maintenance therapy, according to Dominik Dytfeld, MD, of Poznan University of Medical Sciences in Poland.1 Median progression-free survival was 59.0 months with KRd compared with 41.1 with lenalidomide alone (hazard ratio [HR] = 0.56; P = .026), Dr. Dytfeld reported at the 2022 ASCO Annual Meeting.
This is the first randomized phase III trial to indicate superior progression-free survival with extended posttransplant KRd therapy compared with lenalidomide maintenance.— Dominik Dytfeld, MD
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“This is the first randomized phase III trial to indicate superior progression-free survival with extended posttransplant KRd therapy compared with lenalidomide maintenance,” Dr. Dytfeld said.
ATLAS also evaluated a risk-adapted de-escalation approach to continued maintenance using measurable residual disease (MRD) status. Patients with standard-risk cytogenetics on KRd maintenance who achieved MRD negativity after six cycles were switched to lenalidomide alone after two more cycles of KRd. Median progression-free survival for MRD-negative standard-risk patients was not reached in either treatment arm.
Extended KRd after induction and ASCT further improved the depth of response associated with prolonged progression-free survival. Similar findings were made in the FORTE trial, in which extended carfilzomib-based maintenance therapy, with or without ASCT, improved outcomes.2
“We believe that KRd may be a new standard of care in terms of maintenance, especially for standard-risk patients with multiple myeloma who can achieve MRD negativity and then be converted to a de-escalation approach,” Dr. Dytfeld said. He noted that MRD guidance will not only result in longer remissions, but also better tolerability.
ATLAS included 180 patients who received a single ASCT after completion of one or two induction regimens (excluding dexamethasone alone) and had stable disease or better in the first 100 days after ASCT. All patients were enrolled within 12 months of starting induction therapy.
Approximately 20% had high-risk cytogenetics. The majority had received one induction regimen, which was primarily bortezomib, thalidomide, and dexamethasone (VTd). Almost all patients (approximately 90%) had achieved a very good partial response or better.
Patients were randomly assigned to receive KRd or lenalidomide after induction and ASCT. In the KRd arm, standard-risk patients who achieved MRD negativity (10-5 by next-generation sequencing) after cycle 6 had treatment de-escalated to lenalidomide alone after cycle 8; the rest of the patients continued KRd through cycle 36 followed by lenalidomide alone until disease progression.
The primary endpoint was progression-free survival. A key secondary endpoint was the rate of MRD negativity at 6 and 12 months after randomized assignment.
Progression-Free Survival, MRD Negativity Improved
After a median follow-up of 33.8 months, there were 61 progression-free survival events: 23 in the KRd arm vs 38 in the lenalidomide arm. Risk of disease progression was reduced by 44% (P = .026) with KRd. In addition, the advantage of the combination therapy over lenalidomide alone was consistent across cytogenetic risk groups, the number of induction regimens, and post-ASCT response, Dr. Dytfeld reported.
By International Myeloma Working Group criteria, MRD negativity was achieved by cycle 6 in 44% of the KRd arm compared with 27% of the lenalidomide arm (P = .027). By next-generation sequencing, MRD negativity at 10–5 was observed in 50% vs 33% (P = .07), respectively, and at 10–6, it was 33% vs 24%, respectively (P = .26).
The MRD-directed risk-adapted maintenance approach resulted in even better progression-free survival with KRd than was observed in the overall study. Among standard-risk patients, median progression-free survival was not reached in the KRd arm and was 65.4 months in the lenalidomide arm (HR = 0.44; P = .01). For the standard-risk patients who achieved MRD negativity, median progression-free survival was not reached with either KRd or lenalidomide, with KRd favored (HR = 0.23; P = .01).
As of data cutoff, 90.2% of the KRd arm and 87.2% of the lenalidomide arm were still alive. Median overall survival was not reached in the KRd arm and was 61.8 months in the lenalidomide arm (HR = 0.92; P = .86).
In terms of grade ≥ 3 toxicities, patients receiving KRd had more thrombocytopenia (13% vs 7%) and more infections (15% vs 6%), but those treated with lenalidomide had more neutropenia (59% vs 48%). One treatment-related death occurred on the KRd arm.
DISCLOSURE: Dr. Dytfeld reported financial relationships with Amgen, Celgene/Bristol Myers Squibb, Janssen, and Takeda.
1. Dytfeld D, Wrobel T, Jamroziak K, et al: ATLAS: A phase 3 randomized trial of carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma. 2022 ASCO Annual Meeting. Abstract 8001. Presented June 5, 2022.
2. Gay F, Musto P, Rota-Scalabrini D, et al: Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): A randomised, open-label, phase 2 trial. Lancet Oncol 22:1705-1720, 2021.
The invited discussant of the ATLAS trial, Peter M. Voorhees, MD, Professor of Medicine, Chief of the Plasma Cell Disorders Division, at Levine Cancer Institute and Atrium Health/Wake Forest Baptist in North Carolina, applauded the very good outcomes achieved in the study.1 However, he posed the...