Patients with multiple myeloma (MM) who discontinued maintenance therapy based on measurable residual disease (MRD) negativity had a high rate of sustained MRD negativity without disease progression, according to the results of a prospective trial. The MRD2STOP study demonstrated that patients with MRD negativity at the 10-6 threshold (less than one myeloma cell within one million cells analyzed) at the time of maintenance therapy discontinuation had an estimated three-year progression-free survival (PFS) of 85% and a three-year cumulative incidence of MRD resurgence or disease progression of 30%. The results were published in Blood Cancer Journal.1
“These results suggest that MRD negativity using currently available assays — next-generation sequencing (NGS), flow cytometry, and PET scan — may be used to help guide de-escalation of maintenance therapy for patients with MM,” said study author Benjamin A. Derman, MD, of the University of Chicago.
Lenalidomide is usually used for maintenance therapy for MM and can lead to deeper responses following induction therapy or consolidation with autologous hematopoietic cell transplantation (AHCT), including converting patients from an MRD-positive to MRD-negative status. Maintenance therapy has been shown to extend overall survival in meta-analyses.2,3
As induction therapy has evolved to triplet and quadruplet combinations and consequently improved the depth and duration of response for patients with MM, the researchers sought to understand whether patients who reach MRD negativity on maintenance therapy can cease treatment and continue to stay MRD negative and in remission. Prior to the current study, the IFM-2009 study from 2018 had shown that patients who were MRD negative at a threshold of 10-6 after one year of maintenance lenalidomide had a three-year PFS of about 75%.4
“All patients on that study stopped lenalidomide after one year, so it gave us some insight into what happens to patients with MRD negativity who then subsequently stop treatment,” Dr. Derman said. A 2023 study from the Spanish Myeloma group showed that MRD-negative patients who stopped maintenance therapy after two years had a four-year PFS of 82.8%.5
The MRD2STOP study enrolled 47 patients with a median age of 66 years who met the criteria to stop their maintenance therapy. Almost all patients (45 of 47) had been receiving single-agent lenalidomide as their maintenance therapy. The median duration of maintenance after induction or transplant before maintenance therapy was discontinued was 36 months, and 14 patients (30%) received two years or less of consolidation or maintenance therapy. At least one high-risk disease feature was present in 17 (36%) patients at diagnosis. Patients had to be in at least a complete response with no detectable disease by PET scan and MRD negative by flow cytometry and NGS at a sensitivity of 10-6. There were no restrictions based on the type, duration, or intensity of prior induction or consolidation therapies.
The investigators also sought to improve upon the current diagnostics used to assess for MRD by using a CD138+-based selection coupled with clonoSEQ to achieve 10-7 sensitivity on high-volume bone marrow aspirate samples. Using this methodology, they found that at baseline, nine of the 47 patients (19%) were MRD positive at the 10-7 threshold, which was associated with inferior PFS and incidence of disease resurgence, compared with MRD-negative status of less than 10-7.
“Our results support using MRD less than 10−6 as a minimum threshold for a patient-centered discussion around treatment discontinuation for patients with standard-risk disease on single-agent maintenance,” Dr. Derman said. Although maintenance discontinuation in patients with MRD less than 10−6 led to low rates of disease resurgence, the authors concluded that MRD less than 10−7 may be a superior cessation threshold compared with MRD 10-6 that requires further validation.
Disease resurgence, defined as MRD greater than or equal to 10−6, occurred in 11 patients, including five patients with disease progression. One patient died from a second cancer. The estimated three-year cumulative incidence of disease resurgence was 20% for patients with baseline MRD less than 10−7 compared with 75% for MRD greater than or equal to 10−7 (p=0.001). The estimated three-year PFS for patients with 10-7 negativity was 92% compared with only 49% for patients with 10-7 positivity at the time of discontinuation.
According to Dr. Derman, it will be crucial to continue to follow these patients to understand if this method of sensitive MRD testing is in fact identifying patients who are essentially cured of their MM and who will remain MRD negative.
“Our study, along with the GEM2014MAIN and MASTER trials, shows that using MRD to guide decision-making is feasible,” Dr. Derman said. “MRD by NGS is a tool that can be used by any clinician. Implementing workflows in clinics to be able to perform this test is critical. The biggest barrier will be having patients agree to bone marrow biopsies, which remains a barrier in both the community and academic settings.”
Any conflicts of interest declared by the authors can be found in the original article.
References
- Derman BA, Major A, Cooperider J, et al. Discontinuation of maintenance therapy in multiple myeloma guided by multimodal measurable residual disease negativity (MRD2STOP). Blood Cancer J. 2024;14(1):170.
- McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35(29):3279-3289.
- Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(1):57-73.
- Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132(23):2456-2464.
- Rosiñol L, Oriol A, Ríos R, et al. Lenalidomide and dexamethasone maintenance with or without ixazomib, tailored by residual disease status in myeloma. Blood. 2023;142(18):1518-1528.
