Measurement of sustained measurable residual disease (MRD) negativity below 10-5 was the best predictor of outcomes in patients with newly diagnosed multiple myeloma (NDMM), according to the results of a study evaluating optimal MRD-based endpoints to support response-adapted treatment cessation in patients treated with first-line quadruplet induction therapy and autologous hematopoietic cell transplantation (AHCT). The results were published in Blood.
Most patients treated with quadruplet therapy followed by AHCT will achieve MRD negativity at 10-5 with excellent long-term progression-free survival. The current treatment paradigm for these patients is continuous therapy; however, there is increasing interest in using MRD to guide treatment decisions — either intensification or de-escalation — in these patients.
“What is missing in the literature is an objective assessment of different MRD endpoints — 10-5 at one timepoint, 10-6 at one timepoint, 10-5 sustained at one year, 10-6 sustained at one years — and how they compare for identifying patients for treatment de-escalation,” said study researcher Luciano J. Costa, MD, of the University of Alabama at Birmingham.
“Of course, to do that methodologically is not trivial because if someone has sustained MRD negativity at one year, by definition they do not have progression for one year, and we can incur something called immortal time bias,” Dr. Costa said. “We needed to account for that methodologically by using a time-dependent covariate for the analysis.”
The study used data from two groups of patients: the phase II MASTER trial and a prospectively maintained database at the University of Alabama at Birmingham. In MASTER, patients received four cycles of daratumumab, carfilzomib, lenalidomide, and dexamethasone, followed by AHCT. After transplant, patients continued on maintenance therapy, and treatment was stopped if there were two consecutive MRD-negative assessments. In the database, patients received daratumumab, bortezomib, lenalidomide, and dexamethasone for four cycles plus AHCT. Again, treatment cessation was recommended for those with two consecutive MRD-negative assessments.
The researchers used these data to test five short-term efficacy endpoints: stringent complete response (sCR), single datapoint for 10-5, single datapoint for 10-6, sustained MRD negativity at 10-5, and sustained MRD negativity at 10-6.
The best fitting model was based on sustained MRD at less than 10-5 (hazard ratio = 0.23, 95% CI 0.11-0.47).
“What we found was quite interesting,” Dr. Costa said. “The model that included sustained MRD negativity to 10-5 performed similarly, but a little bit better than the model with sustained MRD negativity at 10-6.”
Any model measuring sustained MRD negativity performed better than MRD measurement at a single timepoint, and MRD negativity at a single timepoint performed far better than sCR.
“When we looked at patients who had treatment cessation and looked at these endpoints as a predictor of risk of resurgence of MRD or progression, we found the same results,” Dr. Costa said. “What that tells you is that if you are going to do a clinical trial and want to use an MRD endpoint that is meaningful for predicting future clinically significant events, sustained MRD 10-5 is likely the best one.”
Dr. Costa said this result may seem somewhat counterintuitive but added that “the question here is not which is the best endpoint for a given patient, but which performs better in a cohort of patients.”
The main limitation of the study, Dr. Costa said, is that these data still do not inform clinicians about what to do for patients with multiple high-risk chromosomal abnormalities. Sustained MRD negativity at any threshold appeared inadequate to identify high-risk patients who would be candidates for treatment de-escalation.
“It was disheartening to see that these patients still had a high rate of MRD resurgence and progression, despite achieving sustained MRD negativity. Conversely, for patients with no high-risk chromosome abnormality and with sustained MRD negativity at 10-5 and who discontinued therapy at a second MRD negativity test, the risk of progression or MRD resurgence at four years was only 6%” Dr. Costa said.
In addition, this analysis was performed in patients who received the current standard of care of quadruplet therapy plus AHCT and does not inform the performance of these MRD endpoints among patients who were unable to undergo AHCT.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Giri S, Dhakal B, Callander N, et al. Optimal MRD-based end point to support response-adapted treatment cessation in newly diagnosed multiple myeloma [published online ahead of print, 2025 April 7]. Blood. doi: 10.1182/blood.2024027674.
