Daratumumab's Early Intervention in Myeloma Shows Promising Results

Early intervention with daratumumab (Darzalex) in patients with multiple myeloma who experience minimal residual disease (MRD) relapse has been shown to significantly prolong time to clinical progression and restore MRD negativity in a substantial proportion of cases, according to findings from the PREDATOR-MRD trial (NCT03697655) presented at the 2025 European Hematology Association Congress held in Milan, Italy from June 12 to June 15, 2025.

At a median follow-up of 17.9 months, the results indicated that patients receiving daratumumab experienced a median event-free survival (EFS) that was not reached, whereas those on observation had a median EFS of 9.5 months (Hazard Ratio, HR: 0.20; 95% Confidence Interval, CI: 0.05-0.76; P = .0097). The trial's primary endpoints included event-free survival, time to significant paraprotein relapse, clinical relapse, or death. Notably, 75% of patients in the daratumumab arm re-achieved MRD negativity.

Dr. Krzysztof Jamroziak, MD, PhD, from the Department of Hematology at the Institute of Hematology and Transfusion Medicine in Warsaw, Poland, highlighted in his presentation that MRD monitoring conducted every four months enables the detection of MRD relapse before any biochemical progression in 75% of patients. "PREDATOR-MRD results can serve as proof of concept for larger trials with novel MRD assessment techniques and therapies," he asserted.

The trial involved a screening phase for adults with multiple myeloma who had completed one or two prior lines of therapy and had achieved a complete response with MRD negativity at their most recent appointment. Patients were monitored for MRD reappearance over a 24-month period with assessments every four months. Those who tested MRD positive without significant paraprotein relapse or clinical progression were randomly assigned to receive daratumumab at 16 mg/kg intravenously or 1800 mg subcutaneously weekly for eight weeks, followed by twice-weekly doses for 16 weeks and monthly doses for 48 weeks or until significant paraprotein relapse or clinical progression occurred. The observation group was required to attend regular study visits every four weeks.

The primary endpoints of the trial were event-free survival, time from randomization to significant paraprotein relapse, clinical relapse, or death. Secondary endpoints included time from MRD reappearance to significant paraprotein relapse or clinical relapse in the control arm, efficacy of daratumumab in the treatment arm, safety, and quality of life metrics. The exploratory endpoint included the MRD-negativity rate in the daratumumab arm on day one of cycle three.

Among the 54 patients analyzed during the MRD reappearance observation phase, demographic data revealed that 61.1% were female, with a median age of 59 years (range: 45-70). The performance status based on the Eastern Cooperative Oncology Group (ECOG) classification indicated that 53.7% had a score of 0. International Staging System (ISS) scores were distributed as follows: I (35.2%), II (20.4%), III (22.2%) with 21.1% missing information. A total of 51.8% of the patients were identified with an MRD positivity rate, with four patients concurrently experiencing significant paraprotein relapse and excluded from the analysis.

The median time to MRD recurrence was recorded at 20.8 months (95% CI: 12.4-23.8). In the randomized treatment arm (n = 12) and observation arm (n = 12), the distribution of female patients was equal at 66.7%, while median ages were 57 years (range: 44-68) and 63 years (range: 47-70), respectively. Most patients had an ECOG performance status of 1 (33.3% vs. 75.0%).

The cytogenetic profile indicated standard risk in 41.7% of the treatment arm versus 25.0% in the observation arm, and high risk in 25.0% versus 16.7%, respectively. Participants had received an equal number of prior treatment lines, with the median duration from diagnosis to randomization being 36.3 months against 34.9 months, and from last treatment to randomization being 26.9 months versus 24.5 months.

In the treatment arm, no patients experienced grade 3 or higher adverse effects. Reported hematologic adverse events included anemia (8.3%), lymphopenia (8.3%), and neutropenia (8.3%). Notably, no hematologic adverse effects were recorded in the observation arm. Among non-hematologic adverse events, upper respiratory tract infection was observed in 50.0% of patients receiving treatment, while urinary tract infections were reported in 16.7% and musculoskeletal pain in 41.7%. However, daratumumab did not significantly impact the Global Health Score (P = .59).

The findings from the PREDATOR-MRD trial underscore the potential of early intervention with daratumumab in managing MRD relapse in multiple myeloma, paving the way for larger-scale studies aimed at refining MRD assessment techniques. The implications of this research could significantly enhance treatment protocols and patient outcomes in the field of hematologic oncology.