Maintenance therapy with daratumumab plus lenalidomide led to higher MRD-negativity conversion rates vs lenalidomide alone in newly diagnosed myeloma.
The addition of subcutaneous daratumumab (Darzalex) to lenalidomide (Revlimid) maintenance therapy led to minimal residual disease (MRD)–negativity conversion rates that were higher compared with lenalidomide alone and sustained over time in patients with newly diagnosed multiple myeloma who were MRD positive after autologous stem cell transplant (ASCT), according to updated findings from the phase 3 AURIGA trial (NCT03901963), which were presented at the
Following daratumumab/lenalidomide maintenance therapy (n = 99), the rates of MRD-negative conversion at a sensitivity of 10–5 were 60.6% vs 28.7% with lenalidomide alone (n = 101; odds ratio [OR], 3.92; 95% CI, 2.16-7.14; P < .0001). At a sensitivity of 10–6, the MRD-negative conversion rates were 36.4% vs 13.9%, respectively (OR, 3.59; 95% CI, 1.78-7.23; P = .0003). The rates of complete response (CR) with MRD-negative conversion at a sensitivity of 10–5 were 55.6% vs 23.8%, respectively. The rates of CR with MRD-negative conversion at a sensitivity of 10–6 were 35.4% vs 10.9%, respectively. The MRD-negative conversion rates at a sensitivity of 10–5 favored the daratumumab arm across all prespecified patient subgroups regardless of age and race.
“Overall, the updated efficacy and safety data from AURIGA continue to demonstrate the value of adding subcutaneous daratumumab to lenalidomide maintenance in patients who were MRD positive after transplant,” lead study author Larry Anderson, MD, PhD, FACP, said in the presentation.
Anderson is a professor in the Department of Internal Medicine and a member of the Division of Hematology and Oncology at the University of Texas (UT) Southwestern Medical Center; as well as director of the Myeloma, Waldenström’s, and Amyloidosis Program, leader of the Hematologic Malignancies and Cellular Therapy Clinical Research Program, co-director of the Phase I Clinical Trial Research Program, and co-director of the Cellular Immunotherapy and Autologous Stem Cell Transplant Program at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center in Dallas.
AURIGA enrolled patients 18 to 79 years of age with newly diagnosed multiple myeloma who had received at least 4 cycles of induction therapy and had undergone ASCT within 12 months of the start of induction therapy. Patients needed to have a very good partial response or better at screening and have MRD-positive disease at a sensitivity of 10–5 after ASCT. Patients could not have received prior anti-CD38 therapy and needed to be randomly assigned in AURIGA within 6 months of their ASCT date. Patients were stratified by cytogenetic risk at diagnosis (standard/unknown vs high).
A total of 200 patients were randomly assigned 1:1 to receive up to thirty-six 28-day cycles of maintenance therapy with lenalidomide with or without daratumumab. Daratumumab was administered subcutaneously at 1800 mg weekly in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks in cycle 7 and beyond. Lenalidomide was administered orally at 10 mg daily on days 1 through 26, then at 15 mg daily after cycle 3 if tolerated. MRD data were obtained after cycles 12, 18, 24, and 36.
The primary end point was MRD-negative conversion rate (at a sensitivity of 10–5) from baseline to 12 months after maintenance therapy. Secondary end points included progression-free survival (PFS), overall MRD-negative conversion rate, response rate, duration of CR or better, overall survival (OS), and safety.
Findings published in Blood in January 2025 showed that the MRD-negative conversion rate at a sensitivity of 10–5 by 12 months from the start of the maintenance period was significantly higher with daratumumab plus lenalidomide vs lenalidomide alone, at 50.5% vs 18.8%, respectively (OR, 4.51; 95% CI, 2.37-8.57; P < .0001). The MRD-negative conversion rate at a sensitivity of 10–6 was also significantly higher with the addition of daratumumab, at 23.2% vs 5.0%, respectively (OR, 5.97; 95% CI, 2.15-16.58; P = .0002).2
Baseline demographics and disease characteristics were generally well balanced between the arms in the intention-to-treat population.1 However, the investigators noted imbalances in favor of the lenalidomide monotherapy arm regarding the percentage of patients with of del(17p), which was 3.4% vs 14.1% in the daratumumab arm. Additionally, more patients in the daratumumab arm had modified IMS high-risk criteria, at 18.3% vs 8.9% in the lenalidomide monotherapy arm.
At a median follow-up of 40.3 months, the median duration of study treatment was 33.1 months (range, 0.7-37.5) in the daratumumab arm vs 24.9 months (range, 0-37.7) in the lenalidomide monotherapy arm. In the daratumumab arm, 97.0% of patients received treatment, and the median number of maintenance cycles was 36.0. Among these patients, 88.5%, 78.1%, 51.0%, and 31.3% completed at least 12 cycles, completed at least 24 cycles, completed all cycles, and discontinued all study treatments, respectively. Among patients who discontinued daratumumab (31.3%), the primary reasons for discontinuation were progressive disease (PD; 16.7%), adverse effects (AEs; 6.3%), patient withdrawal (3.1%), physician decision (2.1%), death (2.1%), and patient refusing further study treatment (1.0%). Among the patients who discontinued lenalidomide (daratumumab arm, 36.5%; lenalidomide monotherapy arm, 55.1%), the primary reasons for discontinuation were PD (13.5%; 28.6%), AEs (12.5%; 10.2%), patient withdrawal (3.1%; 4.1%), physician decision (3.1%; 4.1%), death (2.1%; 1.0%), patient refusing further study treatment (1.0%; 5.1%), protocol deviation (0%; 1.0%), and other reasons (1.0%; 1.0%).
Daratumumab/lenalidomide maintenance improved cumulative MRD-negative conversion rates vs lenalidomide alone over time. At 12 months, the MRD-negative conversion rates were 50.5% vs 18.8%, respectively, at a sensitivity of 10–5 (OR, 4.51; 95% CI, 2.37-8.57; P < .0001), and 23.2% vs 5.0%, respectively, at a sensitivity of 10–6 (OR, 5.97; 95% CI, 2.15-16.58; P = .0002). At 18 months, the MRD-negative conversion rates were 56.6% vs 21.8%, respectively, at a sensitivity of 10–5 (OR, 4.81; 95% CI, 2.57-9.00; P < .0001), and 30.3% vs 8.9%, respectively, at a sensitivity of 10–6 (OR, 4.44; 95% CI, 1.96-9.96; P = .0001). At 24 months, the MRD-negative conversion rates were 60.6% vs 26.7%, respectively, at a sensitivity of 10–5 (OR, 4.33; 95% CI, 2.36-7.94; P < .0001), and 35.4% vs 10.9%, respectively, at a sensitivity of 10–6 (OR, 4.51; 95% CI, 2.13-9.56; P < .0001).
The rate of sustained MRD negativity at a sensitivity of 10–5 lasting at least 6 months was more than double in the daratumumab arm vs the lenalidomide-alone arm. The rate of sustained MRD negativity at a sensitivity of 10–5 lasting at least 12 months was almost quadruple with daratumumab plus lenalidomide vs lenalidomide alone.
Investigator-assessed PFS outcomes favored the daratumumab arm, with a median PFS that was not reached vs 47.2 months with lenalidomide alone (HR, 0.55; 95% CI, 0.33-0.91; P = .0183). The 36-month PFS rates were 76.8% and 61.4%, respectively.
Although OS data remained immature at data cutoff, investigators noted an early trend for improved OS that favored daratumumab plus lenalidomide vs lenalidomide alone (HR, 0.42; 95% CI, 0.14-1.20; P = .0954). The 36-month OS rates were 94.7% and 90.5%, respectively.
No new safety concerns were reported with the addition of subcutaneous daratumumab to lenalidomide maintenance. Among patients in the daratumumab/lenalidomide and lenalidomide-alone arms who experienced at least 1 treatment-emergent AE (TEAE; daratumumab/lenalidomide arm, n = 96; lenalidomide-alone arm, n = 98), grade 3/4 TEAEs occurred in 75.0% and 73.5% of patients, respectively, and included neutropenia (49.0%; 45.9%), leukopenia (10.4%; 7.1%), lymphopenia (10.4%; 6.1%), hypokalemia (7.3%; 7.1%), hypertension (7.3%; 4.1%), pneumonia (6.3%; 5.1%), and diarrhea (3.1%; 5.1%). Additionally, grade 3/4 infections occurred in 19.8% and 14.3% of patients, respectively.
Serious TEAEs were reported in 31.3% and 25.5% of patients, respectively, and included pneumonia (5.2%; 5.1%) and pyrexia (3.1%; 0%). TEAEs led to discontinuation of any treatment component, discontinuation of treatment, and death in 14.6%, 12.5%, and 2.1% of patients in the daratumumab arm vs 10.2%, 9.2%, and 1.0% of those in the lenalidomide arm.
Disclosures: Anderson reported serving as a consultant and on advisory boards for AbbVie, Amgen, BeiGene, Bristol Myers Squibb, Celgene, Collector, Johnson & Johnson, Prothena Biosciences, and Sanofi; and serving on a data safety monitoring board for Prothena Biosciences.
