Daratumumab/Lenalidomide Improves MRD– Conversion Rates in Newly Diagnosed Myeloma After ASCT

Ashraf Z. Badros, MB, Ch

Maintenance therapy with subcutaneous daratumumab (Darzalex) combined with lenalidomide (Revlimid) significantly increased minimal residual disease (MRD)–negative conversion rates vs lenalidomide maintenance alone in patients with newly diagnosed multiple myeloma following transplant, according to primary findings from the phase 3 AURIGA trial (NCT03901963) presented during the 21st International Myeloma Society Annual Meeting.

In the intention-to-treat (ITT) population, daratumumab plus lenalidomide more than doubled the MRD-negative conversion rate from baseline to 12 months of maintenance therapy compared with lenalidomide alone. The MRD-negative conversion rates by 12 months were 50.5% and 18.8% in the daratumumab plus lenalidomide (n = 99) and lenalidomide monotherapy (n = 101) arms, respectively (odds ratio [OR], 4.51; 95% CI, 2.37-8.57; P < .0001). Among patients achieving a complete response (CR) or better at any time, these respective rates by 12 months were 61.3% (n = 75) and 25.8% (n = 62; OR, 4.62; 95% CI, 2.20-9.70; P < .0001). In the MRD-evaluable population, these respective rates by 12 months were 56.8% (n = 88) and 23.2% (n = 82; OR, 4.40; 95% CI, 2.26-8.58; P < .0001).

Among patients in the ITT population, the rates of conversion to MRD-negative with a CR or better by 12 months were 44.4% in the daratumumab arm vs 14.9% in the lenalidomide alone arm (OR, 4.61; 95% CI, 2.34-9.09; P < .0001). This MRD-negative conversion rate benefit with the addition of daratumumab to lenalidomide was observed across all clinically relevant patient subgroups, including patients with high-risk and standard-risk disease.

“It is well accepted today that MRD negativity is associated with improved long-term survival outcomes [in multiple myeloma],” Ashraf Z. Badros, MB, ChB, said during the presentation. “To date, no randomized trial has directly compared daratumumab-based maintenance therapy vs standard-of-care [SOC] lenalidomide maintenance, which was the focus of the AURIGA trial.”

Badros is a professor of medicine, director of the Multiple Myeloma Service, and vice chair of the Clinical Research Committee for the Program in Oncology at the University of Maryland School of Medicine in Baltimore.

AURIGA Design and Methodology

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 undergone autologous stem cell transplant (ASCT) within 12 months of the start of induction. Patients needed to have a very good partial response (VGPR) or better to induction therapy at trial screening. Patients were also required to be MRD positive at a 10^–5 sensitivity following ASCT, be naïve to anti-CD38 antibodies, and be randomly assigned in the trial within 6 months of their ASCT date.

Patients were stratified by cytogenetic risk (standard-risk/unknown vs high-risk) and randomly assigned 1:1 to 1 of 2 arms. Patients in both arms (n = 200) received up to 36 28-day cycles of maintenance therapy with oral lenalidomide at 10 mg daily; after cycle 3, the lenalidomide dose could be increased to 15 mg daily if tolerated. Patients in the investigational arm also received subcutaneous daratumumab at 1800 mg once weekly for cycles 1 and 2, once every 2 weeks for cycles 3 through 6, and once every 4 weeks starting in cycle 7 and beyond.

The primary end point was MRD-negative conversion rate from baseline to 12 months after maintenance therapy. Secondary end points included progression-free survival (PFS), overall MRD-negative conversion rate, sustained MRD-negative rate, response rates, duration of CR or better, overall survival, and safety. MRD data were obtained after cycles 12, 18, 24, and 36.

Patient demographics and disease characteristics were generally well balanced between the 2 arms. Badros noted that 20.2% and 23.8% of patients in the daratumumab and lenalidomide alone arms, respectively, were Black. Additionally, high-risk cytogenetics, including deletion 17p, translocation 4;14, and translocation 4;16 were observed in 14.1%, 10.9%, and 6.5% of patients, respectively, in the daratumumab arm, and 3.4%, 13.5%, and 7.9% of patients, respectively, in the lenalidomide alone arm. Overall, more patients in the daratumumab arm than the lenalidomide alone arm presented with high-risk cytogenetics (23.9% vs 16.9%).

Patients in both arms had received a median of 5.0 (range, 4.0-8.0) induction cycles. In total, 78.8% of patients in the daratumumab arm and 83.2% of those in the lenalidomide alone arm had received at least 2 induction cycles that included bortezomib and lenalidomide.

At a median follow-up of 32.3 months, the median duration of study treatment was 30.7 months (range, 0.7-37.5) in the daratumumab arm vs 20.6 months (range, 0-37.7) in the lenalidomide monotherapy arm. At the time of this primary analysis, all patients had completed at least 12 months of maintenance therapy, developed disease progression, died, discontinued therapy, or withdrawn from the study.

Further Efficacy and Safety Data

The increased rates of MRD-negative conversion with the addition of daratumumab to lenalidomide were sustained over time at the 10^–5 threshold. The overall MRD-negative conversion rates were 60.6% in the daratumumab arm vs 27.7% in the lenalidomide alone arm (OR, 4.12; 95% CI, 2.26-7.52; P < .0001). In these respective arms, the rates of patients with sustained MRD negativity for at least 6 months were 35.4% and 13.9% (OR, 3.40; 95% CI, 1.69-6.83; P = .0005).

The benefit with daratumumab plus lenalidomide was also observed when MRD analyses were conducted with a threshold of 10^–6. At this threshold, the MRD-negative conversion rates by 12 months were 23.2% in the daratumumab arm vs 5.0% in the lenalidomide alone arm (OR, 5.97; 95% CI, 2.15-16.58; P = .0002). In these respective arms, the overall MRD-negative conversion rates at a threshold of 10–6 were 36.4% and 12.9% (OR, 3.91; 95% CI, 1.91-7.99; P = .0001).

The rate of CR or better was higher in the daratumumab arm compared with the lenalidomide alone arm, at 75.8% vs 61.4% (OR, 2.00; 95% CI, 1.06-3.69; P = .0255). In the daratumumab arm, the rates of stringent CR (sCR), CR, and VGPR were 50.5%, 25.3%, and 24.2%, respectively. In the lenalidomide monotherapy arm, these respective rates were 35.6%, 25.7%, and 38.6%.

Among patients with a VGPR to induction therapy at baseline, maintenance therapy with daratumumab plus lenalidomide deepened more responses to CR or sCR compared with lenalidomide alone. Of patients in the daratumumab arm with a VGPR at baseline (n = 71), 66.2% achieved a CR or better with maintenance therapy. The respective rates of sCR, CR, and VGPR were 36.6%, 29.6%, and 33.8%. Of patients in the lenalidomide alone arm with VGPR at baseline (n = 71), 45.1% achieved a CR or better with maintenance therapy. The respective rates of sCR, CR, and VGPR were 25.4%, 19.1%, and 54.9%.

At a median follow-up of 32.3 months, the 30-month PFS rates favored the daratumumab arm at 82.7% vs 66.4% with lenalidomide monotherapy (HR, 0.53; 95% CI, 0.29-0.97; P = .0361). Conversion to MRD negativity was associated with improved PFS. In the daratumumab arm, the 30-month PFS rates were 95.2% among patients with MRD-negative disease per the primary end point vs 69.0% among those with MRD-positive disease. In the lenalidomide alone arm, these respective rates were 94.1% and 59.3%.

No new safety concerns emerged in either arm. The most common grade 3 or higher hematologic treatment-emergent adverse effects (TEAEs) among safety-evaluable patients in the daratumumab plus lenalidomide (n = 96) and lenalidomide monotherapy (n = 98) arms were neutropenia (daratumumab arm, 46.9%; lenalidomide monotherapy arm, 41.8%), lymphopenia (10.4%; 5.1%), leukopenia (9.4%; 6.1%), anemia (4.2%; 3.1%), and thrombocytopenia (3.1%; 2.0%). The most common grade 3 or higher nonhematologic TEAEs among safety-evaluable patients in these respective arms were hypokalemia (7.3%; 6.1%), hypertension (7.3%; 4.1%), pneumonia (5.2%; 4.1%), diarrhea (3.1%; 5.1%), fatigue (2.1%; 3.1%), arthralgia (1.0%; 1.0%), COVID-19 (1.0%; 3.1%), headache (1.0%; 0%), pain in extremity (1.0%; 0%), maculopapular rash (1.0%; 2.0%), and back pain (0%; 1.0%).

“The results support the addition of daratumumab, not only in induction and consolidation, but also with SOC lenalidomide maintenance,” Badros concluded.

Reference

Badros A, Foster L, Anderson LD, et al. Subcutaneous daratumumab plus lenalidomide versus lenalidomide alone as maintenance therapy in newly diagnosed multiple myeloma after transplant: primary results from the phase 3 AURIGA study. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-45.