Addition of Daratumumab to Lenalidomide Maintenance Boosts MRD-Negative Conversions in Myeloma Following ASCT

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The addition of subcutaneous daratumumab (Darzalex) to lenalidomide (Revlimid) maintenance demonstrated improved clinical outcomes compared with lenalidomide maintenance alone in patients with newly diagnosed multiple myeloma who underwent autologous stem cell transplant (ASCT) but remained minimal residual disease (MRD) positive post-transplant, according to results from the phase 3 AURIGA study (NCT03901963) presented during the 50th Annual Oncology Nursing Congress.

Findings showed that the 12-month the MRD-negativity rate (10⁻⁵ threshold) was 50.5% for patients treated with daratumumab plus lenalidomide (n = 99) vs 18.8% for those given lenalidomide alone (n = 101; odds ratio [OR], 4.51; 95% CI, 2.37–8.57; P < .0001).

MRD negativity was achieved at any point by 60.6% of patients in the daratumumab arm vs 27.7% of patients in the lenalidomide arm (OR, 4.12; 95% CI, 2.28–7.52; P < .0001).

“Daratumumab [plus] lenalidomide maintenance more than doubled the rates of MRD-negative conversions by 12 months of maintenance therapy vs lenalidomide alone, with the benefit observed across all evaluated subgroups, including patients with high-risk disease or standard-risk disease,” lead study author Todd Milliron, RN, of the Greenebaum Cancer Center at the University of Maryland, and colleauges wrote in a presentation of the data. “A greater proportion of patients treated with daratumumab [and] lenalidomide [also] had their response deepen compared with those treated with lenalidomide alone.”

AURIGA Study Design

AURIGA was a randomized, multicenter trial evaluating the efficacy and safety of subcutaneous daratumumab in combination with lenalidomide vs lenalidomide monotherapy as maintenance therapy in patients with newly diagnosed multiple myeloma who had undergone ASCT.

Eligible patients needed to be 18 to 79 years of age with newly diagnosed multiple myeloma who received at least 4 cycles of induction therapy and ASCT. Patients needed to be in a very good partial response (VGPR) or better at screening, but they needed to have MRD-positive disease following transplant. They were required to be naïve to anti-CD38 monoclonal antibodies, and randomization needed to occur within 6 months of ASCT.

Patients were randomly assigned in a 1:1 ratio to receive 28-day maintenance cycles of daratumumab plus lenalidomide or lenalidomide alone, administered for up to 36 cycles or until progressive disease, unacceptable toxicity, or withdrawal of consent.

In the daratumumab plus lenalidomide arm, patients received subcutaneous daratumumab at 1800 mg weekly during cycles 1 and 2, every two weeks in cycles 3 to 6, and every 4 weeks thereafter, in addition to oral lenalidomide at 10 mg per day on days 1 to 28. Patients in the control arm received lenalidomide monotherapy at the same dosing schedule. Notably, in both arms, patients could receive 15-mg doses of lenalidomide starting in cycle 3, if tolerated.

The primary end point was the MRD-negative conversion rate by 12 months, defined as the proportion of patients who converted from MRD-positive status at baseline to MRD-negative status by 12 months of maintenance therapy without progressive disease or initiation of subsequent antimyeloma therapy. MRD was assessed using next-generation sequencing. Key secondary end points included progression-free survival (PFS), overall MRD-negative response rate, sustained MRD-negative response, duration of complete response (CR), overall survival (OS), and safety.

Baseline Patient Demographics

Demographic and baseline disease characteristics were generally well-balanced between the treatment arms. The majority of patients in the daratumumab arm (61.8%) and the lenalidomide arm (60.4%) were under 65 years of age. Most patients were White (daratumumab arm, 67.7%; lenalidomide arm, 67.3%). ECOG performance status was 0 in 45.5% of patients receiving daratumumab plus lenalidomide and 54.5% of patients receiving lenalidomide alone.

At the time of diagnosis, International Staging System (ISS) disease stages included stage I ( daratumumab arm, 44.0%; lenalidomide arm, 38.8%), stage II (30.8%; 37.8%), and stage III (25.3%; 23.5%). The proportion of patients achieving at least a CR or better at baseline was 28.3% in the daratumumab plus lenalidomide group vs 29.7% in the lenalidomide-only group. Additionally, 68.5% of patients in the daratumumab plus lenalidomide arm and 74.2% in the lenalidomide arm had standard-risk cytogenetics.

Further Analysis of Efficacy and Safety Findings

Additional findings showed that sustained MRD negativity lasting at least 6 months occurred in 35.4% of patients in the daratumumab arm vs 13.9% of patients in the lenalidomide arm (OR, 3.40; 95% CI, 1.69-6.83; P = .0005).

At a more stringent MRD threshold of 10⁻⁶, 23.2% of patients in the daratumumab plus lenalidomide arm achieved MRD negativity at 12 months vs 5.0% in the lenalidomide arm (OR, 6.97; 95% CI, 2.15-18.58; P = .0002).

The CR or better rate was 75.8% in the experimental arm vs 61.4% in the control arm (OR, 2.00; 95% CI, 1.06-3.69; P = .0255). In patients who were in VGPR at baseline, the CR or better rates were 66.2% in the daratumumab arm (n = 71) vs 45.1% in the lenalidomide arm (n = 71).

Data also demonstrated that daratumumab plus lenalidomide reduced the risk of disease progression or death by 47% vs lenalidomide alone (HR, 0.53; 95% CI, 0.29–0.97; P = .0361). The PFS benefit was observed across cytogenetic risk subgroups, including standard-risk (HR, 0.48; 95% CI, 0.24-1.16) and high-risk disease (HR, 0.49; 95% CI, 0.21-1.11).

Regarding safety, the most common grade 3/4 treatment-emergent adverse effects (TEAEs) included neutropenia (daratumumab arm, 46.9%; lenalidomide arm, 41.8%), thrombocytopenia (10.4%; 11.2%), and anemia (5.2%;5.1%). Serious TEAEs occurred in 30.2% and 22.4% of patients, respectively, with pneumonia being the most common (4.2%; 4.1%). Infusion-related reactions occurred in 13.5% of patients in the daratumumab group, most of which were low grade and associated with the first administration.

“No unexpected safety concerns were observed with daratumumab [plus] lenalidomide maintenance; higher rates of grade 3/4 and serious TEAEs should be interpreted in the context of a 10-month longer treatment duration for patients treated with daratumumab plus lenalidomide vs lenalidomide alone,” study authors explained.

Reference

Milliron T, Anderson LD, Chung A, et al. Phase 3 AURIGA study of subcutaneous daratumumab plus lenalidomide versus lenalidomide alone as maintenance therapy in newly diagnosed multiple myeloma after autologous stem cell transplant. Presented at: 50th Annual Oncology Nursing Society Congress; April 9-13, 2025; Denver, CO. Abstract I31.