Addition of Daratumumab to Lenalidomide Maintenance May Improve MRD-Negative Conversion Rates in Newly Diagnosed Myeloma

Lenalidomide (Revlimid) monotherapy currently holds the title of preferred maintenance therapy for newly diagnosed minimal residual disease (MRD)–positive multiple myeloma; however, combining lenalidomide with subcutaneous daratumumab (Darzalex) could provide patients with a safer and more effective treatment option, according to Larry Anderson, MD, PhD, FACP.

Data from the phase 3 AURIGA trial (NCT03901963), which were presented at the 22nd Annual International Myeloma Society (IMS) Meeting and Exposition, showed that patients with newly diagnosed multiple myeloma who were MRD-positive following transplant achieved a MRD-negative conversion rate of 60.6% at a sensitivity of 10-5 after receipt of daratumumab/lenalidomide maintenance (n = 99) vs 28.7% with lenalidomide alone (n = 101; odds ratio [OR], 3.92; 95% CI, 2.16-7.14; P < .0001).1 At a sensitivity of 10–6, these respective rates were 36.4% vs 13.9% (OR, 3.59; 95% CI, 1.78-7.23; P = .0003).

“Overall, these updated safety and efficacy results from the AURIGA trial demonstrate the ongoing benefit of adding daratumumab to lenalidomide as maintenance therapy for patients who are MRD-positive after autologous stem cell transplant [ASCT],” Anderson stated in an interview with OncLive®.

In this interview, Anderson discussed the rationale for conducting the AURIGA trial, how the safety and efficacy of subcutaneous daratumumab plus lenalidomide stacks up against lenalidomide monotherapy in newly diagnosed multiple myeloma, in addition to next steps for the regimen’s development.

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 Southwestern (UTSW) Medical Center in Dallas. He also serves as director of the Myeloma, Waldenström's, and Amyloidosis Program and leads the Hematologic Malignancies and Cellular Therapy Clinical Research Program at UTSW’s Harold C. Simmons Comprehensive Cancer.

OncLive: What was the main goal and design of the AURIGA trial?

Anderson: According to United States guidelines, the current preferred maintenance therapy [for patients with newly diagnosed multiple myeloma and who are MRD-positive after [ASCT] is lenalidomide monotherapy. The AURIGA trial looked at the addition of subcutaneous daratumumab to lenalidomide in comparison with lenalidomide monotherapy for up to 36 months after stem cell transplant for patients who are MRD positive. In the previously presented primary analysis, MRD-negative conversion rates at 12 months were evaluated; the updated efficacy analysis [presented during this year’s IMS Meeting] looks at a 24-month time point.2

MRD was assessed at 12, 18, 24, and 36 months from the beginning of maintenance therapy. Patients were randomly assigned 1:1 to receive either subcutaneous daratumumab and lenalidomide or lenalidomide alone, and were stratified according to high-risk cytogenetics.

What is important to know about the baseline characteristics of patients in AURIGA?

The number of patients in each subgroup was well balanced between cohorts, [in terms of factors like] stage, age, and race.1 One exception [to this] was [patients with] high-risk cytogenetic features. There were more patients with 17p deletion and high-risk cytogenetics based on the modified International Myeloma Working Group 2024 criteria in the subcutaneous daratumumab and lenalidomide cohort compared with the lenalidomide monotherapy cohort. [Patients with these factors] favored the lenalidomide monotherapy cohort.

What were the updated safety and efficacy results presented during the 2025 IMS Meeting?

With a median follow-up of 40.3 months, the duration of study therapy was longer in the subcutaneous daratumumab and lenalidomide cohort vs the lenalidomide monotherapy cohort. The rate of discontinuation due to effects [AEs] was lower in the subcutaneous daratumumab and lenalidomide cohort [compared with the lenalidomide monotherapy cohort]. The rate of patients continuing on maintenance therapy for at least 24 cycles was higher in the subcutaneous daratumumab and lenalidomide cohort [compared with the lenalidomide monotherapy cohort].

The rate of MRD-negative conversion at 24 months was more than doubled at both the 10-5 and 10-6 [sensitivity] thresholds. The rate of 6-month sustained MRD negativity was more than doubled at the 10-5 threshold, and the rate of 12-month sustained MRD-negative conversion was quadrupled for subcutaneous daratumumab and lenalidomide vs lenalidomide alone.

PFS favored the subcutaneous daratumumab and lenalidomide cohort over the lenalidomide monotherapy cohort; the hazard ratio [HR] for 36-month PFS was 0.55. Overall survival (OS) data are currently immature, but there was a trend showing improved OS with subcutaneous daratumumab and lenalidomide vs lenalidomide monotherapy.

There also no increased risk of grade 3 or 4 AEs in the subcutaneous daratumumab and lenalidomide cohort vs the lenalidomide monotherapy cohort. [Additionally,] there was no increased risk for AEs or infections in the subcutaneous daratumumab and lenalidomide cohort compared with the lenalidomide monotherapy cohort in the maintenance setting.

What are the key takeaways from the trial?

Subcutaneous daratumumab with lenalidomide maintenance therapy compared to lenalidomide alone for at least 24 months led to significantly more MRD-negative conversion rates at both 10-5 and 10-6 thresholds, more than doubling the 6-months sustained MRD-negative conversion rates of lenalidomide monotherapy. There was no increase in AEs, a trend towards OS improvement, and a favorable PFS in the subcutaneous daratumumab and lenalidomide cohort compared with the lenalidomide monotherapy cohort.

What are the most important considerations for potentially integrating subcutaneous daratumumab and lenalidomide into clinical practice?

As far as AURIGA goes, these patients were naive to anti-CD38 therapy. These days a lot of patients that are receiving induction therapy with CD38-based therapy may lead to questions of whether this [trial] applies to those patients. I would argue that these data support adding daratumumab to lenalidomide even in patients that have previously received daratumumab because between 12 and 24 months we have seen ongoing improvement in the number of MRD-negative conversions. In general, for patients who are at least still MRD-positive after [ASCT], I have been recommending the addition of daratumumab to lenalidomide for maintenance therapy.

References

1. Anderson L, Chung A, Foster L, et al. Updated efficacy and safety results of subcutaneous daratumumab plus lenalidomide versus lenalidomide alone as maintenance therapy in newly diagnosed multiple myeloma after transplant: AURIGA study. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-47.
2. Bardos A, Foster L, Anderson LD, et al. Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study. Blood. 2025;145(3):300-310. doi.org/10.1182/blood.2024025746