Daratumumab/Lenalidomide Maintenance Deepens Responses, Boosts MRD-Negativity Rates in Myeloma After ASCT

Ashraf Z. Badros, MB, Ch

Primary findings from the phase 3 AURIGA study (NCT03901963) strongly support the use subcutaneous daratumumab (Darzalex) as maintenance therapy alongside standard-of-care (SOC) lenalidomide (Revlimid) to further deepen responses in patients with newly diagnosed multiple myeloma who are minimal residual disease (MRD) positive following autologous stem cell transplant (ASCT), according to Ashraf Z. Badros, MBCHB.¹

Data presented at the 21st International Myeloma Society Annual Meeting showed that from baseline to 12 months, MRD-negative conversion rates increased from 18.8% with lenalidomide monotherapy (n = 101) to 50.5% with the combination (n = 99) in the maintenance setting (odds ratio [OR], 4.51; 95% CI, 2.37-8.57; P < .0001).

For patients who achieved a complete response (CR) or better at any time, MRD-negative conversion 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 combination and lenalidomide monotherapy arms, respectively. Notably, these rates were 56.8% (n = 88) and 23.2% (n = 82; OR, 4.40; 95% CI, 2.26-8.58; P < .0001) in the MRD-evaluable population. This benefit was observed across all clinically relevant patient subgroups, regardless of risk status.

“AURIGA is the first trial to directly compare the addition of daratumumab to lenalidomide vs lenalidomide alone, which is a SOC in the maintenance stage, in multiple myeloma after ASCT,” said Badros, 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. “This is a practicing-informing study, and the results support the addition of daratumumab to lenalidomide in the maintenance phase.”

In an interview with OncLive^®, Badros highlighted key efficacy and safety data from the AURIGA trial; explained the significance of utilizing MRD-negative conversion rate as the primary end point for this study; and contextualized these results with other studies evaluating up-front daratumumab-based induction/consolidation regimens in patients with newly diagnosed multiple myeloma.

OncLive: What was the design and methodology of AURIGA?

Badros: [AURIGA] was a multicenter, open-label trial that [randomly assigned] patients 1:1 to receive daratumumab and lenalidomide vs lenalidomide alone. The trial enrolled [patients with] newly diagnosed multiple myeloma in the United States and Canada. Patients should have received a minimum of 4 induction cycles that did not include daratumumab or isatuximab-irfc [Sarclisa], followed by ASCT within 12 months.

At screening, patients should have achieved a deep response, [defined as a] very good partial response or better, and [they needed to be] MRD-positive by next-generation sequencing at 10^-5 threshold. The trial [stratified] patients by cytogenetic risk, and randomization occurred within 6 months of transplant date. After the trial, we followed patients by MRD testing, so we checked them at cycles 12, 18, 24, and 36. The primary end point of the trial was the MRD-negative conversion rate at 12 months [following the start of] maintenance therapy.

What should be noted regarding patients’ baseline characteristics?

The patient population was newly diagnosed and had received induction [therapy] followed by ASCT. [More than] 20% of patients were African American, which is quite an achievement for this trial. Most trials, especially from Europe, have less than 5% minority representation.

The cytogenetic risk was defined by [the presence of] 17p deletions, 4;14 translocations, and 4;16 translocations. That's considered standard high-risk by protocol. [At diagnosis, 23.9%] of the patients in [the combination arm] had high-risk cytogenetics compared with [16.9%] in the lenalidomide arm.

It is worth noting that imbalance, despite the fact we stratified patients by cytogenetics. Why the imbalance? It was because cytogenetic assessment was performed locally and was conducted both at diagnosis and during stratification. [It also] included revised cytogenetic risks that, in addition to [the above factors], also included 1q gain and amplification, as well as 14;20 translocations. If you look at the revised criteria, patients were [much more] balanced between both arms [34.4% vs 33.7%].

What efficacy data were presented from this study?

We presented the primary results [from AURIGA.] All patients have completed 12 months of therapy, [developed disease progression, died, discontinued therapy, or withdrew from the study.] MRD-negative conversion rate at 12 months was 50.5% for the daratumumab plus lenalidomide arm vs 18.8% for the lenalidomide alone arm, and that difference was statistically significant.

At a median follow-up of 32 months, patients achieved a CR rate of 75.8% vs 61% with daratumumab plus lenalidomide vs lenalidomide alone, [respectively], and there was a 47% reduction in the risk of progression in the daratumumab plus lenalidomide arm. Progression-free survival [PFS] rates at 30 months were 82.7% with daratumumab plus lenalidomide vs 66.4% [with lenalidomide alone]. That trend favors the combination arm.

[Additionally,] a prespecified subgroup analysis was done and showed benefit [with the combination] for MRD-negative conversion in patients that were older, in high-risk groups, and with advanced stages [of disease].

What was the regimen’s overall safety profile in AURIGA, and what might explain the higher incidence of AEs with the combination vs lenalidomide monotherapy?

As with any treatment that includes lenalidomide, we noted an increased risk of infections and discontinuation of treatment. [The rate of] serious adverse effects [AEs] in the daratumumab and lenalidomide arm was 30.2%; for the lenalidomide arm, it was 22.4%. Fourteen percent of patients in the daratumumab and lenalidomide arm discontinued treatment vs 8% in the lenalidomide arm. A few more patients reported more AEs in the [combination arm], but we believe this is related to the duration of treatment.

In the daratumumab and lenalidomide arm, patients stayed on treatment for [a median of] 30.7 months vs 20.6 months in the lenalidomide alone arm. Staying longer on treatment will increase your drug exposure and consequently increase the reporting period for both AEs and the discontinuation of treatment. [Otherwise,] there are no new safety concerns that we can report with this combination.

Why is MRD-negative conversion selected as the primary end point in this study?

The FDA’s Oncologic Drug Advisory Board has [voted in favor of] MRD testing as a primary end point [to support the accelerated approval of novel therapies] in clinical trials [for patients with multiple myeloma]. That will accelerate the approval of drugs in multiple myeloma, rather than waiting for PFS and overall survival [data], which can take years. That's where the importance of a trial like AURIGA comes in; it showed MRD-negativity data, correlating these data with responses, and [we saw a potential] signal for PFS benefit as well.

What are the clinical implications of this research, particularly in the context of phase 3 trials such as GRIFFIN (NCT02874742) and PERSEUS (NCT03710603) with daratumumab induction/consolidation?

The main clinical implication here is that the addition of daratumumab to lenalidomide induced higher MRD-negative conversion rate, deepened CRs, and improved PFS after transplant in a subset of patients who underwent ASCT and were MRD-positive after transplant. We know now that daratumumab is being used up-front in the treatment of [patients with] multiple myeloma during induction in combination with VRd [bortezomib (Velcade), lenalidomide, and dexamethasone]. [GRIFFIN and PERSEUS] showed benefit [with this approach.] PERSEUS is probably the largest trial showing benefit with the addition of daratumumab upfront.

The question is [whether] our data support using daratumumab [as maintenance therapy] even if the patient has received daratumumab up-front [as induction and consolidation therapy]. The answer is no. We don't have that data because our trial focused on patients who did not receive daratumumab up-front. However, if you look at the PERSEUS trial after receiving induction and consolidation with a daratumumab-based regimen, [a large] number of patients were still MRD positive and went on to receive daratumumab and lenalidomide maintenance. In this arm, there was [approximately a] 60% improvement in the MRD-negative conversion rate after consolidation was completed. That's [comparable with] the percentage we're seeing in our trial.

It does not seem that using that up-front daratumumab will dampen responses; if anything, [these data] support using it. [However, AURIGA] does not address directly the group of patients who will receive daratumumab up-front.

What next steps are planned for this research?

There are 2 ongoing trials. One is the [phase 3] SWOG S1803 trial [NCT04071457], which is a much larger trial. That trial will enroll approximately 1400 patients and will evaluate daratumumab and lenalidomide vs lenalidomide alone. It will focus on both patients who [displayed] MRD during induction and patients who did not [display] MRD during induction. That particular trial will also [attempt to] answer the question of how long treatment should be given. If [a patient has] MRD-negative disease at the end of the 2 years, there is a second randomization to stop treatment [in favor of] observation. These types of trials are quite important at this point because no patient would like to stay in treatment forever. Patients like to have a defined period [of treatment]. Now we have a marker [MRD] that we know is prognostic, and [that] may guide treatment. As more trials mature, [they will hopefully inform] us on how to use MRD to [guide the cessation of] maintenance treatment.

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.