Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study

Abstract

No randomized trial has directly compared daratumumab and lenalidomide (D-R) maintenance with standard-of-care lenalidomide (R) alone after transplant. Herein, we report the primary results of the phase 3 AURIGA study evaluating D-R vs R maintenance in patients with newly diagnosed multiple myeloma (NDMM) who had very good or better partial response, were minimal residual disease (MRD)-positive (10-5) and anti-CD38-naïve after transplant. Two hundred patients were randomly assigned (1:1) to D-R (n = 99) or R (n = 101) maintenance for up to 36 cycles. The MRD-negative (10-5) conversion rate by 12 months from start of maintenance (primary end point) was significantly higher for D-R than R (50.5% vs 18.8%; odds ratio [OR], 4.51; 95% confidence interval [CI], 2.37-8.57; P < .0001). MRD-negative (10-6) conversion rate was similarly higher with D-R (23.2% vs 5.0%; OR, 5.97; 95% CI, 2.15-16.58; P = .0002). At median follow-up (32.3 months), D-R achieved a higher overall MRD-negative (10-5) conversion rate (D-R, 60.6% vs R, 27.7%; OR, 4.12; 95% CI, 2.26-7.52; P < .0001) and complete response rate or better (75.8% vs 61.4%; OR, 2.00; 95% CI, 1.08-3.69; P = .0255) vs R. Progression-free survival (PFS) favored D-R vs R (hazard ratio, 0.53; 95% CI, 0.29-0.97); estimated 30-month PFS rates were 82.7% for D-R and 66.4% for R. Incidences of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were slightly higher with D-R than R. In conclusion, D-R maintenance achieved a higher MRD-negative conversion rate and improved PFS after transplant vs R, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT03901963.

Graphical abstract

Figure 1.

CONSORT diagram for AURIGA. Summary of treatment disposition in AURIGA. ∗Three patients were randomly assigned but not treated because of physician decision, too intense study schedule, and protocol deviation (n = 1 each). †Three patients were randomly assigned but not treated because of study tests being too hard, patient not wanting to be on the R-only treatment arm, and patient withdrawal of consent (n = 1 each).

Figure 2.

MRD-negative (10^–5) conversion rate from baseline to 12 months of maintenance treatment. ∗Mantel-Haenszel estimate of the common OR for stratified tables is used. The stratification factor is baseline cytogenetic risk per investigator assessment (high vs standard/unknown), as was used for randomization. An OR >1 indicates an advantage for D-R. †P value <.0001, from Fisher exact test. ‡The ITT analysis set was defined as all patients who were randomly assigned to treatment. §Patients who achieved ≥CR at any time during the study per IMWG computerized algorithm. ||The MRD-evaluable analysis set includes all randomly assigned patients who had an MRD assessment at baseline and had ≥1 postbaseline MRD evaluation. ITT, intent to treat.

Figure 3.

Subgroup analysis of MRD-negative (10^–5) conversion rate from baseline to 12 months of maintenance treatment. ∗High risk is defined as positive for any of the following abnormalities: del(17p), t(14;16), or t(4;14). †Revised high-risk cytogenetics are defined as ≥1 of the following abnormalities: del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21). ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System.

Figure 4.

PFS analysis. PFS analysis in the ITT population∗ overall (A) and by MRD-negative (10^–5) conversion status by 12 months (B). † Estimated 30-month PFS rates are shown. ∗At a median follow-up of 32.3 months, median PFS was 37.9 months in the D-R group and was not reached in the R group. †MRD-negative by 12 months refers to patients who were MRD-positive at baseline and achieved MRD-negative status (at a threshold of 10^–5) by bone marrow aspirate from randomization to 12 months (+2-month window), but before progressive disease and subsequent antimyeloma therapy. Otherwise, patients were considered MRD-positive. ‡Per study protocol, disease assessments stopped at the end of study treatment (cycle 36), after which patients were only followed for survival. At the time of this analysis, the number of patients who reached the end of study treatment was low, thus resulting in a low number of patients at risk. Two D-R events occurred at the tail end of study assessments: 1 reported at 1134 days (37.26 months) and 1 at 1153 days (37.88 months). Because of these events, there was a sudden and steep drop in the Kaplan-Meier curve for D-R. ITT, intent to treat.