Daratumumab (DARA) Plus Lenalidomide Versus Lenalidomide Alone As Maintenance Treatment in Patients with Newly Diagnosed Multiple Myeloma (NDMM) after Frontline Autologous Stem Cell Transplant (ASCT): Use of Minimal Residual Disease (MRD) As a Novel Primary Endpoint in the Phase 3 Auriga Study

Background: DARA, a human anti-CD38 IgGκ monoclonal antibody, is approved in many countries as monotherapy in relapsed/refractory MM (RRMM), in combination with standard-of-care (SoC) regimens in RRMM and upfront in transplant ineligible NDMM. DARA is also under investigation as part of induction, consolidation, and maintenance treatment in patients with NDMM who are transplant eligible. However, no studies have specifically compared DARA maintenance to current SoC maintenance regimens. Although deep response as measured by MRD negativity has been associated with positive long-term clinical outcomes, and previous studies have demonstrated that DARA increases MRD negativity rates when combined with SoC therapy, MRD as a primary end point has not been examined in the context of frontline DARA treatment in NDMM. The ongoing phase 3 AURIGA (MMY3021) study will evaluate whether the addition of DARA to lenalidomide maintenance therapy increases the conversion rate to MRD negativity after 1 year of maintenance treatment, compared to lenalidomide alone, in patients with NDMM who are MRD positive after ASCT.

Study Design and Methods: This ongoing multicenter, open-label, randomized phase 3 study will enroll approximately 214 patients from up to 60 sites in the United States. Patients 18-79 years of age are eligible if they have NDMM, have not been previously treated with an anti-CD38 antibody, have completed 4-8 total cycles of induction therapy (and/or consolidation therapy), have undergone ASCT, have achieved a very good partial response or better by International Myeloma Working Group (IMWG) criteria after ASCT and/or consolidation therapy, are MRD-positive by next-generation flow (NGF) or next-generation sequencing (NGS), at 60-100 days post-ASCT (or ≤60 days post consolidation therapy). Patients will be stratified by cytogenetic risk status (high risk vs standard risk/unknown status) and randomized 1:1 to DARA plus lenalidomide versus lenalidomide alone.

Patients in both arms will receive 10 mg lenalidomide orally continuously during each 28-day cycle. After Cycle 3, if lenalidomide is well tolerated, the dose may be increased to 15 mg at the discretion of the investigator. Patients in the DARA plus lenalidomide arm will receive DARA SC (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE^® drug delivery technology, Halozyme, Inc.]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. Treatment will continue until disease progression, unacceptable toxicity, withdrawal, or for a maximum of 36 cycles. The primary endpoint is the MRD-negativity conversion rate (assessed at a 10^-5 sensitivity threshold) at 12 months of treatment, assessed via NGS. MRD will also be assessed at 6, 18, 24, and 36 months. Importantly, use of the novel primary endpoint of MRD-negativity will allow for earlier assessment of outcomes and evaluation of deeper response than traditional endpoints such as progression-free survival (PFS) and overall survival (OS). Secondary endpoints include overall MRD-negativity rate at any time, duration of MRD negativity, rate of complete response or better (≥CR), duration of ≥CR, PFS, OS, health-related quality of life, and safety. The ClinicalTrials.gov identifier is NCT03901963.