MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide and dexamethasone in newly diagnosed multiple myeloma.

In newly diagnosed multiple myeloma (NDMM), measurable residual disease (MRD) status is prognostically important, but its role in treatment-decisions remains unclear. In a phase II trial (NCT04113018), we assessed daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction followed by a next generation sequencing (NGS) based MRD-adapted strategy. The primary endpoint was rate of complete response and stringent complete response (≥CR) after induction. Flow cytometry was used to profile T cells. Among 39 patients, 21 (54%) achieved ≥CR post-induction (P=0.375) with MRD-negative rates of 59% (10-5) and 41% (10-6). MRD-negative patients (n=24, group A) received lenalidomide maintenance, showing sustained MRD-negativity in 14/18 (77.8%) for ≥12 cycles. MRD-positive transplant-eligible patients (n=8, group B) underwent ASCT, with 5 (62.5%) converting to MRD-negative (10-5) and 3 (37.5%) at 10-6. MRD-positive transplant-ineligible patients (n=4, group C) received KRd consolidation. MRD-negative rates improved to 77% (10-5) and 72% (10-6) at any time. No additional safety concerns were identified beyond those already known for Dara-KRd. With a median follow-up of 30.1 months, three, two and one patient(s) in groups A, B, and C have experienced disease progression or death. The 2-year PFS rate was 82.5%. We observed that the Dara-KRd regimen strongly activated memory T cells, which was associated with an MRD-negative state after induction. Although the primary endpoint was not met, Dara-KRd induction in NDMM achieved high rates of ≥CR and MRD-negativity without new safety concerns. The post-induction MRD-adapted strategy deepened responses in the MRD-positive group while maintaining durable MRD control in the negative group.