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

• Dara-KRd-based, MRD-adapted treatment yielded high sCR rates and MRD-negativity that improved over time.

• Results support randomized studies of therapy de-escalation for patients who are MRD- and escalation for those MRD+ after initial treatment.

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.