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

Abstract: 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 2 trial, we assessed daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) induction followed by...

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Main Authors: Manisha Bhutani, Myra Robinson, David Foureau, Shebli Atrash, Barry Paul, Fei Guo, Jason M. Grayson, Anna Ivanina-Foureau, Mauricio Pineda-Roman, Cindy Varga, Reed Friend, Christopher J. Ferreri, Xhevahire Begic, Sarah Norek, Tiffany Drennan, Michelle B. Anderson, James T. Symanowski, Peter M. Voorhees, Saad Z. Usmani
Format: Article
Language:English
Published: Elsevier 2025-02-01
Series:Blood Advances
Online Access:http://www.sciencedirect.com/science/article/pii/S247395292400675X
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Summary:Abstract: 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 2 trial, we assessed daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) induction followed by a next-generation sequencing–based MRD-adapted strategy. The primary outcome was complete response (CR) and stringent CR (≥CR) after induction. Flow cytometry was used to profile T cells. Among 39 patients, 21 (54%) achieved ≥CR after induction (P = .375), with MRD-negative rates of 59% (10−5) and 41% (10−6). Patients who were MRD-negative (n = 24, group A) received lenalidomide maintenance, showing sustained MRD negativity in 14 of 18 (77.8%) for ≥12 cycles. MRD-positive transplant-eligible patients (n = 8, group B) underwent autologous stem cell transplantation, with 62.5% converting to MRD-negative at 10−5 (37.5% at 10−6) posttransplant. MRD-positive, transplant-ineligible patients (n = 4, group C) received KRd consolidation. Best MRD-negative rates improved to 77% (10−5) and 72% (10−6). No new safety concerns were identified for Dara-KRd. With a median follow-up of 30.1 months, 3, 2, and 1 patient(s) in groups A, B, and C, respectively, have progressed or died. We observed that Dara-KRd strongly activated memory T cells, which was associated with an MRD-negative state post induction. Although the primary outcome was not met, Dara-KRd induction in NDMM achieved high ≥CR and MRD-negative rates without new safety concerns. The post induction MRD-adapted strategy deepened responses in MRD-positive patients and maintained durable MRD control in MRD-negative patients. This trial was registered at www.clinicaltrials.gov as #NCT04113018.
ISSN:2473-9529