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 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.

Graphical abstract

Figure 1.

Post-induction MRD-driven treatment algorithm. Patients were divided into 3 separate groups: group A (MRD negative) received lenalidomide maintenance or no further treatment at the discretion of the investigator; group B (MRD positive, ASCT eligible) underwent ASCT; and group C (MRD positive, ASCT ineligible) received KRd consolidation for up to 12 cycles. Patients in group B could receive up to 12 cycles of KRd consolidation therapy if they remained MRD positive after ASCT. Conversion to MRD-negative status at any protocol specified time point allowed patients to receive lenalidomide maintenance or no further treatment at the investigator’s discretion.

Figure 2.

Patient flow and disposition as of data cutoff (30 October 2023).

Figure 3.

Response and MRD status. (A) shows the IMWG responses and MRD negativity at the end of induction and best response as of data cutoff (30 October 2023) in N = 39 enrolled patients. (B) shows a swimmer plot over time for the depth and duration of response for each patient. Because 26 patients are still on treatment as of data cutoff, responses could still deepen further.

Figure 4.

MRD-negativity rates during treatment in the intention to treat population (N = 39) and concordance between NGS and NGF methods. (A) This table shows the MRD-negativity rates overall and stratified by cytogenetic risk. HRC is defined as del(17p) and/or t(4;14) and/or t(14;16) and/or t(14;20) and/or gain or amplification of 1q. (B-C) Panel B shows the postinduction MRD concordance between NGS and NGF methods at 10⁻⁵ and 10⁻⁶ sensitivity, whereas panel C shows the MRD concordance between NGS and NGF methods at 10⁻⁵ and 10⁻⁶ sensitivity for the best MRD status. Sample size for each of the concordance analyses include patients with results from both NGS and NGF testing at the applicable sensitivity.

Figure 5.

Immune modulatory activity of Dara-KRd on both conventional and unconventional T cells during induction therapy. Peripheral blood mononuclear cells (PBMCs), collected from 36 patients before every other cycle of induction therapy (cycle 1-7) and after induction, were evaluated by flow cytometry. (A-B) CD4 and CD8 T-cell subsets (manually gated from live CD3⁺ cells) distribution, activation (% HLA-DR expression), and proliferation (CD71 MFI) assessment. (C) Conventional (CD4⁺, CD8⁺) and unconventional (CD4⁻/CD8⁻) T-cell identification through dimensional reduction analysis (Uniform Manifold Approximation and Projection; R export from live CD3⁺ cells). (D) Radar plots representing immunological clusters associated with treatment outcomes. (E) Mixed model analysis of immune clusters associated with depth of clinical response after Dara-KRd induction (CR/sCR vs PR/VGPR). (F) Hierarchical clustering analysis of immune clusters associated with MRD positivity. For the immune analysis MRD positivity is defined as detectable MRD at the highest level of sensitivity by either NGS or NGF (MRD positive vs MRD negative). The red box indicates immunotypes enriched for patients with MRD negativity. (G) Mixed model analysis of immune clusters and T-cell fitness markers (LAG3) associated MRD status after induction; P values indicate time × MRD status interaction. Error bars represent standard error of the mean. MFI, mean fluorescence intensity.