Treatment of high-risk newly diagnosed multiple myeloma with minimal residual disease-guided therapy：daratumumab, carfilzomib, lenalidomide, and dexamethasone (DKRd) Free

Background MM is a highly heterogeneous malignant tumor, some patients derive limited benefit from current standard treatments, exhibiting an OS of less than 2-3 years, classified as high-risk MM. Early identification and personalized treatment are crucial for this subgroup. The continuous advancement of MRD detection technology has established MRD negativity not only as a reflection of superior response depth but also as a powerful prognostic indicator. Currently, daratumumab, carfilzomib, lenalidomide and dexamethasone (DKRd) regimen, has demonstrated superior efficacy and survival outcomes in international studies, however China lacks a unified treatment protocol and practice for HRMM, so it is necessary to provide new therapeutic options and corresponding dosages, thereby improving prognosis and reducing the overall disease burden.

Methods Patients who possessed high-risk karyotypic abnormalities recognized by the mSMART or NCCN guidelines: t(4;14), t(14;16), t(14;20), del(17p) and/or TP53 mutation, del(1p32), or 1q21 gain/amplification, were enrolled into a prospective, single-center, single-arm clinical study (NCT06409702) in The First Affiliated Hospital of Soochow University between May 2024 and May 2025. All patients were allowed to receive one cycle of VRD before enrolled. After three cycles of DKRd, TE MM patients underwent stem cell collection and ASCT, followed by two additional cycles of DKRd consolidation and then DKR (daratumumab, carfilzomib, lenalidomide) maintenance therapy. TIE MM patients received four more consolidation cycles of DKRd and then DKR maintenance. Patients with sustaining MRD negativity for over one year could transition to lenalidomide-only maintenance. The study aimed to evaluate the efficacy and safety of the DKRd in HR-NDMM patients, with the primary endpoint being the NGF-MRD（10^-5) and NGS-MRD（10^-6)-negative rate after consolidation therapy.

Results This study included data from 58 patients for analysis, with a median age of 59 years (range 36-71). 9 patients (16%) were pPCL, and 9 patients (16%) had EMD. Patients frequently presented anemia (69%), hypoalbuminemia (64%), high urinary protein (36%), and hypercalcemia (9%). CPCs≥0.2% were detected in 26 patients (45%). 91% patients were DS stage III, 29% ISS stage III, 22% R-ISS stage III, 62% R2-ISS stage III and 17% stage IV. Cytogenetic abnormalities included 81% 1q21 gain/amp (3 copies: 47%, ≥4 copies: 34%), 22% del(1p32), 19% del(17p), 43% t(4;14), 17% t(11;14), 9% t(14;16), and 19% TP53 mutation, with 76% ≥double-hit.

Following induction therapy, the ORR was 92.8%, all ≥VGPR, and the ≥CR rate was 59.5%. The NGF-MRD negativity rate was 81.5%, and the NGS- MRD negativity rate was 75%. 30 patients underwent autologous stem cell collection, with a success rate (≥2.0* 10⁶ CD34+ cells/kg) of 93.3% and an optimal rate (≥4.0*10⁶CD34⁺ cells/kg) of 60%. After ASCT or eight cycles of therapy, an ORR of 82.3%, all in CR+sCR. The NGF-MRD negativity rate was 91.7%, and the NGS-MRD negativity rate was 84.6%.

Hematological AEs were common (52%), including 42% neutropenia and 26% thrombocytopenia, mostly in grade I-II. Non-hematological AEs included 17% respiratory infections, hepatic dysfunction 4 cases, and hypertension 2 cases controlled with medication.

One patient withdrew due to a severe daratumumab allergic reaction, three due to disease progression, one died from the disease, and one died from sepsis. With a median follow-up of 5 months (range 1-14), the estimated 12-month PFS rate was 88.3%, and the estimated 12-month OS rate was 93.2%.

Conclusion HR-NDMM patients exhibited higher tumor burden and more complex cytogenetic abnormalities, nevertheless, the DKRd regimen demonstrated remarkably favorable efficacy in this study, achieving significant MRD negativity rates. Treatment responses deepened progressively through induction, transplantation, and consolidation phases. This regimen has proved safe and reliable, ensuring clinical safety and successful stem cell collection, thereby providing substantial survival benefits for these high-risk patients.