Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone for Newly Diagnosed Multiple Myeloma

The MASTER clinical trial utilized a combination therapy of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) to treat newly diagnosed multiple myeloma (NDMM). The prosecution employed next-generation sequencing (NGS) to assess minimal residual disease (MRD) and determine the appropriate use and duration of Dara-KRd following autologous hematopoietic cell transplantation (AHCT). Patients with two consecutive MRD-negative assessments were considered for treatment cessation. This multicenter, single-arm, phase II clinical trial included newly diagnosed multiple myeloma (NDMM) patients with planned enrichment for high-risk cytogenetic abnormalities (HRCAs). The patients underwent Dara-KRd induction, AHCT, and Dara-KRd consolidation, as per their MRD status. Minimal residual disease (MRD) was assessed using next-generation sequencing after induction therapy, after autologous hematopoietic cell transplantation, and at intervals of four cycles (up to a maximum of eight cycles) during consolidation therapy. The study’s primary endpoint was the attainment of minimal residual disease negativity, defined as a level below 10-5. Patients who have achieved two consecutive negative assessments for the minimal residual disease have been enrolled in a program of MRD surveillance without active treatment.

Of the 123 participants, 43% did not exhibit any High-Risk Coronary Artery (HRCA) symptoms, 37% displayed one HRCA symptom, and 20% presented with two or more HRCA symptoms. The median age of the subjects was 60 years, ranging from 36 to 79 years. Additionally, 96% of the participants had a minimal residual disease trackable by next-generation sequencing. The median duration of follow-up for the study was 25.1 months. 80% of the patients achieved minimal residual disease negativity, with 78%, 82%, and 79% of patients with 0, 1, and 2+ high-risk cytogenetic abnormalities (HRCA), respectively. Additionally, 66% of patients attained MRD levels below 10-6, and 71% achieved two consecutive MRD-negative assessments during therapy, thereby entering treatment-free surveillance. The two-year progression-free survival rate was found to be 87%. Patients with 0, 1, and 2 or more high-risk chromosomal abnormalities had survival rates of 91%, 97%, and 58%, respectively. The 12-month cumulative incidence of minimal residual disease resurgence or progression following therapy cessation was 4%, 0%, and 27% for patients with 0, 1, or 2+ high-risk chromosomal abnormalities, respectively. The prevalent severe adverse events observed were pneumonia (6%) and venous thromboembolism (3%). The utilization of Dara-KRd, AHCT, and MRD response-adapted consolidation in the treatment of newly diagnosed multiple myeloma patients results in a significant proportion of patients achieving minimal residual disease negativity. This approach presented the possibility of minimal residual disease monitoring as a substitute for continuous maintenance therapy for patients with zero or one high-risk cytogenetic abnormality.

Source:https://pubmed.ncbi.nlm.nih.gov/34898239/

Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT03224507

Costa LJ, Chhabra S, Medvedova E, Dholaria BR, Schmidt TM, Godby KN, Silbermann R, Dhakal B, Bal S, Giri S, D’Souza A, Hall A, Hardwick P, Omel J, Cornell RF, Hari P, Callander NS. Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2022 Sep 1;40(25):2901-2912. doi: 10.1200/JCO.21.01935. Epub 2021 Dec 13. PMID: 34898239.