352TiP Randomized phase III study of daratumumab (D) versus bortezomib plus D as a maintenance therapy after D-MPB for elderly or non-elderly patients refusing transplant with untreated multiple myeloma (JCOG1911, B-DASH study)

Daratumumab (D), melphalan, prednisolone, and bortezomib (D-MPB) was established as a standard of care for transplant-ineligible (TI) newly diagnosed multiple myeloma (NDMM) based on the results of the phase III ALCYONE trial (Mateos MV et al. NEJM 2018). As progression-free survival (PFS) decreased more sharply during the D maintenance phase than during the D-MPB phase in the ALCYONE trial, intensification of D maintenance therapy is considered necessary to improve D-MPB treatment outcomes. JCOG1911 is a phase III, multicenter, randomized trial designed to evaluate the superiority of adding bortezomib (every 2 weeks) to D maintenance therapy (every 4 weeks) (Arm B) compared with D maintenance therapy (Arm A) in TI patients with NDMM treated with D-MPB. Maintenance therapy will be administered for up to 24 courses. The primary endpoint is PFS from randomization. The trial uses a two-stage registration process in which patients are initially registered before D-MPB induction and those who respond to D-MPB are then secondarily registered and randomized to Arm A or B. Randomization is adjusted for institution, depth of response to D-MPB, cytogenetic risk, and age. The target sample size for randomization is 166, assuming a 2-year PFS of 65% in Arm A and 76% in Arm B, 1-sided α of 5%, and power of 70%. An accrual period is 5 years; the first patient was randomized on Jan-2022. An exploratory biomarker sub-study of JCOG1911 (JCOG1911A1) is also ongoing. Bone marrow aspirates are collected before D-MPB (t1) and on disease progression/relapse after D-MPB (t2). After purification by CD138 sorting, genomic DNA (gDNA) is extracted from the bone marrow samples. Targeted-capture sequencing of gDNA obtained at t1, covering 214 MM-related genes, will be performed to investigate the prognostic impact of genetic alterations in patients treated with D-MPB. In addition, whole-exome sequencing of paired gDNA obtained at t1 and t2 will be performed to investigate the mechanisms of resistance to D-MPB. jRCTs031200320; 21-Jan-2021. D. Maruyama. The National Cancer Center Research and Development Fund (2020-J-3, 2023-J-03) The Japan Agency for Medical Research and Development (grant number: JP21ck0106685 to D.M.).