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)

Background

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.

Trial design

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.

Clinical trial identification

jRCTs031200320; 21-Jan-2021.

Legal entity responsible for the study

D. Maruyama.

Funding

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.).

Disclosure

T. Suzuki: Financial Interests, Personal, Invited Speaker: Janssen, Sanofi, Bristol Myers Squibb, Symbio, Chugai Pharmaceutical. D. Maruyama: Financial Interests, Institutional, Research Funding: Janssen, Sanofi, Takeda, Bristol Myers Squibb/Celgene, Chugai, Meiji Seika Pharma, MSD, Asahi Kasei Pharma, AstraZeneca, AbbVie, Incyte Japan, Eisai, Otsuka, Kyowa Kirin, Genmab, SymBio, Eli Lilly, Novartis, Mundipharma, Ono Pharmaceutical; Financial Interests, Personal, Invited Speaker: Janssen, Sanofi, Takeda, Bristol Myers Squibb/Celgene, Chugai, Meiji Seika Pharma, MSD, Asahi Kasei Pharma, AstraZeneca, AbbVie, Incyte Japan, Eisai, Otsuka, Kyowa Kirin, Genmab, SymBio, Eli Lilly, Novartis, Mundipharma, Ono Pharmaceutical; Financial Interests, Personal, Advisory Board: Janssen. K. Kataoka: Financial Interests, Personal, Invited Speaker: Celgene, Astellas Pharma, Novartis, AstraZeneca, Janssen Pharmaceutical, SymBio Pharmaceuticals, Bristol Myers Squibb, Pfizer, Nippon Shinyaku, Daiichi Sankyo, Alexion Pharmaceuticals, AbbVie, MeijiSeika Pharma, Sanofi, Ono Pharmaceutical, Eisai, Kyowa Kirin, Sumitomo Dainippon Pharma, Otsuka Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical; Financial Interests, Institutional, Other, scholarship: Ono Pharmaceutical, Eisai, Kyowa Kirin, Sumitomo Dainippon Pharma, Chugai Pharmaceutical, Takeda Pharmaceutical, Asahi Kasei Pharma, Otsuka Pharmaceutical, Shionogi, Teijin Pharma, Japan Blood Products Organization, Mochida Pharmaceutical, JCRP pharmaceuticals, Nippon Shinyaku; Financial Interests, Institutional, Research Funding: Otsuka Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical. H. Nagai: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb/Celgene, Takeda, Janssen, Ono Pharmaceutical, Sanofi; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb/Celgene, Takeda, Janssen, Ono Pharmaceutical, AbbVie, MSD, Symbio. All other authors have declared no conflicts of interest.