Efficacy and Safety of Once-Weekly Cyclophosphamide-Bortezomib-Dexamethasone (CBD) Regimen As Induction Therapy Prior to Autologous Stem Cell Transplantation in Japanese Patients with Newly Diagnosed Multiple Myeloma. -a Phase 2 Multicenter Trial-
Authors: Kudo Daisuke , Komeno Takuya , Yoshida Chikashi , Tsutsumi Ikuyo Ota , Ohashi Kazuteru , Kakihana Kazuhiko , Kobayashi Takeshi , Doki Noriko , Najima Yuho , Igarashi Aiko , Hori Mitsuo , Okoshi Yasushi , Fujio Takayuki , Shinagawa Atsushi , Yamamoto Masahide , Takano Hina , Kumagai Takashi , Yamamoto Koh , Toyota Shigeo , Nakamura Yuichi , Kojima Hiroshi 
Published: October 2019

Abstract
Introduction: Although a previous study with small numbers of patients (Pts) reported comparable efficacy and less toxicity of once-weekly CBD as an induction compared to twice-weekly CBD for newly diagnosed MM (NDMM) Pts (Blood 2010; 115:3416-3417), it has never been verified thereafter.
Methods: This multicenter, single-arm, open-label, phase 2 study was conducted at 13 institutions in Japan. Pts aged 15-65 years with NDMM were eligible. Additional inclusion criteria were ECOG PS 0-2 and adequate organ functions. Pts with ≥G2 peripheral neuropathy (PN) were excluded. Pts were enrolled between January 2013 and November 2015. Induction chemotherapy consisted of four 28-day cycles of cyclophosphamide (CPA: 300 mg/m2, PO), bortezomib (1.3 mg/m2, SC), and dexamethasone (40 mg/body, PO) each administered on day 1, 8, 15, and 22. Stem cells were mobilized by administering CPA plus G-CSF. High-dose therapy (HDT) prior to ASCT was performed using melphalan (200 mg/m2). The primary endpoint was the post-induction ≥nCR rate. Observation was stopped on August 31, 2016.
Results: A total of 38 Pts with median age of 61 (47-65 years old) were enrolled. ISS stages were I, II, and III in 10, 18, and 10 patients, respectively. Among the 34 chromosomal data-available Pts, del 13 and hypoploidy were observed in 2 and 1, respectively. During the induction, only one patient developed G4 hematological AE. G3 infectious AE was observed in 4 Pts (10.5%). Three Pts (7.9%) developed G4 non-hematological AE. PN was observed in 2 Pts (all <G3). No Pts died during the induction phase. Totally, 2 Pts dropped out during the induction due to non-hematological AE, and 6 Pts dropped out after the induction due to insufficient efficacy. Post-induction ORR was 73.7%, including 10.5% CR, 2.6% nCR, and 23.7% VGPR by ITT analysis. Although 30 Pts proceeded to stem cell mobilization, 6 Pts dropped out (harvest failure; 4, protocol violation; 1, physician's decision; 1). Accordingly, HDT/ASCT was performed in 24 Pts (63.2%). The post-HDT/ASCT ORR was 63.2%, including 10.5% CR, 10.5% nCR, and 10.5% VGPR by ITT analysis. In the 24 Pts who completed HDT/ASCT, ≥nCR and >VGPR rates improved from 16.7% to 33.3% and from 41.7% to 50.0%, respectively (Fig.1). The median follow-up duration was 578.5 days. PFS at 1, 2, and 3 years was 78.0%, 55.3% and 48.4%, respectively, with a median PFS of 816 days. OS at 1 and 2 years was 97.3% and 82.7%, respectively (Fig.2). The median OS was not reached. The therapeutic efficacy and feasibility of the present study were compared with those in our previous study with the VAD/BD induction regimen, which contained one cycle of VAD followed by 3 cycles of twice-weekly BD (Int J Myeloma 2015; 5:15-22). Although the percentage of Pts discontinuing the induction chemotherapy due to AE was lower for the CBD regimen (5.3% vs 19.5%, p=0.0894), discontinuation due to poor response showed the tendency to be more frequent (15.8% vs 4.9%, p=0.145). There was no significant difference in PFS or OS between these 2 studies.
Conclusion: Although once-weekly CBD is a well-tolerated standard induction chemotherapy prior to ASCT for most Japanese patients, its therapeutic power may be too low to achieve a deep response.

Disclosures
Hori: ONO Pharmaceutical Co., Ltd: Other: Post-marketing surveillance study fees; Sanofi: Other: Post-marketing surveillance study fees; Mundipharma: Other: Post-marketing surveillance study fees.