Bortezomib-Based Therapy without Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma Patients with t(4;14): A Canadian National Trial,
Authors: Reece Donna E. , Rodriguez Giovanni Piza , Szwajcer David , Minuk Leonard A , Pantoja Mariela , Belch Andrew , Shustik Chaim , Stakiw Julie , White Darrell J. , Chen Christine , Kukreti Vishal , Tiedemann Rodger E. , Sebag Michael , Jenkins Gayle , Bahlis Nizar J , Le Lisa W , Trudel Suzanne 
Published: October 2019

Abstract 3982

Newly diagnosed multiple myeloma (MM) patients (pts) with t(4;14) identified by FISH who undergo a single ASCT after older induction regimens have a median progression-free survival (PFS) of only 8–9 months (mos) and median overall survival (OS) of 18 mos (Chang H, et al. Bone Marrow Transplan t 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). Given the efficacy of bortezomib in t(4;14) disease, we designed a phase II study based on this agent in which ASCT was not performed as part of first-line therapy. Pts received induction therapy with four 21-day cycles of pegylated liposomal doxorubicin 30 mg/m2on day 4, bortezomib 1.3 mg/m2on days 1, 4, 8, 11 and dexamethasone 40 mg on days 1–4, 8–11, 15–18 of cycle 1 and on days 1–4 and 11–14 of cycles 2–4 (DBD), followed by post-induction therapy with eight 28-day cycles of oral cyclophosphamide 300 mg/m2on days 1, 8, 15, 22, bortezomib 1.5 mg/m2 on days 1,8,15 and prednisone 100 mg q 2 days (CyBor-P). Maintenance therapy with dexamethasone 40 mg/weekly was then administered until disease progression. Although elective stem cell collection was recommended after induction therapy, routine ASCT was not performed in the absence of disease progression. Between February 2008-May 2011, 383 newly diagnosed MM pts were screened for t(4;14) in 8 Canadian centers, and 43 (11.2%) were found to be positive by FISH. Five did not meet the CRAB criteria for symptomatic MM, 7 were ineligible, 3 declined participation and 28 were entered onto study. One of these was later determined to have a variant abnormality of chromosome 4, but not t(4;14), and underwent ASCT after induction therapy; this pt is included in the safety analysis only. The median age was 60 years (range 42–69) and 63% were male. The median percent of nuclei positive for t(4;14) by FISH in the initial bone marrow (unpurified) was 26% (range 2–62), serum β2-microglobulin 239 nmol/L (range 43–1695) and albumin 36 g/L (range 28–48); ten pts had ISS stage 1,10 had stage 2 and 7 had stage 3 MM. Immunoglobulin subtype included IgGκ in 7, IgAκ in 6, IgAλ in 6, IgGλ in 5 and IgMλ in 1. Using modified uniform criteria, the best response in 23 evaluable pts includes: sCR in 6 (26%), CR in 4 (17%), VGPR in 9 (39%), PR in 2 (9%) and SD in 2 (9%). Median F/U is 13.5 mos (range 1.2–35); 6 have progressed at median of 3 mos on study (range 1–11). Four pts have died (due to progression in 3 and complex medical problems/consent withdrawal in 1 in VGPR). SAEs were reported in 7 pts; only 6 pts (21%) developed grade 2 peripheral neuropathy, which necessitated dose reductions of bortezomib in 4. The actuarial 2-yr PFS is 47.7% (95%CI 25.9–87.9%), median PFS is 23. 2 months and 2-yr OS is 76.8% (95%CI 58.3–100%); the median OS has not yet been reached. We conclude: 1) the incidence of t(4;14) by FISH in newly-diagnosed MM pts is 11.2%; which appears to be lower than the 15% anticipated 2) 11.6% of these are asymptomatic; 3) this bortezomib-based regimen is well-tolerated; 4) the overall response rate (sCR + CR + VGPR + PR) is 91% with 82% achieving ≥ VGPR and 43% ≥ CR; 5) the PFS and OS with this approach compare favorably with those seen with older studies of single or double ASCT, and even with some recently reported trials using more modern induction regimens before ASCT, in pts with t(4;14); and 6) the use of more effective maintenance therapy, including agents targeting the aberrations associated with t(4;14), would be of interest in future trials.

Disclosures:

Reece: Millennium: Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol, Meyers, Squibb: Honoraria, Research Funding; Amgen: Honoraria. Off Label Use: Bortezomib regimens other than VMP (boretzomib, melphalan and prednisone)for initial therapy of myeloma. Piza Rodriguez:Celgene: Unrestricted educational grant; Otsuka: Honoraria. Belch:Ortho/Janssen: Honoraria; Celgene: Honoraria. White:Celgene: Consultancy, Honoraria, Research Funding; Ortho/Janssen: Honoraria, Research Funding. Chen:Celgene: Research Funding. Kukreti:Celgene: Honoraria.