Retrospective Matched-Pair Analysis Of The Efficacy and Safety Of Bortezomib Plus Dexamethasone Versus Bortezomib Monotherapy In Patients (Pts) With Relapsed Multiple Myeloma (MM)
Authors: Dimopoulos Meletios A. , Orlowski Robert Z. , Facon Thierry , Sonneveld Pieter , Anderson Kenneth C. , Beksac Meral , Benboubker Lotfi , Roddie Huw , Potamianou Anna , Couturier Catherine , Feng Huaibao , Ataman Ozlem , van de Velde Helgi , Richardson Paul G. 
Published: October 2019

Abstract

Introduction
The activity of bortezomib (VELCADE®, Vc) ± dexamethasone (Dex) in relapsed MM is well established. Results from several studies suggest that adding Dex to Vc (Vc-Dex) can improve response rates in pts with suboptimal response to Vc alone; however, randomized comparative data in relapsed MM are lacking, and, although Vc-Dex is widely used in routine clinical practice, the benefit of adding Dex from first relapse remains unclear. We conducted a retrospective analysis of the efficacy and safety of second-line treatment with Vc-Dex vs Vc among propensity score-matched pairs to control for differences in baseline characteristics and allow meaningful cross-study comparisons.

Methods
Pt-level data from 3 clinical trials of single-agent Vc (APEX, Richardson et al. NEJM 2005; DOXIL–MMY3001, Orlowski et al. JCO 2007) and Vc-Dex (MMY2045, Dimopoulos et al. Haematologica 2013) were used in this analysis; follow-up for each study was complete. Only pts with 1 prior therapy were included. In all studies, pts received Vc 1.3 mg/m2 IV on days 1, 4, 8, 11 in 21-day cycles. In MMY2045, pts additionally received Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, 12 in 21-day cycles. Responses were per EBMT/IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v2.0/3.0. Clinical variables associated with study drug tolerability or outcomes, which were collected consistently across all studies, were used in logistic regression analysis to calculate a propensity score against which pts’ data were matched; these 13 variables were age, body surface area (BSA), ECOG PS, myeloma type, presence of extramedullary plasmacytomas, % plasma cells in bone marrow biopsy, prior transplant, prior immunomodulatory drugs (IMiDs), prior Dex, and baseline hemoglobin levels, platelet count, creatinine clearance, and albumin levels. Efficacy and safety were then compared between the matched groups. Kaplan-Meier methodology was used for time-to-event analyses.

Results
Across the 3 studies, 384 pts received 1 prior therapy and were eligible for inclusion. Propensity score matching identified 109 pt pairs; baseline characteristics are shown in the table. For Vc-Dex vs Vc, respectively, median time since diagnosis was 2.7 vs 2.0 years, median treatment duration was 19.6 vs 17.6 weeks, and median cumulative Vc dose was 27.02 vs 28.60 mg/m2. Overall response rate (ORR) was significantly higher for Vc-Dex vs Vc (75% vs 41%, p<0.001; Table). Median progression-free survival (PFS, 11.9 vs 6.4 months, p=0.051) and median time to progression (TTP, 13.6 vs 7.0 months, p=0.003) were longer for Vc-Dex vs Vc. Median overall survival (OS) was not reached in either group (p=0.884); 1-/2-year OS rates were 78.7%/68.4% (Vc-Dex) and 86.4%/62.2% (Vc). Results were similar in regression sensitivity analyses (covariate-adjusted and propensity score-weighted). Vc-Dex and Vc had similar safety profiles, including rates of grade ≥3 thrombocytopenia, infections, and peripheral neuropathy (PN) (Table).

Conclusion
In this analysis of MM pts at first relapse, Vc-Dex was associated with significantly higher ORR and longer median TTP and PFS compared with Vc alone. The lack of difference in OS may be due to subsequent salvage therapies received. Addition of Dex to Vc was not associated with increased toxicity. These data indicate the potential benefit of using Vc-Dex from first relapse in MM.

Disclosures:
Dimopoulos: ORTHO-BIOTECH: Consultancy, Honoraria. Orlowski:Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Resverlogix: Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Facon:Amgen: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Sonneveld:Janssen: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Anderson:Celgene: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Gilead: Consultancy; Acetylon: Equity Ownership; Oncopep: Equity Ownership. Beksac:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Benboubker:Celgene: Consultancy. Potamianou:Janssen Pharmaceuticals: Employment. Couturier:Janssen EMEA: Employment. Feng:Janssen R & D, LLC: Employment. Ataman:Janssen-Cilag: Employment. van de Velde:Johnson & Johnson: Equity Ownership; Janssen Research & Development: Employment. Richardson:Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees.