Updated Results from the Phase 2 Centaurus Study of Daratumumab (DARA) Monotherapy in Patients with Intermediate-Risk or High-Risk Smoldering Multiple Myeloma (SMM)
Authors: Landgren Ola , Cavo Michele , Chari Ajai , Cohen Yael C , Spencer Andrew , Voorhees Peter M. , Estell Jane , Sandhu Irwindeep , Jenner Matthew , Williams Catherine , van de Donk Niels WCJ , Beksac Meral , Goldschmidt Hartmut , Moreau Philippe , Kuppens Steven , Bandekar Rajesh , Neff Tobias , Cortoos Annelore , Clemens Pamela L , Qi Ming , Adams Homer , Hofmeister Craig C 
Published: October 2019

Abstract
Introduction: Multiple myeloma (MM) evolves from precursor disorders such as monoclonal gammopathy of undetermined significance (MGUS) and SMM (Landgren O, et al. Blood 2009. 113[22]:5412-5417). Currently, there are no approved therapies for SMM, and guidelines recommend close monitoring of SMM patients (pts) and initiating treatment only upon progression to MM. However, therapeutic intervention at the SMM stage, especially in pts at higher risk of progression to MM, may yield clinical benefit and prevent the development of MM-associated complications. DARA is a CD38-targeting IgG1κ monoclonal antibody with on-tumor and immunomodulatory mechanisms of action. Based on the demonstrated efficacy and favorable safety profile of DARA monotherapy in pts with relapsed/refractory MM (RRMM; Usmani SZ, et al. Blood 2016. 128[1]:37-44), we hypothesized that DARA could delay progression from SMM to MM. A prespecified primary analysis (15.8-month median follow-up) of the phase 2 CENTAURUS study (NCT02316106) revealed that DARA monotherapy was active and well tolerated in pts with intermediate- or high-risk SMM (Hofmeister CC, et al. ASH 2017. Abstract 510). Here, we present updated data from CENTAURUS based on 10 months of additional follow-up.
Methods: Eligible pts had had a confirmed diagnosis of high-risk or intermediate-risk SMM for <5 years. Pts were randomized (1:1:1) to receive 8-week cycles of DARA 16 mg/kg intravenously on 1 of 3 treatment schedules. Pts on the Long dosing schedule received DARA QW (Cycle 1), Q2W (Cycles 2-3), Q4W (Cycles 4-7), and Q8W (Cycles 8-20). On the Intermediate dosing schedule (Int), pts received DARA QW (Cycle 1) and Q8W (Cycles 2-20). Pts on the Short dosing schedule received 1 cycle of DARA QW. Rate of complete response (CR) or better and progressive disease (PD)/death rate (defined as the ratio of pts with an event [PD or death] to the total follow-up for all pts) were co-primary endpoints. CR and PD were defined per 2014 International Myeloma Working Group criteria (Rajkumar et al. Lancet Oncol 2014;15[12]:e538-e548). Biochemical progression and biochemical/diagnostic (BOD) progression were defined as previously reported (Hofmeister CC, et al. ASH 2017. Abstract 510).
Results: A total of 123 pts were randomized (41 pts per arm). The median (range) age was 61.0 (31-81) years, and the median (range) time from initial SMM diagnosis to randomization was 6.83 (0.40-56.0) months. In total, 73% of pts were of IgG subtype. Median treatment duration was 25.8 months in both the Long and Int arms and 1.6 months in the Short arm (Table 1). In the Long, Int, and Short arms, 17%, 22%, and 5% of pts, respectively, discontinued treatment; reasons included PD (7%, 10%, and 0%, respectively), adverse events (AEs; 7%, 2%, and 5%, respectively), refusal of further treatment (5% in Int), withdrawal of consent (2% each in Long and Int), and death (2% in Int).
At a median (range) follow-up of 25.9 (0-33.2) months, overall response and ≥CR rates were higher in the Long and Int arms than in the Short arm (Table 2); in the combined Long and Int arms, the ≥CR rate was 7%. Median PFS based on SLiM-CRAB criteria was not reached in any arm; 24-month PFS rates were 90% (Long), 82% (Int), and 75% (Short; Figure 1A). PD/death rates indicate a median PFS of ≥24 months in all arms (Table 2). Median PFS based on BOD criteria was reached in the short arm only (14.8 months); 24-month PFS rates were 78% (Long), 70% (Int), and 27% (Short; Figure 1B).
Safety results are summarized in Table 1. In all arms, no hematologic treatment-emergent AE was observed in ≥10% of pts, and the rates of grade 3/4 infections were ≤5%. Deaths occurred in 1 pt (2%) in the Int arm (due to heart failure not related to DARA) and 1 pt (2%) in the Short arm (due to PD); no deaths were observed in the Long arm. No deaths occurred within 30 days of the last DARA dose.
Conclusions: After median follow-up of 25.9 months, a more pronounced BOD PFS benefit was observed in the Long and Int arms compared with the Short arm. The safety profile of DARA monotherapy in SMM remains consistent with other single-agent DARA studies, and no new safety signals were observed with longer follow-up. Because dose intensity was associated with efficacy in SMM pts, an extended, dose-intensive schedule was selected for an ongoing phase 3 study of DARA monotherapy versus active monitoring in SMM (AQUILA).

Disclosures
Landgren: Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Chari:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Research Funding; The Binding Site: Consultancy. Cohen:Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Voorhees:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Novartis: Consultancy, Other: served on an IRC; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Speakers Bureau. Estell:Janssen: Membership on an entity's Board of Directors or advisory committees. Sandhu:Bioverativ: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Jenner:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Williams:Takeda: Honoraria, Other: travel support, Speakers Bureau; Celgene: Honoraria, Other: travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Other: travel support, Speakers Bureau; Novartis: Honoraria. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Beksac:Amgen,Janssen-Cilag,Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Chugai: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Amgen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuppens:Janssen Research & Development: Employment. Bandekar:Janssen Research & Development: Employment. Neff:Janssen Research & Development: Employment. Cortoos:Janssen Research & Development: Employment. Clemens:Janssen Research & Development, LLC: Employment. Qi:Janssen: Employment. Adams:Janssen Pharmaceutical R&D: Employment. Hofmeister:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.