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510 Daratumumab Monotherapy for Patients with Intermediate or High-Risk Smoldering Multiple Myeloma (SMM): Centaurus, a Randomized, Open-Label, Multicenter Phase 2 Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Immunotherapy in Myeloma and Amyloid
Sunday, December 10, 2017: 5:45 PM
Bldg C, Lvl 1, Hall C4 (Georgia World Congress Center)

Craig C Hofmeister, MD1, Ajai Chari2*, Yael Cohen3*, Andrew Spencer, MD4, Peter M. Voorhees, MD5, Jane Estell6*, Christopher P. Venner7*, Irwindeep Sandhu8*, Matthew W Jenner9*, Cathy Williams10*, Michele Cavo, MD11*, Niels WCJ Van De Donk12, Meral Beksac13*, Steven Kuppens14*, Rajesh Bandekar15*, Tobias Neff16, Christoph Heuck16*, Ming Qi16*, Hartmut Goldschmidt, MD17 and Ola Landgren, MD, PhD18

1Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
2Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY
3Department of Hematology, Tel-Aviv Sourasky (Ichilov) Medical Center, Tel Aviv, Israel
4Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, Australia
5Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
6Haematology Department, Concord Cancer Centre, Concord Hospital, Concord, NSW, Australia
7Cross Cancer Institute, Edmonton, AB, Canada
8Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
9Southampton General Hospital, Southampton, United Kingdom
10Centre for Clinical Haematology, Nottingham University Hospital, Nottingham, United Kingdom
11”Seràgnoli” Institute of Hematology Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
12Department of Hematology, VU University Medical Center, Amsterdam, Netherlands
13Department of Hematology, Ankara University, Ankara, Turkey
14Janssen Research & Development, Beerse, Belgium
15Janssen Research & Development, LLC, Spring House, PA
16Janssen Research & Development, Spring House, PA
17University Hospital Heidelberg and German Cancer Research Center, Heidelberg, Germany
18Myeloma Service, Memorial Sloan-Kettering Cancer Center, New York, NY

Introduction: A large prospective study (N = 77,469) showed that multiple myeloma (MM) evolves from a premalignant asymptomatic precursor stage (Landgren et al. Blood 2009;113[22]:5412-7). For SMM, current guidelines recommend monitoring patients (pts) every 3-6 months for active MM before initiating treatment. Early intervention to delay or prevent evolution of SMM to active disease could benefit pts. Daratumumab (DARA) is a human anti-CD38 monoclonal antibody approved as monotherapy and in combination with standard of care regimens in pts with relapsed and/or refractory multiple myeloma (RRMM). DARA has several mechanisms of action, including immunomodulation, and is well-tolerated in RRMM pts. We hypothesized that DARA may delay the progression of SMM to symptomatic MM. Here, we present preliminary data from a phase 2 study (CENTAURUS: NCT02316106) evaluating 3 DARA dosing schedules in pts with intermediate or high-risk SMM.

Methods: Pts had a diagnosis of SMM of <5 years, did not receive prior anti-SMM or antimyeloma therapy, and showed no evidence of MM or primary amyloid light chain amyloidosis. Intermediate or high-risk SMM was defined as ≥10% to <60% plasma cells in the bone marrow and ≥1 of the following: serum M-protein ≥3 g/dL; urine M-protein >500 mg/24 h; abnormal involved:uninvolved free light chain (FLC) ratio (<0.126 or >8) with serum M-protein <3 g/dL but ≥1 g/dL; and/or involved serum FLC ≥100 mg/L with an abnormal FLC ratio (<0.126 or >8), but not ≥100.

Pts were randomized to 1 of 3 treatment arms receiving DARA 16 mg/kg intravenously in 8-week cycles. In the long intense dosing schedule (Long), DARA was administered weekly (QW) in cycle 1, every other week in cycle 2-3, every 4 weeks in cycle 4-7, and every 8 weeks (Q8W) up to cycle 20. In the intermediate dosing schedule (Int), DARA was given QW in cycle 1, and Q8W up to cycle 20. In the short intense dosing schedule (Short), DARA was given QW for 1 cycle. In addition to serologic monitoring by IMWG criteria, MRI was performed every 6 months for the first 3 years.

The 2 co-primary endpoints were complete response (CR) rate and progressive disease (PD; as defined by 2014 IMWG criteria for SMM [Rajkumar et al. Lancet Oncology 2014;15:e538-48])/death rate (proportion of pts who progressed to MM or died per pt-year). Other efficacy endpoints included overall response rate (ORR), progression-free survival (PFS), time to next treatment, and overall survival rate at 4 years. We report a prespecified interim analysis of CR, which was planned to occur 6 months after randomization of the last pt. The pre-specified interim analysis of PD/death rate is planned at 12 months after randomization of the last pt.

Results: A total of 123 pts were enrolled (41 pts in each arm). The median (range) time since initial SMM diagnosis was 6.83 (0.4-56) months. The number of pts with ≥2 risk factors at screening were balanced between treatment arms (81% for Long and Int; 83% in Short), but more pts with high bone marrow aspirate plasma cell percentage (≥30-<60%) were enrolled in Long (26%) compared to Int and Short (14% and 16%, respectively). In Arm Long, Int, and Short, 10%, 10% and 5% of pts discontinued treatment, respectively. Reasons for discontinuation included adverse events (5%, 2%, and 5%, respectively), PD (2%, 5%, and 0%, respectively), pt refused further treatment (2% in Int) and withdrawal of consent (2% in Long).

Safety data, including the most common treatment-emergent adverse events (TEAEs) are summarized in the Table 1. No hematologic TEAE was >10% across all arms. Rates of grade 3/4 infection (pneumonia or sepsis) were ≤5% in all arms. Infusion-related reactions occurred in 56%, 37%, and 55% of pts; 2% in Long, 0% in Int, and 3% in Short were grade 3/4. At the time of clinical cut-off, no deaths were observed.

With median follow-up of 9.6 (range, 0-17.9) months, ORR was numerically higher in Long than Int and Short (Table 2). Median PFS was not reached in any treatment arm (Figure). The estimated 12-month PFS rates were 98%, 93%, and 89% in Long, Int, and Short, respectively.

Updated data including the pre-specified analysis of the PD/death rate will be presented.

Conclusions: DARA was well tolerated in SMM, with a safety profile similar to that in RRMM. Follow up for efficacy is ongoing. A phase 3 study (SMM3001) is planned to evaluate long intense dosing with subcutaneous administration of DARA in high-risk SMM pts.

Disclosures: Hofmeister: Thrassos: 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: Research Funding; Bristol-Myers Squibb: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Takeda: Research Funding; Roche: Research Funding. Chari: Pharmacyclics: Research Funding; Acetylon Pharmaceuticals: Other: Research funding (to AC's institution); Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Research funding (to AC's institution); travel; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Biotest: Other: Research funding (to AC's institution); Onyx: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Spencer: Amgen: Consultancy, Honoraria, Research Funding. Voorhees: Celgene: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Oncopeptides: Consultancy. Estell: Janssen: Membership on an entity's Board of Directors or advisory committees. Venner: Celgene, Janssen: Research Funding; Celgene, Janssen, Takeda, Amgen, Merck: Honoraria. Sandhu: Janssen, Celgene, Takeda, Novartis: Honoraria. Jenner: Chugai: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support , Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Williams: Janssen: Honoraria, Other: travel support, Speakers Bureau; Celgene: Honoraria, Other: travel support, Speakers Bureau; Takeda: Honoraria, Other: travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Cavo: Janssen: Honoraria; Celgene:: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria. Van De Donk: Janssen, Celgene, Bristol-Myers Squibb, Amgen: Research Funding. Beksac: Janssen, Amgen, Celgene, Takeda, Bristol-Myers Squibb: Honoraria; Janssen, Amgen, Celgene, Bristol-Myers Squibb: Speakers Bureau; Janssen, Amgen, Celgene, Takeda: Membership on an entity's Board of Directors or advisory committees. Kuppens: Janssen: Employment. Bandekar: Janssen: Employment; Johnson & Johnson, LLC: Equity Ownership. Neff: Janssen: Employment. Heuck: Janssen: Employment. Qi: Janssen: Employment; Johnson & Johnson, LLC: Equity Ownership. Goldschmidt: Chugai: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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