Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS)

Abstract

Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI], 0.014-0.096), 0.102 (80% CI, 0.044-0.160), and 0.206 (80% CI, 0.118-0.295), respectively, translating to a median PFS ≥24 months in all arms (P < 0.0001, <0.0001, and =0.0213, respectively). With longer follow-up (median follow-up, 25.9 months), CR rates were 4.9%, 9.8%, and 0% for intense, intermediate, and short dosing, respectively. PD/death rates for intense, intermediate, and short dosing were 0.059 (80% CI, 0.025-0.092), 0.107 (80% CI, 0.058-0.155), and 0.150 (80% CI, 0.089-0.211), respectively, again translating to a median PFS ≥ 24 months in all arms (P < 0.0001 for all arms). Twenty-four-month PFS rates were 89.9% (90% CI, 78.5-95.4%), 82.0% (90% CI, 69.0-89.9%), and 75.3% (90% CI, 61.1-85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.

Trial registration: ClinicalTrials.gov NCT02316106.

Conflict of interest statement

COL received grant support from the National Institutes of Health, Food and Drug Administration, Multiple Myeloma Research Foundation, International Myeloma Foundation, Leukemia & Lymphoma Society, Perelman Family Foundation, Rising Tides Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, and Karyopharm; received honoraria from/served on advisory committees for Adaptive Biotechnologies Corp, Amgen, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Karyopharm, Merck, Pfizer, Takeda, and The Binding Site; and served on independent data monitoring committees for Takeda, Novartis, and Janssen. AC received research funding from Pharmacyclics and served as a consultant for, received research funding from, and served on advisory committees for Amgen, Array BioPharma, Celgene, Janssen, Millennium, Takeda, and Novartis. YCC received research funding from Amgen and Takeda; served on advisory boards for Janssen and Takeda; served on a speakers bureau for Amgen; and received travel grants from Janssen, Bristol-Myers Squibb, and Neopharm. AS received research funding and honoraria from Janssen. PV served as a consultant for Celgene, Janssen, Bristol-Myers Squibb, Novartis, Takeda, and Oncopeptides and is on speakers bureaus for Amgen, Celgene, and Janssen. JAE served on advisory committees for Janssen and Celgene. IS received honoraria from Janssen, Celgene, Takeda, Amgen, and Novartis. MWJ received honoraria from and served on speakers bureaus for Janssen, Celgene, Takeda, Amgen, and Novartis and served on advisory committees for Janssen, Celgene, Takeda, Amgen, Novartis, and Chugai. MC received honoraria from Janssen, Celgene, Amgen, Bristol-Myers Squibb, and Takeda. NWCJvdD received research funding from Janssen, Celgene, Bristol-Myers Squibb, Novartis, and Amgen. MB served on an advisory committee and a speakers bureau for Janssen, Amgen, Celgene, and Takeda. PM served on advisory committees for Celgene, Janssen, Takeda, Novartis, Amgen, and Roche. HG consulted for and received honoraria from Celgene, Janssen-Cilag, Novartis, Bristol-Myers Squibb, Chugai, and Art Tempi; served on speakers bureaus for Adaptive Biotechnologies, Celgene, Janssen-Cilag, Bristol-Myers Squibb, Amgen, and Takeda; received compensation for travel expenses from Celgene, Bristol-Myers Squibb, Janssen-Cilag, Chugai, Amgen, and Takeda; and received research funding from Bristol-Myers Squibb, Celgene, Chugai, Janssen-Cilag, Sanofi, Novartis, Takeda, Amgen, and Mundipharma. SK, RB, TN, and CH are employees of Janssen. PLC and MQ are employees of Janssen and hold equity in Johnson & Johnson. CCH is an investigator for trials conducted by Bristol-Myers Squibb, Oncolytics Biotech, Sanofi, Celgene, Janssen, Takeda, Kite, Juno, Karyopharm, GlaxoSmithKline, Novartis, Roche, AstraZeneca, Amgen, and Aduro Biotech; received institutional research funding from Celgene, Janssen, Takeda, Roche, Karyopharm, and Bristol-Myers Squibb; served on an advisory committee for Oncopeptides, Celgene, Adaptive Biotechnologies, and Thrasos Therapeutics; and received honoraria from AXIS Medical Education, PleXus Communications, priME Oncology, TRM Oncology, DAVA Oncology, American Society of Clinical Oncology, International Myeloma Foundation, Multiple Myeloma Research Foundation, Adaptive Biotechnologies, and Thrasos Therapeutics. CW has nothing to disclose. Janssen Research & Development LLC sponsored this trial, collaborated with the academic authors on its design, compiled and maintained the data, and agreed to publish this paper.

Figures

Fig. 1. Study design and patient flow diagram.

a Study design. b Patient flow diagram through the clinical cutoff date.aQW once weekly, Q2W every 2 weeks, Q4W every 4 weeks, Q8W every 8 weeks, IV intravenously, PD progressive disease, LPFD last patient first dose, CR complete response, MM multiple myeloma, SMM smoldering multiple myeloma, IMWG International Myeloma Working Group, FLC free light chain, PC plasma cell. aJune 29, 2018. bPD was defined per the 2014 IMWG criteria for MM [6] plus additional IMWG FLC progression criteria (a ≥25% increase from nadir in the difference between involved and uninvolved FLC levels [absolute increase must be >10 mg/dl]) [21]. cA patient could have multiple reasons for exclusion and therefore be counted in more than one category. dBone marrow PCs ≥10% to <60% plus serum M-protein ≥3 g/dl (IgA ≥2 g/dl), urine M-protein >500 mg/24 h, or abnormal FLC ratio (<0.126 or >8) and serum M-protein <3 g/dl but ≥1 g/dl. eBone marrow PCs ≥10% to <60% plus serum M-protein ≥3 g/dl (IgA ≥2 g/dl), urine M-protein >500 mg/24 h, abnormal FLC ratio (<0.126 or >8) and serum M-protein <3 g/dl but ≥1g/dl, or absolute involved serum FLC ≥100 mg/l with an abnormal FLC ratio (<0.126 or >8, but not ≤0.01 or ≥100).

Fig. 2. PFS.

PFSa with progression defined based a on diagnosticb criteria and b on biochemicalc or diagnostic criteria.dPFS progression-free survival, IMWG International Myeloma Working Group, MM multiple myeloma, FLC free light chain. aPFS was assessed in the intent-to-treat population. bDiagnostic progression was defined per the 2014 IMWG criteria for MM [6] plus additional IMWG FLC progression criteria (a ≥25% increase from nadir in the difference between involved and uninvolved FLC levels [absolute increase must be >10 mg/dl]) [21]. cBiochemical progression was defined as a measurable increase of ≥25% from nadir value in any of the following at any point during follow-up: serum M-component (absolute increase must be ≥0.5 g/dl), urine M-component (absolute increase must be ≥200 mg/24 h), and, in patients without measurable serum and urine M-protein, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dl). dBased on the clinical cutoff date of June 29, 2018.