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.
| Original language | English |
|---|---|
| Pages (from-to) | 1840-1852 |
| Number of pages | 13 |
| Journal | Leukemia |
| Volume | 34 |
| Issue number | 7 |
| Early online date | 1 Jan 2020 |
| DOIs | |
| Publication status | Published - 1 Jul 2020 |
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In: Leukemia, Vol. 34, No. 7, 01.07.2020, p. 1840-1852.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma
T2 - a randomized, open-label, multicenter, phase 2 study (CENTAURUS)
AU - Landgren, C. Ola
AU - Chari, Ajai
AU - Cohen, Yael C.
AU - Spencer, Andrew
AU - Voorhees, Peter
AU - Estell, Jane A.
AU - Sandhu, Irwindeep
AU - Jenner, Matthew W.
AU - Williams, Catherine
AU - Cavo, Michele
AU - van de Donk, Niels W.C.J.
AU - Beksac, Meral
AU - Moreau, Philippe
AU - Goldschmidt, Hartmut
AU - Kuppens, Steven
AU - Bandekar, Rajesh
AU - Clemens, Pamela L.
AU - Neff, Tobias
AU - Heuck, Christoph
AU - Qi, Ming
AU - Hofmeister, Craig C.
N1 - Funding Information: Conflict of interest 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, Kar-yopharm, 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. Funding Information: Acknowledgements The authors thank the patients who participated in this study, all of the study investigators (including Brandi Reeves), the staff members at the study sites, the data and safety monitoring committee, and the staff members who were involved in data collection and analyses (Kirsten Lantz). This study (ClinicalTrials.gov identifier: NCT02316106) was funded by Janssen Research & Development, LLC. Medical writing and editorial support were provided by Kimberly Carmony, PhD (MedErgy), and were funded by Janssen Global Services, LLC. COL was supported by Memorial Sloan Ketteringʼs Core Grant (P30 CA008748). CCH was supported by Winship Cancer Institute’s Core Grant (P30 CA138292). Results of these analyses were presented, in part, at the 59th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9–12, 2017, Atlanta, GA, USA and at the 60th American Society of Hematology (ASH) Annual Meeting & Exposition, December 1–4, 2018, San Diego, CA, USA. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85079436497&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41375-020-0718-z
DO - https://doi.org/10.1038/s41375-020-0718-z
M3 - Article
C2 - 32024950
SN - 0887-6924
VL - 34
SP - 1840
EP - 1852
JO - Leukemia
JF - Leukemia
IS - 7
ER -