Randomized Controlled Trial

. 2024 Apr 22;14(1):69.

doi: 10.1038/s41408-024-01030-w.

Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk

Natalie S Callander¹, Rebecca Silbermann², Jonathan L Kaufman³, Kelly N Godby⁴, Jacob Laubach⁵, Timothy M Schmidt⁶, Douglas W Sborov⁷, Eva Medvedova², Brandi Reeves⁸, Binod Dhakal⁹, Cesar Rodriguez¹⁰, Saurabh Chhabra⁹, Ajai Chari¹⁰, Susan Bal⁴, Larry D Anderson Jr¹¹, Bhagirathbhai R Dholaria¹², Nitya Nathwani¹³, Parameswaran Hari⁹, Nina Shah¹⁴, Naresh Bumma¹⁵, Sarah A Holstein¹⁶, Caitlin Costello¹⁷, Andrzej Jakubowiak¹⁸, Tanya M Wildes¹⁶, Robert Z Orlowski¹⁹, Kenneth H Shain²⁰, Andrew J Cowan²¹, Huiling Pei²², Annelore Cortoos²³, Sharmila Patel²³, Thomas S Lin²³, Smith Giri²⁴, Luciano J Costa⁴, Saad Z Usmani²⁵, Paul G Richardson⁵, Peter M Voorhees²⁶

Affiliations

¹ University of Wisconsin Carbone Cancer Center, Madison, WI, USA. nsc@medicine.wisc.edu.
² Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
³ Winship Cancer Institute, Emory University, Atlanta, GA, USA.
⁴ University of Alabama at Birmingham Hospital, Birmingham, AL, USA.
⁵ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁶ University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
⁷ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁸ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Division of Hematology/Oncology, Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ, USA.
¹⁰ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Myeloma, Waldenstrӧm's and Amyloidosis Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.
¹² Vanderbilt University Medical Center, Nashville, TN, USA.
¹³ Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹⁴ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁵ Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
¹⁶ Division of Oncology & Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁷ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹⁸ University of Chicago Medical Center, Chicago, IL, USA.
¹⁹ Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁰ Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
²¹ Division of Medical Oncology, University of Washington, Seattle, WA, USA.
²² Janssen Research & Development, LLC, Titusville, NJ, USA.
²³ Janssen Scientific Affairs, LLC, Horsham, PA, USA.
²⁴ Division of Hematology & Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁵ Memorial Sloan Kettering Cancer Center, New York, NY, USA. usmanis@mskcc.org.
²⁶ Levine Cancer Institute, Atrium Health Wake Forest Baptist, Charlotte, NC, USA. Peter.Voorhees@atriumhealth.org.

PMID: 38649340
PMCID: PMC11035596
DOI: 10.1038/s41408-024-01030-w

Randomized Controlled Trial

Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk

Natalie S Callander et al. Blood Cancer J. 2024.

. 2024 Apr 22;14(1):69.

doi: 10.1038/s41408-024-01030-w.

Authors

Affiliations

¹ University of Wisconsin Carbone Cancer Center, Madison, WI, USA. nsc@medicine.wisc.edu.
² Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
³ Winship Cancer Institute, Emory University, Atlanta, GA, USA.
⁴ University of Alabama at Birmingham Hospital, Birmingham, AL, USA.
⁵ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁶ University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
⁷ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁸ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Division of Hematology/Oncology, Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ, USA.
¹⁰ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Myeloma, Waldenstrӧm's and Amyloidosis Program, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.
¹² Vanderbilt University Medical Center, Nashville, TN, USA.
¹³ Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹⁴ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁵ Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
¹⁶ Division of Oncology & Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁷ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹⁸ University of Chicago Medical Center, Chicago, IL, USA.
¹⁹ Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁰ Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
²¹ Division of Medical Oncology, University of Washington, Seattle, WA, USA.
²² Janssen Research & Development, LLC, Titusville, NJ, USA.
²³ Janssen Scientific Affairs, LLC, Horsham, PA, USA.
²⁴ Division of Hematology & Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁵ Memorial Sloan Kettering Cancer Center, New York, NY, USA. usmanis@mskcc.org.
²⁶ Levine Cancer Institute, Atrium Health Wake Forest Baptist, Charlotte, NC, USA. Peter.Voorhees@atriumhealth.org.

PMID: 38649340
PMCID: PMC11035596
DOI: 10.1038/s41408-024-01030-w

Abstract

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10^-5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high-risk disease (≥2 HRCAs). Video Abstract.

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Conflict of interest statement

RS served as a consultant or in an advisory role for Sanofi-Aventis, Janssen Oncology, and Oncopeptides; and received research funding from Sanofi. JLK consulted for AbbVie, Janssen, Roche/Genentech, Bristol Myers Squibb, Celgene, and Tecnopharma; received research funding from AbbVie, Amgen, Bristol Myers Squibb, Fortis Therapeutics, Heidelberg Pharma, Janssen, Novartis, Roche/Genentech, Sutro Biopharma, and Takeda; received honoraria from AbbVie, Janssen, Roche/Genentech, and Tecnopharma; and holds a membership on a board or advisory committee for Incyte and TG Therapeutics. JL received honoraria from Great Debates & Updates – Hematologic Malignancies. TMS received consulting fees from BioLineRx, Janssen, and Sanofi; and received support for attending meetings and/or travel from Sanofi. DWS consulted for, holds membership on an entity’s board of directors for, or served on advisory committees for Arcellx, GSK, and Janssen; and consulted for Bristol Myers Squibb, Pfizer, AbbVie, and Sanofi. BR received honoraria from Incyte, Bristol Myers Squibb, and PharmaEssentia. BD received consulting fees from Janssen, Sanofi, Genentech, and AbbVie; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Sanofi, Janssen, Karyopharm Therapeutics, Bristol Myers Squibb, and GSK; and participated on a data safety monitoring board or advisory board for Amgen, Takeda, Janssen, Sanofi, Arcellx, and Natera. CR consulted for Janssen, Bristol Myers Squibb, Takeda, AbbVie, Karyopharm Therapeutics, and Artiva; and served on a speakers bureau for Janssen, Bristol Myers Squibb, Takeda, AbbVie, Karyopharm Therapeutics, and Artiva. SC received research funding from Janssen, AbbVie, C4 Therapeutics, Takeda, and CARSgen Therapeutics; and received honoraria from Janssen, Sanofi, and GSK. SB received grants or contracts from an entity from the Amyloidosis Foundation; and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Adaptive Biotechnologies. LDA holds a membership on an entity’s board of directors or advisory committees for, served as a consultant for, and received honoraria from GSK, Bristol Myers Squibb, Celgene, Janssen, Amgen, Oncopeptides, Karyopharm Therapeutics, AbbVie, BeiGene, Sanofi, and Cellectar Biosciences. BRD received research funding from Pfizer, Janssen, Takeda, MEI, Angiocrine, and Poseida; and served on a speakers bureau for Jazz Pharmaceuticals and Celgene. PH served as a consultant for and received honoraria from Sanofi, Amgen, Janssen, Karyopharm Therapeutics, Takeda, and Kite; was a consultant for and received honoraria and research funding from Bristol Myers Squibb; received research funding from Millennium and Spectrum Pharmaceuticals; received honoraria from Novartis, Incyte, GSK, and AbbVie; and was a consultant for Pharmacyclics. NS received research funding from Bristol Myers Squibb/Celgene, Janssen, bluebird bio, Sutro Biopharma, TeneoBio, Poseida, Nektar, and Precision Biosciences; served as a consultant for GSK, Amgen, Indapta Therapeutics, Sanofi, CareDx, Kite, Karyopharm Therapeutics, Oncopeptides, and CSL Behring; and is a current employee and equity holder of AstraZeneca. NB served on a speakers bureau for Amgen, Sanofi, and Genzyme; and served on an advisory board for Sanofi, Genzyme, and Janssen. SAH served as a consultant for Bristol Myers Squibb/Celgene, Janssen, Takeda, Pfizer, Oncopeptides, GSK, Secura Bio, and Sanofi; and received research funding from Bristol Myers Squibb and Oncopeptides. CC received honoraria from Takeda, Bristol Myers Squibb, Pfizer, and Janssen. AJ served as a consultant or in an advisory role for and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, GSK, Janssen, Karyopharm Therapeutics, and Sanofi. TMW served as a consultant for Carevive, Janssen, Seagen, and Sanofi. RZO received research funding from Asylia Therapeutics, Biotheryx, Heidelberg Pharma, CARsgen Therapeutics, Bristol Myers Squibb/Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, and Takeda Pharmaceuticals North America; received honoraria from and holds a membership on an entity’s board of directors or advisory committees for AbbVie, Biotheryx, Bristol Myers Squibb, Janssen Biotech, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Sanofi-Aventis, and Takeda Pharmaceuticals North America; and is a current stockholder of Asylia Therapeutics. KHS received honoraria from Bristol Myers Squibb, Janssen, GSK, Adaptive Biotechnologies, Sanofi, Takeda, and Amgen; served as an ad hoc member of an advisory committee for GSK, Janssen, and Bristol Myers Squibb; served on a speakers bureau for GSK, Bristol Myers Squibb, Sanofi, Karyopharm Therapeutics, Takeda, Janssen, Adaptive Biotechnologies, and Amgen; received research funding from AbbVie and Karyopharm Therapeutics; and is the principal investigator of clinical trials sponsored by Janssen and Bristol Myers Squibb, with all research outside the scope of the submitted work. AJC served as a consultant for and received research funding from Janssen, Bristol Myers Squibb, and AbbVie; received research funding from Harpoon, Sanofi-Aventis, and Nektar; was a consultant for Allogene, EUSA, GSK, and Secura Bio; and received research funding from and holds a membership on an entity’s board of directors or advisory committees for Adaptive Biotechnologies. SG received honoraria from Carevive and OncLive; and received research funding from Carevive and Pack Health. LJC served as a consultant or in an advisory role for AbbVie, Amgen, Celgene, Karyopharm Therapeutics, and Sanofi; served on a speakers bureau for Amgen and Sanofi; received honoraria from Amgen, Celgene, Janssen, Karyopharm Therapeutics, and Sanofi; and received research funding from Amgen and Janssen. SZU served as a consultant for Celgene, Amgen, Janssen Oncology, Seattle Genetics, Takeda, GSK, Karyopharm Therapeutics, AbbVie, SkylineDx, Merck, Oncopeptides, Genentech, Gilead Sciences, and Bristol Myers Squibb/Celgene; served on a speakers bureau for Takeda, Amgen, Janssen Oncology, Sanofi, and Bristol Myers Squibb/Celgene; and received research funding from Celgene and Array BioPharma. PGR received research funding from Oncopeptides, Celgene/Bristol Myers Squibb, Takeda, and Karyopharm Therapeutics; and served on advisory committees for Oncopeptides, Celgene/Bristol Myers Squibb, Takeda, Karyopharm Therapeutics, Janssen, Sanofi, Secura Bio, GSK, Regeneron Pharmaceuticals, AstraZeneca, and Protocol Intelligence. PMV served as a consultant for, received honoraria from, and holds a membership on an entity’s board of directors or advisory committees for AbbVie, Bristol Myers Squibb, Karyopharm Therapeutics, Regeneron Pharmaceuticals, and Sanofi. HP, A Cortoos, SP, and TSL are current equity holders and employees of Janssen. NSC, KNG, EM, A Chari, and NN have nothing to disclose.

Figures

**Fig. 1. Rates of ≥CR (best response on study) by cytogenetic risk status* among patients who received D-KRd in MASTER^† and D-RVd in GRIFFIN^‡.**
Rates of ≥CR were assessed based on International Uniform Response Criteria Consensus Recommendations, and percentages were calculated with the number of patients in the treatment group as the denominator. ≥CR complete response or better, D-KRd daratumumab plus carfilzomib/lenalidomide/dexamethasone, D-RVd daratumumab plus lenalidomide/bortezomib/dexamethasone, HRCA high-risk cytogenetic abnormality. *HRCAs include any of the following genetic abnormalities: del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21) (≥3 copies of chromosome 1q21). Patients were grouped into categories: standard risk (0 HRCA), high risk (1 HRCA), or ultra-high risk (≥2 HRCAs). ^†Evaluable patients in MASTER included all enrolled patients (0 HRCA, n = 53; 1 HRCA, n = 46; ≥2 HRCAs, n = 24). ^‡Evaluable patients in GRIFFIN were the response-evaluable population (0 HRCA, n = 66; 1 HRCA, n = 33; ≥2 HRCAs, n = 13).

**Fig. 2. PFS by cytogenetic risk status* among patients who received D-KRd in MASTER and D-RVd in GRIFFIN.**
Kaplan–Meier estimates of PFS among patients in the ITT population by cytogenetic risk status (0 HRCA, 1 HRCA, or ≥2 HRCAs) are shown for (A) MASTER and (B) GRIFFIN. Median PFS was not reached for any group. PFS progression-free survival, D-KRd daratumumab plus carfilzomib/lenalidomide/dexamethasone, D-RVd daratumumab plus lenalidomide/bortezomib/dexamethasone, HRCA high-risk cytogenetic abnormality. *HRCAs include any of the following genetic abnormalities: del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21) (≥3 copies of chromosome 1q21). Patients were grouped into categories: standard risk (0 HRCA), high risk (1 HRCA), or ultra-high risk (≥2 HRCAs).

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References

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Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk

Affiliations

Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk

Authors

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Abstract

Conflict of interest statement

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