A Study Comparing Daratumumab, VELCADE (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) With VELCADE, Lenalidomide, and Dexamethasone (VRd) in Participants With Untreated Multiple Myeloma and for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy

NCT ID: NCT03652064

Last Updated: 2025-11-10

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 395 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-06
• Study Completion Date: 2026-01-31

Brief Summary

The purpose of this study to determine if the addition of daratumumab to bortezomib + lenalidomide + dexamethasone (VRd) will improve overall minimal residual disease (MRD) negativity rate compared with VRd alone.

Detailed Description

This study will evaluate participants with newly diagnosed multiple myeloma (MM) for whom hematopoietic stem cell transplant is not planned as initial therapy. The data available from other available studies suggests that addition of daratumumab with Velcade (bortezomib), lenalidomide, and dexamethasone [VRd] is anticipated to improve the response rates and the depth of response and may lead to improved long-term outcomes in newly diagnosed participants with MM. Daratumumab targets CD38, a protein expressed on the surface of MM cells and other hematopoietic cells. Bortezomib is a proteasome inhibitor, which plays a critical role in the pathogenesis of MM. Lenalidomide has cytotoxic effects on myeloma cells and is capable of inducing apoptosis, or programmed cell death and dexamethasone induces apoptosis in MM cells. The rationale for the study is to utilize the subcutaneous (SC) formulation of daratumumab instead of the intravenous (IV) formulation, which is expected to provide similar exposure and is expected to limit additional toxicity to participants, treated with this quadruplet regimen. The study will consist of 3 phases: Screening (up to 28 days before randomization), Treatment phase (from Cycle 1 [21 days] Day 1 and continues until disease progression) and Follow up (Postintervention). Efficacy evaluations will include measurements of tumor burden/residual disease, myeloma proteins, bone marrow examinations, skeletal surveys, extramedullary plasmacytomas, and serum calcium corrected for albumin. Participants will undergo procedures like electrocardiogram (ECG), chest x-rays or full dose chest CT scans, Pulmonary function test (PFT), spirometry etc. during the course of study. Participants will also be monitored closely for adverse events (AEs), laboratory abnormalities, and clinical response. The duration of the study will be approximately 6.5 years.

Conditions

Multiple Myeloma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Bortezomib + Lenalidomide + Dexamethasone (VRd) and Rd

Participants will receive bortezomib 1.3 milligram per square meter (mg/m\^2) as subcutaneous (SC) injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 (cycle of 28 days); dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond (each cycle is of 28 days) followed by lenalidomide-dexamethasone (Rd) until disease progression or unacceptable toxicity.

Group Type: ACTIVE_COMPARATOR

Bortezomib

Intervention Type: DRUG

Bortezomib 1.3 mg/m\^2 will be administered by SC injection twice weekly on Days 1, 4, 8, and 11 of each 21-day cycle for Cycles 1-8.

Lenalidomide

Intervention Type: DRUG

Lenalidomide will be self-administered at a dose of 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 and beyond until disease progression or unacceptable toxicity whichever occurs first.

Dexamethasone

Intervention Type: DRUG

Dexamethasone will be self-administered orally, 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 of each 21-day cycle for Cycles 1-8. During Cycle 9 and beyond dexamethasone, will be self-administered orally at a total dose of 40 mg on Days 1, 8, 15, 22 of each 28-day cycle.

Daratumumab + VRd (D-VRd) and DRd

Participants will receive daratumumab 1800 mg as SC injection once every week for Cycles 1 to 2, then every 3 weeks for Cycles 3 through 8 and every 4 weeks for Cycle 9 and beyond; bortezomib 1.3 mg/m\^2 as SC injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9; dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond followed by daratumumab-lenalidomide-dexamethasone (DRd) until disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Daratumumab

Intervention Type: DRUG

Daratumumab (1800 mg) will be administered by SC injection once every week for Cycles 1 to 2, then every 3 weeks for Cycles 3-8. For Cycle 9 and beyond, participants will receive daratumumab 1800 mg SC once every 4 weeks until documented disease progression or unacceptable toxicity.

Bortezomib

Intervention Type: DRUG

Bortezomib 1.3 mg/m\^2 will be administered by SC injection twice weekly on Days 1, 4, 8, and 11 of each 21-day cycle for Cycles 1-8.

Lenalidomide

Intervention Type: DRUG

Lenalidomide will be self-administered at a dose of 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 and beyond until disease progression or unacceptable toxicity whichever occurs first.

Dexamethasone

Intervention Type: DRUG

Dexamethasone will be self-administered orally, 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 of each 21-day cycle for Cycles 1-8. During Cycle 9 and beyond dexamethasone, will be self-administered orally at a total dose of 40 mg on Days 1, 8, 15, 22 of each 28-day cycle.

Interventions

Daratumumab

Daratumumab (1800 mg) will be administered by SC injection once every week for Cycles 1 to 2, then every 3 weeks for Cycles 3-8. For Cycle 9 and beyond, participants will receive daratumumab 1800 mg SC once every 4 weeks until documented disease progression or unacceptable toxicity.

Intervention Type: DRUG

Bortezomib

Bortezomib 1.3 mg/m\^2 will be administered by SC injection twice weekly on Days 1, 4, 8, and 11 of each 21-day cycle for Cycles 1-8.

Intervention Type: DRUG

Lenalidomide

Lenalidomide will be self-administered at a dose of 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 and beyond until disease progression or unacceptable toxicity whichever occurs first.

Intervention Type: DRUG

Dexamethasone

Dexamethasone will be self-administered orally, 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 of each 21-day cycle for Cycles 1-8. During Cycle 9 and beyond dexamethasone, will be self-administered orally at a total dose of 40 mg on Days 1, 8, 15, 22 of each 28-day cycle.

Intervention Type: DRUG

Other Intervention Names

JNJ-54767414; DARZALEX; Velcade; Revlimid

Eligibility Criteria

Inclusion Criteria

• Diagnosis of multiple myeloma as documented per International Myeloma Working Group (IMWG) criteria Monoclonal plasma cells in the bone marrow greater than or equal to (>=)10 percentage (%) or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria. CRAB criteria: Hypercalcemia: serum calcium greater than (>) 0.25 millimoles per liter (mmol/L) (>1 milligram per deciliter [mg/dL]) higher than upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL); Renal insufficiency: creatinine clearance less than (<) 40 milliliter per minute (mL/min) or serum creatinine >177 micro millimoles per liter (umol/L) (>2 mg/dL); Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL; Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT.

Biomarkers of Malignancy: Clonal bone marrow plasma cell percentage >=60%; Involved: uninvolved serum free light chain (FLC) ratio >=100; >1 focal lesion on magnetic resonance imaging (MRI) studies

• Must have measurable disease, as assessed by central laboratory
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
• A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing
• A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 3 months after receiving the last dose of any component of the treatment regimen

Exclusion Criteria

• Frailty index of >=2 according to Myeloma Geriatric Assessment score
• Prior therapy for multiple myeloma other than a short course of corticosteroids (not to exceed 40 mg of dexamethasone, or equivalent per day, total of 160 mg dexamethasone or equivalent)
• Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years of date of randomization (exceptions are adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years)
• Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5
• Focal radiation therapy within 14 days of randomization with the exception of palliative radiotherapy for symptomatic pain management. Radiotherapy within 14 days prior to randomization on measurable extramedullary plasmacytoma is not permitted even in the setting of palliation for symptomatic management

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen Research & Development, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Janssen Research & Development, LLC Clinical Trial

Role: STUDY_DIRECTOR

Janssen Research & Development, LLC

Locations

Innovative Clinical Research Inc

Cerritos, California, United States

Baptist MD Anderson

Jacksonville, Florida, United States

Fort Wayne Medical Oncology and Hematology, Inc.

Fort Wayne, Indiana, United States

Norton Healthcare

Louisville, Kentucky, United States

Tufts Medical Center

Boston, Massachusetts, United States

Boston University Medical Center

Boston, Massachusetts, United States

Cancer And Hematology Centers of Western Michigan PC

Grand Rapids, Michigan, United States

Saint Lukes Hospital Saint Lukes Cancer Specialists

Kansas City, Missouri, United States

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States

San Juan Oncology Associates

Farmington, New Mexico, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

NYU Winthrop

Mineola, New York, United States

Levine Cancer Institute

Charlotte, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

Good Samaritan Hospital Corvallis

Corvallis, Oregon, United States

University Of Pittsburgh Medical Center UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, United States

Gibbs Cancer Center

Spartanburg, South Carolina, United States

University of Texas, MD Anderson Cancer Center

Houston, Texas, United States

University of Virginia

Charlottesville, Virginia, United States

Universidade Estadual De Campinas

Campinas, , Brazil

Liga Norte Riograndense Contra O Cancer

Natal, , Brazil

Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da PUCRS

Porto Alegre, , Brazil

Ministerio da Saude Instituto Nacional do Cancer

Rio de Janeiro, , Brazil

Instituto de Educacao, Pesquisa e Gestao em Saude Instituto Americas (COI)

Rio de Janeiro, , Brazil

Instituto de Ensino e Pesquisa São Lucas

São Paulo, , Brazil

Real e Benemerita Associacao Portuguesa de Beneficencia

São Paulo, , Brazil

Instituto Brasileiro de Controle do Cancer - Sao Camilo Oncologia

São Paulo, , Brazil

Hospital Santa Cruz

São Paulo, , Brazil

Clinica Medica Sao Germano S/S LTDA

São Paulo, , Brazil

Arthur J E Child Comprehensive Cancer Centre

Calgary, Alberta, Canada

Cross Cancer Institute

Edmonton, Alberta, Canada

The Gordon & Leslie Diamond Health Care Center

Vancouver, British Columbia, Canada

QEII Health Sciences Centre

Halifax, Nova Scotia, Canada

Brampton Civic Hospital

Brampton, Ontario, Canada

Victoria Hospital

London, Ontario, Canada

Lakeridge Health Oshawa

Oshawa, Ontario, Canada

McGill University Health Centre

Montreal, Quebec, Canada

CHU de Quebec L Hotel Dieu de Quebec

Québec, Quebec, Canada

Fakultni nemocnice Brno

Brno, , Czechia

Fakultni nemocnice Hradec Kralove

Hradec Králové, , Czechia

Fakultni Nemocnice Ostrava

Ostrava, , Czechia

Fakultni nemocnice Plzen, Hemato-onkologicke oddeleni

Pilsen, , Czechia

Vseobecna fakultni nemocnice v Praze

Prague, , Czechia

CHU Henri Mondor

Créteil, , France

Centre Hospitalier Départmental La Roche sur Yon

La Roche-sur-Yon, , France

Hopital Claude Huriez

Lille, , France

Institut Paoli Calmettes

Marseille, , France

CHU de Montpellier Hopital Saint Eloi

Montpellier, , France

CHU de Bordeaux - Hospital Haut-Leveque

Pessac, , France

Strasbourg Oncologie Libérale

Strasbourg, , France

Institut Universitaire du cancer de Toulouse-Oncopole

Toulouse, , France

phase 3 - Hämatoonkologischer Studienkreis am Klinikum Aschaffenburg

Aschaffenburg, , Germany

Universitatsklinikum Freiburg

Freiburg im Breisgau, , Germany

St. Josef-Krankenhaus Hamm-Bockum-Hövel

Hamm, , Germany

Institut für Versorgungsforschung

Koblenz, , Germany

Universitatsmedizin Leipzig

Leipzig, , Germany

Klinikum Großhadern der Ludwig-Maximilians-Universität

München, , Germany

Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II,

Tübingen, , Germany

Barzilai Medical Center

Ashkelon, , Israel

Hillel Yaffe Medical Center

Hadera, , Israel

Rambam Med.Center - Hematology Institute

Haifa, , Israel

Carmel Medical Center

Haifa, , Israel

Meir Hospital

Kfar Saba, , Israel

Rabin Medical Center

Petah Tikva, , Israel

Sheba Medical Center

Ramat Gan, , Israel

Sourasky (Ichilov) Medical Center

Tel Aviv, , Israel

Fukuoka University Hospital

Fukuoka, , Japan

Ogaki Municipal Hospital

Gifu, , Japan

Kanazawa University Hospital

Kanazawa, , Japan

Kobe City Medical Center General Hospital

Kobe, , Japan

National Hospital Organization Kumamoto Medical Center

Kumamoto, , Japan

University Hospital Kyoto Prefectural University of Medicine

Kyoto, , Japan

National Hospital Organization Matsumoto Medical Center

Matsumoto, , Japan

Matsuyama Red Cross Hospital

Matsuyama, , Japan

Nagoya City University Hospital

Nagoya, , Japan

National Hospital Organization Okayama Medical Center

Okayama, , Japan

Japanese Red Cross Osaka Hospital

Osaka, , Japan

National Hospital Organization Shibukawa Medical Center

Shibukawa, , Japan

Japanese Red Cross Medical Center

Shibuya City, , Japan

VU Medisch Centrum

Amsterdam, , Netherlands

Albert Schweitzer ziekenhuis-lokatie Dordwijk

Dordrecht, , Netherlands

Erasmus MC

Rotterdam, , Netherlands

Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im Ks B Markiewicza

Brzozów, , Poland

Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich

Chorzów, , Poland

Uniwersyteckie Centrum Kliniczne

Gdansk, , Poland

Swietokrzyskie Centrum Onkologii SPZOZ w Kielcach

Kielce, , Poland

NSSU Szpital Uniwersytecki w Krakowie

Krakow, , Poland

Centrum Onkologii Ziemi Lubelskiej im sw Jana z Dukli

Lublin, , Poland

Uniwersytecki Szpital Kliniczny w Poznaniu

Poznan, , Poland

Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka

Słupsk, , Poland

Instytut Hematologii i Transfuzjologii

Warsaw, , Poland

Narodowy Instytut Onkologii im Marii Sklodowskiej Curie Panstwowy Instytut Badawczy

Warsaw, , Poland

Hosp. Univ. Fundacion Alcorcon

Alcorcón, , Spain

Hosp. Del Mar

Barcelona, , Spain

Hosp. Univ. de Guadalajara

Guadalajara, , Spain

Hosp. Univ. Pta. de Hierro Majadahonda

Majadahonda, , Spain

Hosp. Quiron Madrid Pozuelo

Pozuelo de Alarcón, , Spain

Hosp. Mutua Terrassa

Terrassa, , Spain

Gulhane Egitim ve Arastirma Hastanesi

Ankara, , Turkey (Türkiye)

Hacettepe University Medical Faculty

Ankara, , Turkey (Türkiye)

Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital

Ankara, , Turkey (Türkiye)

Ankara University School of Medicine Cebeci Hospital

Ankara, , Turkey (Türkiye)

Istanbul University Istanbul Medical Faculty

Istanbul, , Turkey (Türkiye)

Dokuz Eylul University Medical Faculty

Izmir, , Turkey (Türkiye)

Ondokuz Mayis University

Samsun, , Turkey (Türkiye)

Monklands District General Hospital

Airdrie, , United Kingdom

Blackpool Victoria Hospital

Blackpool, , United Kingdom

University Hospital Wales

Cardiff, , United Kingdom

Colchester Hospital University NHS

Colchester, , United Kingdom

Leicester Royal Infirmary - Haematology

Leicester, , United Kingdom

Altnagelvin Hospital

Londonderry, , United Kingdom

The Royal Oldham Hospital

Oldham, , United Kingdom

Derriford Hospital

Plymouth, , United Kingdom

New Cross Hospital

Wolverhampton, , United Kingdom

Countries

United States; Brazil; Canada; Czechia; France; Germany; Israel; Japan; Netherlands; Poland; Spain; Turkey (Türkiye); United Kingdom

References

Usmani SZ, Facon T, Hungria V, Bahlis NJ, Venner CP, Braunstein M, Pour L, Marti JM, Basu S, Cohen YC, Matsumoto M, Suzuki K, Hulin C, Grosicki S, Legiec W, Beksac M, Maiolino A, Takamatsu H, Perrot A, Turgut M, Ahmadi T, Liu W, Wang J, Chastain K, Vermeulen J, Krevvata M, Lopez-Masi L, Carey J, Rowe M, Carson R, Zweegman S. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. 2025 Apr;31(4):1195-1202. doi: 10.1038/s41591-024-03485-7. Epub 2025 Feb 5.

Reference Type: DERIVED

PMID: 39910273 (View on PubMed)

Other Identifiers

54767414MMY3019

Identifier Type: OTHER

Identifier Source: secondary_id

2018-001545-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2023-507312-13-00

Identifier Type: REGISTRY

Identifier Source: secondary_id

CR108529

Identifier Type: -

Identifier Source: org_study_id