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

Multiple Myeloma Clinical Trial

Official title:

A Phase 3 Study Comparing Daratumumab, VELCADE (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) With VELCADE, Lenalidomide, and Dexamethasone (VRd) in Subjects With Untreated Multiple Myeloma and for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03652064
• Other study ID #: CR108529
• Secondary ID: 2018-001545-1354
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 6, 2018
• Est. completion date: October 31, 2028

Study information

• Verified date: June 2024
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 395
• Est. completion date: October 31, 2028
• Est. primary completion date: August 29, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• 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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Brazil	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	Instituto de Educacao, Pesquisa e Gestao em Saude Instituto Americas (COI)	Rio de Janeiro
Brazil	Ministerio da Saude - Instituto Nacional do Cancer	Rio de Janeiro
Brazil	Instituto Brasileiro de Controle do Cancer - Sao Camilo Oncologia	Sao Paulo
Brazil	Instituto de Ensino e Pesquisa São Lucas	Sao Paulo
Brazil	Real e Benemerita Associacao Portuguesa de Beneficencia	Sao Paulo
Brazil	Clinica Sao Germano	São Paulo
Brazil	Hospital Santa Cruz	São Paulo
Canada	Brampton Civic Hospital	Brampton	Ontario
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	QEII Health Sciences Centre	Halifax	Nova Scotia
Canada	Victoria Hospital	London	Ontario
Canada	McGill University Health Centre	Montreal	Quebec
Canada	Lakeridge Health Oshawa	Oshawa	Ontario
Canada	CHU de Quebec L Hotel Dieu de Quebec	Quebec
Canada	The Gordon & Leslie Diamond Health Care Center	Vancouver	British Columbia
Czechia	Fakultni nemocnice Brno	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Fakultni nemocnice Plzen, Hemato-onkologicke oddeleni	Plzen
Czechia	Vseobecna fakultni nemocnice v Praze	Praha 2
France	CHU Henri Mondor	Creteil N/a
France	Centre Hospitalier Départmental La Roche sur Yon	La Roche sur Yon Cedex 9
France	Hopital Claude Huriez	Lille
France	Institut Paoli Calmettes	Marseille Cedex 9
France	CHU de Montpellier, Hopital Saint-Eloi	Montpellier
France	CHU de Bordeaux - Hospital Haut-Leveque	Pessac cedex
France	Strasbourg Oncologie Libérale	Strasbourg
France	Institut Universitaire du cancer de Toulouse-Oncopole	Toulouse cedex 9
Germany	phase 3 - Hämatoonkologischer Studienkreis am Klinikum Aschaffenburg	Aschaffenburg
Germany	Universitatsklinikum Freiburg	Freiburg
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,	Tuebingen
Israel	Barzilai Medical Center	Ashkelon
Israel	Hillel Yaffe Medical Center	Hadera
Israel	Carmel Medical Center	Haifa
Israel	Rambam Med.Center - Hematology Institute	Haifa
Israel	Meir Hospital	Kfar Saba
Israel	Rabin Medical Center	Petah-Tiqva
Israel	Sheba Medical Center	Ramat Gan
Israel	Sourasky (Ichilov) Medical Center	Tel Aviv
Japan	Fukuoka University Hospital	Fukuoka
Japan	Ogaki Municipal Hospital	Gifu
Japan	Kanazawa University Hospital	Kanazawa
Japan	Kobe City Medical Center General Hospital	Kobe City
Japan	National Hospital Organization Kumamoto Medical Center	Kumamoto-shi
Japan	University Hospital Kyoto Perfectural 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
Netherlands	VU Medisch Centrum	Amsterdam
Netherlands	Albert Schweitzer ziekenhuis-lokatie Dordwijk	Dordrecht
Netherlands	Erasmus MC	Rotterdam
Poland	Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im Ks B Markiewicza	Brzozow
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	Slupsk
Poland	Instytut Hematologii i Transfuzjologii	Warszawa
Poland	Narodowy Instytut Onkologii im Marii Sklodowskiej Curie Panstwowy Instytut Badawczy	Warszawa
Spain	Hosp. Univ. Fundacion Alcorcon	Alcorcon
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 Alarcon, Madrid
Spain	Hosp. Mutua Terrassa	Terrassa
Turkey	Ankara University School of Medicine Cebeci Hospital	Ankara
Turkey	Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital	Ankara
Turkey	Gulhane Egitim ve Arastirma Hastanesi	Ankara
Turkey	Hacettepe University Medical Faculty	Ankara
Turkey	Istanbul University Istanbul Medical Faculty	Istanbul
Turkey	Dokuz Eylul University Medical Faculty	Izmir
Turkey	Ondokuz Mayis Universitesi Tip Fakultesi	Samsun
United Kingdom	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 States	Boston University Medical Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Innovative Clinical Research Inc	Cerritos	California
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Cleveland Clinic	Cleveland	Ohio
United States	Good Samaritan Hospital Corvallis	Corvallis	Oregon
United States	San Juan Oncology Associates	Farmington	New Mexico
United States	Fort Wayne Medical Oncology and Hematology, Inc.	Fort Wayne	Indiana
United States	Cancer And Hematology Centers of Western Michigan PC	Grand Rapids	Michigan
United States	University of Texas, MD Anderson Cancer Center	Houston	Texas
United States	Baptist MD Anderson	Jacksonville	Florida
United States	Saint Luke's Hospital - Saint Luke's Cancer Specialists	Kansas City	Missouri
United States	Norton Healthcare	Louisville	Kentucky
United States	NYU Winthrop	Mineola	New York
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	University of Pittsburgh Medical Center (UPMC) - Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Gibbs Cancer Center	Spartanburg	South Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Czechia,  France,  Germany,  Israel,  Japan,  Netherlands,  Poland,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants with Negative Minimal Residual Disease (MRD) Status	Percentage of participants who achieve MRD negative status by evaluation of bone marrow aspirates using next generation sequencing (NGS) at 10^-5 threshold will be assessed.	After randomization and prior to progressive disease (PD) or the start of subsequent anti-myeloma therapy approximately 2.5 years
Secondary	Progression-Free Survival (PFS)	PFS is defined as the duration from date of randomization to either PD or death, whichever comes first. International Myeloma Working Group (IMWG) criteria for PD: Increase of 25 percentage (%) from lowest response value in any one of following: Serum M-component (absolute increase must be >= 0.5 gram per deciliter [g/dL],) Urine M-component (absolute increase must be >=200 mg/24 hours), participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >10 milligrams per deciliter [mg/dL]), participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow PC% (absolute percentage must be >=10%), definite development of new bone lesions or soft tissue plasmacytomas or increase in size of bone lesions or tissue plasmacytomas and development of hypercalcemia (serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.	From randomization to either disease progression or death whichever occurs first (approximately 6 years, or 9 years if the adaptive approach is decided at the interim)
Secondary	MRD Negative Rate	Percentage of participants who have achieved MRD negative status will be assessed and landmark timepoints (12, 18 and 24 months). MRD negativity will be evaluated as a potential surrogate for PFS and overall survival (OS) in multiple myeloma treatment.	12,18 and 24 Months
Secondary	Durable MRD Negative Rate	Durable MRD negativity rate is defined as the number of participants who have achieved MRD negative status (at 10^-5) at 2 bone marrow aspirates examinations that are a minimum of 1 year apart, without any examination showing MRD positive status in between.	Throughout the study (approximately 6 year)
Secondary	Overall Response Rate (ORR)	ORR is defined as the percentage of participants who achieve partial response (PR) or better responses prior to subsequent anti-myeloma therapy in accordance with IMWG criteria, during or after the study treatment. IMWG criteria for PR: greater than or equal to (>=) 50 reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90 % or to less than (<) 200 mg/24 hours, If the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, >=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was >=30%. In addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required.	Up to the end of the study (approximately 6 years)
Secondary	Very Good Partial Response (VGPR) or Better Rate	VGPR or better rate is defined as the percentage of participants achieving VGPR and complete response (CR) (including stringent complete response [sCR]) prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria during or after the study treatment. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or greater than or equal to (>=) 90 % reduction in serum M-protein plus urine M-protein <100 milligram per 24 hours (mg/24 hours); CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry (IHC), immunofluorescence or 2- to 4 color flow cytometry.	Approximately 6 years
Secondary	Complete Response (CR) or Better Rate	CR or better rate is defined as the percentage of participants achieving CR or sCR prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria during or after the study treatment.	Approximately 6 years
Secondary	PFS on the Next Line of Therapy	The PFS on the next line of therapy is defined as the time from randomization to progression on the next line of treatment or death, whichever comes first. Disease progression will be based on investigator judgment.	Time from randomization to progression on the next line of treatment or death, whichever comes first (up to approximately 6 years, or 9 years if the adaptive approach is decided at the interim)
Secondary	Overall Survival (OS)	OS is defined as the time from the date of randomization to the date of the participant's death due to any cause.	From randomization until the participant's death from any cause (up to approximately 6 years, or 9 years if the adaptive approach is decided at the interim)
Secondary	Time to Response	Time to response is defined as the time between the randomization and the first efficacy evaluation at which the participant meets all criteria for PR or better.	From randomization until PR or better until approximately 6 years
Secondary	Duration of Response (DOR)	DOR is calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of PD, as defined in the IMWG evaluation before the start of any subsequent anti-myeloma therapy.	From initial documentation of response to the date of PD until approximately 6 years
Secondary	Maximum Observed Serum Concentration (Cmax) of Daratumumab	The Cmax is the maximum observed serum concentration of daratumumab.	Predose Cycle 1, Day 1 (C1D1), C3D1, C9D1, C12D1, and post dose C1D4, C3D4, Post-treatment Week 8 (Cycle 1 to 8 is of 21 days; Cycle 9 and onwards are of 28 days)
Secondary	Minimum Observed Serum Concentration (Cmin) of Daratumumab	The Cmin is the minimum observed serum concentration of daratumumab.	Predose, C1D1 (each cycle of 28 days), C3D1, C9D1, C12D1, and post dose C1D4, C3D4, Post-treatment Week 8 (Cycle 1 to 8 is of 21 days; Cycle 9 and onwards are of 28 days)
Secondary	Number of Participants with Anit-daratumumab Antibodies	Number of participants with anti-daratumumab antibodies will be assessed.	Predose, C1D1 (each cycle of 28 days), C9D1, C12D1, Post-treatment Week 8 (Cycle 1 to 8 is of 21 days; Cycle 9 and onwards are of 28 days)
Secondary	Number of Participants with Anit-rHuPH20 Antibodies	Number of participants with anti-recombinant human hyaluronidase (rHuPH20) antibodies will be assessed.	Predose, C1D1 (each cycle of 28 days), C9D1, C12D1, Post-treatment Week 8 (Cycle 1 to 8 is of 21 days; Cycle 9 and onwards are of 28 days)
Secondary	Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 item (EORTC QLQ-C30)	The EORTC- QLQ-Core-30 includes 30 items that make up 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, and nausea/vomiting), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The recall period is 1 week ("past week") and responses are reported using a verbal and numeric rating scales. The item and scale scores are transformed to a 0 to 100 scale. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms.	Baseline, up to 6 years (end of study)
Secondary	Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20-item (EORTC QLQ-MY20)	The EORTC QLQ-MY20 is a validated, self -administered instrument to assess QoL in persons with MM. This 20-item questionnaire measures the following domains: symptom scales, including disease symptoms (6 items) and symptoms related to side effects of treatment (10 items); function scale and future perspective (3 items); and body image (1 item).	Baseline, up to 6 years (end of study)
Secondary	Change from Baseline in HRQoL as Assessed by EuroQol Five Dimension Five Level Questionnaire (EQ-5D-5L)	The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The scores for the 5 separate questions are categorical and cannot be analyzed as cardinal numbers.	Baseline, up to 6 years (end of study)