Daratumumab, VELCADE (Bortezomib), Lenalidomide and Dexamethasone Compared to VELCADE, Lenalidomide and Dexamethasone in Subjects With Previously Untreated Multiple Myeloma

NCT03710603 | Active Not Recruiting Phase 3 Results DMC FDA Drug

• 1 other identifier: EMN17/54767414MMY3014
• Study Type: interventional
• Target: 709
• Locations: 13 countries
• Sites: 13

Brief Summary

Background of the study: The combination of daratumumab with VRd is anticipated to further improve response rates in patients and may lead to improved long-term outcomes in newly diagnosed patients with multiple myeloma. Given this potential, and based upon the initial safety and efficacy observed in the ongoing Phase 2 Study MMY2004, as well as continued positive results with daratumumab in various disease settings and combination regimens, this Phase 3 study is designed to demonstrate improved outcomes for patients treated with daratumumab+VRd. The Phase 3 study will utilize the subcutaneous (SC) formulation of daratumumab instead of the IV formulation utilized in the Phase 2 study, which may limit additional toxicity to patients treated with the quadruplet regimen.

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS)

  PFS was defined as duration from date of randomization to either progressive disease (PD)/death whichever occurred first. PD was defined as meeting any one of the following criteria: Increase of \>= 25 % in level of serum M-protein form lowest response value and absolute increase must be \>= 0.5 g/dL; Increase of \>=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be \>=200 mg/24 hours; Only in participants without measurable serum and urine M-protein levels; increase of \>=25% in difference between involved and uninvolved FLC levels from lowest response value and absolute increase must be \> 10 mg/dL; Definite increase in size of existing bone lesions or soft tissue plasmacytomas; Definite development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to PC proliferative disorder.

  From the date of randomization to either progressive disease or death whichever occurred first, up to a maximum follow-up time of 54.41 months.

Secondary Outcomes (14)

• Overall MRD Negativity Rate

  From randomization to the clinical cutoff date. Maximum follow up was 54.41 months.

• Percentage of Participants With Overall Response Rate (ORR)

  From randomization to the clinical cutoff date. Maximum follow up was 54.41 months

• Percentage of Participants With Overall Complete Response (CR) or Better

  From randomization to the clinical cutoff date. Maximum follow up was 54.41 months

• Progression-free Survival on the Next Line of Therapy (PFS2)

  From randomization to the clinical cutoff date. Maximum follow up was 54.41 months

• Overall Survival (OS)

  From randomization to the clinical cutoff date. Maximum follow up was 54.41 months

Study Arms (2)

Velcade Lenalidomide dexamethasone (VRd)

ACTIVE COMPARATOR

VRd: subjects will receive VRd for induction and consolidation, followed by lenalidomide (R) maintenance until disease progression or unacceptable toxicity.

Drug: Velcade; Drug: Lenalidomide; Drug: dexamethasone

Daratumumab + VRd (D-VRd)

EXPERIMENTAL

D-VRd: Subjects will receive D-VRd for induction and consolidation followed by daratumumab and lenalidomide maintenance until disease progression or unacceptable toxicity. Minimal residual disease (MRD)-negative subjects in Arm B will stop therapy with daratumumab after sustained MRD negativity for 12 months and after a minimum of 24 months of maintenance therapy. These subjects will continue lenalidomide maintenance therapy until disease progression or unacceptable toxicity. After stopping daratumumab therapy, subjects with sustained MRD negativity should restart therapy with daratumumab if there is a recurrence of MRD or a confirmed loss of Complete Response (CR) without International Myeloma Working Group (IMWG)-defined disease progression. After reinitiating daratumumab, the subject will continue daratumumab and lenalidomide therapy until disease progression or unacceptable toxicity.

Drug: Daratumumab; Drug: Velcade; Drug: Lenalidomide; Drug: dexamethasone

Interventions

dexamethasone DRUG

Dexamethasone will be administered PO at 40 mg daily on Days 1-4 and Days 9-12 of each 28-day cycle during induction and consolidation (Cycles 1-6). On daratumumab administration days, during induction/consolidation, dexamethasone may be administered intravenously 1 hour before the daratumumab administration. On days when daratumumab is not administered, dexamethasone is administered PO. Dexamethasone tablets are to be taken with or immediately after a meal or snack, preferably in the morning.

Daratumumab + VRd (D-VRd); Velcade Lenalidomide dexamethasone (VRd)

Daratumumab DRUG

Daratumumab will be given at a dose of 1800 mg SC weekly in Cycles 1 and 2, then every 2 weeks in Cycles 3-6. In maintenance Cycles 7+, subjects will receive daratumumab once every 4 weeks until disease progression or unacceptable toxicity. MRD-negative subjects will stop daratumumab after sustained MRD negativity for 12 months \& after a min. of 24 months of maintenance. Daratumumab should be restarted at recurrence of MRD or confirmed loss of CR without disease progression.

Also known as: Velcade (bortezomib), lenalidomide, dexamethasone

Daratumumab + VRd (D-VRd)

Velcade DRUG

Bortezomib will be given at a dose of 1.3 mg/m2 SC twice a week (Days 1, 4, 8, and 11) in Cycles 1-6; four 28-day induction cycles (Cycles 1 to 4), and two 28-day consolidation cycles (Cycles 5-6). Subjects will not receive bortezomib after Cycle 6. On treatment days when both bortezomib and daratumumab are administered, bortezomib must be administered after the daratumumab administration.

Also known as: bortezomib

Daratumumab + VRd (D-VRd); Velcade Lenalidomide dexamethasone (VRd)

Lenalidomide DRUG

Lenalidomide will be administered PO at 25 mg on Days 1 to 21 in Cycles 1-6; four 28-day induction cycles and two 28-day consolidation cycles. Following consolidation, subjects will then start maintenance therapy, during which they will receive lenalidomide 10 mg daily PO on Days 1 to 28 (continuously) of each 28-day cycle until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, if well tolerated, the lenalidomide dose may be increased to 15 mg daily, at the discretion of the investigator.

Daratumumab + VRd (D-VRd); Velcade Lenalidomide dexamethasone (VRd)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• to 70 years of age, inclusive.
• Monoclonal plasma cells in the bone marrow ≥10% 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 \>0.25 mmol/L (\>1 mg/dL) higher than upper limit of normal (ULN) or \>2.75 mmol/L (\>11 mg/dL)
• Renal insufficiency: creatinine clearance \<40 mL/min or serum creatinine \>177 μmol/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, CT, or Positron-emission tomography (PET)-CT
• Biomarkers of Malignancy:
• a. Clonal bone marrow plasma cell percentage ≥60% b. Involved: uninvolved serum free light chain (FLC) ratio ≥100 c. \>1 focal lesion on magnetic resonance imaging (MRI) studies
• Measurable disease as defined by any of the following:
• Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
• Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio
• Newly diagnosed subjects for whom high-dose therapy and autologous stem cell transplantation (ASCT) is part of the intended treatment plan.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
• Clinical laboratory values meeting the following criteria during the Screening Phase (Screening hematology and chemistry tests should be repeated if done more than 3 days before C1D1):

You may not qualify if:

• Prior or current systemic therapy or stem cell transplant (SCT) for any plasma cell dyscrasia, with the exception of emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
• 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.
• 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).
• Radiation therapy within 14 days of randomization.
• Plasmapheresis within 28 days of randomization.
• Clinical signs of meningeal involvement of multiple myeloma.
• Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) \<50% of predicted normal (for subjects ≥65 years old FEV1 \<50% or diffusing capacity of the lungs for carbon monoxide \[DLCO\] \<50%)
• Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
• Any of the following:
• Seropositive for human immunodeficiency virus (HIV)
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\]). Subjects with resolved infection (ie, subjects who are positive for antibodies to hepatitis B core antigen \[antiHBc\] and/or antibodies to hepatitis B surface antigen \[antiHBs\]) must be screened using real-time PCR measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by polymerase chain reaction (PCR).
• Seropositive for hepatitis C (HCV) (anti-HCV antibody positive or HCV-RNA quantitation positive), except in the setting of a sustained virologic response (SVR), defined as viremia at least 12 weeks after completion of antiviral therapy.
• Concurrent medical or psychiatric condition or disease (such as but not limited to, systemic amyloidosis, POEMS, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
• Any of the following:
• myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV)

Sponsors & Collaborators

• Stichting European Myeloma Network: lead
• Janssen Research & Development, LLC: collaborator

Study Sites (13)

Alfred Hospital

Melbourne, Australia

Location

University Hospital Leuven

Leuven, Belgium

Location

University Hospital Ostrava

Ostrava, Czechia

Location

Odense University Hospital

Odense, Denmark

Location

CHRU Hôtel Dieu

Nantes, France

Location

Regional General Hospital Alexandra

Athens, Greece

Location

Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi Di Ancona

Ancona, Italy

Location

Erasmus MC

Rotterdam, Netherlands

Location

Oslo University Hospital

Oslo, Norway

Location

Uniwersytet Jagiellonski Collegium Medicum

Krakow, Poland

Location

Hospital Clinic I Provincial de Barcelona

Barcelona, Spain

Location

Kantonsspital St. Gallen

Sankt Gallen, Switzerland

Location

Ankara University

Ankara, Turkey (Türkiye)

Location

Related Publications (4)

• Bertamini L, Fokkema C, Rodriguez-Otero P, van Duin M, Terpos E, D'Agostino M, van der Velden VHJ, van de Donk NWCJ, Delforge M, Driessen C, Hajek R, Einsele H, Vangsted A, Vieyra D, Attar R, Sitthi-Amorn A, Carson R, Schjesvold F, Robak P, Beksac M, Spencer A, Broijl A, Cupedo T, Moreau P, Boccadoro M, Sonneveld P. Circulating tumor cells predict myeloma outcomes in patients treated with daratumumab, bortezomib, lenalidomide, and dexamethasone. Blood. 2026 Jan 22;147(4):431-442. doi: 10.1182/blood.2025030113.

  PMID: 41060326 DERIVED

• Sanchez Salas JA, Moreno Belmonte MJ, Poveda Garcia A, Ruiz Ruiz E, Soler Espejo E, Cabanas Perianes V, Garcia Hernandez AM. Intestinal Perforation Secondary to Bortezomib-Induced Autonomic Neuropathy. Clin Case Rep. 2025 Apr 1;13(4):e70340. doi: 10.1002/ccr3.70340. eCollection 2025 Apr.

  PMID: 40171013 DERIVED

• Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Ho PJ, Beksac M, Hulin C, Antonioli E, Leleu X, Mangiacavalli S, Perrot A, Cavo M, Belotti A, Broijl A, Gay F, Mina R, Nijhof IS, van de Donk NWCJ, Katodritou E, Schjesvold F, Sureda Balari A, Rosinol L, Delforge M, Roeloffzen W, Silzle T, Vangsted A, Einsele H, Spencer A, Hajek R, Jurczyszyn A, Lonergan S, Ahmadi T, Liu Y, Wang J, Vieyra D, van Brummelen EMJ, Vanquickelberghe V, Sitthi-Amorn A, de Boer CJ, Carson R, Rodriguez-Otero P, Blade J, Moreau P; PERSEUS Trial Investigators. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Jan 25;390(4):301-313. doi: 10.1056/NEJMoa2312054. Epub 2023 Dec 12.

  PMID: 38084760 DERIVED

• Swan D, Henderson R, McEllistrim C, Naicker SD, Quinn J, Cahill MR, Mykytiv V, Lenihan E, Mulvaney E, Nolan M, Parker I, Natoni A, Lynch K, Ryan AE, Szegezdi E, Krawczyk J, Murphy P, O'Dwyer M. CyBorD-DARA in Newly Diagnosed Transplant-Eligible Multiple Myeloma: Results from the 16-BCNI-001/CTRIAL-IE 16-02 Study Show High Rates of MRD Negativity at End of Treatment. Clin Lymphoma Myeloma Leuk. 2022 Nov;22(11):847-852. doi: 10.1016/j.clml.2022.07.011. Epub 2022 Jul 21.

  PMID: 35985959 DERIVED

Related Links

• website European Myeloma Network

MeSH Terms

Conditions

Multiple Myeloma

Interventions

daratumumab; Bortezomib; Lenalidomide; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: Sarah Lonergan
• Organization: Stichting European Myeloma Network (EMN)

sarah.lonergan@emn.life

+31 10 268 70 65

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2018
• First Posted: October 18, 2018
• Study Start: December 14, 2018
• Primary Completion: August 1, 2023
• Study Completion (Estimated): November 1, 2029
• Last Updated: February 10, 2026
• Results First Posted: December 24, 2024

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

TU (1); DK (1); NO (1); FR (1); IT (1); NL (1); PL (1); GR (1); BE (1); ES (1); AU (1); CZ (1); CH (1)