TriangleNCT03652064 · CITED IN SOURCE DOCUMENTS
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
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE3
- Status at capture
- COMPLETED
- Registry last update
- 2026-06-02
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.
Open the original ClinicalTrials.gov record → · Download preserved record
What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Primary Analysis: Overall Minimal Residual Disease (MRD) Negative Rate
Final Progression-Free Survival (PFS) Analysis : Overall Minimal Residual Disease (MRD) Negative Rate
Complete Response (CR) or Better Rate
Progression-Free Survival (PFS)
MRD Negativity Rate at 1 Year
Overall Response Rate (ORR)
Durable MRD Negative Rate
Very Good Partial Response (VGPR) or Better Rate
Duration of Response (DOR)
Time to Response
PFS on the Next Line of Therapy
Overall Survival (OS)
Overall MRD Negativity Rate in High-risk Molecular Subgroups
PFS in High-risk Molecular Subgroups
Maximum Observed Serum Concentration (Cmax) of Daratumumab
Minimum Observed Serum Concentration (Cmin) of Daratumumab
Number of Participants With Anti-daratumumab Antibodies
Number of Participants With Anti-recombinant Human Hyaluronidase PH20 (Anti-rHuPH20) Antibodies
Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 Item (EORTC QLQ-C30)
Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20-item (EORTC QLQ-MY20)
Mean Change From Baseline in EuroQol Five Dimension Five Level Questionnaire (EQ-5D-5L)
Adverse events
Limitations, agreements, and source contact
Who could take part
- 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
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- 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. Participants aged greater than (\>)75 years or body mass index (BMI) less than (\<) 18.5 kilograms per meters (kg/m\^2) will receive dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle.
- intervention Names
- Drug: Bortezomib
- Drug: Lenalidomide
- Drug: Dexamethasone
- label
- Bortezomib + Lenalidomide + Dexamethasone (VRd) and Rd
- type
- ACTIVE_COMPARATOR
- description
- 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. Participants aged \>75 years or BMI \<18.5 kg/m\^2 will receive Dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle.
- intervention Names
- Drug: Daratumumab
- Drug: Bortezomib
- Drug: Lenalidomide
- Drug: Dexamethasone
- label
- Daratumumab + VRd (D-VRd) and DRd
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- Daratumumab + VRd (D-VRd) and DRd
- description
- 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.
- name
- Daratumumab
- other Names
- JNJ-54767414
- DARZALEX
- type
- DRUG
- arm Group Labels
- Bortezomib + Lenalidomide + Dexamethasone (VRd) and Rd
- Daratumumab + VRd (D-VRd) and DRd
- description
- 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.
- name
- Bortezomib
- other Names
- Velcade
- type
- DRUG
- arm Group Labels
- Bortezomib + Lenalidomide + Dexamethasone (VRd) and Rd
- Daratumumab + VRd (D-VRd) and DRd
- description
- 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.
- name
- Lenalidomide
- other Names
- Revlimid
- type
- DRUG
- arm Group Labels
- Bortezomib + Lenalidomide + Dexamethasone (VRd) and Rd
- Daratumumab + VRd (D-VRd) and DRd
- description
- 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.
- name
- Dexamethasone
- type
- DRUG
Study design
- allocation
- RANDOMIZED
- intervention Model
- PARALLEL
- masking Info
- masking
- NONE
- primary Purpose
- TREATMENT
Enrollment
- count
- 395
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- Overall MRD negativity rate was defined as the percentage of participants who achieved complete response (CR) or better response and had MRD negative status (at 10\^5) by bone marrow biopsy or aspirate after randomization but prior to progressive disease (PD), subsequent anti-myeloma therapy, or both. CR or better rate was defined as the percentage of participants achieving CR or stringent complete response (sCR) prior to subsequent anti-myeloma therapy in accordance with the International Myeloma Working Group (IMWG) criteria during or after the study treatment. CR was defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and less than (\<) 5 percent (%) plasma cells (PCs) in bone marrow. sCR was defined as CR plus normal free light chain (FLC) ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
- measure
- Primary Analysis: Overall Minimal Residual Disease (MRD) Negative Rate
- time Frame
- From randomization (Day 1) up to 27.9 months
- description
- Overall MRD negativity rate was defined as the percentage of participants who achieved CR or better response and had MRD negative status (at 10\^5) by bone marrow biopsy or aspirate after randomization but prior to PD, subsequent anti-myeloma therapy, or both. CR or better rate was 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. CR was defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and \< 5 % PCs in bone marrow. sCR was defined as CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
- measure
- Final Progression-Free Survival (PFS) Analysis : Overall Minimal Residual Disease (MRD) Negative Rate
- time Frame
- From randomization (Day 1) up to 64.8 months
- secondary Outcomes
- measure
- Complete Response (CR) or Better Rate
- time Frame
- From randomization (Day 1) up to 64.8 months
- measure
- Progression-Free Survival (PFS)
- time Frame
- From randomization (Day 1) up to 64.8 months
- measure
- MRD Negativity Rate at 1 Year
- time Frame
- At 1 Year
- measure
- Overall Response Rate (ORR)
- time Frame
- From randomization (Day 1) up to 64.8 months
- measure
- Durable MRD Negative Rate
- time Frame
- From randomization (Day 1) up to 64.8 months
- measure
- Very Good Partial Response (VGPR) or Better Rate
- time Frame
- From randomization (Day 1) up to 64.8 months
- measure
- Duration of Response (DOR)
- time Frame
- From randomization (Day 1) up to 64.8 months
- measure
- Time to Response
- time Frame
- From randomization (Day 1) up to 64.8 months
- measure
- PFS on the Next Line of Therapy
- time Frame
- From randomization (Day 1) up to 64.8 months
- measure
- Overall Survival (OS)
- time Frame
- From screening (-28 Days) up to 64.8 months
- measure
- Overall MRD Negativity Rate in High-risk Molecular Subgroups
- time Frame
- From randomization (Day 1) up to 64.8 months
- measure
- PFS in High-risk Molecular Subgroups
- time Frame
- From randomization (Day 1) up to 64.8 months
Full study description
- 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.
Source references
- references
- citation
- Zweegman S, Facon T, Hungria V, Bahlis NJ, Venner CP, Braunstein M, Pour L, Marti J, Basu S, Cohen YC, Matsumoto M, Suzuki K, Hulin C, Legiec WM, Beksac M, Maiolino A, Takamatsu H, Perrot A, Turgut M, Liu W, Wang J, Van Brummelen E, Krevvata M, Lopez-Masi L, Carey J, Borgsten F, Rowe M, Carson R, Usmani SZ. Daratumumab in Transplant-Ineligible or -Deferred Newly Diagnosed Multiple Myeloma: Minimal Residual Disease in CEPHEUS. Blood Adv. 2026 Jun 3:bloodadvances.2026019937. doi: 10.1182/bloodadvances.2026019937. Online ahead of print.
- pmid
- 42234958
- type
- DERIVED
- citation
- 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.
- pmid
- 39910273
- type
- DERIVED
- citation
- Abdallah N, Kumar SK. Up-Front Treatment of Elderly (Age >/=75 Years) and Frail Patients With Multiple Myeloma. J Natl Compr Canc Netw. 2024 Nov;22(9):e247039. doi: 10.6004/jnccn.2024.7039.
- pmid
- 39536451
- type
- DERIVED
Source notices and limitations
Discovery and provenance
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- ted on <a href="https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm">Drugs@FDA</a> .</p><h2>Efficacy and Safety</h2><p>Efficacy was evaluated in CEPHEUS (NCT03652064), an open-label, randomized, active-controlled trial in patients with newly diagnosed multiple myeloma who were ineligible for ASCT or refused ASCT as initial
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Preserved source evidence · Not medical advice