Phase 3 Evaluation of Daratumumab with Bortezomib, Lenalidomide, and Dexamethasone Versus Bortezomib, Lenalidomide, and Dexamethasone in Untreated Multiple Myeloma
- Trial ID
- 2023-506125-10-00
- Protocol
- EMN1754767414MMY3014
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 study is to determine if the addition of **daratumumab** to the combination of VELCADE (bortezomib), lenalidomide, and dexamethasone (VRd) will prolong progression-free survival (PFS) in patients with previously untreated **multiple myeloma** who are eligible for high-dose therapy. PFS is defined as the time from randomization to disease progression or death, assessed by the International Myeloma Working Group (IMWG) criteria. This is clinically relevant as prolonging PFS can potentially improve patient outcomes and delay the need for subsequent therapies.
Secondary objectives include: - Determining if the addition of daratumumab to VRd improves clinical outcomes as measured by minimal residual disease (MRD) negativity rate, overall response rate (ORR), very good partial response (VGPR) or better, complete response (CR) or better, stringent complete response (sCR), time to response, duration of response, progression-free survival on the next line of therapy (PFS2), and overall survival (OS). - Assessing the safety profile of daratumumab+VRd (D-VRd). - Evaluating the pharmacokinetics (PK) of daratumumab. - Determining the immunogenicity of daratumumab and rHuPH20. - Evaluating patient-reported outcomes (PROs) and medical resource utilization (MRU). - Evaluating stem cell yield after mobilization. - Evaluating time to engraftment post-autologous stem cell transplantation (ASCT). - Evaluating the benefit/risk of stopping daratumumab upon sustained MRD negative status.
Participants
The clinical trial involves a total of **143 participants** diagnosed with **Multiple Myeloma**. The study population includes both male and female subjects, aged between **18 to 70 years**. Participants were selected based on specific inclusion criteria, ensuring they have measurable disease and meet the necessary health status requirements, such as adequate bone marrow, liver, and renal function. The trial includes individuals who are newly diagnosed and for whom high-dose therapy and autologous stem cell transplantation are part of the intended treatment plan. Lifestyle considerations include adherence to contraceptive measures for both male and female participants of reproductive potential, as well as restrictions on sperm and egg donation during and after the study period. The trial population is not limited to a specific gender, and it includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of adding **daratumumab** to a regimen of **VELCADE** (bortezomib), **lenalidomide**, and **dexamethasone** (D-VRd) compared to the regimen without daratumumab (VRd) in patients with previously untreated **multiple myeloma**. This is a Phase 3, randomized, double-blind, controlled trial. The primary objective is to assess progression-free survival (PFS), defined as the time from randomization to disease progression or death. The trial is expected to run from November 28, 2018, to May 24, 2029, with participant involvement lasting up to 109 weeks, depending on individual response and treatment tolerability.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, reproductive status, and specific clinical laboratory values. The screening phase will also involve assessments to ensure adequate bone marrow, liver, and renal function. Following successful screening, participants will be randomized into one of the two treatment arms. Regular follow-up visits will be scheduled to monitor treatment response, adverse events, and compliance with the study protocol. These visits will include clinical evaluations, laboratory tests, and imaging studies as necessary.
The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent. Participants will be monitored for safety and efficacy endpoints throughout the study, with secondary endpoints including minimal residual disease (MRD) negativity rates, overall response rates, and overall survival. The trial will adhere to strict ethical guidelines, ensuring informed consent and participant safety at all stages.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments to evaluate their efficacy in subjects with previously untreated **multiple myeloma**. The primary experimental medication is **DARZALEX** (daratumumab), which is provided as a 1800 mg solution for injection. This medication is administered via the subcutaneous route. The maximum daily dose is 1800 mg, with a total maximum dose of 212.4 g over a treatment period of up to 109 days. DARZALEX is classified as an orphan drug and is produced by Janssen-Cilag International NV.
Another experimental medication used in the trial is **VELCADE** (bortezomib), available as a 3.5 mg powder for solution for injection. This medication is administered subcutaneously, with a maximum daily dose of 1.30 mg/m² and a total maximum dose of 31.2 mg/m² over a treatment period of up to 6 days. VELCADE is categorized as an antineoplastic agent and is also produced by Janssen-Cilag International NV.
**Revlimid** (lenalidomide) is used in various dosages, including 5 mg, 10 mg, and 15 mg hard capsules. These are administered orally, with a maximum daily dose of 25 mg and a total maximum dose of 45.57 g over a treatment period of up to 109 days. Revlimid is classified under other immunosuppressants and is manufactured by Bristol-Myers Squibb Pharma EEIG.
**DEXAMETHASONE** is included as a non-experimental treatment in the study. It is provided in a pharmaceutical form denoted as PHF00245MIG and is administered orally. The maximum daily dose is 40 mg, with a total maximum dose of 1.92 g over a treatment period of up to 6 days. Dexamethasone is classified as a glucocorticoid.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The study aims to determine if the addition of daratumumab to the VELCADE, lenalidomide, and dexamethasone (VRd) regimen will prolong progression-free survival (PFS) compared to the VRd regimen alone.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from the date of randomization to the date of disease progression or death due to any cause, whichever occurs first. Secondary endpoints include post-consolidation Minimal Residual Disease (MRD) negativity rate, overall MRD negativity rate, overall Objective Response Rate (ORR), rate of Very Good Partial Response (VGPR) or better, rate of Complete Response (CR) or better, and rate of stringent Complete Response (sCR). These are defined as the proportions of subjects who achieved Partial Response (PR) or better, VGPR or better, CR or better, or sCR per the International Myeloma Working Group (IMWG) criteria at various stages such as post-induction, post-transplant, post-consolidation, and overall.
Additional secondary endpoints include Progression-Free Survival on the next line of therapy (PFS2), Overall Survival (OS), time to response (PR or better), time to CR/sCR, duration of response (PR or better), duration of CR, duration of sCR, and duration of MRD-negative status. These are calculated from the date of the initial documentation of a response to the date of the first documented evidence of disease progression or death due to progressive disease, whichever occurs first. Pharmacokinetic concentrations of daratumumab, immunogenicity of daratumumab and rHuPH20, changes in Health-Related Quality of Life (HRQoL), symptoms, and functioning using EORTC questionnaires and the EQ-5D-5L, stem cell yield after mobilization, and time to engraftment post-autologous stem cell transplantation (ASCT) are also evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 18 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: 1. 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) 2. Renal insufficiency: creatinine clearance <40mL/min or serum creatinine >177 μmol/L (>2 mg/dL) 3. Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL 4. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT Biomarkers of Malignancy: a. Clonal bone marrow plasma cell percentage ≥60% b. Involved: uninvolved serum FLC ratio ≥100 c. >1 focal lesion on magnetic resonance imaging (MRI) studies
- Measurable disease as defined by any of the following: a. Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or b. 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 is part of the intended treatment plan.
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 (see Attachment 1).
- 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): Adequate bone marrow function: a. Hemoglobin ≥7.5 g/dL (≥4.65 mmol/L; prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted however transfusions are not permitted within 7 days of randomization to achieve this minimum hemoglobin count); b. Absolute neutrophil count (ANC) ≥1.0 x 10^9/L (G-CSF use is permitted); c. Platelet count ≥50 x 10^9/L if bone marrow is >50% involved in myeloma. Otherwise ≥75 x 10^9/L Adequate liver function: a. Aspartate aminotransferase (AST) ≤2.5 x ULN; b. Alanine aminotransferase (ALT) ≤2.5 x ULN; c. Total bilirubin ≤1.5 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin ≤1.5 x ULN) Adequate renal function: a. Estimated creatinine clearance ≥30 mL/min. Creatinine clearance may be calculated using Cockcroft-Gault, eGFR (Modified Diet in Renal Disease [MDRD]; Attachment 2), or CKD-epi formula b. Corrected serum calcium ≤13.5 mg/dL (≤3.4 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L) (see Attachment 3) NOTE: For Criteria 7-11, contraceptive (birth control) use by men or women should be consistent with local regulations regarding the acceptable methods of contraception for those participating in clinical studies. Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for subjects in clinical studies.
- Criterion modified per Amendment 2. 7.1 Female subjects of reproductive childbearing potential (defined as post-menarche until post-menopause unless permanently sterilized) must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the treatment period, during any dose interruptions, and for 3 months after the last dose of any component of the treatment regimen. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug and is consistent with the usual lifestyle of the subject. This birth control method must include one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy with confirmation of procedure) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
- 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. For requirements during the Treatment Phase, refer to Section 4.3.
- 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.
- Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 3 months after discontinuing study treatment (even after a successful vasectomy).
- Male subjects of reproductive potential must not donate sperm during the study or for 3 months after the last dose of study treatment.
- Criterion modified per Amendment 2 12.1 Signed an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. Subjects in emergency situations that do not allow for collection of informed consent are excluded.
- Able to adhere to the prohibitions and restrictions specified in this protocol.
Exclusion Criteria
- Prior or current systemic therapy or 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).
- Criterion modified per Amendment 2 4.1 Radiation therapy for treatment of plasmacytoma within 14 days of randomization (palliative radiation for pain control secondary to lytic lesion is allowed within 14 days of randomization).
- Plasmapheresis within 28 days of randomization.
- Clinical signs of meningeal involvement of multiple myeloma.
- Criterion modified per Amendment 2 7.1 Pulmonary: a. Subjects <65 years old with chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal b. Subjects ≥65 years old with a FEV1 <50% or diffusing capacity of the lungs for carbon monoxide [DLCO] <50%
- Moderate or severe persistent asthma within the past 2 years (see Attachment 4), 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).
- Criterion modified per Amendment 2 9.1 Criterion modified per Amendment 4 Any of the following: a. Known to be seropositive for human immunodeficiency virus (HIV). HIV antibody testing at screening should be performed per local health guidelines. b. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [Anti-HBc] and/or antibodies to hepatitis B surface antigen [Anti-HBs]) 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 (Anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. c. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia 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.
- Criterion modified per Amendment 2 11.1 Any of the following: a. 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) b. uncontrolled cardiac arrhythmia c. screening 12-lead ECG showing a baseline QT interval >470 msec (exception: subjects with pacemaker) d. screening ECHO or MUGA scan for subjects aged >65-70: left ventricular ejection fraction (LVEF) <40%
- Received a strong CYP3A4 inducer within 5 half-lives prior to randomization (Flockhart 2016: http://medicine.iupui.edu/flockhart/)
- Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the Investigator's Brochure), or sensitivity to mammalian-derived products or lenalidomide or its excipients.
- Criterion modified per Amendment 2 14.1 Not able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Subject is taking any prohibited medications as per Section 8.3. Subject is deprived of their freedom by a judicial or administrative decision, or subject is in psychiatric care. Subject is subjected to a legal protection measure or unable to provide their consent.
- Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen. Or, subject is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen.
- Major surgery within 2 weeks before randomization or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty is not considered major surgery.
- Criterion modified per Amendment 2 17.1 Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks or 5 half-lives of the respective drug/investigational medicinal product (IMP) (whichever is longer) before randomization or is currently enrolled in an interventional investigational study.
- Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information.
- Gastrointestinal disease that may significantly alter the absorption of oral drugs
- Vaccination with live attenuated vaccines within 4 weeks of first study agent administration
- Unable or unwilling to undergo antithrombotic prophylactic treatment. NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a subject’s clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the study. Section 17.4, Source Documentation, describes the required documentation to support meeting the enrollment criteria.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 28 Nov 2018 | 15 |
 Czechia | Not Recruiting | 28 Nov 2018 | 35 |
 Denmark | Not Recruiting | 28 Nov 2018 | 20 |
 France | Not Recruiting | 28 Nov 2018 | 167 |
 Germany | Not Recruiting | 28 Nov 2018 | 40 |
 Greece | Not Recruiting | 28 Nov 2018 | 22 |
 Italy | Not Recruiting | 28 Nov 2018 | 140 |
 The Netherlands | Not Recruiting | 28 Nov 2018 | — |
 Norway | Not Recruiting | 28 Nov 2018 | 15 |
 Poland | Not Recruiting | 28 Nov 2018 | 19 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DARZALEX 1800 mg solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1800 | 109 | PRD8157846 |
Revlimid 10 mg hard capsules | Other | HARD CAPSULES | ORAL | 25 | 109 | PRD9264283 |
Revlimid 15 mg hard capsules | Other | HARD CAPSULES | ORAL | 25 | 109 | PRD9264282 |
Lenalidomide Mylan 10 mg hard capsules | Other | HARD CAPSULES | ORAL | 25 | 109 | PRD11828374 |
Revlimid 15 mg hard capsules | Other | HARD CAPSULES | ORAL | 25 | 109 | PRD9264288 |
Revlimid 5 mg hard capsules | Other | HARD CAPSULES | ORAL | 25 | 109 | PRD9264287 |
DEXAMETHASONE | Other | PHF00245MIG | ORAL | 40 | 6 | SCP10332310 |
Lenalidomide Mylan 15 mg hard capsules | Other | HARD CAPSULES | ORAL | 25 | 109 | PRD11828376 |
Lenalidomide Mylan 5 mg hard capsules | Other | HARD CAPSULES | ORAL | 25 | 109 | PRD11828369 |
Revlimid 5 mg hard capsules | Other | HARD CAPSULES | ORAL | 25 | 109 | PRD9264284 |