A Study of combination of Daratumumab, VELCADE (bortezomib), Lenalidomide, and Dexamethasone (D-VRd) compared to VELCADE, Lenalidomide, and Dexamethasone (VRd) in participants with Previously Untreated Multiple Myeloma
- Conditions
- Multiple MyelomaMedDRA version: 21.0Level: LLTClassification code 10028228Term: Multiple myelomaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2018-002992-16-NL
- Lead Sponsor
- European Myeloma Network (EMN)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 813
1. 18 to 70 years of age, inclusive.
2. 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
3. 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
4. Newly diagnosed subjects for whom high-dose therapy and autologous stem cell transplantation is part of the intended treatment plan.
5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
6. 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 109/L (G-CSF use is permitted);
c. Platelet count =50 x 109/L if bone marrow is >50% involved in myeloma. Otherwise =75 x 109/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 (MDRD), 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)
7. Female subjects of reproductive childbearing potential 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 or 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. 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) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prio
1. 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.
2. 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.
3. 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).
4. Radiation therapy for treatment of plasmacytoma within 14 days of randomization.
5. Plasmapheresis within 28 days of randomization.
6. Clinical signs of meningeal involvement of multiple myeloma.
7. a. Subjects <65 years old with Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal
7. b. Subjects =65 years old with a FEV1 <50% or diffusing capacity of the lungs for carbon monoxide [DLCO] <50%)
8. 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).
9. Any of the following:
a. Known to be seropositive for human immunodeficiency virus (HIV)
b. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]).
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.
10. Concurrent medical or psychiatric condition or disease (eg, 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.
11. 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%
12. Received a strong CYP3A4 inducer within 5 half-lives prior to randomization
(Flockhart 2016: http://medicine.iupui.edu/flockhart/)
13. 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.
14. 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 prev
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method