Multiple Myeloma MedDRA version: 21.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Darzalex
Product Name: Daratumumab co-formulated with recombinant human hyaluronidase (rHuPH20)
Product Code: JNJ-54767414
Pharmaceutical Form: Solution for injection
INN or Proposed INN:
Sponsors
European Myeloma Network (EMN)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 177 µmol/L (>2 mg/dL) 3. Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin 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). Contracep
Exclusion criteria
Exclusion criteria: 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 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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: to determine if the addition of daratumumab to bortezomib, lenalidomide, and dexamethasone (VRd) will prolong progression-free survival (PFS) defined as the time from the date of randomization to the date of disease progression (assessed by International Myeloma Working Group [IMWG] criteria) or death, compared with VRd alone. ;Secondary Objective: Key secondary objectives include the following: • To determine if the addition of daratumumab to VRd will improve clinical outcome as measured by: - Minimal residual disease (MRD) negativity rate post-consolidation and overall MRD negativity rate achieved at any time during the study - Overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR) at post-induction, post-transplant, post-consolidation, and overall - Time to response - Duration of response - Progression-free survival on the next line of therapy (PFS2) - Overall survival (OS) • To assess the safety profile of daratumumab+VRd (D-VRd) ;Primary end point(s): PFS (progression-free survival) is defined as the time from the date of randomization to the date of disease progression or death due to any cause, whichever occurs first. ;Timepoint(s) of evaluation of this end point: For the entire duration of the study. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary efficacy endpoints are: • Post-consolidation MRD negativity rate, defined as the proportion of subjects who achieve MRD negativity (at or below the threshold of 10^-5) at the end of consolidation. • Overall MRD negativity rate, defined as the proportion of subjects who achieve MRD negativity (10^-5) at any time during the study. • Overall ORR, rate of VGPR or better, rate of CR or better, and rate of sCR, defined as the proportions of subjects who achieved PR or better (or VGPR or better, or CR or better, or sCR) per the IMWG criteria at post-induction, post-transplant, post-consolidation, and overall. • Post-consolidation ORR, rate of VGPR or better rate of CR or better, and rate of sCR, defined as the proportions of subjects who achieved PR or better (or VGPR or better, or CR or better, or sCR) by the end of consolidation per the IMWG criteria. • Progression-free survival on the next line of therapy (PFS2) is defined as the time from randomization to progression on the next line of treatment or death, whichever comes first. • OS, measured from the date of from randomization to the date the subject's death. • Time to response (PR or better), time to CR/sCR are defined as the time from randomization to date of initial response (or initial CR/sCR,). • Duration of response (PR or better), duration of CR, duration of sCR, and duration of MRD-negative status, are calculated from the date of the initial documentation of a response (PR or better), or CR or better, or sCR, or MRD-negative status to the date of the first documented evidence of disease progression, as defined in the IMWG criteria, or death due to PD whichever occurs first. • Pharmacokinetic concentrations of daratumumab • Immunogenicity of daratumumab and rHuPH20 • Change in health-related quality of life, symptoms, and functioning using two European Organization for Research and Treatment of Cancer (EORTC) questionnaires and the EuroQol Group Five Dimensions | — |
Countries
Australia, Belgium, Czechia, Czech Republic, Denmark, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Spain, Switzerland, Turkey
Contacts
Public ContactClinical Trials Information
European Myeloma Network (EMN)
Outcome results
None listed