Multiple Myeloma MedDRA version: 21.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864
Conditions
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). Contraception must begin 4 weeks prio
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) or that could prevent
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: A) To determine if the addition of daratumumab to VRd will improve clinical out-come as measured by: A.1) MRD negativity rate post-consolidation and overall MRD negativity rate achieved at any time during the study A.2) ORR, rate of VGPR or better, rate of CR or better, rate of sCR at post-induction, A.3) post-transplant, post-consolidation, and overall A.4) Time to response A.5) Duration of response A.6) Progression-free survival on the next line of therapy (PFS2) A.7) Overall survival (OS) B) To assess the safety profile of daratumumab+VRd (D-VRd) C) To evaluate pharmacokinetics (PK) of daratumumab D) To determine the immunogenicity of daratumumab and rHuPH20 E) To evaluate patient-reported outcomes (PROs) and medical resource utilization (MRU) F) To evaluate stem cell yield after mobili-zation G) To evaluate time to engraftment post-ASCT H) To evaluate the benefit/risk of stopping daratumumab upon sustained MRD-negative status;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: 1) 1st interim analysis (143 events) will be conducted at approximately 33 months after first patient dosed. 2) 2nd interim analysis (185 events) will be conducted at approximately 44 months after first patient dosed. 3) Final analysis (285 events) will be conducted at approximately 76 months after first patient dosed | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: For Secondary efficacy endpoints except Overall Survival, the time points of evaluation are: 1) 1st interim analysis (143 events) will be conducted at approximately 33 months after first patient dosed. 2) 2nd interim analysis (185 events) will be conducted at approximately 44 months after first patient dosed. 3) Final analysis (285 events) will be conducted at approximately 76 months after first patient dosed For Overall Survival, besides the above 3 time points, a final analysis of OS will be conducted at 9 years after the last subject randomized or 310 death events have occurred. ;Secondary end point(s): A.1a) Post-consolidation MRD negativity rate, de-fined as the proportion of subjects who achieve MRD negativity (at or be-low the threshold of 10^-5) at the end of consolidation. A.1b) Overall MRD negativity rate, defined as the proportion of subjects who achieve MRD negativity (10^-5) at any time during the study. A.2) Overall ORR, rate of VGPR or better, rate of CR or better, and rate of sCR, defined as the proportions of sub-jects 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. A.3) 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. A.4) Time to response (PR or better), time to CR/sCR are defined as the time from randomziation to date of initial response (or initial CR/sCR,). A.5) 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 de-fined in the IMWG | — |
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