A Phase III Study Comparing Lenalidomide and Daratumumab (R-Dara) vs Lenalidomide and Dexamethasone (Rd) in Frail Subjects with Previously Untreated Multiple Myeloma who are Ineligible for High Dose Therapy. MedDRA version: 20.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864
Conditions
Sponsors
CHRU de Lille
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Subject must be at least 65 years of age. 2.Subject must have documented multiple myeloma satisfying the CRAB criteria and measurable disease defined as: •Monoclonal plasma cells in the bone marrow =10% or presence of a biopsy proven plasmacytoma •Measurable disease as defined by any of the following: -IgG myeloma: Serum monoclonal paraprotein (M-protein) level =1.0 g/dL or urine M-protein level =200 mg/24 hours; or -IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level =0.5 g/dL or urine M-protein level =200 mg/24 hours; or -Light chain multiple myeloma: Serum immunoglobulin free light chain =10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio (only measurable with freelite® by Binding site). 3.Newly diagnosed and not considered candidate for high-dose chemotherapy with SCT. 4.Subject must have a Frailty Score = 2 5.Subject must have within 5 days prior to first drug intake (C1D1) pretreatment clinical laboratory values meeting the following criteria during the Screening Phase: a) hemoglobin =7.5 g/dL (=4.65 mmol/L; prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted); b) absolute neutrophil count =1.0 x 109/L (granulocyte colony stimulating factor [GCSF] use is permitted); c) platelet count =70 x 109/L for subjects in whom 50 × 109/L (transfusions are not permitted to achieve this minimum platelet count). d) aspartate aminotransferase (AST) =2.5 x upper limit of normal (ULN); e) alanine aminotransferase (ALT) =2.5 x ULN; f) total bilirubin =2.0 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin =2.0 x ULN); g) creatinine clearance=30mL/min(for lenalidomide dose adjustment for subjects with creatinine clearance 30-60 mL/min). Creatinine clearance may be calculated using the Cockcroft-Gault formula h) corrected serum calcium =14 mg/dL (=3.5 mmol/L); 6. Measurable ISS with ß2-microglobulin and albumin values for randomization 7.A man who is sexually active with a woman of childbearing potential must agree to use a latex or synthetic condom, even if they had a successful vasectomy. All men must also not donate sperm during the study, for 4 weeks after the last dose of lenalidomide, and for 4 months after the last dose of daratumumab. Women participating in this study must be postmenopausal. 8.Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF. 9. Subjects affiliated with an appropriate social security system. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 294
Exclusion criteria
Exclusion criteria: 1.Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. 2.Subject has a diagnosis of Waldenström’s disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions. 3.Subject has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment. 4.Subject has a history of malignancy (other than multiple myeloma) within 5 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years). 5.Subject has had radiation therapy within 14 days of randomization. 6.Subject has had plasmapheresis within 28 days of randomization. 7.Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma. 8.Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second 470 msec 12.Subject has known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure). 13.Subject has plasma cell leukemia (according to World Health Organization [WHO] criterion: =20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). 14.Subject is known or suspected of not being 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to compare the efficacy of daratumumab SC injection when combined with lenalidomide (R-Dara SC) to that of lenalidomide and dexamethasone (Rd), in terms of PFS in frail subjects with newly diagnosed myeloma who are not candidates for high dose chemotherapy and autologous stem cell transplant.;Secondary Objective: 1.Time-to-treatment failure. 2.Time-to-next treatment. 3.PFS2 time. 4.Overall survival. 5.Complete remission (CR). 6.Very good partial response (VGPR) or better. 7.Overall response (CR + VGPR + partial response [PR]). 8.Occurrence of grade 3 or more side effects. 9.Safety and tolerability of Daratumumab SC when administered in combination with R. 10.Treatment effects on patient reported outcomes and heath economic/resource utilization. 11.Minimal residual disease (MRD) negative rate at 12 months. 12. Event Free Survival;Primary end point(s): The primary endpoint is PFS time, which is defined as the duration from the date of randomization to either progressive disease, or death, whichever occurs first. Disease progression will be determined according to the 2016 IMWG criteria.;Timepoint(s) of evaluation of this end point: Throughout the study using the IMWG response criteria. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1.Time-to-treatment failure, defined as time from randomization to discontinuation of therapy for any reason including death, progression, toxicity. 2.Time to next treatment, defined as the time from randomization to the start of the next-line treatment. 3.PFS2 time, defined as the time from randomization to progression on the next line of treatment or death, whichever comes first. Disease progression will be based on investigator judgment. For those subjects who are still alive and not yet progressed on the next line of treatment, they will be censored on the last date of follow-up. 4.Overall survival (OS) time, measured from the date of randomization to the date of the subject’s death. If the subject is alive or the vital status is unknown at last contact, then the subject’s data will be censored at the date the subject was last known to be alive. 5.CR, defined as: -Negative immunofixation of serum and urine, and -Disappearance of any soft tissue plasmacytomas, and -<5% plasma cells (PCs) in bone marrow -For those IgG Kappa myeloma subjects with at least =2g/l M-protein on 2 consecutive visits, no additional M-proteins detected, urine and FLC normal (suspected daratumumab interference on immunofixation), a reflex assay using anti-idiotype antibody (DIRA test) will be utilized to confirm daratumumab interference and rule out false positive immunofixation (for patients with uncommon kappa light chain myeloma, appearance of a band <or = 2g/l on electrophoresis typed IgG kappa on immunofixation and migrating to the same level as the light chain involved, is required). Patients who have confirmed daratumumab interference, but meet all other clinical criteria for CR, will be considered CR. 6.VGPR or better, defined as VGPR or CR according to the IMWG criteria during or after the study treatment at the time of data cutoff. 7.Overall response, defined as CR or VGPR or PR, according to the IMWG criteria, during or after the study treatment. 8.Col | — |
Countries
Belgium, France
Contacts
Public ContactKEMKEM Aomar
CHRU de Lille
Outcome results
None listed