Multiple Myeloma MedDRA version: 21.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864
Conditions
Sponsors
Janssen-Cilag International N.V.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Newly diagnosed and not considered candidate for high-dose chemotherapy with stem cell transplantation due to: ?Being age =65years,or ?age 18-65years with presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with SCT or who refuse high-dose chemotherapy with SCT as initial treatment 2.Diagnosis of multiple myeloma as documented per International Myeloma Working Group Criteria: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 >0.25mmol/L (>1mg/dL) higher than upper limit of normal (ULN) or >2.75mmol/L (>11mg/dL) 2.Renal insufficiency:creatinine clearance 177 µmol/L (>2mg/dL) 3.Anemia:hemoglobin >2g/dL below the lower limit of normal or hemoglobin 50×109/L (transfusions are not permitted within 7 days) d.aspartate aminotransferase (AST) =2.5 x ULN e.alanine aminotransferase (ALT) =2.5 x ULN f.total bilirubin =1.5 x ULN, except in subjects with congenital bilirubinemia,such as Gilbert syndrome (direct bilirubin =2.0 x ULN) g.Estimated creatinine clearance (CrCl) =30 mL/min.Creatinine clearance can be calculated using the Cockcroft-Gault formula (Appendix 8 [Section 10.8]) or eGFR (MDRD; Appendix 9 [Section10.9]), or CKD-epi formula or for subjects with over- or underweight, CrCl may be measured from a 24-hours urine collection using the formula provided in Appendix 8 [Section 10.8]). If Cockcroft-Gault formula is used and body mass index (BMI) is =30 kg/m2 then adjusted body weight should be used in calculation (Appendix 8 [Section 10.8]) h.corrected serum calcium =13.5 mg/dL (=3.4 mM/L);or free ionized calcium =6.5 mg/dL (=1.6 mM/L) 6.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 for 3months 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 o
Exclusion criteria
Exclusion criteria: Any potential subject who meets any of the following criteria will be excluded from participating in the study: 1. Frailty index of =2 according to Myeloma Geriatric Assessment score. 2.1 Prior therapy for multiple myeloma other than a short course of corticosteroids (not to exceed 40 mg of dexamethasone, or equivalent per day, total of 160 mg dexamethasone or equivalent). 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 noninvasive 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. 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. 5.1 Focal radiation therapy within 14 days of randomization with the exception of palliative radiotherapy for symptomatic pain management. Radiotherapy within 14 days prior to randomization on measurable extramedullary plasmacytoma is not permitted even in the setting of palliation for symptomatic management. 6. Plasmapheresis within 28 days of randomization. 7. Clinical signs of meningeal involvement of multiple myeloma. 8. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted. (FEV1 testing is required for subjects suspected of having COPD). 9. Moderate or severe persistent asthma within the past 2 years, uncontrolled asthma of any classification. (Subjects who have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study). 10.2 Subject is: 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]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to total hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (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 virus (HCV; anti-HCV antibody positive or HCV-RNA quantitation positive), except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy. 11. 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 study procedures or results, or that in the opinion of the investigator would constitute a hazard if enrolled in the study. 12. Has clinically significant cardiac disease, including: ? Myocardial infarction within 6 months before signing the informed consent form (ICF), or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, Ne
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to determine if the addition of daratumumab to VRd will improve overall minimal residual disease (MRD) negativity rate compared with VRd alone.;Secondary Objective: ?To determine if the addition of daratumumab to VRd will improve clinical outcome as measured by: -PFS -MRD negativity rate at 1 year -Durability of MRD negativity -ORR of very good partial response (VGPR) or better, and rate of complete response (CR) or better -Time to response -Duration of response -Time to next treatment -Progression-free survival on the next line of therapy (PFS2; defined as time from randomization to progression on the next line of therapy or death, whichever comes first) -Overall survival (OS) ?To evaluate medical resource utilization ?To evaluate the pharmacokinetics (PK) of daratumumab ?To determine the immunogenicity of daratumumab and recombinant human hyaluronidase PH20 (rHuPH20) ?To assess the safety profile of daratumumab + VRd (D-VRd) ?To evaluate clinical efficacy (ie, overall MRD negativity rate and PFS) of daratumumab when added to VRd in cytogenetic high-risk subgroups ?To evaluate patient-reported outcomes (PROs).;Primary end point(s): Overall MRD negativity rate, which is defined as the proportion of subjects who have achieved MRD negative status (at 10^-5) by bone marrow aspirate after randomization and prior to progressive disease (PD) or subsequent anti myeloma therapy. Subjects who have achieved MRD negative status on or after PD or after the switch to subsequent anti-myeloma therapy before PD, will not be considered MRD negative in the primary endpoint analysis.;Timepoint(s) of evaluation of this end point: One year after the last subject is administered their first dose of study treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. PFS defined as the duration from the date of randomization to either progressive disease (PD) or death, whichever comes first. Disease progression will be determined according to the International Myeloma Working Group (IMWG) criteria. For subjects who have not progressed and are alive, data will be censored at the last disease evaluation before the start of any subsequent anti-myeloma therapy. 2. MRD negativity rate at 1 year. 3. Durable MRD negativity rate is defined as the proportion of subjects who have achieved MRD negative status (at 10^-5) at 2 bone marrow aspirate examinations that are a minimum of 1 year apart, without any examination showing MRD positive status in between. 4. Overall response rate is defined as the proportion of subjects who achieve PR or better responses prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria, during or after the study treatment. 5. VGPR or better rate is defined as the proportion of subjects achieving VGPR and CR (including stringent complete response [sCR]) prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria during or after the study treatment. 6. CR or better rate is defined as the proportion of subjects achieving CR or sCR prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria during or after the study treatment. 7. Progression-free survival on the next line of therapy is 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. Subjects who are still alive and not yet progressed on the next line of treatment will be censored on the last date of followup. 8. Overall survival is measured from the date of randomization to the date of the subject's death due to any cause. If the subject is alive or the vital status is unknown, then the subject's data will be censored at the date the subject was last known t | — |
Countries
Brazil, Canada, Czech Republic, France, Germany, Israel, Japan, Korea, Republic of, Netherlands, Poland, Spain, Turkey, United Kingdom, United States
Contacts
Public ContactClinical Registry group
Janssen-Cilag International N.V.
Outcome results
None listed