A Phase 3 Study Comparing Daratumumab, VELCADE (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) With VELCADE, Lenalidomide, and Dexamethasone (VRd) in Subjects With Untreated Multiple Myeloma and for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 395
- 试验地点
- 169
- 主要终点
- Primary Analysis: Overall Minimal Residual Disease (MRD) Negative Rate
研究概览
简要总结
The purpose of this study to determine if the addition of daratumumab to bortezomib + lenalidomide + dexamethasone (VRd) will improve overall minimal residual disease (MRD) negativity rate compared with VRd alone.
详细描述
This study will evaluate participants with newly diagnosed multiple myeloma (MM) for whom hematopoietic stem cell transplant is not planned as initial therapy. The data available from other available studies suggests that addition of daratumumab with Velcade (bortezomib), lenalidomide, and dexamethasone [VRd] is anticipated to improve the response rates and the depth of response and may lead to improved long-term outcomes in newly diagnosed participants with MM. Daratumumab targets CD38, a protein expressed on the surface of MM cells and other hematopoietic cells. Bortezomib is a proteasome inhibitor, which plays a critical role in the pathogenesis of MM. Lenalidomide has cytotoxic effects on myeloma cells and is capable of inducing apoptosis, or programmed cell death and dexamethasone induces apoptosis in MM cells. The rationale for the study is to utilize the subcutaneous (SC) formulation of daratumumab instead of the intravenous (IV) formulation, which is expected to provide similar exposure and is expected to limit additional toxicity to participants, treated with this quadruplet regimen. The study will consist of 3 phases: Screening (up to 28 days before randomization), Treatment phase (from Cycle 1 [21 days] Day 1 and continues until disease progression) and Follow up (Postintervention). Efficacy evaluations will include measurements of tumor burden/residual disease, myeloma proteins, bone marrow examinations, skeletal surveys, extramedullary plasmacytomas, and serum calcium corrected for albumin. Participants will undergo procedures like electrocardiogram (ECG), chest x-rays or full dose chest CT scans, Pulmonary function test (PFT), spirometry etc. during the course of study. Participants will also be monitored closely for adverse events (AEs), laboratory abnormalities, and clinical response. The duration of the study will be approximately 6.5 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •- Diagnosis of multiple myeloma as documented per International Myeloma Working Group (IMWG) criteria Monoclonal plasma cells in the bone marrow greater than or equal to (>=)10 percentage (%) 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: Hypercalcemia: serum calcium greater than (>) 0.25 millimoles per liter (mmol/L) (>1 milligram per deciliter [mg/dL]) higher than upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL); Renal insufficiency: creatinine clearance less than (<) 40 milliliter per minute (mL/min) or serum creatinine >177 micro millimoles per liter (umol/L) (>2 mg/dL); Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL; Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT.
- •Biomarkers of Malignancy: Clonal bone marrow plasma cell percentage >=60%; Involved: uninvolved serum free light chain (FLC) ratio >=100; >1 focal lesion on magnetic resonance imaging (MRI) studies
- •Must have measurable disease, as assessed by central laboratory
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
- •A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing
- •A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 3 months after receiving the last dose of any component of the treatment regimen
排除标准
- •Frailty index of >=2 according to Myeloma Geriatric Assessment score
- •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)
- •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)
- •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
- •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
研究组 & 干预措施
Daratumumab + VRd (D-VRd) and DRd
Participants will receive daratumumab 1800 mg as SC injection once every week for Cycles 1 to 2, then every 3 weeks for Cycles 3 through 8 and every 4 weeks for Cycle 9 and beyond; bortezomib 1.3 mg/m^2 as SC injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9; dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond followed by daratumumab-lenalidomide-dexamethasone (DRd) until disease progression or unacceptable toxicity. Participants aged >75 years or BMI <18.5 kg/m^2 will receive Dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle.
干预措施: Lenalidomide (Drug)
Daratumumab + VRd (D-VRd) and DRd
Participants will receive daratumumab 1800 mg as SC injection once every week for Cycles 1 to 2, then every 3 weeks for Cycles 3 through 8 and every 4 weeks for Cycle 9 and beyond; bortezomib 1.3 mg/m^2 as SC injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9; dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond followed by daratumumab-lenalidomide-dexamethasone (DRd) until disease progression or unacceptable toxicity. Participants aged >75 years or BMI <18.5 kg/m^2 will receive Dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle.
干预措施: Daratumumab (Drug)
Bortezomib + Lenalidomide + Dexamethasone (VRd) and Rd
Participants will receive bortezomib 1.3 milligram per square meter (mg/m^2) as subcutaneous (SC) injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 (cycle of 28 days); dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond (each cycle is of 28 days) followed by lenalidomide-dexamethasone (Rd) until disease progression or unacceptable toxicity. Participants aged greater than (>)75 years or body mass index (BMI) less than (<) 18.5 kilograms per meters (kg/m^2) will receive dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle.
干预措施: Bortezomib (Drug)
Bortezomib + Lenalidomide + Dexamethasone (VRd) and Rd
Participants will receive bortezomib 1.3 milligram per square meter (mg/m^2) as subcutaneous (SC) injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 (cycle of 28 days); dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond (each cycle is of 28 days) followed by lenalidomide-dexamethasone (Rd) until disease progression or unacceptable toxicity. Participants aged greater than (>)75 years or body mass index (BMI) less than (<) 18.5 kilograms per meters (kg/m^2) will receive dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle.
干预措施: Lenalidomide (Drug)
Bortezomib + Lenalidomide + Dexamethasone (VRd) and Rd
Participants will receive bortezomib 1.3 milligram per square meter (mg/m^2) as subcutaneous (SC) injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 (cycle of 28 days); dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond (each cycle is of 28 days) followed by lenalidomide-dexamethasone (Rd) until disease progression or unacceptable toxicity. Participants aged greater than (>)75 years or body mass index (BMI) less than (<) 18.5 kilograms per meters (kg/m^2) will receive dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle.
干预措施: Dexamethasone (Drug)
Daratumumab + VRd (D-VRd) and DRd
Participants will receive daratumumab 1800 mg as SC injection once every week for Cycles 1 to 2, then every 3 weeks for Cycles 3 through 8 and every 4 weeks for Cycle 9 and beyond; bortezomib 1.3 mg/m^2 as SC injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9; dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond followed by daratumumab-lenalidomide-dexamethasone (DRd) until disease progression or unacceptable toxicity. Participants aged >75 years or BMI <18.5 kg/m^2 will receive Dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle.
干预措施: Dexamethasone (Drug)
Daratumumab + VRd (D-VRd) and DRd
Participants will receive daratumumab 1800 mg as SC injection once every week for Cycles 1 to 2, then every 3 weeks for Cycles 3 through 8 and every 4 weeks for Cycle 9 and beyond; bortezomib 1.3 mg/m^2 as SC injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9; dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond followed by daratumumab-lenalidomide-dexamethasone (DRd) until disease progression or unacceptable toxicity. Participants aged >75 years or BMI <18.5 kg/m^2 will receive Dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle.
干预措施: Bortezomib (Drug)
结局指标
主要结局
Primary Analysis: Overall Minimal Residual Disease (MRD) Negative Rate
时间窗: From randomization (Day 1) up to 27.9 months
Overall MRD negativity rate was defined as the percentage of participants who achieved complete response (CR) or better response and had MRD negative status (at 10\^5) by bone marrow biopsy or aspirate after randomization but prior to progressive disease (PD), subsequent anti-myeloma therapy, or both. CR or better rate was defined as the percentage of participants achieving CR or stringent complete response (sCR) prior to subsequent anti-myeloma therapy in accordance with the International Myeloma Working Group (IMWG) criteria during or after the study treatment. CR was defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and less than (\<) 5 percent (%) plasma cells (PCs) in bone marrow. sCR was defined as CR plus normal free light chain (FLC) ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
Final Progression-Free Survival (PFS) Analysis : Overall Minimal Residual Disease (MRD) Negative Rate
时间窗: From randomization (Day 1) up to 64.8 months
Overall MRD negativity rate was defined as the percentage of participants who achieved CR or better response and had MRD negative status (at 10\^5) by bone marrow biopsy or aspirate after randomization but prior to PD, subsequent anti-myeloma therapy, or both. CR or better rate was defined as the percentage of participants achieving CR or sCR prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria during or after the study treatment. CR was defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and \< 5 % PCs in bone marrow. sCR was defined as CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
次要结局
- PFS on the Next Line of Therapy(From randomization (Day 1) up to 64.8 months)
- Overall Survival (OS)(From screening (-28 Days) up to 64.8 months)
- Overall MRD Negativity Rate in High-risk Molecular Subgroups(From randomization (Day 1) up to 64.8 months)
- PFS in High-risk Molecular Subgroups(From randomization (Day 1) up to 64.8 months)
- Durable MRD Negative Rate(From randomization (Day 1) up to 64.8 months)
- Very Good Partial Response (VGPR) or Better Rate(From randomization (Day 1) up to 64.8 months)
- Complete Response (CR) or Better Rate(From randomization (Day 1) up to 64.8 months)
- Duration of Response (DOR)(From randomization (Day 1) up to 64.8 months)
- Time to Response(From randomization (Day 1) up to 64.8 months)
- Progression-Free Survival (PFS)(From randomization (Day 1) up to 64.8 months)
- MRD Negativity Rate at 1 Year(At 1 Year)
- Overall Response Rate (ORR)(From randomization (Day 1) up to 64.8 months)
- Maximum Observed Serum Concentration (Cmax) of Daratumumab(Predose on Day 1 and post dose on Day 4 of Cycles 1, 3 (each cycle consisted of 21 days); Predose on Day 1 of Cycles 9 and 12 (each cycle consisted of 28 days); Post treatment Week 8)
- Minimum Observed Serum Concentration (Cmin) of Daratumumab(Predose on Day 1 and post dose on Day 4 of Cycles 1 and 3 (each cycle consisted of 21 days); Predose on Day 1 of Cycles 9 and 12 (each cycle consisted of 28 days); Post treatment Week 8)
- Number of Participants With Anti-daratumumab Antibodies(Predose on Day 1 of Cycles 1, 9, and 12 (Cycle 1 consisted of 21 days, Cycles 9 and 12 consisted of 28 days); and Post-Treatment Week 8)
- Number of Participants With Anti-recombinant Human Hyaluronidase PH20 (Anti-rHuPH20) Antibodies(Predose on Day 1 of Cycles 1, 9, and 12 (Cycle 1 consisted of 21 days, Cycles 9 and 12 consisted of 28 days); and Post-Treatment Week 8)
- Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 Item (EORTC QLQ-C30)(From screening (-28 Days) up to 64.8 months)
- Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 20-item (EORTC QLQ-MY20)(From screening (-28 Days) up to 64.8 months)
- Mean Change From Baseline in EuroQol Five Dimension Five Level Questionnaire (EQ-5D-5L)(From screening (-28 Days) up to 64.8 months)