Phase II, Multicenter, Randomized Study to Evaluate Safety and Efficacy of MRD-guided Therapy With Reduced Versus Standard Dose of Belantamab Mafodotin in Combination With Pomalidomide and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma (REBEL)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 228
- 主要终点
- Overall Response Rate (ORR)
研究概览
简要总结
This study is testing whether a lower dose of belantamab mafodotin used together with pomalidomide and dexamethasone can provide similar effectiveness with fewer side effects compared with the standard dose in patients with relapsed or refractory multiple myeloma.
Participants will be randomly assigned to receive either a reduced dose or a standard dose of belantamab mafodotin in combination with pomalidomide and dexamethasone. The study will evaluate treatment response, side effects, and minimal residual disease (MRD), which is a measure of the number of myeloma cells that remain after treatment. The goal is to determine whether treatment can be optimized while maintaining disease control and reducing treatment-related toxicity.
详细描述
Multiple myeloma remains an incurable plasma cell malignancy despite substantial advances in treatment. Although currently available therapies have improved patient outcomes, most patients eventually experience disease relapse and require additional treatment options. Therefore, there remains a need to optimize therapeutic strategies that can provide durable disease control while minimizing treatment-related toxicity.
Belantamab mafodotin is a B-cell maturation antigen (BCMA)-targeted antibody-drug conjugate that has demonstrated clinically meaningful anti-myeloma activity in patients with relapsed or refractory multiple myeloma. Combination treatment with belantamab mafodotin, pomalidomide, and dexamethasone represents a promising therapeutic approach for this patient population. However, treatment-related adverse events, particularly ocular toxicities, may require dose modifications or treatment interruptions and can affect the overall treatment experience.
The REBEL study has been designed to investigate whether a reduced-dose strategy of belantamab mafodotin can maintain clinical benefit while improving tolerability. The study will also evaluate the use of minimal residual disease (MRD) assessment as part of a treatment-guidance approach. MRD has emerged as an important measure of treatment response and may provide additional information about the depth and durability of disease control in multiple myeloma.
By evaluating treatment effectiveness, safety, and MRD outcomes, this study aims to generate evidence that may support a more individualized approach to belantamab mafodotin-based therapy in patients with relapsed or refractory multiple myeloma. The results may help define treatment strategies that optimize the balance between disease control and treatment burden.
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
- •Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the REBEL study protocol.
- •Male or female, 18 years or older (at the time consent is obtained).
- •Have a confirmed diagnosis of MM as defined by the IMWG criteria.
- •Eastern Cooperative Oncology Group performance status of 0-
- •Have been previously treated with at least 1 prior line of MM therapy, including a lenalidomide-containing regimen (lenalidomide must have been administered for at least 2 consecutive cycles), and must have documented disease progression during or after their most recent therapy.
- •Must have at least ONE aspect of measurable disease, defined as one the following:
- •Urine M-protein excretion ≥200 mg/24 h, or
- •Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L), or
- •Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum free light chain ratio (<0.26 or >1.65) only if the patient has no measurable urine or serum M spike.
- •Have undergone autologous stem cell transplant (autoSCT) or are considered transplant ineligible. Participants with a history of autoSCT are eligible for study participation provided the following eligibility criteria are met:
- •AutoSCT was >100 days prior to the first dose of study medication
- •No active bacterial, viral, or fungal infection(s) present
- •All prior treatment-related toxicities (defined by National Cancer Institute Common Toxicity Criteria for Adverse Events v5.0) must be Grade ≤1 at the time of enrolment, except for alopecia and Grade ≤ 2 peripheral neuropathy.
- •Compliance with contraceptive precautions in accordance with the protocol.
- •Organ System Function - adequate organ system functions as defined by the laboratory assessments
- •Hematologic:
- •Absolute neutrophil count - ≥1.5× 10 9/L (Without growth factor support for the past 14 days, excluding erythropoietin)
- •Hemoglobin - ≥8.0 g/dL
- •Platelets - ≥75 × 10 9/L
- •Total bilirubin - ≤1.5 × ULN; (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)
- •Alanine aminotransferase (ALT) - ≤2.5 × ULN
- •Renal o eGFR ≥30 mL/min/1.73 m2 (as calculated by MDRD formula)
排除标准
- •Active plasma cell leukemia, amyloidosis, POEMS syndrome, allogeneic SCT or currently active GvHD.
- •Anti-MM therapy or use of an investigational drug within 14 days or five half-lives (whichever is shorter) preceding the first dose of study drug; Prior treatment with a monoclonal antibody drug within 30 days of receiving the first dose of study drugs.
- •Plasmapheresis within 7 days prior to the first dose of study drug.
- •Prior treatment with pomalidomide and belantamab mafodotin in any treatment line.
- •Evidence of cardiovascular risk including: current clinically significant (CS) untreated arrhythmias (eg. CS ECG abnormalities, 2nd degree (Mobitz Type II) or 3rd degree AV block); history of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of Screening; heart failure NYHA III or IV class; uncontrolled hypertension.
- •Any major surgery within the last 4 weeks.
- •Any other active malignancy, except the disease is medically stable for at least 2 years or not require active therapy other than hormonal.
- •Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to belantamab mafodotin, drugs chemically related, or any of the components of the study treatment.
- •Evidence of active mucosal or internal bleeding.
- •Cirrhosis or current unstable liver or biliary disease assessed by Investigator. Stable non-cirrhotic chronic liver disease is acceptable if other entry criteria are met.
- •Intolerance or contraindications to anti-viral prophylaxis.
- •Active, uncontrolled bacterial, fungal, or viral infection. Active infections must be resolved at least 14 days prior to enrollment.
- •Known HIV infection, unless the participant can meet all of the following criteria:
- •Established ART for at least 4 weeks and HIV viral load < 400 copies/mL within Screening Period.
- •CD4+ T-cell (CD4+) counts ≥350 cells/μL.
- •No history of AIDS-defining opportunistic infections within the last 12 months. NOTE: consideration must be given to ART and prophylactic antimicrobials that may have a drug-drug interaction and/or overlapping toxicities with belantamab mafodotin or other combination products as relevant.
- •Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months before the first dose of the study intervention, unless the participant can meet the following criteria:
- •RNA test negative.
- •Successful antiviral treatment (usually 8 weeks duration) is required, followed by a negative HCV RNA test after a washout period of at least 4 weeks.
- •Participants with hepatitis B will be excluded unless the patient is:
- •HBcAb+, HBsAg- with undetectable HBV DNA at screening.
- •HBsAg+ at screening or within 3 months before first study dose, but has undetectable HBV DNA, and a highly effective antiviral treatment started at least 4 weeks prior to first dose of study intervention.
- •Presence of active serious renal conditions (e.g., requiring dialysis or any other condition that could affect the participant's safety). Isolated proteinuria due to MM is acceptable if other criteria are fulfilled.
- •Ongoing Grade 3 or higher peripheral neuropathy or neuropathic pain
- •Active or history of venous thromboembolism within the past 3 months.
- •Contraindications to anti-thrombotic prophylaxis.
- •Current corneal disease except for mild punctate keratopathy.
- •Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (also lab abnormalities) that could interfere with participant's safety, obtaining ICF or compliance to the study procedures.
- •Pregnant or lactating female.
研究组 & 干预措施
Arm B - Standard-Dose Belantamab Mafodotin Plus Pomalidomide and Dexamethasone
Participants receive a standard-dose regimen of belantamab mafodotin administered intravenously in combination with pomalidomide and dexamethasone. Belantamab mafodotin is administered at 2.5 mg/kg in Cycle 1 and 1.9 mg/kg every 4 weeks thereafter according to the protocol-defined schedule. Pomalidomide is administered orally on Days 1-21 of each 28-day cycle, and dexamethasone is administered orally once weekly. Participants may continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or another protocol-defined reason for discontinuation.
干预措施: Belantamab Mafodotin (Drug)
Arm B - Standard-Dose Belantamab Mafodotin Plus Pomalidomide and Dexamethasone
Participants receive a standard-dose regimen of belantamab mafodotin administered intravenously in combination with pomalidomide and dexamethasone. Belantamab mafodotin is administered at 2.5 mg/kg in Cycle 1 and 1.9 mg/kg every 4 weeks thereafter according to the protocol-defined schedule. Pomalidomide is administered orally on Days 1-21 of each 28-day cycle, and dexamethasone is administered orally once weekly. Participants may continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or another protocol-defined reason for discontinuation.
干预措施: Pomalidomide (Drug)
Arm A - Reduced-Dose Belantamab Mafodotin Plus Pomalidomide and Dexamethasone
Participants receive a reduced-dose regimen of belantamab mafodotin administered intravenously in combination with pomalidomide and dexamethasone. Belantamab mafodotin is administered at 2.5 mg/kg in Cycle 1 and 1.9 mg/kg thereafter according to the protocol-defined schedule. Pomalidomide is administered orally on Days 1-21 of each 28-day cycle, and dexamethasone is administered orally once weekly. Participants may continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or another protocol-defined reason for discontinuation.
干预措施: Pomalidomide (Drug)
Arm A - Reduced-Dose Belantamab Mafodotin Plus Pomalidomide and Dexamethasone
Participants receive a reduced-dose regimen of belantamab mafodotin administered intravenously in combination with pomalidomide and dexamethasone. Belantamab mafodotin is administered at 2.5 mg/kg in Cycle 1 and 1.9 mg/kg thereafter according to the protocol-defined schedule. Pomalidomide is administered orally on Days 1-21 of each 28-day cycle, and dexamethasone is administered orally once weekly. Participants may continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or another protocol-defined reason for discontinuation.
干预措施: Belantamab Mafodotin (Drug)
Arm A - Reduced-Dose Belantamab Mafodotin Plus Pomalidomide and Dexamethasone
Participants receive a reduced-dose regimen of belantamab mafodotin administered intravenously in combination with pomalidomide and dexamethasone. Belantamab mafodotin is administered at 2.5 mg/kg in Cycle 1 and 1.9 mg/kg thereafter according to the protocol-defined schedule. Pomalidomide is administered orally on Days 1-21 of each 28-day cycle, and dexamethasone is administered orally once weekly. Participants may continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or another protocol-defined reason for discontinuation.
干预措施: Dexamethasone (Drug)
Arm B - Standard-Dose Belantamab Mafodotin Plus Pomalidomide and Dexamethasone
Participants receive a standard-dose regimen of belantamab mafodotin administered intravenously in combination with pomalidomide and dexamethasone. Belantamab mafodotin is administered at 2.5 mg/kg in Cycle 1 and 1.9 mg/kg every 4 weeks thereafter according to the protocol-defined schedule. Pomalidomide is administered orally on Days 1-21 of each 28-day cycle, and dexamethasone is administered orally once weekly. Participants may continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or another protocol-defined reason for discontinuation.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Overall Response Rate (ORR)
时间窗: From randomization up to approximately 6 years
Overall Response Rate (ORR), defined as the proportion of participants achieving at least a partial response according to International Myeloma Working Group (IMWG) response criteria.
Incidence of Grade 2 or Higher Ocular Toxicity
时间窗: From randomization up to approximately 6 years
Incidence of ocular toxicity of at least Grade 2 severity, assessed using the keratopathy and visual acuity (KVA) scale and National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
次要结局
- Incidence and Severity of Adverse Events(From first study treatment dose up to approximately 6 years)
- Undetectable Measurable Residual Disease (uMRD) Rate(At 6, 12, 18, 24, 30, 36, and 42 months from randomization)
- Sustained Undetectable Measurable Residual Disease (uMRD) Negativity Rate(From randomization up to approximately 6 years)
- Overall Response Rate (ORR)(From randomization up to approximately 6 years)
- Complete Response (CR) Rate(From randomization up to approximately 6 years)
- Very Good Partial Response (VGPR) Rate(From randomization up to approximately 6 years)
- Duration of Response (DoR)(From first documented response up to approximately 6 years)
- Progression-Free Survival (PFS)(From randomization up to approximately 6 years)
- Overall Survival (OS)(From randomization up to approximately 6 years)
- Duration of CR-MRD-Negative Disease (DoR-MRD)(From first documented CR-MRD-negative disease up to approximately 6 years)
- Change From Baseline in EORTC QLQ-C30 Score(From randomization up to approximately 6 years)
- Change From Baseline in EORTC QLQ-MY20 Score(From randomization up to approximately 6 years)