Carfilzomib - Lenalidmide - Dexamethasone (KRd) Versus Lenalidomi - Dexamethasone (Rd) in Newly Diagnosed Myeloma Patients Not Eligible for Autologous Stem Cell Transplantation: a Randomized Phas III Trial
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 84
- 试验地点
- 40
- 主要终点
- Minimal residual disease (MRD)
研究概览
简要总结
The combination of lenalidomide plus low-dose dexamethasone (Rd) is considered the new standard for elderly newly diagnosed multiple myeloma (NDMM) patients. The combination carfilzomib plus lenalidomide-dexamethasone (KRd) in relapsed-refractory MM patients improved the progression-free survival (PFS) of approximately 1 year compared to standard Rd treatment. In a small phase 2 trial (23 pts) the KRd combination in elderly NDMM pts showed a complete response (CR) rate of 79% and a PFS at 3 years of 80%. Cardiovascular adverse events are the most limiting toxicities, especially in elderly patients.
详细描述
This protocol is a randomized, multicenter study designed to determine the MRD negativity and the PFS of KRd treatment regimen.
Patients will be randomized in a 1:1 ratio to receive carfilzomib-lenalidomide-dexamethasone (KRd - Arm A) or lenalidomide-dexamethasone (Rd - Arm B).
Patients will be stratified basing on international staging system (ISS) and fitness status using a web-based procedure completely concealed to study participants.
All consecutive patients ≥ 65 years with newly diagnosed MM will be enrolled in a large randomized study during a period of 24 months.
Patients will be treated until disease progression or intolerance to the therapy. The only exception is for patients enrolled in KRd arm who achieve at least a VGPR during the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after one and two years of therapy): these patients will stop carfilzomib administration after 2 years, whereas treatment with lenalidomide and dexamethasone will be continued.
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
- 65 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed symptomatic MM based on either standard CRAB criteria (at least 10% of clonal bone marrow plasma cells plus CRAB defined as the onset of any of the following clinical symptoms: hypercalcemia, renal failure, anemia and bone lesions) or at least 10% of bone marrow plasma cells plus the presence of at least one of the following biomarkers of malignancy:
- •60% or greater clonal plasma cells on bone marrow examination;
- •Serum involved/uninvolved free light chain (FLC) ratio of 100 or greater;
- •More than one focal lesion on magnetic resonance imaging (MRI) that is at least 5 mm or greater in size.
- •Patient not eligible for ASCT (age ≥ 65 years or abnormal cardiac, pulmonary and liver function).
- •Patient defined as fit or intermediate according to the IMWG (International Myeloma Working Group) frailty score
- •Patient has given voluntary written informed consent.
- •Patient is able to be compliant with hospital visits and procedures required per protocol.
- •Patient agrees to use acceptable methods for contraception.
- •Patient has measurable disease according to IMWG criteria.
- •Patient has ECOG (Eastern Cooperative Oncology Group) performance status <
- •Pre-treatment clinical laboratory values within 30 days before randomization:
- •Platelet count ≥50 x 109/L (≥30 x 109 /L if myeloma involvement in the bone marrow is > 50%)
- •Absolute neutrophil count (ANC) ≥ 1 x 109/L without the use of growth factors
- •Corrected serum calcium ≤14 mg/dL (3.5 mmol/L)
- •Alanine transaminase (ALT): ≤ 3 x the ULN
- •Total bilirubin: ≤ 2 x the ULN
- •Calculated or measured creatinine clearance: ≥ 30 mL/minute.
- •LVEF≥ 40%: 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation; multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available
- •Pre-treatment blood pressure value < 140/90 mmHg even with adequate therapy: 24 hours blood pressure monitoring is the preferred method of evaluation; blood pressure diary at home for 2 weeks is acceptable.
- •Females of childbearing potential (FBCP) comply with the conditions of the Pregnancy Prevention Plan, including confirmation that she has an adequate level of understanding.
- •FBCP must follow the Pregnancy Prevention Plan and use a highly effective and an additional barrier contraception method simultaneously for 4 weeks before starting therapy, during treatment and dose interruptions and for at least 30 days after the last dose of study drugs*
- •Males must use an effective barrier method of contraception if sexually active with FCBP during the treatment and for at least 90 days after the last administration of study drug/s. Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of carfilzomib.
排除标准
- •Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the screening or place the subject at unacceptable risk.
- •Patient defined as frail according to the IMWG frailty score.
- •Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid < to the equivalent of dexamethasone 40 mg/day for 4 days).
- •Pregnant or lactating females.
- •Presence of:
- •Clinical active infectious hepatitis type A, B, C or HIV
- •Acute active infection requiring antibiotics or infiltrative pulmonary disease
- •Pulmonary hypertension and interstitial lung disease
- •Uncontrolled arrhythmias or history of QT prolongation
- •Myocardial infarction or unstable angina ≤ 6 months or other clinically significant heart disease
- •Peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 5.0 (Appendix A)
- •Uncontrolled hypertension defined as persistent hypertension (>140/90 mmHg) regardless treatment with 3 drugs, including a diuretic.
- •Contraindication to any of the required drugs or supportive treatments and hypersensitivity to any excipient of the study drugs.
- •Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
- •Invasive malignancy within the past 3 years.
- •Administration of any experimental drug within 4 weeks prior the baseline or within 5 drug half-lives.
研究组 & 干预措施
KRd (Experimental Arm)
Carfilzomib (K):
- 20 mg/m2 IV on day 1 of cycle 1;
- 56 mg/m2 IV on days 8 and 15 in cycle 1;
- 56 mg/m2 IV on days 1, 8 and 15 in cycles 2-12;
- 56 mg/m2 on days 1 and 15 from cycle 13 and onwards.
Lenalidomide (R):
- 25 mg orally on days 1-21 of each cycle.
Dexamethasone (d):
- 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycle.
Until PD or intolerance. Only patients that achieve at least a VGPR within the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib after 2 years of treatment, and will continue with lenalidomide and dexamethasone administration.
干预措施: Carfilzomib (Drug)
KRd (Experimental Arm)
Carfilzomib (K):
- 20 mg/m2 IV on day 1 of cycle 1;
- 56 mg/m2 IV on days 8 and 15 in cycle 1;
- 56 mg/m2 IV on days 1, 8 and 15 in cycles 2-12;
- 56 mg/m2 on days 1 and 15 from cycle 13 and onwards.
Lenalidomide (R):
- 25 mg orally on days 1-21 of each cycle.
Dexamethasone (d):
- 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycle.
Until PD or intolerance. Only patients that achieve at least a VGPR within the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib after 2 years of treatment, and will continue with lenalidomide and dexamethasone administration.
干预措施: Lenalidomide (Drug)
KRd (Experimental Arm)
Carfilzomib (K):
- 20 mg/m2 IV on day 1 of cycle 1;
- 56 mg/m2 IV on days 8 and 15 in cycle 1;
- 56 mg/m2 IV on days 1, 8 and 15 in cycles 2-12;
- 56 mg/m2 on days 1 and 15 from cycle 13 and onwards.
Lenalidomide (R):
- 25 mg orally on days 1-21 of each cycle.
Dexamethasone (d):
- 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycle.
Until PD or intolerance. Only patients that achieve at least a VGPR within the first year of treatment and in sustained MRD negativity (MRD negative at least at 10-5 after 1 and 2 years of therapy) will stop carfilzomib after 2 years of treatment, and will continue with lenalidomide and dexamethasone administration.
干预措施: Dexamethasone (Drug)
Rd (Control Arm)
Lenalidomide (R):
-25 mg orally on days 1-21 of each cycle.
Dexamethasone (d):
-40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycles.
Until PD or intolerance.
干预措施: Lenalidomide (Drug)
Rd (Control Arm)
Lenalidomide (R):
-25 mg orally on days 1-21 of each cycle.
Dexamethasone (d):
-40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycles.
Until PD or intolerance.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Minimal residual disease (MRD)
时间窗: 5 years
1. Minimal residual disease (MRD): unit of measure is not applicable, MRD is expressed as a pure number
Progression-free survival (PFS)
时间窗: 5 years
2. Progression-free survival (PFS): unit of measure is not applicable, PFS is expressed as a pure number
次要结局
- Rate of drug reduction or drug discontinuation(5 years)
- Cardiovascular assessment(5 years)
- Rate of dose reduction, drug discontinuation and toxicities(5 years)
- Response rate(5 years)
- Progression-free survival 2 (PFS2)(5 years)
- Time to progression (TTP)(5 years)
- Duration of response (DOR)(5 years)
- Overall survival (OS)(5 years)
- Time to next therapy (TNT)(5 years)
- MRD negativity(5 years)
- Prognostic factors(5 years)