Induction Therapy With Bortezomib-melphalan and Prednisone (VMP) Followed by Lenalidomide and Dexamethasone (Rd) Versus Carfilzomib, Lenalidomide and Dexamethasone (KRd) Plus/Minus Daratumumab, 18 Cycles, Followed by Consolidation and Maintenance Therapy With Lenalidomide and Daratumumab: Phase III, Multicenter, Randomized Trial for Elderly Fit Newly Diagnosed Multiple Myeloma Patients Aged Between 65 and 80 Years
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 462
- 试验地点
- 58
- 主要终点
- Efficacy in terms of numbers of compleat responses
研究概览
简要总结
The study is designed as a randomized, controlled, open-label, assessor blind, multicenter superiority trial with three parallel groups, and primary endpoint of immunophenotypic complete responses at 18 months after randomization. Block randomization will be performed with a 1:1:1 allocation ratio.
Patients will be randomized up front to 3 arms. Patients will receive "standard" PETHEMA arm for fit elderly VMP x 9 + Rd x 9 (arm 1, control arm), a KRd regimen (arm 2a) (18 cycles) or a Carfilzomib-lenalidomida-dexametasona regimen combined with DARATUMUMAB (arm 2b) (18 cycles).
详细描述
After 18 cycles, patients not having received daratumumab before (arm 1 and 2a), will receive consolidation with 4 cycles of Lenalidomida-dexamethasone at low dose-DARATUMUMAB.
At this point (after 22 months on treatment for the VMP-Rd and KRd arm and after 18 months of the Carfilzomib-lenalidomida-dexametasona-DARATUMUMAB arm) patients will be stratified according MRD status by flow and in both MRD- and MRD+ groups, patients will be randomized with a 1:1 allocation ratio to:
- no further treatment or
- continuous treatment with DARATUMUMAB-R (daratumumab plus lenalidomide up to 2 years and then lenalidomide continuous until progression).
Patients on no maintenance that show biological relapse will be rechallenged with DARATUMUMAB-R.
The translational part will be very robust with dysplasia monitoring (especially relevant for the Bortezomib-melfalán-prednisona + Lenalidomida-dexamethasone at low dose arm), clonal evolution/resistance follow up and immune reconstitution longitudinal follow up alongside with MRD status (at diagnosis, 9 months, 18 months, 22 months and treatment discontinuation).
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 80 Years（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed multiple myeloma patients who require start active treatment according to the IMWG published in 2014
- •Age between 65 and 80 years, both included
- •Fit patient assessed using the comprehensive health status assessment scale (Geriatric Assessment in Hematology, GAH scale, annex 11) (0-94 points GAH scale). Patients with a punctuation ≤42 will be included.
- •Signed informed consent
- •Patients must have measurable disease, defined as follows:
- •For secretory Multiple Myeloma, measurable disease is defined as the presence of quantifiable monoclonal component, ≥ 0.5 g/dL or, the urine light chains excretion is 200 mg/24h or higher.
- •For poor secretory or non secretory Multiple Myeloma, the level of the affected serum free light chain must be ≥ 10 mg/dL (≥ 100 mg/L, with an abnormal free light-chain ratio)
- •Eastern Cooperative Oncology Group (ECOG) Performance status ≤2
- •Life expectancy more than 3 months
- •Adequate organ functions:
- •Platelet count ≥ 50000/mm3, hemoglobin ≥ 8 g/dl and absolute neutrophil count ≥ 1000/mm
- •Lower values are allowed only if they are due to BM infiltration.
- •Aspartate Transaminase (AST) and Alanine Transaminase (ALT) ≤ 2.5 x Upper Limit of Normal.
- •Total bilirubin: ≤2 x Upper Limit of Normal. Serum creatinine ≤ 2 mg/dl. Calcium ≤14mg/dl or corrected serum calcium ≤14mg/dl in patients whose albumin level is out of range Left ventricle ejection fraction ≥ 40%
- •At the discretion of the investigator patient must be able to adhere to all study requirements.
- •Male patients that receives lenalidomide should commit to use of a condom while taking the study drug every time he has sexual contact with a pregnant female of female of childbearing potential even if he has undergone a successful vasectomy; or practice complete abstinence (when this is the preferred and usual lifestyle of the subject); including during periods of dose interruptions and for at least 30 days after treatment completion. Also males under lenalidomide should commit not to donate semen or sperm during study drug treatment, including during periods of dose interruptions, and for at least 90 days after treatment completion.
- •NOTE: Given the age of patients to be included on this Clinical Trial (between 65 and 80 years, both included), there is no possibility of Females of Childbearing Potential (FCBP), therefore the Pregnancy Prevention Program (annex 12) has been modified accordingly.
排除标准
- •Patients older than 81 years or younger than 65
- •Patients that do not qualify for fit according to the GAH scale (annex 11) (>43 points GAH scale)
- •Patients who have previously received treatment for multiple myeloma, except for steroid pulses in case of emergency, the administration of bisphosphonates or antialgesic radiotherapy or due to the presence of plasmacytomas requiring some emergency.
- •Men who does not agree to use a condom every time he has sexual contact with a pregnant female or female of childbearing potential, even if he has undergone a successful vasectomy, or men who does not agree to practice complete abstinence (if this is the preferred and usual lifestyle of the subject).
- •Left ventricular ejection fraction <40% Prior history of malignancies, other than multiple myeloma (except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or the breast), unless the patient has been free of the disease for ≥ 5 years.
- •Other relevant diseases or adverse clinical conditions:
- •Myocardial infarction within the 6 months prior to inclusion in the clinical trial A NYHA functional class III-IV, heart failure, uncontrolled angina, uncontrolled ventricular arrhythmia or acute ischemia detected electrocardiographically or conduction system anomalies.
- •History of significant neurological or psychiatric disorders. Active infection. Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis).
- •Poorly controlled arterial hypertension. Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form.
- •Human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive or active hepatitis C infection
- •Limitation of the patient's ability to comply with the treatment or follow-up protocol.
- •Uncontrolled endocrine diseases (i.e. diabetes mellitus, hypothyroidism or hyperthyroidism) (i.e. requiring relevant changes in medication within the last month, or hospital admission within the last 3 months).
- •Patients having a peripheral neuropathy ≥ Grade 2 within the 14 days prior to inclusion.
- •Known hypersensibility to any of the study drugs or their excipients.
- •Patients treated with any investigational drug during the previous 30 days.
- •Patients with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
- •Patients who are unable or unwilling to undergo antithrombotic therapy.
- •Patients with severe chronic obstructive pulmonary disease (COPD) or asthma with forced expiratory volume in the first minute (FEVI) less than 50%.
研究组 & 干预措施
VMP x 9 + Lenalidomida-dexamethasone x 9
Bortezomib-melfalán-prednisone. Melfalán: 9mg/m2D1-4. Prednisone: 60mg/m2D1-4. Bortezomib: 1.3mg/m2 One 6 week cycleD1, 4, 8, 11, 22, 25, 29 and 32; followed by eight4-week cycleD1, 8, 15 and 22 Lenalidomida-dexametasona at low dose
干预措施: Lenalidomide. (Drug)
VMP x 9 + Lenalidomida-dexamethasone x 9
Bortezomib-melfalán-prednisone. Melfalán: 9mg/m2D1-4. Prednisone: 60mg/m2D1-4. Bortezomib: 1.3mg/m2 One 6 week cycleD1, 4, 8, 11, 22, 25, 29 and 32; followed by eight4-week cycleD1, 8, 15 and 22 Lenalidomida-dexametasona at low dose
干预措施: Bortezomib (Drug)
VMP x 9 + Lenalidomida-dexamethasone x 9
Bortezomib-melfalán-prednisone. Melfalán: 9mg/m2D1-4. Prednisone: 60mg/m2D1-4. Bortezomib: 1.3mg/m2 One 6 week cycleD1, 4, 8, 11, 22, 25, 29 and 32; followed by eight4-week cycleD1, 8, 15 and 22 Lenalidomida-dexametasona at low dose
干预措施: Dexamethasone (Drug)
VMP x 9 + Lenalidomida-dexamethasone x 9
Bortezomib-melfalán-prednisone. Melfalán: 9mg/m2D1-4. Prednisone: 60mg/m2D1-4. Bortezomib: 1.3mg/m2 One 6 week cycleD1, 4, 8, 11, 22, 25, 29 and 32; followed by eight4-week cycleD1, 8, 15 and 22 Lenalidomida-dexametasona at low dose
干预措施: Prednisone (Drug)
VMP x 9 + Lenalidomida-dexamethasone x 9
Bortezomib-melfalán-prednisone. Melfalán: 9mg/m2D1-4. Prednisone: 60mg/m2D1-4. Bortezomib: 1.3mg/m2 One 6 week cycleD1, 4, 8, 11, 22, 25, 29 and 32; followed by eight4-week cycleD1, 8, 15 and 22 Lenalidomida-dexametasona at low dose
干预措施: Melphalan (Drug)
Carfilzomib-lenalidomida-dexamethasone regimen
carfilzomib: 1 st cycle: 20mg/m2 day 1 and 36 mg/m2 days 2, 8, 9 & 15, 16. 2nd cycle: 36 mg/m2 days 1, 2, 8, 9 & 15, 16. Cycles 3-18: 56 mg/m2 days 1, 8 & 15.Lenalidomida: 25 mg, d1-21 Dexamethasone : 40 mg, d1, 8, 15, 2218 28-day cycle
干预措施: Lenalidomide. (Drug)
Carfilzomib-lenalidomida-dexamethasone regimen
carfilzomib: 1 st cycle: 20mg/m2 day 1 and 36 mg/m2 days 2, 8, 9 & 15, 16. 2nd cycle: 36 mg/m2 days 1, 2, 8, 9 & 15, 16. Cycles 3-18: 56 mg/m2 days 1, 8 & 15.Lenalidomida: 25 mg, d1-21 Dexamethasone : 40 mg, d1, 8, 15, 2218 28-day cycle
干预措施: Carfilzomib (Drug)
Carfilzomib-lenalidomida-dexamethasone regimen
carfilzomib: 1 st cycle: 20mg/m2 day 1 and 36 mg/m2 days 2, 8, 9 & 15, 16. 2nd cycle: 36 mg/m2 days 1, 2, 8, 9 & 15, 16. Cycles 3-18: 56 mg/m2 days 1, 8 & 15.Lenalidomida: 25 mg, d1-21 Dexamethasone : 40 mg, d1, 8, 15, 2218 28-day cycle
干预措施: Dexamethasone (Drug)
Carfilzomib-lenalidomida-dexamethason with daratumumab
Carfilzomib: 1 st cycle: 20mg/m2 day 1 and 36 mg/m2 days 2, 8, 9 & 15, 16. 2nd cycle: 36 mg/m2 days 1, 2, 8, 9 & 15, 16. Cycles 3-18: 56 mg/m2 days 1, 8 & 15. Lenalidomida: 25 mg, d1-21 Dexamethasone: 40 mg, d1, 8, 15, 22. Daratumumab 1800mg SC Days 1, 8, 15, 22 of cycles 1-2; Days 1 and 15 of cycles 3 and 4; Day 1 of cycles 5 to 18
干预措施: Lenalidomide. (Drug)
Carfilzomib-lenalidomida-dexamethason with daratumumab
Carfilzomib: 1 st cycle: 20mg/m2 day 1 and 36 mg/m2 days 2, 8, 9 & 15, 16. 2nd cycle: 36 mg/m2 days 1, 2, 8, 9 & 15, 16. Cycles 3-18: 56 mg/m2 days 1, 8 & 15. Lenalidomida: 25 mg, d1-21 Dexamethasone: 40 mg, d1, 8, 15, 22. Daratumumab 1800mg SC Days 1, 8, 15, 22 of cycles 1-2; Days 1 and 15 of cycles 3 and 4; Day 1 of cycles 5 to 18
干预措施: Carfilzomib (Drug)
Carfilzomib-lenalidomida-dexamethason with daratumumab
Carfilzomib: 1 st cycle: 20mg/m2 day 1 and 36 mg/m2 days 2, 8, 9 & 15, 16. 2nd cycle: 36 mg/m2 days 1, 2, 8, 9 & 15, 16. Cycles 3-18: 56 mg/m2 days 1, 8 & 15. Lenalidomida: 25 mg, d1-21 Dexamethasone: 40 mg, d1, 8, 15, 22. Daratumumab 1800mg SC Days 1, 8, 15, 22 of cycles 1-2; Days 1 and 15 of cycles 3 and 4; Day 1 of cycles 5 to 18
干预措施: Daratumumab (Drug)
Carfilzomib-lenalidomida-dexamethason with daratumumab
Carfilzomib: 1 st cycle: 20mg/m2 day 1 and 36 mg/m2 days 2, 8, 9 & 15, 16. 2nd cycle: 36 mg/m2 days 1, 2, 8, 9 & 15, 16. Cycles 3-18: 56 mg/m2 days 1, 8 & 15. Lenalidomida: 25 mg, d1-21 Dexamethasone: 40 mg, d1, 8, 15, 22. Daratumumab 1800mg SC Days 1, 8, 15, 22 of cycles 1-2; Days 1 and 15 of cycles 3 and 4; Day 1 of cycles 5 to 18
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Efficacy in terms of numbers of compleat responses
时间窗: 18 months
Rate of immunophenotypic complete responses at 18 months, of the standard treatment in Spain for newly diagnosed multiple myeloma patients not candidates to stem cell transplantation,
次要结局
未报告次要终点