Carfilzomib, Lenalidomide, and Dexamethasone Re-induction Followed by the 2nd ASCT in Multiple Myeloma Patients Relapsed After the 1st ASCT

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of salvage treatment with carfilzomib/lenalidomide/dexamethasone (KRD) followed by 2nd autologous stem cell transplantation (ASCT) and lenalidomide maintenance in patients with relapsed myeloma after 1st ASCT.

Detailed Description
-----------------
This is a single-arm phase II study to assess the efficacy and safety of KRD followed by 2nd ASCT - lenalidomide maintenance for 18 months in patients with relapsed multiple myeloma after 1st ASCT who are 70 years of age or younger. A total of 58 participants will be recruited. As a re-induction therapy 6 cycles of KRD (K, 27mg/m2, D1,2,8,9,15,16; R, 25 mg, D1-21; D, 40mg weekly, every 28 days) will be administered. If a patient achieves at least partial response, 2nd ASCT + lenalidomide 10mg for 18 months will be proceeded. Study will be continued until disease progression, unacceptable toxicity, or completion of pre-planned schedule. Response will be assessed using the International Myeloma Working Group(IMWG) response criteria and the safety profiles will be described using the NCI-CTCAE v5.0. Participants who discontinue therapy will be followed every 3 months for 3 years if they are on subsequent treatment, disease-free or dead.

Official Title
-----------------
Phase II, Single-arm Trial of Carfilzomib, Lenalidomide, and Dexamethasone Re-induction Followed by the 2nd ASCT in Multiple Myeloma Patients Relapsed After the 1st ASCT

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Lenalidomide maintenance


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 20 70 Progressive disease after 1st ASCT Duration of response after 1st ASCT > 12 months Measurable disease (+) Serum M-protein ≥ 1 g/dL Urine M-protein ≥ 200 mg/24 hr Serum Free Light Chain(FLC) assay: involved FLC level ≥10 mg/dL (serum Free Light Chain ratio is abnormal) Adequate organ function for induction & ASCT Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L Platelets ≥ 50 x 109/L (≥ 30 x 109/L if myeloma involvement is > 50% in the bone marrow) Hemoglobin ≥ 8.0 g/dL Creatinine clearance ≥ 30 mL/minute Serum Bilirubin ≤ 1.5 x upper limit of normal Aspartate aminotransferase(AST) and Alanine aminotransferase(ALT) ≤ 3 x upper limit of normal Eastern Cooperative Oncology Group performance scale 0 2 Survival expectancy > 3 months Adequately controlled hepatitis B(HBV) & hepatitis C(HCV) Written informed consent Optimal contraceptions Exclusion Criteria: Prior refractoriness or intolerance to carfilzomib Prior refractoriness or intolerance to lenalidomide/dexamethasone Any treatment after progressive disease after 1st ASCT. High-dose dexamethasone or palliative radiation is permitted. Waldenstroem's macroglobulinemia, POEMS syndrome, or plasma cell leukemia Pregnant or nursing lactating women Myocardial infarct within 6 months, heart failure of New York Heart Association(NYHA) Class III IV, uncontrolled ventricular arrhythmia, severe coronary arterial obstructive disease Uncontrolled hypertension (Defined as an average systolic blood pressure >= 160 mmHg or diastolic >= 100 mmHg) or diabetes Grade 3 4 neuropathy HIV infection Severe or uncontrolled medical conditions, laboratory abnormalities, or psychiatric disorders that may preclude the participation of the study by the physician's discretion Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment Diagnosis of other malignant disease other than myeloma within 5 year. Exceptions are properly treated non-melanomatous skin cancers, cervical intraepithelial neoplasia, prostate cancer that do not require treatment, or properly excised well-differentiated thyroid cancers

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm of Lenalidomide maintenance<br>[KRd #1 6, Every 4 weeks] D1, 2, 8, 9, 15,16 Carfilzomib 20mg/m2 + 5% dextrose in water 50 mL over 10 mins (From Cycle1Day8 27mg/m2) D1 - 21 Lenalidomide 25mg P.O. D1, 8, 15, 22 Dexamethasone 40mg IV or PO [Autologous stem cell transplantation phase] [Lenalidomide maintenance phase, Every 4 weeks] D1-28 Lenalidomide 10 mg | Drug: Lenalidomide maintenance<br>* Lenalidomide maintenance after carfilzomib, lenalidomide, and dexamethasone re-induction followed by the 2nd ASCT.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year progression free survival rate | percentage of patients who are disease free or alive at 2-years | 2-years after the written consent | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate after KRd #6 | percentage of patients who achieve complete response | total 6 cycles (each cycle is 28 days) of induction therapy | 
| Complete response rate after ASCT | percentage of patients who achieve complete response | at the time of 2nd ASCT (within 60 days after ASCT) | 
| Overall response rate | percentage of patients who achieve at least partial response | assessed for approximately 3 years after administration | 
| Time to response | from the time of written consent to the time of achieving at least partial response | assessed for approximately 3 years after administration | 
| Duration of response | from the time of achieving at least partial response to the time of progressive disease | assessed for approximately 3 years after administration | 
| Overall survival | from the time of written consent to the time of death or last follow-up | assessed for approximately 3 years after administration | 
| Safety of KRd induction therapy, 2nd ASCT, and lenalidomide maintenance therapy | treatment-emergent adverse events | assessed for approximately 2 years during administration | 
| Rate of the successful stem cell harvest | percentage of patients who collected cluster of differentiation(CD34+) hematopoietic stem cells > 2 x 10^6 cells/kg | total 6 cycles (each cycle is 28 days) of induction therapy |