Primary end-point:
2-year progression free survival rate

Secondary end-point:
- Complete response rate after KRd #6
- Complete response rate after ASCT
- Overall response rate
- Time to response
- Duration of response
- Progression free survival
- Overall survival
- Safety profiles
- Rate of the successful stem cell harvest

Brief description of background, hypothesis, and clinical research plan:
Multiple myeloma is the second most common malignant blood disease in the world, especially in Korea. Recent advances in therapeutic performance due to the emergence of new mechanisms and the development of preservative treatments are remarkable, but most patients experience recurrence even after obtaining full coverage through primary care. The treatment of the highest evidence to slow the recurrence is to perform a combination of proteasome inhibitors such as bortezomib and immuno-regulatory drugs (IMiD) such as thalidomide and lentalimomide, and then to be treated primarily by high-capacity melfalan. Despite these treatments, most patients recur, and the development of new treatments for them is imperative. In patients with multiple myeloma that recurred after primary ASCT, secondary ASCT is one of the options. KRd combined therapy is a standard therapy that can be used in patients with multiple myeloma that has recurrent since its effectiveness and safety have been proven, and the benefits have been equally observed in patients who have recurred since the first ASCT. On the other hand, for patients with long periods of time with primary care, it can be assumed that an effective induction therapy called KRd will maximize the benefits of secondary ASCT. In addition, considering that clinical performance has improved compared to KRd alone therapy when KRd and ASCT were performed together in primary care, it is expected that a combination of KRd and ASCT in recurrent patients will be expected to improve clinical performance. Therefore, these test-takers would like to propose a two-phase test for patients under the age of 70 and reoccurring after the first ASCT to implement KRd combined therapy and the second ASCT.

Treatment

[KRd #1-6]
- Patients who have signed the consent form start administering KRd in 21 days.
- Response assessment is conducted every cycle, and if a progressive lesion or intolerable toxicity occurs, the test is rejected and treatment is continued in other cases.
- After a total of 6 cycles of KRd combined therapy, ASCT is performed if a response above the partial response is obtained.
- If there are no stem cells already collected, it is recommended to collect them within 3~4 cycles and at least 2 x 10^6 CD34+ cells/kg should be collected. The administration of sampling protocol, plerixafor, G-CSF, etc. is conducted by the institution and the tester. Delay in KRd-induced anticancer therapy due to hematopoietic stem cell collection is allowed, but it should be resumed as soon as possible according to institutional circumstances.

[Autobiological stem cell transformation paper]
- After the end of the 6th cycle of KRd, proceed with ASCT within 6 weeks.
- Preservative treatment or preservation treatment during the transplant period shall be carried out under the guidance of each institution or the doctor in charge.

[Lenalidomide maintenance paper]
- After the end of ASCT, a reaction assessment is conducted within 60 days, and the administration of lenalidomide maintenance is started within 100 days for patients without progressive diagnosis.
- During the maintenance therapy period, response assessment is performed every cycle for the first 12 months and every 2 cycles until the next 18 months. and if a progressive lesion or intolerable toxicity occurs, the test is rejected and treatment is continued in other cases.
- Maintenance therapy can be administered up to 18 months in total.

[Follow-up period]
- Primary analysis and reporting are conducted when the 27th assessable patient performs a post-ASCT response assessment.
- Secondary analysis and reporting are conducted when all assessable patients conduct a post-ASCT response assessment.
- Final analysis and reporting shall be carried out at the time when all assessable patients are evaluated for two years of inactivity.
- Patients who have completed maintenance should track the condition and survival of the disease every three months for 3years. Patients who are eliminated from this study due to disease progression or adverse reaction shall only track their survival every three months if they receive follow-up treatment, and if they do not receive follow-up treatment, they shall track their condition and survival every three months.

Arm Label

Target Number of Participant

Arm Type

Arm Description

[KRd #1-6]
- Patients who have signed the consent form start administering KRd in 21 days.
- Response assessment is conducted every cycle, and if a progressive lesion or intolerable toxicity occurs, the test is rejected and treatment is continued in other cases.
- After a total of 6 cycles of KRd combined therapy, ASCT is performed if a response above the partial response is obtained.
- If there are no stem cells already collected, it is recommended to collect them within 3~4 cycles and at least 2 x 10^6 CD34+ cells/kg should be collected. The administration of sampling protocol, plerixafor, G-CSF, etc. is conducted by the institution and the tester. Delay in KRd-induced anticancer therapy due to hematopoietic stem cell collection is allowed, but it should be resumed as soon as possible according to institutional circumstances.

[Autobiological stem cell transformation paper]
- After the end of the 6th cycle of KRd, proceed with ASCT within 6 weeks.
- Preservative treatment or preservation treatment during the transplant period shall be carried out under the guidance of each institution or the doctor in charge.

[Lenalidomide maintenance paper]
- After the end of ASCT, a reaction assessment is conducted within 60 days, and the administration of lenalidomide maintenance is started within 100 days for patients without progressive diagnosis.
- During the maintenance therapy period, response assessment is performed every cycle for the first 12 months and every 2 cycles until the next 18 months. and if a progressive lesion or intolerable toxicity occurs, the test is rejected and treatment is continued in other cases.
- Maintenance therapy can be administered up to 18 months in total.

[Follow-up period]
- Primary analysis and reporting are conducted when the 27th assessable patient performs a post-ASCT response assessment.
- Secondary analysis and reporting are conducted when all assessable patients conduct a post-ASCT response assessment.
- Final analysis and reporting shall be carried out at the time when all assessable patients are evaluated for two years of inactivity.
- Patients who have completed maintenance should track the condition and survival of the disease every three months for 3years. Patients who are eliminated from this study due to disease progression or adverse reaction shall only track their survival every three months if they receive follow-up treatment, and if they do not receive follow-up treatment, they shall track their condition and survival every three months.

Gender

Age

Description

1. Age 20~70
2. Progressive disease after 1st ASCT
3. Duration of response after 1st ASCT > 12 months
4. 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)
5. 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
6. Eastern Cooperative Oncology Group performance scale 0~2
7. Survival expectancy > 3 months
8. Adequately controlled hepatitis B(HBV) & hepatitis C(HCV)
9. Written informed consent
10. Optimal contraceptions

1. Prior refractoriness or intolerance to carfilzomib
2. Prior refractoriness or intolerance to lenalidomide/dexamethasone
3. Any treatment after progressive disease after 1st ASCT. High-dose
dexamethasone or palliative radiation is permitted.
4. Waldenstroem’s macroglobulinemia, POEMS syndrome, or plasma cell
leukemia
5. Pregnant or nursing lactating women
6. Myocardial infarct within 6 months, heart failure of New York Heart
Association(NYHA) Class III~IV, uncontrolled ventricular arrhythmia,
severe coronary arterial obstructive disease
7. Uncontrolled hypertension (Defined as an average systolic blood
pressure >= 160 mmHg or diastolic >= 100 mmHg) or diabetes
8. Grade 3~4 neuropathy
9. HIV infection
10. Severe or uncontrolled medical conditions, laboratory abnormalities, or
psychiatric disorders that may preclude the participation of the study by
the physician’s discretion
11. 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
12. 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

2-year progression free survival rate

The point of view of all patients who have obtained the consent form, in which no disease progress or death has occurred for two years.

Complete response rate after KRd #6

The full response rate is calculated as the fraction of patients who have completed the treatment with stringent CR or CR.

Complete response rate after ASCT

The full response rate is calculated as the fraction of patients who have completed the treatment with stringent CR or CR.

Overall response rate

The overall response rate is calculated as the fraction of patients who have obtained sCR, CR, VGPR, or PR throughout the entire treatment period.

Time to response

The time up to the response is defined as the period from the date of the acquisition of the consent to the date of initial acquisition of the response, among patients who have obtained sCR, CR, VGPR, or PR.

Duration of response

The duration of the reaction is defined as the time when the disease progress or death was confirmed from the time the dismantling response was first obtained among patients who obtained sCR, CR, VGPR, or PR.

Progression free survival

The inexhaustible survival period is defined as the period from the date of the acquisition of the agreement to the time of the disease's progression, or death for any cause, or finally to the time when the disease is not progressing or survival is confirmed.

Overall survival

The entire survival period is defined as the period from the date of the acquisition of the consent form to the date of death or the last time the survival was confirmed.

Safety profiles

Safety is assessed only for patients who have received at least one KRd treatment.

Rate of the successful stem cell harvest

The success rate of hematopoietic stem cell collection is defined as the fraction of patients who have collected 2.0 x 106 CD34+ cells/kg or more during the KRd induction therapy period.