A Study of X-VRD Combined With CART-ASCT-CART2 Treatment in NDMM Patients With P53 Abnormalities

Study Overview
=================
Brief Summary
-----------------
This is a single-arm, open-label study to evaluate the efficacy and safety of XVRD(Selinexor, Bortezomib, Lenalidomide and Dexamethasone) regimen combined with CART-ASCT-CART2 in Chinese patients with newly diagnosed multiple myeloma with p53 gene abnormalities.

Detailed Description
-----------------
The study is a prospective, single-arm, single-centre, phase II study designed to evaluate the efficacy and safety of treatment with the XVRd (short for Selinexor, Bortezomib, Lenalidomide, Dexamethasone) regimen in combination with the CART-ASCT-CART2 in newly diagnosed multiple myeloma patients with P53 gene abnormalities. Patients received 3 courses of induction therapy with X-VRd followed by a first infusion of CAR-T cells. Patients then received 3 courses of XVR consolidation therapy, followed by ASCT and second infusion of CAR-T cells. XR maintenance therapy starts on day 100 after ASCT

Official Title
-----------------
Selinexor Plus VRd Combined With CART-ASCT-CART2 as First-line Therapy for Newly Diagnosed Multiple Myeloma Patients With P53 Abnormalities：a Prospective, One-arm, Single-center Phase II Study

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

Intervention / Treatment
-----------------
* Biological: anti-BCMA CAR-T
* Drug: Selinexor-VRD


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Willing and able to give written informed consent (ICF) . Age ≥ 18 years and ≤ 65 years. Meet the internationally accepted Criteria for the diagnosis of newly diagnosed multiple myeloma (Chinese guidelines for the diagnosis and management of multiple myeloma (revised in 2022) criteria) Patients have not received previous anti-multiple myeloma-related chemotherapy, have not received previous extensive pelvic radiotherapy (more than half of the pelvic area), and have not received previous anti-multiple myeloma hormone therapy, except for those who have used hormones for no more than 14 days for symptom control. The patient have one or more measurable multiple myeloma lesion, must include one of the following conditions: Serum M protein≥1.0 g/dL(10g/L) Urine M protein≥200 mg/24h Serum free light chain(sFLC): κ/λ FLC ratio is abnormal and affected FLC ≥10mg / dL p53 gene abnormalities: Plasma cells were enriched by CD138 immunomagnetic and then detected by FISH. Cut-off ≥20%., or P53 mutation by second-generation sequencing. Bone marrow sample is confirmed as BCMA-positive by flow cytometry or pathological examination; ECOG scores 0 - 1; No active infection All screening blood biochemistry: tests should be performed according to the protocol and within 14 days before enrollment. Screening laboratory values must meet the following criteria： a.TBIL<1.5 x upper limit of normal (ULN) (<3 x ULN in patients with Gilbert's syndrome); b.AST and ALT <3 x ULN.; c. Creatinine clearance ≥ 60mL/min (calculated using Cockroft-Gault formula). 12)normal pulmonary function and oxygen saturation ≥ 92% on room air. 13) Routine blood tests (performed within 7 days, no RBC transfusion, no G-CSF/GM-CSF/platelet agonists, no drug correction within 14 days before screening, no PLT transfusion within 7 days) : WBC ≥ 1.5 x 109/L, ANC ≥ 1.0 x 109/L, Hb ≥ 85 g/L PLY ≥ 75 x 109/L (if BMPC < 50%) or PLT ≥ 50 x 109/L (if BMPC ≥ 50%) 14) Patients must be able to take prophylactic anticoagulant therapy as recommended by the study. 15) The woman is not breastfeeding, is not pregnant and agrees not to be pregnant during the study period and for the following 12 months. Male patients agreed that their spouse would not become pregnant during the study period and for 12 months thereafter. 18) Willing and able to complete the study procedures and follow-up examinations. Exclusion Criteria: Plasma cell leukemia. Documented active amyloidosis. Multiple myeloma with central nervous system (CNS) invasion Unsuitable for autologous stem cell transplantation, such as severe cardiopulmonary disorders Prior exposure to selective inhibitors of nuclear export (SINE) compounds, including Selinexor. Patients with peripheral neuropathy greater than grade 2 or peripheral neuropathy greater than grade 2 with pain at baseline, regardless of whether they were currently receiving medical therapy Known intolerance, hypersensitivity, or contraindication to glucocorticoids, bortezomib, lenalidomide, Selinexor and BCMA-CART cellular products. Patients with unstable or active cardiovascular system disease, meeting any of the following: Unstable angina pectoris, symptomatic myocardial ischaemia, myocardial infarction or coronary artery reconstruction within 180 days prior to the first dose. Uncontrolled hypertension (>140/90 mmHg with blood pressure fluctuations of more than 180/100 mmHg over a 6-month period). Uncontrolled and clinically significant conduction abnormalities (e.g. patients with ventricular arrhythmias controlled by antiarrhythmic medication), not excluding patients with 1st degree atrioventricular (AV) block or asymptomatic left anterior bundle branch block/right bundle branch block (LAFB/RBBB)). Congestive heart failure (CHF) classification ≥ grade 3 as defined by the New York Heart Association (NYHA). Left ventricular ejection fraction (LVEF) <50% on echocardiography. History of stroke or intracranial haemorrhage within 12 months prior to screening. Presence of a serious thrombotic event prior to treatment. Known positive serology for HIV or HIV seropositivity. Active hepatitis B or C infection. Screening requires serologic testing for hepatitis. If hepatitis B surface antigen and hepatitis B core antibody were positive, a negative DNA polymerase chain reaction (PCR) result was needed before enrollment (after anti-hepatitis B therapy, a negative DNA polymerase PCR result was confirmed before enrollment). If the hepatitis C antibody was positive, the RNA PCR test should be negative prior to enrollment Life expectancy of <3 months Women who are pregnant or breastfeeding Any active gastrointestinal dysfunction that affects the patient's ability to swallow tablets, or any active gastrointestinal dysfunction that may affect the absorption of the studied treatment medication Subjects had major surgery within 2 weeks before randomization (for example, general anesthesia), or is not fully recovered from the surgery, or surgery is arranged during study period. Received live attenuated vaccine within 4 weeks prior to study treatment. According to the researcher's judgement, any condition including but not limited to serious mental illness, medical illness or other symptoms/conditions that may affect study treatment, compliance, or the capability of providing informed consent. Necessary medication or supportive therapy is contraindicated with study treatment. Any diseases or complications that may interfere with the study. Patients are not willing to or cannot comply with study scheme.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 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: X-VRD Combined With CART-ASCT-CART2<br>X-VRD：Selinexor Plus Bortezomib, Lenalidomide and Dexamethasone Selinexor 60mg oral on day 1,8,15,22 for 28-days cycles. Bortezomib SC 1.3mg/sqm on day 1,8,15,22, Lenalidomide oral 25 mg on day 1-21, and Dexamethasone 40mg on day 1,8,15,22 in a 28-day cycle. Autologous BCMA-directed CAR-T cells, Double infusion intravenously at a target dose of 2 x 10^6 anti-BCMA CAR+T cells/kg respectively. Participants will receive XVRD induction, first CAR-T infusion,XVR consolidation, ASCT and second CAR-T infusion. Maintenance therapy was initiated on day 100 and entered the follow-up period, | Biological: anti-BCMA CAR-T<br>* Autologous BCMA-directed CAR-T cells, double infusion intravenously at a target dose of 2.0 x 10^6 anti-BCMA CAR+T cells/kg.<br>Drug: Selinexor-VRD<br>* Selinexor Plus Bortezomib, Lenalidomide and Dexamethasone<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete response rate (CRR) | CRR(including sCR / CR , based on IMWG 2016 efficacy evaluation criteria) | after induction therapy, 1 month after the first CAR-T cell transfusion, the consolidation therapy ends, 12 months after the second CAR-T cell transfusion | 
| Overall response rate (ORR) | ORR(including sCR / CR / VGPR / PR, based on IMWG 2016 efficacy evaluation criteria) | after induction therapy, 1 month after the first CAR-T cell transfusion, the consolidation therapy ends, 12 months after the second CAR-T cell transfusion | 
| Negative MRD rate | Rate of negative minimal residual disease | after induction therapy, 1 month after the first CAR-T cell transfusion, the consolidation therapy ends, 12 months after the second CAR-T cell transfusion | 
| Overall Survival (OS) | Occurrence of death regardless of cause | 1 year | 
| Progression free survival (PFS) | Duration from start of study treatment to PD or death (regardless of cause), whichever comes first | 1 year | 
| Duration of Remission(DOR) | Duration from the first evaluation of at least partial remission (PR) to the onset of disease progression or death due to disease progression (whichever occurs first) | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of treatment-emergent adverse events (TEAEs) | The incidence of treatment-emergent adverse events (TEAEs) | 2 year |