CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
2. Age ≥ 18 years and ≤ 65 years.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.
4. Life expectancy at least 3 months
5. Definitive diagnosis of pPCL: meet the diagnosis criteria of multiple myeloma (refer to the Chinese guidelines for the diagnosis and management of multiple myeloma (revised 2022) criteria) and meeting any of the following:

   1. the proportion of tumor plasma cells in peripheral blood leukocytes ≥ 5%;
   2. absolute value of peripheral blood tumorigenic plasma cells exceeds 2×10\^9/L.
6. Patients have not received previous anti-myeloma related therapy.
7. Measurable disease, as defined by at lease one of the following:

   1. Serum monoclonal paraprotein (M-protein) level ≥5g/L.
   2. urine M-protein level ≥200 mg/24 hours.
   3. If the serum and urine M-protein are unmeasurable, abnormal serum free light chain (FLC) ratio and affected FLC ≥10 mg/dL.
8. Bone marrow sample is confirmed as BCMA-positive by flow cytometry or pathological examination.
9. 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) : ANC ≥ 1.0 x 10\^9/L, PLT ≥ 50 x 10\^9/L.
10. 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:

    1. Total bilirubin\<1.5 x upper limit of normal (ULN);
    2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST);
    3. Creatinine clearance ≥ 50mL/min (calculated using Cockroft-Gault formula).
11. Patients must be able to take prophylactic anticoagulant therapy as recommended by the study.
12. 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.
13. Willing and able to complete the study procedures and follow-up examinations.

Exclusion Criteria:

1. Secondary plasma cell leukemia.
2. With central nervous system (CNS) involvement.
3. Ineligible for autologous stem cell transplantation, such as severe cardiopulmonary disorders.
4. Known intolerant, allergic, or resistant to glucocorticoids, bortezomib, lenalidomide, Venetoclax, Selinexor and BCMA-CART cellular products.
5. Patients 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.
6. Patients with unstable or active cardiovascular system disease, meeting any of the following:

   1. Unstable angina pectoris, symptomatic myocardial ischaemia, myocardial infarction or coronary artery reconstruction within 180 days prior to the first dose.
   2. Uncontrolled hypertension (\>140/90 mmHg with blood pressure fluctuations of more than 180/100 mmHg over a 6-month period).
   3. 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)).
   4. Congestive heart failure (CHF) classification ≥ grade 3 as defined by the New York Heart Association (NYHA).
   5. Left ventricular ejection fraction (LVEF) \<50% on echocardiography.
   6. History of stroke or intracranial haemorrhage within 12 months prior to screening.
   7. Presence of a serious thrombotic event prior to treatment.
7. Known positive serology for HIV or HIV seropositivity.
8. 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.
9. Ongoing active infection.
10. Prior history of malignancies, unless free of the disease for ≥ 5 years.
11. Pregnant or breast feeding females.
12. 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.
13. According to the researcher's judgment, 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.
14. Necessary medication or supportive therapy is contraindicated with study treatment.
15. Any other medical condition or comorbidity that might interfere with subject's participation.
16. Patients undergoing other experimental therapies.
17. Patients are not willing to or cannot comply with study scheme.

主要终点：Safety and Tolerability · The incidence of treatment-emergent adverse events (TEAEs) · 2 year；Overall response rate (ORR) · ORR(including sCR / CR / VGPR / PR, based on IMWG criteria) · after induction therapy, 1 month after the first CAR-T cell transfusion, the consolidation therapy ends, 6 months after the second CAR-T cell transfusion；Progression free survival (PFS) · Is defined as time from first induction date to first documentation of PD, or death due to any cause, whichever occurs first. · 1 year
次要终点：Complete response rate (CRR)；Overall survival (OS)；MRD-negative Rate；Duration of Remission (DOR)

• VRD-based regimen Combined CART-ASCT-CART2 · EXPERIMENTAL · VRD：Bortezomib, Lenalidomide and Dexamethasone 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 (2-4)±20％ x 10\^6 anti-BCMA CAR+T cells/kg respectively. Participants will receive VRD-based induction, first CAR-T infusion, VR consolidation, ASCT followed by the second CAR-T infusion, and R maintenance.

This is a single-arm, open-label study to evaluate the efficacy and safety of VRD-based Regimen (Bortezomib, Lenalidomide and Dexamethasone) combined with CART-ASCT-CART2 in Chinese patients with newly diagnosed primary plasma cell leukemia.