A Study of VRd-based Regimen Combined With CART-ASCT-CART2 Treatment in NDMM Patients With P53 Abnormalities

VRd-based Regimen 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

This is a single-arm, open-label study to evaluate the efficacy and safety of VRD(Bortezomib, Lenalidomide and Dexamethasone)-based regimen combined with CART-ASCT-CART2 in patients with newly diagnosed multiple myeloma with p53 gene abnormalities.

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Biological: anti-BCMA CAR-T; Drug: VRD-based Regimen

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 VRd (short for Bortezomib, Lenalidomide, Dexamethasone)-based 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 VRd-based regimen followed by a first infusion of CAR-T cells. Patients then received 3 courses of consolidation therapy, followed by ASCT and second infusion of CAR-T cells. R maintenance therapy starts on day 100 after ASCT

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gang An, PhD&MD; Phone Number: 86-022-23909171; Email: angang@ihcams.ac.cn

Study Locations

• China
  • Tianjin, China
    • Recruiting
    • Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences
    • Contact: Gang An, PhD&MD; Phone Number: 008613502181109; Email: angang@ihcams.ac.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Willing and able to give written informed consent (ICF) .
2. Age ≥ 18 years and ≤ 65 years.
3. 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)
4. 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.

5. 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
6. 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.
7. ECOG scores 0 - 1;
8. No active infection
9. 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).
10. normal pulmonary function and oxygen saturation ≥ 92% on room air.
11. 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%)
12. Patients must be able to take prophylactic anticoagulant therapy as recommended by the study.
13. 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.
14. Willing and able to complete the study procedures and follow-up examinations.

Exclusion Criteria:

1. Plasma cell leukemia.
2. Documented active amyloidosis.
3. Multiple myeloma with central nervous system (CNS) invasion
4. Unsuitable for autologous stem cell transplantation, such as severe cardiopulmonary disorders
5. 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
6. Known intolerance, hypersensitivity, or contraindication to BCMA-CART cellular products.

7. 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.
8. Known positive serology for HIV or HIV seropositivity.
9. 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
10. Life expectancy of <3 months
11. Women who are pregnant or breastfeeding
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. 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.
14. Received live attenuated vaccine within 4 weeks prior to study treatment.
15. 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.
16. Necessary medication or supportive therapy is contraindicated with study treatment.
17. Any diseases or complications that may interfere with the study.
18. Patients are not willing to or cannot comply with study scheme.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: VRD-based Regimen Combined With CART-ASCT-CART2; Autologous BCMA-directed CAR-T cells, Double infusion intravenously at a target dose of 2-4 x 10^6 anti-BCMA CAR+T cells/kg respectively. Participants will receive VRD-based regimen induction, first CAR-T infusion, 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; Autologous BCMA-directed CAR-T cells, double infusion intravenously at a target dose of 2.0-4.0 x 10^6 anti-BCMA CAR+T cells/kg.; Drug: VRD-based Regimen; Bortezomib, Lenalidomide and Dexamethasone

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The CART cell duration in vivo	The copies of BCMA-CART DNA in peripheral blood with qPCR method	1 year

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2023
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: April 28, 2023
• First Submitted That Met QC Criteria: May 8, 2023
• First Posted (Actual): May 9, 2023

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 17, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell
• Other Study ID Numbers: CAC-MM-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes