A Study of Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by BCMA CAR-T Therapy in Transplant-Ineligible Patients With Primary Plasma Cell Leukemia

Study Overview
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Brief Summary
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This is a single-arm, open-label study to evaluate the efficacy and safety of VRD-based regimen combined with BCMA CAR-T in transplant-ineligible patients with primary plasma cell leukemia

Detailed Description
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The study is a prospective, single-arm, single-centre, phase II study designed to evaluate the efficacy and safety of treatment with VRD-based regimen combined with BCMA CAR-T in transplant-ineligible patients with primary plasma cell leukemia. Patients received 3 courses of induction therapy with VRD-based regimen followed by infusion of BCMA CAR-T cells. Patients then received 3 courses of VR consolidation therapy, followed by VR maintenance therapy.

Official Title
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Safety and Efficiency of VRd Combining BCMA CAR-T Regimen for Transplant-ineligible Patients With Primary Plasma Cell Leukemia: a Prospective, Single-arm, Single-center, Phase II Study.

Conditions
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Plasma Cell Leukemia

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years and ≤ 75 years. Participants with documented primary plasma cell leukemia according to IMWG diagnostic criteria (circulating plasma cells ≥5%, determined by morphology on peripheral blood smear; or absolute value of peripheral blood tumorigenic plasma cells exceeds 2×10^9/L). Measurable disease, at screening as defined by any of the following: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or Light chain MM without measurable disease in serum or urine: serum Ig free-light chain (FLC) ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio. Not considered for high-dose chemotherapy with Autologous Stem Cell Transplant (ASCT) due to: Ineligible due to advanced age (≥65); or Ineligible evaluated by researchers; or Eastern Cooperative Oncology Group Performance Status grade of 3 or 4; or Repeated hematopoietic stem cell mobilization failure； or Deferral of high-dose chemotherapy with ASCT as initial treatment. Bone marrow sample is confirmed as BCMA-positive by flow cytometry or pathological examination. 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<2 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 ≥ 30mL/min (calculated using Cockroft-Gault formula). 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 ≥ 70 g/L PLT ≥ 75 x 109/L (if BMPC < 50%) or PLT ≥ 50 x 109/L (if BMPC ≥ 50%). Patients must be able to take prophylactic anticoagulant therapy as recommended by the study. 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. Exclusion Criteria: Documented active amyloidosis. Documented with central nervous system (CNS) invasion. Prior exposure to any BCMA-targeted therapy or CAR-T therapy. 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, and BCMA-CART cellular products. Seropositive for human immunodeficiency virus (HIV) Hepatitis B infection Hepatitis C infection Life expectancy of <6 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 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. 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
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VRD-based Regimen Combined With BCMA CART<br>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, infusion intravenously at a target dose of 2-4 x 10^6 anti-BCMA CAR+T cells/kg. Participants will receive VRD-based induction, BCMA CAR-T infusion, VR consolidation, VR maintenance. | Biological: anti-BCMA CAR-T<br>* Autologous BCMA-directed CAR-T cells, infusion intravenously at a target dose of 2.0-4.0 x 10^6 anti-BCMA CAR+T cells/kg.<br>Drug: VRD-based regimen<br>* Bortezomib, Lenalidomide and Dexamethasone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | The incidence of treatment-emergent adverse events (TEAEs) | Up to 2 year | 
| MRD-negative rate | achieving MRD-negative, as determined by NGS/NGF after consolidation treatment | within 1 week after consolidation treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate (CRR) | CR or better is defined as percentage of participants who achieve a CR response or Stringent Complete Response (sCR) response accoording to the IMWG criteria | within 1 week after induction therapy, 1 month after the CAR-T cell transfusion, within 1 week after consolidation therapy | 
| Progression free survival (PFS) | Progression free survival is defined as the time from the date of diagnosis to the date of first documented PD, as defined in the IMWG criteria, or death due to any cause, whichever occurs first | Up to 2 year | 
| Overall Survival (OS) | Overall survival is measured from the date of diagnosis to the date of the participant's death. | Up to 5 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) | Up to 2 year |