BACKGROUND:
* Multiple myeloma (MM) is a malignancy of plasma cells.
* MM is nearly always incurable.
* T cells can be genetically modified to express chimeric antigen receptors (CARs) that specifically target malignancy-associated antigens.
* Autologous T cells genetically modified to express CARs targeting the B-cell antigen cluster of differentiation 19 (CD19) have caused complete remissions in a small number of patients with leukemia or lymphoma. These results demonstrate that CAR-expressing T cells have anti-malignancy activity in humans.
* B-cell maturation antigen (BCMA) is a protein expressed by normal plasma cells and the malignant plasma cells of multiple myeloma.
* BCMA is not expressed by normal cells except for plasma cells and some mature B cells.
* We have constructed an anti-BCMA CAR that can specifically recognize BCMA-expressing target cells in vitro and eradicate BCMA-expressing tumors in mice.
* Anti-BCMA-CAR-expressing T cells have not been previously tested in humans.
* We hypothesize that anti-BCMA-CAR-expressing T cells will specifically eliminate
BCMA-expressing MM cells in patients
-Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and neurological toxicities. Elimination of normal plasma cells and unknown toxicities are also possible.
OBJECTIVES:
Primary
-Determine the safety and feasibility of administering T cells expressing an anti- BCMA CAR to patients with MM.
Secondary
* Evaluate the in vivo persistence of anti-BCMA CAR T cells
* Assess for evidence of anti-myeloma activity by anti-BCMA CAR T cells
ELIGIBILITY
* Patients must have measurable MM defined as a serum M-protein greater than or equal to 0.4 g/dL or a urine M-protein greater than or equal to 200 mg/24 hours or an involved serum free light chain (FLC) level greater than or equal to 10 mg/dL (provided FLC ratio is abnormal) or a biopsy-proven plasmacytoma.
* Patients must have previously received at least 3 different treatment regimens for MM.
* Patients must have a normal creatinine and a normal cardiac ejection fraction.
* An Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2 is required.
* Patients on any anticoagulant medications except aspirin are not eligible.
* No active infections are allowed.
* Absolute neutrophil count greater than or equal to 1000/ L, platelet count greater than or equal to 45,000/ L, hemoglobin greater than or equal to 8g/dL
* Alanine aminotransferase (ALT) and aspartate transaminase (AST) less than or equal to 2.5-fold higher than the upper limit of normal
* At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids) and the required leukapheresis.
* At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids) and initiation of protocol treatment.
* Bone marrow plasma cells must be 30% or less of total bone marrow cells 30 days or less prior to the start of protocol treatment.
* The patient's MM will need to be assessed for BCMA expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (NIH). If unstained, paraffinembedded bone marrow or plasmacytoma sections are available from prior biopsies, these can be used to determine BCMA expression by immunohistochemistry; otherwise patients will need to come to the NIH for a bone marrow biopsy or other biopsy of a plasmacytoma to determine BCMA expression. The sample for BCMA expression can come from a biopsy obtained at any time before enrollment.
DESIGN:
* This is a phase I dose-escalation trial
* Patients will undergo leukapheresis
* T-cells obtained by leukapheresis will be genetically modified to express an anti- BCMA CAR
* Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the intent of enhancing the activity of the infused anti-BCMA-CAR-expressing T cells.
* The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m\^2 daily for 3 days and fludarabine 30 mg/m\^2 daily for 3 days. Fludarabine will be given on the same days as the cyclophosphamide.
* Two days after the chemotherapy ends, patients will receive an infusion of anti- BCMA-CAR-expressing T cells.
* The initial dose level of this dose-escalation trial will be 0.3x10\^6 CAR+ T cells/kg of recipient bodyweight.
* The cell dose administered will be escalated until a maximum tolerated dose is determined for patients in which less than 50% of total bone marrow cells are plasma cells.
With Amendment C, all patients with 50% or greater bone marrow plasma cells will receive 3x10(6) anti-BCMA CAR T cells/kg.
* Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to monitor for toxicity.
* Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 4, 6, 9, and 12 months after the CAR T-cell infusion.
* Repeat treatments are possible for patients with residual MM and no greater than grade 2 toxicity with an initial treatment.
* Re-enrollment will be allowed for a small number of subjects.
