PRIMARY OBJECTIVE:
I. To evaluate the safety of adoptive therapy with ex vivo expanded autologous CD8+ plus CD4+
T cells transduced to express a human B cell maturation antigen (BCMA)-targeting chimeric
antigen receptor (CAR) for patients with relapsed or treatment refractory multiple myeloma.
SECONDARY OBJECTIVES:
I. To determine the duration of in vivo persistence and the phenotype of long lived CAR-T
cells.
II. To determine the degree to which adoptively transferred T cells traffic to multiple
myeloma (MM) cells in the bone marrow (BM) and function in vivo.
III. To estimate the antitumor activity of adoptively transferred BCMA-specific
CAR-expressing T lymphocytes (BCMA CAR-T cells).
OUTLINE: This is a dose-escalation study of BCMA-specific CAR-expressing T lymphocytes.
Patients undergo leukapheresis to obtain their immune cells, from which CAR-T cells are
produced. A few weeks later, patients then receive cyclophosphamide and fludarabine on days
-4 to -2. Beginning 36-96 hours after chemotherapy, patients receive BCMA-specific
CAR-expressing T lymphocytes intravenously (IV) over 20-30 minutes on day 0. Patients may
receive a second dose of BCMA-specific CAR-expressing T lymphocytes IV with or without
additional cytoreductive chemotherapy at the discretion of the principal investigator or
their designee (sub-investigator).
After completion of study treatment, patients are followed up at 60, 90, 120, 180, and 365
days and then annually up to 15 years.
Inclusion Criteria:
- Have the capacity to give informed consent
- Eastern Cooperative Oncology Group (ECOG) performance status score =< 2.
- Have measurable disease by International Myeloma Working Group (IMWG) criteria based
on one or more of the following findings:
- Serum M-protein >= 1 g/dL
- Urine M-protein >= 200 mg/24 hour
- Involved serum free light chain (sFLC) level >= 10 mg/dL with abnormal
kappa/lambda ratio
- Measurable biopsy-proven plasmacytomas (>= 1 lesion that has a single diameter >=
2 cm)
- Bone marrow plasma cells >= 30%
- Have a diagnosis of BCMA+ MM (>= 5% BCMA+ by flow cytometry on CD138 co-expressing
plasma cells obtained within 45 days of study enrollment); the MM diagnosis must be
confirmed by internal pathology review of a fresh biopsy specimen at the Fred
Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA)
- Have relapsed or treatment refractory disease with >= 10% CD138+ malignant plasma
cells (IHC) on BM core biopsy, either:
- Following autologous stem cell transplant (ASCT)
- Or, if a patient has not yet undergone ASCT, the individual must:
- Be transplant ineligible, due to age, comorbidity, patient choice, insurance
reasons, concerns of rapidly progressive disease, and/or discretion of
attending physician and principal investigator and,
- Demonstrate disease that persists after > 4 cycles of induction therapy and
that is double refractory (persistence/progression) after therapy with both
a proteasome inhibitor and immunomodulatory drug (IMiD) administered either
in tandem, or in sequence; > 4 cycles of therapy are not required for
patients with a diagnosis of plasma cell leukemia
- Patients receiving retreatment do not need to meet the > 10% CD138+
malignant plasma cells (immunohistochemistry staining method [IHC]) on
BM core biopsy
- Male and female patients of reproductive potential must be willing to use an effect
contraceptive method before, during, and for at least 4 months after the CAR T cell
infusion
Exclusion Criteria:
- History of another primary malignancy that requires intervention beyond surveillance
or that has not been in remission for at least 1 year (the following are exempt from
the 1 year limit: non-melanoma skin cancer, curatively treated localized prostate
cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion
on papanicolaou [PAP] smear)
- Active hepatitis B, hepatitis C at the time of screening
- Patients who are (human immunodeficiency virus [HIV]) seropositive
- Subjects with uncontrolled active infection
- > 1 hospital admission (lasting 5 days or more) for documented infection in prior 6
months
- Presence of acute or chronic graft-versus-host disease (GVHD) requiring active
treatment unless limited to skin involvement and managed with topical steroid therapy
alone
- History of any one of the following cardiovascular conditions within the past 6
months: Class III or IV heart failure as defined by the New York Heart Association
(NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or
other clinically significant cardiac disease as determined by the principal
investigator (PI) or designee
- History of clinically relevant or active central nervous system (CNS) pathology such
as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia,
Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis, active
central nervous system MM involvement and/or carcinomatous meningitis; subjects with
previously treated central nervous systems involvement may participate, provided they
are free of disease in the CNS (documented by flow cytometry performed on the
cerebrospinal fluid [CSF] within 14 days of enrollment) and have no evidence of new
sites of CNS activity
- Pregnant or breastfeeding females
- Allogeneic HSCT or donor lymphocyte infusion within 90 days of leukapheresis.
- Use of any of the following:
- Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or
equivalent) within 7 days prior to leukapheresis; physiologic replacement,
topical, and inhaled steroids are permitted
- Cytotoxic chemotherapeutic agents within 1 week of leukapheresis; oral
chemotherapeutic agents are allowed if at least 3 half-lives have elapsed prior
to leukapheresis
- Lymphotoxic chemotherapeutic agents within 2 weeks of leukapheresis
- Daratumumab (or other anti-CD38 therapy) within 30 days of leukapheresis
- Experimental agents within 4 weeks of leukapheresis unless progression is
documented on therapy and at least 3 half-lives have elapsed prior to
leukapheresis
- Absolute neutrophil count (ANC) < 1000/mm^3, or per PI discretion if cytopenia thought
to be related to underlying myeloma.
- Hemoglobin (Hgb) < 8 mg/dl, or per PI discretion if cytopenia thought to be related to
underlying myeloma.
- Platelet count < 50,000/mm^3, or per PI discretion if cytopenia thought to be related
to underlying myeloma.
- Active autoimmune disease requiring immunosuppressive therapy
- Major organ dysfunction defined as:
- Creatinine clearance < 20 ml/min
- Significant hepatic dysfunction (serum glutamic-oxaloacetic transaminase [SGOT] >
5 x upper limit of normal; bilirubin > 3.0 mg/dL)
- Forced expiratory volume in 1 second (FEV1) of < 50% predicted or diffusion
capacity of the lung for carbon monoxide (DLCO) (corrected) < 40% (patients with
clinically significant pulmonary dysfunction, as determined by medical history
and physical exam should undergo pulmonary function testing)
- Anticipated survival of < 3 months
- Contraindication to cyclophosphamide or fludarabine chemotherapy
- Patients with known AL subtype amyloidosis
- Uncontrolled medical, psychological, familial, sociological, or geographical
conditions that do not permit compliance with the protocol, as judged by the PI; or
unwillingness or inability to follow the procedures required in the protocol
