CS1-CAR T Therapy Following Chemotherapy in Treating Patients With Relapsed or Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of intravenous (i.v.) delivered autologous CS1‐CAR
T cells for research participants with recurrent/refractory multiple myeloma (MM).

SECONDARY OBJECTIVES:

I. Evaluate the response rates at days 28, 100, and 180 post CAR T cell infusion.

II. Measure the persistence of CS1‐CAR T cells in blood and marrow. III. Measure phenotype
and anti‐tumor functionality of CS1‐CAR T cells in marrow and blood.

IV. Measure the levels of cytokines in blood and marrow, and soluble CS‐1 in blood post
infusion as a surrogate indicator of CAR T cell activity.

V. Evaluate CS‐1 expression on MM cancer cells before, during and at progressive disease (PD)
to determine antigenic loss.

OUTLINE: This is a dose-escalation study of CS1-CAR T cells.

Patients undergo leukapheresis over 2-4 hours. Beginning 3-4 weeks, patients receive
cyclophosphamide intravenously (IV) on days -4 and/or -3 or fludarabine IV and
cyclophosphamide IV on days -5 to -3. Patients then undergo CS1-CAR T therapy over 10-15
minutes on day 0. After 28 days, patients may undergo an optional second CS1-CAR T therapy.

After completion of study treatment, patients are followed up at 1 day, at least every 2 days
for up to a minimum of 14 days, weekly for 1 month, monthly for 1 year, then periodically for
up to 15 years.

Inclusion Criteria:

- Documented informed consent of the participant and/or legally authorized
representative.

- Assent, when appropriate, will be obtained per institutional guidelines.

- Karnofsky Performance Status (KPS) of >= 70%.

- Life expectancy >= 16 weeks.

- Participant must have a confirmed diagnosis of active MM as defined by the
International Myeloma Working Group (IMWG) criteria.

- Participant must have measurable disease defined as meeting at least one of the
criteria below:

- Serum M‐protein >= 0.5 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%.

- Participant must have relapsed or refractory disease after at least 3 prior treatment
regimens with the following requirements:

- Participant must have received prior treatment with an immunomodulatory agent.

- Participant must have received prior treatment with a proteasome inhibitor.

- Participant must have received prior treatment with an anti‐CD38 antibody.

- Participants who were not candidates to receive one or more of the above
treatments are eligible; however, the reason must be clearly documented in the
case report form.

- Note: induction chemotherapy, autologous stem-cell transplantation (ASCT), and
maintenance therapy should be considered as 1 "regimen."

- If performed, autologous transplant must have been >= 90 days before enrollment.

- Total serum bilirubin =< 2.0 mg/dL.

- Participants with Gilbert syndrome may be included if their total bilirubin is =< 3.0.

- Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN).

- Alanine aminotransferase (ALT) < 2.5 x ULN.

- Serum creatinine =< 2.5 x ULN or estimated creatinine clearance of >= 40 mL/min per
the Cockcroft‐Gault formula, and the participant is not on hemodialysis.

- Absolute neutrophil count >= 1000/uL. Transfusions and growth factors must not be used
to meet these requirements at initial screening.

- Hemoglobin (Hb) >= 8 g/dl. Transfusions and growth factors must not be used to meet
these requirements at initial screening.

- Platelet count >= 50,000/uL (>= 30,000/uL if bone marrow plasma cells are >= 50% of
cellularity). Transfusions and growth factors must not be used to meet these
requirements at initial screening.

- Left ventricular ejection fraction >= 45% within 8 weeks before enrollment.

- Oxygen (O2) saturation >= 92%.

- Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test.

- If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required.

- Agreement by females and males of childbearing potential to use an effective method of
birth control or abstain from heterosexual activity for the course of the study
through at least 3 months after the last dose of protocol therapy.

- Childbearing potential defined as not being surgically sterilized (men and women)
or have not been free from menses for > 1 year (women only).

Exclusion Criteria:

- Prior allogeneic stem cell transplantation.

- Autologous transplantation =< 90 days of enrollment.

- Growth factors within 14 days of enrollment.

- Platelet transfusions within 7 days of enrollment.

- Participants receiving any other investigational agents, or concurrent biological,
chemotherapy, or radiation therapy.

- Participants with known additional malignancy that is progressing or required active
treatment within the last 2 years. Exceptions include basal cell carcinoma of the
skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has
undergone potentially curative therapy.

- Participants with toxicities from prior therapies, with the exception of peripheral
neuropathy attributable to bortezomib, that have not recovered to grade =< 2 according
to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 criteria or to the
subject's prior baseline.

- Participants with known active hepatitis B or C infection; research participants who
are human immunodeficiency virus (HIV) positive based on testing performed within 4
weeks of enrollment; research participants with any signs or symptoms of active
infection, positive blood cultures or radiological evidence of infections.

- Participants with active auto‐immune disease, including connective tissue disease,
sarcoidosis, multiple sclerosis, inflammatory bowel disease or have a history of
severe (as judged by the principal investigator) autoimmune disease that will require
prolonged immunosuppressive therapy.

- Have New York Heart Association (NYHA) Class III or IV heart failure, unstable angina,
or a history of recent (within 6 months) myocardial infarction.

- Participants with a history or presence of clinically relevant central nervous system
(CNS) pathology such as uncontrolled seizure disorder, stroke, severe brain injuries,
dementia, cerebellar disease or psychosis.

- Participants with known active central nervous system (CNS) involvement by malignancy.
Subjects with prior CNS disease that has been effectively treated will be eligible if
treatment was completed at least 3 months prior to enrollment with no evidence of
symptomatic disease and stable abnormalities on repeat imaging.

- Participants with plasma cell leukemia (PCL) or symptomatic amyloidosis. However,
participants with a prior history of PCL are not excluded.

- Participants with any known contraindications to leukapheresis, cyclophosphamide,
fludarabine, cetuximab or tocilizumab.

- Dependence on corticosteroids.

- Defined as doses of corticosteroids of greater than or equal to 10 mg/day of
prednisone or equivalent doses of other corticosteroids.

- Note: Topical and inhaled corticosteroids in standard doses and physiologic
replacement for subjects with adrenal insufficiency are allowed.

- Participants with inadequate venous access for leukapheresis, and who are either
unable to or unwilling to have a supportive line (temporary or other) placed for the
procedure.

- Females only: Pregnant or breastfeeding.

- Any other condition that would, in the Investigator's judgment, contraindicate the
subject's participation in the clinical study due to safety concerns with clinical
study procedures.

- Prospective subjects who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics).