Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma

Phase A: Safety Run-in to test the safety of CART-BCMA + huCART19 as split-dose infusions
after lymphodepleting chemotherapy with cyclophosphamide + fludarabine in patients who have
relapsed/refractory myeloma after two prior regimens but who are responding to their current
therapy. Phase A Expansion: To occur once safety is demonstrated in Phase A. - Phase B:
Randomization Phase in which patients responding to first or second-line therapy will receive
either CART-BCMA alone (Cohort

1) or CART-BCMA + huCART19 (Cohort 2) as split-dose infusions after lymphodepleting
chemotherapy with cyclophosphamide + fludarabine. Phase C: Single-dose infusion phase to test
the safety of single-dose infusion of CART-BCMA alone (Cohort 1) and CART-BCMA + huCART19
(Cohort 2) as single-dose infusions after lymphodepleting chemotherapy with cyclophosphamide
+ fludarabine in patients responding to first- or second-line therapy.

Inclusion Criteria:

- Subjects must have a diagnosis of multiple myeloma according to IMWG 2014 criteria106
with any of the following high-risk features:

1. Beta-2-microglobulin ≥ 5.5 mg/L and LDH greater than upper limit of normal. Note:
subjects in whom LDH and/or Beta-2-microglobulin were not measured prior to
initiation of systemic therapy may qualify based on measurements obtained after
initiation of systemic therapy.

2. High-risk FISH features: deletion 17p, t(14;16), t(14;20), t(4;14) in conjunction
with Beta- 2-microglobulin ≥ 5.5 mg/L (i.e., revised ISS stage 3). Note: subjects
in whom Beta-2-microglobulin was not measured prior to initiation of systemic
therapy may qualify based on measurements obtained after initiation of systemic
therapy.

3. Metaphase karyotype with >3 structural abnormalities except hyperdiploidy

4. Plasma cell leukemia (>20% plasma cells in peripheral blood) at any time prior to
enrollment

5. Failure to achieve partial response or better (by IMWG 2016 criteria1) to initial
therapy with an "imid/PI" combination (thalidomide, lenalidomide, or pomalidomide
in combination with bortezomib, ixazomib, or carfilzomib).

Early progression on first-line therapy, defined as progression (according to
IMWG 2016 criteria1)

i. Within one year of starting first-line therapy with an "imid/PI"combination ii.
Within six months of completing first line therapy with an "imid/PI"combination (i.e.
a patient who receives an "imid/PI" combination, transitions to observation or
maintenance therapy, and progresses within six months of this transition) iii. Within
one year of a high-dose melphalan and autologous stem cell transplantation (Phase A
subjects only) 2. Subjects must meet the following criteria with respect to prior
myeloma therapy:

a. Phase A and Phase A Expansion:

a. Subjects must have disease that has relapsed after or has been refractory to at
least two regimens, including a proteasome inhibitor and thalidomide analog
(thalidomide, lenalidomide, pomalidomide). Refractoriness is defined as disease
progression on-therapy or within 60 days of stopping therapy.

b. Subjects must have achieved at least a minimal response (as defined by IMWG 2016
criteria1) to their current regimen.

c. Subjects must not have received prior treatment with anti-BCMA cellular therapy.
Subjects may have received treatment with other BCMA-directed agents (e.g., anti-BCMA
antibody-drug conjugates or bispecific antibodies).

b. Phases B and C:

1. Subjects must be in their first line of multiple myeloma therapy, with the
following exception: subjects who have advanced to second-line therapy due to
disease progression during first-line therapy are eligible if such progression
occurred within six months of beginning first-line therapy. Lines of therapy are
defined by IMWG 2016 criteria1.

2. Subjects must not have received cytotoxic chemotherapy (e.g., doxorubicin,
cyclophosphamide, etoposide, cisplatin) with the following exceptions:

i. Low-dose weekly cyclophosphamide (≤500 mg/m2/week) ii. Continuous infusion
cyclophosphamide, if limited to a single cycle. c. Subjects must not have undergone
autologous or allogeneic stem cell transplantation. d. Subjects must have initiated
systemic therapy for multiple myeloma ≤1 year prior to enrollment.

e. Subjects must have received at least 3 complete cycles of their current regimen and
have achieved at least a minimal response (as defined by IMWG 2016 criteria1) to the
most recent line of therapy.

3. Subjects must not have achieved a complete or stringent complete response according
to IMWG 2016 criteria1 at time of enrollment unless clonal plasma cells are detectable
in bone marrow by flow cytometry. (I.e., subjects in complete or stringent complete
response are eligible if minimal residual disease can be documented by bone marrow
flow cytometry). 4. Subjects must have signed written, informed consent. 5. Subjects
must be ≥ 18 years of age. 6. Subjects must have adequate vital organ function:

1. Serum creatinine ≤ 2.5 or creatinine clearance ≥30 ml/min (measured or estimated
according to CKD-EPI) and not dialysis-dependent.

2. Absolute neutrophil count ≥1000/μl and platelet count ≥50,000/μl (≥30,000/μl if
bone marrow plasma cells are ≥50% of cellularity).

3. SGOT ≤ 3x the upper limit of normal and total bilirubin ≤ 2.0 mg/dl (except for
patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome).

4. Left ventricular ejection fraction (LVEF) ≥ 45%. LVEF assessment must have been
performed within 8 weeks of enrollment.

7. Toxicities from prior/ongoing therapies, with the exception of peripheral
neuropathy attributable to multiple myeloma therapy, must have recovered to grade
≤ 2 according to the CTCAE 4.03 5.0 criteria or to the subject's prior baseline.

8. Subjects must have an ECOG performance status of 0-2. 9. Subjects must be
willing to forego first-line ASCT. 10. Subjects of reproductive potential must
agree to use acceptable birth control methods, as described in protocol Section
4.3.

Exclusion Criteria:

1. Pregnant or lactating women

2. Inadequate venous access for or contraindications to leukapheresis.

3. Active hepatitis B, hepatitis C, or HIV infection, or other active,
uncontrolled infection.

4. Any uncontrolled medical or psychiatric disorder that would preclude
participation as outlined.

5. NYHA Class III or IV heart failure (see Appendix 2), unstable angina, or a
history of recent (within 6 months) myocardial infarction or sustained (>30
seconds) ventricular tachyarrhythmias.

6. Have active auto-immune disease, including connective tissue disease,
uveitis, sarcoidosis, inflammatory bowel disease, or multiple sclerosis, or
have a history of severe (as judged by the investigator) autoimmune disease
requiring prolonged immunosuppressive therapy.

7. Have prior or active central nervous system (CNS) involvement (e.g.
leptomeningeal disease, parenchymal masses) with myeloma. Screening for this
(e.g. with lumbar puncture) is not required unless suspicious symptoms or
radiographic findings are present. Subjects with calvarial disease that
extends intracranially and involves the dura will be excluded, even if CSF
is negative for myeloma.