This is an open-label phase 1 study to assess the safety and pharmacodynamics of CART-BCMA,
with or without huCART19, in patients responding to first- or second-line therapy for
high-risk multiple myeloma. The regimen evaluated in this study is based on established
safety of CARTBCMA demonstrated in UPCC 14415/IRB#822756 at dose of 5x108 cells, administered
as split infusions, following cyclophosphamide 1.5 g/m2 in patients with relapsed/refractory
myeloma. This study tests CART-BCMA (1) as consolidation of early therapy for multiple
myeloma, (2) with addition of fludarabine to the lymphodepleting chemotherapy regimen, (3) in
combination with huCART19, and (4) as a single rather than split-dose infusion.
- 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
3. Metaphase karyotype with >3 structural abnormalities except hyperdiploidy
4. Plasma cell leukemia (>20% plasma cells in peripheral blood) at any time prior to
5. Failure to achieve partial response or better (by IMWG 2016 criteria) 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
a. Phase A and Phase A Expansion:
a. i. Subjects must: i. 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); OR ii. have disease that has relapsed after
or has been refractory to one prior regimen if their prior/current therapy
collectively has included all of the following: an "imid/PI" combination,
pomalidomide, lenalidomide, daratumumab, and carfilzomib. 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
criteria) 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 achieved at least a minimal response (as defined by IMWG 2016
criteria) to their overall systemic therapy for multiple myeloma and be clinically
stable on their current regimen in the judgement of the investigator.
3. Subjects must not have achieved a complete or stringent complete response according
to IMWG 2016 criteria 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 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 (Phase B and C only). 10. Subjects of
reproductive potential must agree to use acceptable birth control methods, as
described in protocol Section 4.3.
1. Pregnant or lactating women
2. Active hepatitis B, hepatitis C, or HIV infection, or other active,
3. Any uncontrolled medical or psychiatric disorder that would preclude
participation as outlined.
4. 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.
5. 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.
6. 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.