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

Inclusion Criteria: 1. Subjects must have a diagnosis of multiple myeloma according to IMWG 2014 criteria106 with any of the following high-risk features. Subjects in the Phase A Expansion are not required to have any 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: at least one of the following \[deletion 17p, t(14;16), t(14;20), t(4;14)\] 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 physician-investigator confirmation of eligibility. 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). 6. 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 meet the following criteria with respect to prior multiple myeloma therapy: 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. Note: 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 physician-investigator confirmation of eligibility. e. Subjects must have achieved at least a minimal response (as defined by IMWG 2016 criteria1) 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 stringent complete response according to IMWG 2016 criteria1 at time of physician-investigator confirmation of eligibility unless clonal plasma cells are detectable in bone marrow by flow cytometry (I.e., subjects in stringent complete response are eligible if minimal residual disease can be documented by bone marrow flow cytometry) or if residual disease is detectable by imaging such as PET/CT, CT, or MRI. 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 physician-investigator confirmation of eligibility. 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 patients only). 10. Subjects of reproductive potential must agree to use acceptable birth control methods, as described in the protocol. Exclusion Criteria: 1. Pregnant or lactating women 2. RETIRED WITH PROTOCOL V6 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, 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 physician-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.