Inclusion Criteria:
1. Aged 18-70 years;
2. Diagnosis of relapsed or refractory multiple myeloma(MM): 1) measurable disease at
screening as defined by any of the following: serum monoclonal paraprotein (M-protein)
level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or light chain MM without
measurable disease in the serum or the urine: serum immunoglobulin free light chain
≥10 mg/dL and abnormal serum immunoglobulin kappa/lambda free light chain ratio. Light
chain MM without measurable disease in the serum or the urine is a specific definition
in this study, which refers to subjects whose M-protein in the serum and M-protein in
the urine is undetectable; 2) received at least 2 standard regimens, determined as
progressive disease (PD) by IMWG criteria; received at least 3 prior lines of
treatment for MM, undergone at least 1 complete cycle of treatment for each line,
unless PD was documented by IMWG criteria as the best response to the regimen; 3)
received a proteasome inhibitor(PI) and an immunomodulatory therapy (IMiD); 4)
documented disease progression during, or within 12 months of, most recent
anti-myeloma therapy.
3. Histologically confirmed positive expression of CD19 and/or BCMA 3 months prior to
enrollment;
4. Eastern cooperative oncology group (ECOG) performance status of 0 to 1;
5. Adequate organ function is defined as: 1) hemoglobin≥8.0g/dL(did not receive red blood
cell transfusion ≤7 days prior to laboratory tests; recombinant human erythropoietin
is allowed); 2) platelet count >50×10^9/L(did not receive blood transfusion ≤7 days
prior to laboratory tests); 3) ANC ≥0.75×10^9/L(did not receive supportive treatment
≤7 days prior to laboratory tests; growth factors are allowed); 4) total bilirubin
<2×ULN (for subjects with congenital hyperbilirubinemia such as Gilbert's syndrome,
direct bilirubin≤1.5×ULN); 5) creatinine clearance (according to MDRD formulas or 24h
urine collection result) ≥40 mL/min/1.73m^2; 6) ALT and AST <3×ULN; 7) corrected serum
calcium ≤12.5 mg/dL (≤3.1 mmol/L), or free calcium ion ≤6.5 mg/dL(≤1.6 mmol/L); 8)
oxygen saturation >92% on non-oxygen-assistance state;
6. Females of childbearing potential must have a negative serum hypersensitive β-human
chorionic gonadotropin (β-hCG) or urine pregnancy test result, at screening, and prior
to lymphodepletion;
7. Females of childbearing potential must agree to use a highly effective contraception
continuously from signing informed consent form until ≥100 days after CAR-T infusion
(when continuously correctly used, failure rate <1% per year). Highly effective
contraception include, user-independent method: 1) implantable progesterone
contraceptives which can inhibit ovulation; 2) intrauterine device (IUD); Intrauterine
hormone release system; 3) partner has a vasectomy; user-dependent method: 1) compound
hormone contraceptives which can inhibit ovulation (contain estrogen and progesterone,
oral/vaginal/transdermal administration); 2) progesterone contraceptives which can
inhibit ovulation (oral administration or injection);
8. Except for highly effective contraception, males must agree to use barrier
contraception (such as condom plus spermicidal foam/gel/film/suppository) during
sexual contact with a female of childbearing potential, to use condom during sexual
contact with a pregnant female, from signing informed consent form until ≥100 days
after CAR-T infusion; females and males must agree to avoid ovum/oocyte/sperm
donation, during the study period and ≥100 days after CAR-T infusion. Note: hormone
contraceptives may interact with the study treatment, thus reducing the contraceptive
effect;
9. Subject must sign an inform consent form indicating that he or she understands the
purpose of and procedures required for the study and is willing to participate in the
study. Consent is to be obtained prior to the initiation of any study-related tests or
procedures that are not part of standard-of-care for the subject's disease;
10. Willing and able to adhere to the prohibitions and restrictions specified in this
protocol.
Exclusion Criteria:
1. History of CAR-T treatment, the target of CAR-T is not limited;
2. History of anti-CD19 or anti-BCMA treatment;
3. Concomitant invasive malignancy other than diagnosis or treatment of other
radically-cured malignancies without malignant change ≥3 years prior to enrollment or
adequately- treated non-melanoma skin cancer without malignant change evidence;
4. Received targeted therapy, epigenetic therapy, experimental drug therapy, or
experimental invasive medical device <14 days or 5 half-lives (according to the
shorter one) prior to leukapheresis; received monoclonal antibody <21 days prior to
leukapheresis; received cytotoxic chemotherapy, PI, radiotherapy <14 days prior to
leukapheresis (for radiotherapy, if the radiation field is no more than 5% of bone
marrow reserve, whenever radiotherapy ended, the subject is allowed to participate in
the study); received IMiD <7 days prior to leukapheresis;
5. Toxicities related to prior therapy did not relieve to baseline or ≤ grade 1, except
for peripheral neuropathy and alopecia;
6. The following cardiac conditions: New York Heart Association(NYHA) grade III or IV
congestive heart failure; myocardial infarction or coronary artery bypass graft (CABG)
≤6 months prior to enrollment; history of clinically significant ventricular
arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to
dehydration; history of severe non-ischemic cardiomyopathy; impaired cardiac function
(LVEF <45%) as assessed by echocardiogram or multiple-gated acquisition (MUGA) scan
(performed ≤ 8 weeks prior to leukapheresis);
7. Systemic or local corticosteroid therapy of greater than 5 mg/day of prednisone (or
equivalent dose of another corticosteroid) within 2 weeks prior to leukapheresis;
8. Received either of the following: an allogeneic stem cell transplant for MM; an
autologous stem cell transplant ≤ 12 weeks prior to leukapheresis;
9. Known active central nervous system (CNS) involvement or emergence of meninges
involvement clinical signs;
10. Stroke or convulsions ≤ 6 months prior to ICF signing;
11. Presence of plasma cell leukemia(plasma cell >2.0×10^9/L), Waldenstrom's
macroglobulinemia, POEMS syndrome(polyneuropathy, organomegaly, endocrinopathy,
monoclonal protein disease, skin changes) or primary amyloidosis(AL) at screening;
12. Seropositive for human immunodeficiency virus (HIV); Hepatitis B infection as defined
according to the American Society of Clinical Oncology (ASCO) guidelines. In the event
the infection status is unclear, quantitative levels are necessary to determine the
infection status. Hepatitis C (anti-hepatitis C virus [HCV] antibody positive or
HCV-RNA quantitation positive) or known to have a history of hepatitis C;
13. Attenuated live vaccine ≤4 weeks prior to enrollment;
14. Known life threatening allergies, hypersensitivity, or intolerance to CAR-T cells or
its ingredients, including dimethylsulfoxide;
15. Serious underlying medical condition, such as: evidence of serious active viral,
bacterial, or uncontrolled systemic fungal infection; active autoimmune disease or a
history of autoimmune disease within 3 years; overt clinical evidence of dementia or
altered mental status; hereditary bleeding/ coagulating disease, a history of
non-traumatic bleeding or thromboembolism, other disease that may increase bleeding
risk;
16. Presence of any problems that may be detrimental to the subjects' receiving/tolerating
planned treatment and the subject's understanding ICF; presence of any condition that
the investigators think it is inappropriate for the subject to anticipate the trial
(such as damaging health); presence of any condition that may deter, limit, or
obfuscate protocol-defined evaluation.
