Inclusion Criteria:
1. Patients must have a diagnosis of active multiple myeloma as defined by the updated
IMWG (International Myeloma Working Group) criteria, and meet one or more of the
following criteria:
1. Serum M protein ≥ 1 g/dL；
2. Urine M protein ≥ 200 mg/24hrs;
3. Serum free light chain (sFLC) ≥ 10 mg/dL with abnormal sFLC κ/λ ratio.
2. Have received at least 3 prior lines of therapy for multiple myeloma. Note: According
to IMWG guidelines, a single line of therapy includes a full course of monotherapy,
combination therapy with multiple drugs, or sequential treatment with multiple
regimens (e.g., the use of a 3-6 cycle regimen of bortezomib combined with
dexamethasone, followed by stem cell transplantation, consolidation therapy, and
lenalidomide maintenance therapy, is considered a single line of therapy). Unless the
best response was documented as progressive disease (PD) or the subject was intolerant
to the therapy.
3. Prior therapy should include proteasome inhibitors (PIs), immunomodulatory drugs
(IMiDs), and anti-CD38 antibodies.
4. Evaluated by investigator based on IMWG standards, subjects have a confirmed (through
testing at a central or local laboratory) PD during or within 12 months following the
most recent anti-myeloma treatment.
5. Voluntarily signed a written informed consent form (ICF).
6. The signing of ICF complies with the requirements of GCP and relevant national laws
and regulations.
7. Males or females, aged 18-75 years old (including the thresholds).
8. Subjects should be willing and able to comply with the study visit schedule and other
protocol requirements.
9. ECOG (Eastern Cooperative Oncology Group) performance score 0-1.
10. Estimated life expectancy ≥ 3 months.
11. Adequate functional reserve of organs:
1. Neutrophil count ≥ 0.75×10^9/L (growth factor support is allowed, but no
supportive treatment is allowed within 7 days prior to screening); Hemoglobin ≥
8.0 g/dL (no red blood cell transfusion within 7 days prior to screening,
recombinant human erythropoietin is allowed); Platelet count ≥ 50×10^9/L (no
platelet transfusion within 7 days prior to screening); Lymphocyte count ≥
0.3×10^9/L;
2. ALT/AST ≤ 3× ULN (upper limit of normal); Total bilirubin ≤ 2× ULN (in subjects
with Gilbert syndrome, direct bilirubin ≤ 1.5× ULN is required);
3. Creatinine clearance ≥ 40 mL/min, calculated by Cockcroft-Gault;
4. Left ventricular ejection fraction (LVEF) ≥ 45% with no evidence of pericardial
effusion as diagnosed by echocardiography; No clinically significant
electrocardiogram abnormality observed;
5. Baseline oxygen saturation ≥ 95% on room air; No clinically significant pleural
effusion observed.
12. Female subjects with fertility must:
1. Have a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test
confirmed by investigators during screening and before undergoing lymphodepletion
with cyclophosphamide and fludarabine.
2. Agree and be able to use effective contraception continuously from screening to
at least 1 year after GC012F infusion. Contraception must include one highly
effective and one additional effective (barrier) method, initiated from screening
until at least 1 year after GC012F infusion or until two consecutive flow
cytometry tests show the absence of CAR-T cells (whichever occurs later).
3. Agree to avoid breastfeeding during the study period until at least 1 year after
GC012F infusion or until two consecutive flow cytometry tests show the absence of
CAR-T cells (whichever occurs later).
13. Male subjects must agree to use condoms during sexual contact with pregnant females or
females with fertility for at least 1 year after GC012F infusion, even if a successful
vasectomy has been performed.
14. Sufficient venous access for leukapheresis collection, and no other contraindications
to leukapheresis.
Exclusion Criteria:
1. Prior treatment with CAR-T products for any target.
2. Have any of the following concomitant treatment history:
1. Received a total of ≥ 70 mg of prednisone or an equivalent dose of other
corticosteroids within 7 days prior to leukapheresis;
2. Investigators believe that patients has comorbidities requiring the systemic use
of corticosteroids (a total of ≥ 70 mg of prednisone or an equivalent dose of
other corticosteroids) or other immunosuppressive drugs within 12 weeks after the
start of the study treatment;
3. Received a live-attenuated vaccine within 4 weeks prior to leukapheresis or
lymphodepletion;
4. Received any anticancer therapy, including but not limited to radiation therapy,
cytotoxic therapy, PIs, IMiDs, targeted therapy, epigenetic therapy, or
experimental drug treatment, within 14 days prior to leukapheresis (if radiation
field covers ≤ 5% of bone marrow, subjects can be enrolled regardless of the end
date of radiation therapy);
5. Received monoclonal antibody for treating multiple myeloma within 21 days prior
to leukapheresis.
3. Patients' corticosteroid maintenance doses are greater than physiological replacement
doses (i.e., prednisone ≥ 7.5 mg/day or hydrocortisone ≥ 12 mg/m^2/day).
4. Patients with any of the following heart diseases:
1. Congestive heart failure (NYHA classification ≥ III);
2. Experienced myocardial infarction or underwent coronary artery bypass grafting
(CABG) within 6 months prior to screening;
3. Clinically significant ventricular arrhythmias or a history of unexplained
syncope not due to vasovagal reaction or dehydration; or a QTc interval > 480 ms
during screening;
4. History of severe non-ischemic cardiomyopathy.
5. Patients requiring assisted oxygenation or mechanical ventilation or with oxygen
saturation <95% on room air (patients with oxygen saturation <95%, but with lung
function test results showing carbon monoxide diffusing capacity and forced expiratory
volume in 1 second > 45% of predicted value, may be enrolled).
6. Patients with hypertension that is uncontrolled by drug therapy.
7. Patients with clinically significant bleeding symptoms or definite bleeding tendencies
(e.g., gastrointestinal bleeding, bleeding gastric ulcers, etc.), hereditary or
acquired bleeding and thrombotic tendencies (e.g., hemophilia, coagulation disorders,
hypersplenism, etc.) within 90 days prior to screening; have experienced arteriovenous
thrombotic events (e.g., cerebrovascular diseases (including cerebral hemorrhage,
cerebral infarction, etc.), deep vein thrombosis, and/or pulmonary embolism) within
180 days prior to screening.
8. Accompanied by other uncontrolled malignancies. The following are excluded:
early-stage tumors that have received radical treatment (carcinoma in situ or grade 1
tumors, or non-ulcerated primary melanoma with a depth < 1 mm and no involvement of
lymph nodes), basal cell skin cancer, squamous cell skin cancer, cervical carcinoma in
situ, or breast carcinoma in situ that has received potential radical treatment.
9. Have received any of the following treatments:
1. Received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) within
6 months prior to leukapheresis. Patients undergoing allo-HSCT who have
discontinued all immunosuppressive drugs for 6 weeks prior to leukapheresis and
have no manifestations of graft-versus-host disease (GVHD) may be enrolled.
2. Received an autologous hematopoietic stem cell transplantation (auto-HSCT) within
≤ 12 weeks prior to leukapheresis.
10. Severe underlying medical conditions, such as:
1. Evidence of active viral or bacterial infection (requiring systemic antimicrobial
therapy) or uncontrolled systemic fungal infection;
2. Active autoimmune diseases or a history of autoimmune disease within the past 3
years;
3. Significant clinical evidence of dementia or altered mental status;
4. History of any central nervous system (CNS) or neurodegenerative diseases, (e.g.,
epilepsy, seizures, paralysis, aphasia, stroke, severe brain injury, dementia,
Parkinson's disease, psychiatric disorders).
11. Patients have CNS metastases or CNS involvement (including cranial neuropathies or
mass lesions and leptomeningeal disease).
12. Positive results in any of the following tests:
1. HIV antibody positive;
2. HBsAg positive; or HBcAb positive, with HBV DNA titer higher than the lower limit
of detection;
3. HCV antibody positive, with HCV RNA titer higher than the lower limit detection;
or known history of Hepatitis C, but did not complete antiviral treatment for ≥24
weeks;
4. Syphilis antibody positive.
13. Accompanied by plasma cell leukemia (peripheral blood plasma cells > 2.0×10^9/L),
Waldenstrom macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly,
endocrinopathy, monoclonal gammopathy of undetermined significance, skin changes), or
primary amyloidosis.
14. Patients have a history of severe hypersensitivity or allergy.
15. Contraindication or hypersensitivity to fludarabine, cyclophosphamide, and any
component of experimental product.
16. Surgery plan within 2 weeks prior to leukapheresis or during the study (except for
local anesthesia surgery, but not performed within 2 weeks after CAR-T infusion).
17. Pregnant or lactating, or planning to have a pregnancy during or within 1 year after
treatment.
18. Acute toxicities (except for hematological toxicities and alopecia) caused by previous
treatments have not recovered to ≤ grade 1.
19. Participated in other clinical trials within 4 weeks prior to ICF signing, or ICF
signing date is within 5 half-lives of the drug from the last medication in the last
drug clinical trial (whichever is longer).
20. Any situation in which investigators believe that participation in this study is not
in the subject's best interests, or any situation that may hinder patients'
participation in the entire trial or confuse the assessment.
