A Phase III Study of Eque-cel in Subjects with Len-refractory RRMM (FUMANBA-03)

This is a multicenter, randomized, controlled, open-label, phase III clinical study to evaluate the efficacy of Equecabtagene Autoleucel Injection versus standard therapy in subjects with lenalidomid-refractory RRMM who have received 1-2 lines of prior therapy.

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accounts for more than 10%-20% of hematologic malignancies worldwide, leading to marrow failure and bone destruction. Equecabtagene Autoleucel (eque-cel) is an autologous chimeric antigen receptor T-cell (CAR-T) therapy that targets B-cell maturation antigen (BCMA), which expressed on both mature B lymphocytes and malignant plasma cells. The primary objective for this study is to compare the efficacy of eque-cel versus standard therapy in lenalidomid-refractory RRMM. Subjects will undergo screening with informed consent. After enrollment, randomization will be conducted followed by study treatment in experimental or control group. A follow-up phase will include assessments for safety, efficacy evaluation and pharmacokinetics monitoring (experimental arm) . The duration of this trial is about 6 years.

Eligibility Criteria:
Inclusion Criteria:

1. 18 to 75 years of age (inclusive of critical values), either gender.
2. The subject was previously diagnosed with multiple myeloma and had received 1-2 lines of therapy (including chemotherapy regimens based on proteasome inhibitors and immunomodulatory agents, with each line of therapy receiving at least 1 full cycle ; Documented disease progression during or within 12 months after the most recent anti-myeloma therapy.
3. Subjects was lenalidomide-refractory during prior therapy.
4. ECOG score of 0 or 1.
5. Subjects must have appropriate organ function and meet all of the following laboratory test results before enrollment:

(1) Haematology: absolute neutrophil count (ANC) ≥1×10\^9/L (support with growth factor is allowed, but must not have received supportive treatment within 7 days before the laboratory test); Absolute lymphocyte count (ALC) ≥0.3×10\^9/L; Platelets ≥50×10\^9 / L (must not have received platelet transfusion within 7 days prior to laboratory test); Hemoglobin ≥60g/L (must not have received red blood cells transfusion within 7 days prior to laboratory test); (2) Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times of upper limit of normal (ULN); Serum total bilirubin ≤1.5 times of ULN; (3) Renal function: creatinine clearance (CrCl) calculated by Cockcroft-Gault formula ≥ 40 ml/min; (4) Coagulation: fibrinogen≥1.0 g/L; activated partial thromboplastin time (APTT) ≤ 1.5×ULN, pro-thrombin time (PT) ≤ 1.5 × ULN; (5) Pulse oxygen saturation \> 91%; (6) Left ventricular ejection fraction (LVEF)≥50%;

6. Subjects agree to use effective tools or drug contraception (excluding safe period contraception) after signing the informed consent form.

7. Subjects must agree to sign or personally sign an ethics committee-approved informed consent form before starting any screening procedures.

Exclusion Criteria:

1. Subjects who have used or required long-term immune-suppressive agents (e.g., cyclosporine or systemic steroids) within 14 days prior to enrollment, but the use of physiological substitutes, intermittent, topical, and inhaled steroids is allowed.
2. Subjects who have undergone autologous haematopoietic stem cell transplantation (Auto-HSCT) within 12 weeks prior to randomization, or who have previously undergone allogeneic haematopoietic stem cell transplantation (Allo-HSCT).
3. Subjects received the following anti-tumor treatments before enrollment: (1)Treated with an immunomodulator within 7 days, or; (2)Received plasma exchange, radiotherapy (except local radiotherapy for myeloma-related bone lesions), cytotoxic chemotherapy, treatment with proteasome inhibitors or other investigational drug within 14 days, or; (3) Treatment with monoclonal antibody for multiple myeloma within 21 days, or; (4) Received other anti-cancer therapy within 14 days or at least 5 half-lives (whichever is shorter) prior to enrollment.
4. Significant cardiac disorder.
5. Unstable systemic disease as judged by the investigator: including but not limited to severe liver, renal, or metabolic disease requiring medication.
6. The subject will not be able to participate in this study if the investigator determines that the subject meets any of the following conditions: (1) Subjects with a history of allergic reaction to the excipient components (DMSO and albumin) of Eque-cel, fludarabine, cyclophosphamide, tocilizumab, or; (2) Subjects who are intolerant to dexamethasone, or; (3) Subjects who have a Life-threatening allergy, hypersensitivity reaction, or intolerance to pomalidomide and/or its excipients (intolerance is defined as discontinuation of prior treatment due to any AE related to pomalidomide) or;
7. Have malignancies other than multiple myeloma within 5 years before screening, excluding cervical carcinoma in situ after radical surgery, basal cell or squamous cell skin cancer, localized cancer of prostate after radical prostatectomy, breast ductal carcinoma in situ after radical mastectomy or carcinoma papillary thyroid after radical thyroidectomy.
8. Subjects suspected or confirmed to have central nervous system involvement of MM during the screening period.
9. Subjects with concurrent plasma cell leukemia(defined as plasma cell proportion in peripheral blood \> 5%), Waldenström macroglobulinaemia, POEMS syndrome (polyneuropathy, organ hypertrophy, endocrinopathy, monoclonal protein and skin changes) or primary amyloidosis during screening period.
10. Have extramedullary multiple myeloma-extraosseous (EM-E); have multiple extramedullary multiple myeloma-bone related (EM-B) and the maximum transverse diameter of any lesion is \>3cm; have a single EM-B and the maximum transverse diameter of the lesion is \>3cm.
11. Had major surgery within 2 weeks prior to randomization or planned to have surgery within 2 weeks after study treatment (except for subjects who were scheduled to have surgery under local anesthesia).
12. Subject with uncontrollable infection.
13. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and hepatitis B virus (HBV) DNA quantification in peripheral blood was higher than the lower limit of detection; hepatitis C virus (HCV) antibody positive and hepatitis C virus (HCV) RNA positive in peripheral blood; Human immunodeficiency virus (HIV) antibody positive; Syphilis test positive; positive cytomegalovirus (CMV) DNA.
14. Pregnant or breastfeeding women.
15. The subject has a history of central nervous system disorder within 6 months prior to signing the informed consent form.
16. Non-hematological toxicity reactions due to prior treatment have not resolved to baseline or ≤ Grade 1 (NCI-CTCAE v5.0, alopecia, Grade 2 peripheral neuropathy were excepted).
17. Subjects had other conditions that the investigator considered unsuitable for enrollment.