Efficacy and Safety of Anitocabtagene Autoleucel in Participants With Newly Diagnosed Multiple Myeloma (GEM-AnitoFIRST)

Exclusion Criteria

• •1. Active or prior history of central nervous system (CNS) or meningeal involvement of MM.
• •2. Cardiac atrial or cardiac ventricular MM involvement.
• •3. Diagnosis of primary amyloidosis (AL), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia (PCL), active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or Waldenstrom's macroglobulinemia at the time of screening.
• •4. Active malignancy (other than MM) requiring ongoing treatment for disease control within the last 24 months. Myelodysplastic syndrome (even without ongoing treatment) is not permitted. Allowed malignancy exceptions are:
• •1. Localized skin cancer (melanoma and nonmelanoma) that has been completely resected and considered curative within the last 24 months is eligible.
• •2. Cervix carcinoma in situ that has been completely resected and considered curative within the last 24 months is eligible.
• •3. Bladder carcinoma in situ that has been completely resected and considered curative within the last 24 months is eligible.
• •4. Breast carcinoma in situ that has been completely resected and considered curative within the last 24 months is eligible. Hormonal therapy after curative-intent treatment is permitted.
• •5. Prostate cancer that is low grade and localized (Grade Group 1, has not spread to nearby lymph nodes \[N0\] or metastasized \[M0\]) within the last 24 months is eligible, including cases under surveillance only as part of standard of care. Androgen deprivation therapy is permitted.
• •6. Localized renal cell carcinoma (≤ Stage 2) that has been completely resected and considered curative within the last 24 months is eligible.
• •7. Localized (Stage 1) colorectal cancer that has been completely resected and considered curative (without need for adjuvant chemotherapy) within the last 24 months is eligible.
• •5. Any prior systemic anti-myeloma treatment (including BCMA-directed treatment) and/or radiotherapy before enrollment. Palliative radiation and corticosteroids (up to cumulative dose of 160mg prednisone or equivalent, and not requiring ongoing therapy) prior to enrollment are permitted. Participants must have recovered from all radiation-related toxicities. Patients with radiation-induced lung injury (RILI, radiation pneumonitis) during screening are excluded.
• •6. Prior allogeneic stem cell transplant (allo-SCT) (even if for another malignancy)
• •7. Live vaccine ≤ 4 weeks before enrollment and/or anticipating needing the vaccine during study period.
• •8. Presence or suspicion of fungal, bacterial, viral, or other infection that is systemic uncontrolled or requiring IV antimicrobials for management. Simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted if the participant is responding to active treatment and satisfies the criteria of being afebrile (i.e., temperature \< 38°C) for at least 24 hours prior to the investigator confirming the participant's eligibility.
• •9. Acute or chronic active hepatitis A, B, or C infection. Participants with a history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines or applicable country guidelines.
• •10. Human immunodeficiency virus (HIV)-seropositive.
• •11. Participants with history or presence of chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \< 50% of predicted normal will not be permitted to receive anti-CD38 monoclonal antibody in combination with VRd therapy; Note: FEV1 testing is required for participants who are planned
• •12. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months before enrollment.
• •a. History or presence of intracranial or CNS disorder, such as hemorrhage, dementia, altered mental status, cerebellar disease, or any autoimmune disease with CNS involvement, PRES, or cerebral edema with confirmed structural defects by appropriate imaging. History of stroke or transient ischemic attack within 12 months before enrollment, or seizure disorders requiring active anticonvulsive medication. Patient with history of neurodegenerative disease (e.g., Parkinson's or Alzheimer's disease) must be excluded.
• •13. Peripheral neuropathy of Grade 3 or higher (per CTCAE v5.0; participants with Grade 2 peripheral neuropathy are eligible).
• •14. History of solitary plasmacytoma
• •15. History of autoimmune disease (e.g., Crohn's disease, rheumatoid arthritis, systemic lupus) resulting in or requiring systemic immunosuppression or systemic disease-modifying agents within 2 years.
• •16. History of concomitant genetic syndrome associated with bone marrow failure, such as Fanconi anemia, Kostmann syndrome, or Shwachman-Diamond syndrome.
• •17. History of DVT or PE within 6 months before enrollment. Anticoagulants (e.g., warfarin, low-molecular weight heparin, Factor Xa inhibitors) are allowed if DVT/PE occurred \> 6 months before enrollment, and if the participant is on a stable maintenance dose.
• •18. Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, G/J tube, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters such as Port-a-Cath or Hickman catheter are permitted.
• •19. Major surgery within 28 days before enrollment, or planned surgery required during study participation.
• •20. Any medical, neurologic or psychiatric condition that in the investigator's opinion is likely to interfere with study procedures including assessment of safety or efficacy of the study treatment.
• •21. Females who are pregnant or breastfeeding (due to the potentially dangerous effects of the lymphodepleting chemotherapy or induction regimen on the fetus or infant).
• •22. Participants of both sexes who are not willing to practice highly effective birth control from the time of consent through 12 months following lymphodepleting chemotherapy administration, 12 months after the completion of anitocabtagene autoleucel, 5 months after the last dose of isatuximab, 3 months after the last dose of daratumumab, bortezomib, or 28 days after the last dose of lenalidomide, whichever is longer (refer to Section 12.2). Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential. Participants of both sexes must also comply with any relevant REMS or aRMMs as part of an RMP. Additional information is in Section 6.3.1.
• •23. As per the investigator's judgment, the participant is unlikely to complete all protocol required study visits or procedures, including follow-up visits, or comply with or tolerate the study requirements for participation (e.g., participants who are at a risk for a thromboembolic event and are not willing to take venous thromboembolism prophylaxis should be excluded).
• •24. Contraindication to fludarabine or cyclophosphamide.
• •25. History of allergy or hypersensitivity to any study agent or study drug components. Participants with a history of severe hypersensitivity reaction to dimethyl sulfoxide (DMSO) are excluded.