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

Inclusion Criteria:

1. Newly diagnosed Multiple Myeloma according to the IMWG criteria published in 2014.

2. For cohort A, patients will ≤ 70 years of age.

3. For the cohorts B and C, patients will be ≤ 80 years of age.

4. Measurable disease at screening per IMWG, defined as any of the following:

5. Serum M-protein level ≥ 1 g/dL or urine M-protein level ≥ 200 mg/24 hours; or

6. Light chain MM without measurable disease in the serum or urine: serum freelight chain ≥ 10 mg/dL and abnormal serum free light chain ratio.

• Note: Local laboratory results may be used to establish measurable diseaseat screening if the results are ≥ 125% of requirements.

3. Only participants who are candidates to receive either D-VRd or Isa-VRd inductionregimens, as determined by the investigator, should be considered for this study.

4. Male or female aged 18 years or older and has capacity to give informed consent.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Adequate hematological function defined as the following:

• Hemoglobin count ≥ 7.5 g/dL (without any red blood cell [RBC] transfusionwithin 7 days prior to the test result; use of recombinant human erythropoietinis permitted).

• Absolute neutrophil count (ANC) ≥ 500/μL (without non-PEGylated myeloid growthfactor support within 7 days or PEGylated myeloid growth factor support within 14 days prior to the test result).

• Platelet count ≥ 75,000/μL (unless secondary to bone marrow or spleeninvolvement of MM, in which platelet count ≥ 50,000/μL is permitted) withoutany platelet cell transfusion within 7 days prior to the test result. Bonemarrow involvement by MM is demonstrated by bone marrow aspiration or biopsy.Spleen involvement by MM is demonstrated by splenomegaly.

• Absolute lymphocyte count (ALC) ≥ 100/μL.

• PTT/PT/INR < 1.5x upper limit of normal (ULN), unless on a stable dose ofanticoagulant for a thromboembolic even (subjects with a history ofthromboembolic stroke or history of Grade 2 or greater hemorrhage within 1 yearare excluded.

7. Adequate renal, hepatic, pulmonary, and cardiac function defined as the following:

• Estimated glomerular filtration rate (eGFR) (as estimated by Chronic KidneyDisease Epidemiology Collaboration [CKD-EPI] equation [Section 12.14]) ≥ 45mL/min.

• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 xULN.

• Total bilirubin ≤ 1.5 mg/dL, except in participants with Gilbert's syndrome ordocumented MM liver or pancreatic involvement where ≤ 3 x ULN is permitted.

• Cardiac ejection fraction ≥ 45% with no evidence of clinically significantpericardial effusion as determined by echocardiogram (ECHO). Multigatedacquisition (MUGA) scan may be used if an ECHO is not available at the site.

• No evidence of Grade 2 or higher (per National Cancer Institute [NCI] CommonTerminology Criteria for Adverse Events [CTCAE] version [v]5.0) pleuraleffusion or ascites (participants with Grade 1 pleural effusion or ascites areeligible).

• Baseline oxygen saturation >92% on room air.

8. Females of childbearing potential must have a medically supervised negative serum orurine pregnancy test with a sensitivity of at least 25 mIU/mL (females who haveundergone surgical sterilization or who have been postmenopausal for at least 2years are not considered to be of childbearing potential; refer to Section 12.2).

9. Willing to comply with and able to tolerate study procedures, including consent toparticipate in separate Long-term Safety Follow-up lasting up to 15 years perauthorities´ guidance.

Exclusion Criteria:

1. Active or prior history of central nervous system (CNS) or meningeal involvement ofMM.

2. Cardiac atrial or cardiac ventricular MM involvement.

3. Diagnosis of primary amyloidosis (AL), monoclonal gammopathy of undeterminedsignificance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia (PCL),active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonalprotein, and skin changes) or Waldenstrom's macroglobulinemia at the time ofscreening.

4. Active malignancy (other than MM) requiring ongoing treatment for disease controlwithin the last 24 months. Myelodysplastic syndrome (even without ongoing treatment)is not permitted. Allowed malignancy exceptions are:

5. Localized skin cancer (melanoma and nonmelanoma) that has been completelyresected and considered curative within the last 24 months is eligible.

6. Cervix carcinoma in situ that has been completely resected and consideredcurative within the last 24 months is eligible.

7. Bladder carcinoma in situ that has been completely resected and consideredcurative within the last 24 months is eligible.

8. Breast carcinoma in situ that has been completely resected and consideredcurative within the last 24 months is eligible. Hormonal therapy aftercurative-intent treatment is permitted.

9. Prostate cancer that is low grade and localized (Grade Group 1, has not spreadto nearby lymph nodes [N0] or metastasized [M0]) within the last 24 months iseligible, including cases under surveillance only as part of standard of care.Androgen deprivation therapy is permitted.

10. Localized renal cell carcinoma (≤ Stage 2) that has been completely resectedand considered curative within the last 24 months is eligible.

11. Localized (Stage 1) colorectal cancer that has been completely resected andconsidered curative (without need for adjuvant chemotherapy) within the last 24months is eligible.

12. Any prior systemic anti-myeloma treatment (including BCMA-directed treatment) and/orradiotherapy before enrollment. Palliative radiation and corticosteroids (up tocumulative dose of 160mg prednisone or equivalent, and not requiring ongoingtherapy) prior to enrollment are permitted. Participants must have recovered fromall radiation-related toxicities. Patients with radiation-induced lung injury (RILI,radiation pneumonitis) during screening are excluded.

13. Prior allogeneic stem cell transplant (allo-SCT) (even if for another malignancy)

14. Live vaccine ≤ 4 weeks before enrollment and/or anticipating needing the vaccineduring study period.

15. Presence or suspicion of fungal, bacterial, viral, or other infection that issystemic uncontrolled or requiring IV antimicrobials for management. Simple urinarytract infections and uncomplicated bacterial pharyngitis are permitted if theparticipant is responding to active treatment and satisfies the criteria of beingafebrile (i.e., temperature < 38°C) for at least 24 hours prior to the investigatorconfirming the participant's eligibility.

16. Acute or chronic active hepatitis A, B, or C infection. Participants with a historyof hepatitis infection must have cleared their infection as determined by standardserological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines or applicable country guidelines.

17. Human immunodeficiency virus (HIV)-seropositive.

18. Participants with history or presence of chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normalwill not be permitted to receive anti-CD38 monoclonal antibody in combination withVRd therapy; Note: FEV1 testing is required for participants who are planned

19. 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 withCNS involvement, PRES, or cerebral edema with confirmed structural defects byappropriate imaging. History of stroke or transient ischemic attack within 12 monthsbefore enrollment, or seizure disorders requiring active anticonvulsive medication.Patient with history of neurodegenerative disease (e.g., Parkinson's or Alzheimer'sdisease) must be excluded.

20. Peripheral neuropathy of Grade 3 or higher (per CTCAE v5.0; participants with Grade 2 peripheral neuropathy are eligible).

21. History of solitary plasmacytoma

22. History of autoimmune disease (e.g., Crohn's disease, rheumatoid arthritis, systemiclupus) resulting in or requiring systemic immunosuppression or systemicdisease-modifying agents within 2 years.

23. History of concomitant genetic syndrome associated with bone marrow failure, such asFanconi anemia, Kostmann syndrome, or Shwachman-Diamond syndrome.

24. 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/PEoccurred > 6 months before enrollment, and if the participant is on a stablemaintenance dose.

25. Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube,indwelling Foley catheter, biliary drain, G/J tube, orpleural/peritoneal/pericardial catheter). Dedicated central venous access catheterssuch as Port-a-Cath or Hickman catheter are permitted.

26. Major surgery within 28 days before enrollment, or planned surgery required duringstudy participation.

27. Any medical, neurologic or psychiatric condition that in the investigator's opinionis likely to interfere with study procedures including assessment of safety orefficacy of the study treatment.

28. Females who are pregnant or breastfeeding (due to the potentially dangerous effectsof the lymphodepleting chemotherapy or induction regimen on the fetus or infant).

29. Participants of both sexes who are not willing to practice highly effective birthcontrol from the time of consent through 12 months following lymphodepletingchemotherapy administration, 12 months after the completion of anitocabtageneautoleucel, 5 months after the last dose of isatuximab, 3 months after the last doseof daratumumab, bortezomib, or 28 days after the last dose of lenalidomide,whichever is longer (refer to Section 12.2). Females who have undergone surgicalsterilization or who have been postmenopausal for at least 2 years are notconsidered to be of childbearing potential. Participants of both sexes must alsocomply with any relevant REMS or aRMMs as part of an RMP. Additional information isin Section 6.3.1.

30. As per the investigator's judgment, the participant is unlikely to complete allprotocol required study visits or procedures, including follow-up visits, or complywith or tolerate the study requirements for participation (e.g., participants whoare at a risk for a thromboembolic event and are not willing to take venousthromboembolism prophylaxis should be excluded).

31. Contraindication to fludarabine or cyclophosphamide.

32. History of allergy or hypersensitivity to any study agent or study drug components.Participants with a history of severe hypersensitivity reaction to dimethylsulfoxide (DMSO) are excluded.