CARAMEL: This study is investigating CAR-T cell therapy in people with relapsed or refractory myeloma with extramedullary diseaseCAR-T Cell Therapy in RelApsed/Refractory Myeloma With ExtrameduLlary Disease - an in Vivo Imaging and Molecular Monitoring Study

Exclusion

Patients who meet any of the following criteria will be excluded from study entry:

1. Known nickel or Pd sensitivity
2. Weight >105 Kg and/or height >185 cm
3. Known claustrophobia
4. Prior treatment with CAR-T therapy directed at any target
5. Received a cumulative dose of corticosteroids equivalent to ≥70mg of prednisone within the 7 days prior to planned apheresis
6. Any prior therapy that is targeted to BCMA
7. Vaccination with an investigational vaccine or live attenuated vaccine (except for COVID-19) within 4 weeks prior to planned conditioning

8. Patient received any anti-tumour therapy as follows, prior to planned apheresis:

   • Targeted therapy, epigenetic therapy, or treatment with an investigational drug or use of an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less
   • Investigational vaccine within 4 weeks
   • Monoclonal antibody treatment within 21 days
   • Cytotoxic therapy within 14 days
   • Radiotherapy within 14 days. However, if the radiation is given for palliative purposes and the radiation portal covered ≤5% of the bone marrow reserve, the patient is eligible irrespective of the end date of radiotherapy

9. Active malignancies (i.e., progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are:

   • Non-muscle invasive bladder cancer treated within the last 24 months that is considered completely cured
   • Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured
   • Non-invasive cervical cancer treated within the last 24 months that is considered completely cured

   • Localised prostate cancer (N0M0):

     • With a Gleason score of ≤6, treated within the last 24 months or untreated and under surveillance
     • With a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence, or
     • History of localised prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence
   • Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localised breast cancer and receiving anti-hormonal agents and considered to have a very low risk of recurrence
   • Malignancy that is considered cured with minimal risk of recurrence
10. Plasma cell leukaemia at the time of screening (>2.0 x 109/L plasma cells by standard differential), Waldenström's macroglobulinaemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary amyloid light-chain amyloidosis
11. Contraindications or known life-threatening allergies, hypersensitivity, or intolerance to any of the study treatments (if known) or any of their excipients, including boron, mannitol, and dimethyl sulfoxide (refer to IB), or local product prescribing information for complete lists of excipients
12. Pregnant or breast-feeding or planning to become pregnant while enrolled in this study or within 1 year after receiving cilta-cel infusion
13. Plans to father a child while enrolled in this study or within 1 year after receiving cilta-cel infusion
14. Stroke or seizure within 6 months prior to signing PICF

15. Received either of the following:

    • An allogenic stem cell transplant within 6 months before planned apheresis. Patients who received an allogeneic transplant must have stopped all immunosuppressive medications for 6 weeks without signs of graft-versus-host disease. Patients with active graft-versus-host disease are excluded
    • An ASCT ≤12 weeks before planned apheresis
16. Known active, or prior history of, CNS involvement or exhibits clinical signs of meningeal involvement of MM

17. Any of the following criterion related to infectious diseases:

    • Seropositive for HIV
    • Hepatitis B infection: In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status (Appendix 6)
    • Hepatitis C infection (defined as anti -HCV antibody positive or HCV-RNA positive) or known to have a history of hepatitis C NOTE: For patients with positive HCV antibody due to prior resolved disease can be enrolled, only if a confirmatory HCV RNA test is undetectable. For patients with known history of HCV infection, confirmation of sustained virologic response is required for study eligibility, defined as undetectable HCV RNA ≥24 weeks after completion of antiviral therapy.

18. Serious underlying medical or psychiatric condition or disease, that is likely to interfere with study procedures or results, or that in the opinion of the Investigator would constitute a hazard for participating in this study, such as:

    • Requirement of continuous supplemental oxygen
    • Evidence of active viral or bacterial infection, requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection
    • Active autoimmune disease
    • Overt clinical evidence of dementia or altered mental status
    • Any history of Parkinson's disease or other neurodegenerative disorder

    • Clinically significant cardiac conditions, such as:

      • NYHA Class III or IV congestive heart failure (Appendix 7) Short title: CARAMEL Page 60 of 128 Version: 1.0 Date: 17th November 2022
      • Myocardial infarction or coronary-artery-bypass graft ≤6 months prior to planned apheresis
      • 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 ECHO or MUGA scan performed ≤8 weeks before planned apheresis
19. Major operations or surgical procedures within 2 weeks prior to bridging therapy, or has surgery planned during the study or within 2 weeks after study treatment administration Note: patients with planned surgical procedures to be conducted under local anaesthesia may participate.
20. Frailty index of ≥ 2 according to Myeloma Geriatric Assessment score (Appendix 8)
21. Any issue that would impair the ability of the patient to receive or tolerate the planned treatment, to understand informed consent or any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments