CAR-T Cell Therapy in RelApsed/Refractory Myeloma With ExtrameduLlary Disease - an in Vivo Imaging and Molecular Monitoring Study

Inclusion Criteria: Patients must meet all the following criteria for study entry:

1. Patient has provided written informed consent
2. Patient is >18 years of age at the time of consent
3. Patient has a documented diagnosis of MM according to the IMWG diagnostic criteria (Appendix 1)
4. Measurable extramedullary disease by any imaging modality (at least one site ofdisease ≥1cm that has never received radiotherapy or has progressed followingradiotherapy). Presence of biochemical measurable disease is not required
5. Have received at least 2 prior lines of therapy including a PTI and an IMiD. Patientmust have undergone at least 1 complete cycle of treatment for each line of therapy,unless PD was the best response to the line of therapy (Appendix 2) Note: inductionwith or without haematopoietic stem cell transplant, consolidation and maintenancetherapy is considered a single line of therapy.
6. Have an ECOG Performance Status score of 0 or 1 (Appendix 3)
7. Have a life expectancy of ≥3 months, as judged by the Investigator
8. Able to undergo apheresis for mononuclear cell collection
9. Have clinical laboratory values meeting the following criteria within 7 days prior toregistration (enrolment):

• Haemoglobin ≥80g/L (recombinant human erythropoietin use is permitted)
• ANC ≥1 × 109/L (prior growth factor support is permitted but must be withoutsupport in the 7 days prior to the laboratory test)
• Platelet count ≥50 × 109/L
• Absolute lymphocyte count ≥0.3 × 109/L
• AST ≤3.0× ULN
• ALT ≤3.0× ULN
• Total bilirubin ≤2.0× ULN; except in patients with congenital bilirubinaemia,such as Gilbert's syndrome (in which case direct bilirubin ≤2.0× ULN is required)
• Calculated CrCl ≥40mL/min calculated by the Cockcroft-Gault formula (Appendix 4),nuclear medicine assessment or a 24-hour urine collection

10. When a woman is of childbearing potential, the patient must commit either toabstaining continuously from heterosexual intercourse or agree to practice 2 methodsof reliable birth control simultaneously. Where one of the methods is highly effectivemethod of contraception (failure rate of <1% per year when used consistently andcorrectly; see examples below) and one other effective method (i.e., male latex orsynthetic condom, diaphragm, or cervical cap) and patient must agree to remain on bothmethods from the time of signing the PICF until at least 1 year after receiving acilta-cel infusion (Appendix 5). Reliable contraception is indicated even where therehas been a history of infertility, unless it is due to hysterectomy. WOCBP should bereferred to a qualified provider of contraceptive methods, if needed. Examples ofhighly effective contraceptives include:

• User-independent methods: 1) implantable progestogen-only hormone contraceptionassociated with inhibition of ovulation; 2) intrauterine device; intrauterinehormone-releasing system; 3) vasectomised partner
• User-dependent method: progestogen-only hormone contraception associated withinhibition of ovulation (oral or injectable)

11. A man must commit either to abstaining continuously from heterosexual intercourse or aman who is sexually active with a WOCBP or a pregnant woman must agree to use abarrier method of contraception (e.g., latex or synthetic condom with spermicidalfoam/gel/film/cream/suppository) from the time of signing the PICF until at least 1year after receiving a cilta-cel, even if they have undergone a successful vasectomy
12. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively,until at least 1 year after receiving a cilta-cel infusion
13. Patient must be willing and able to adhere to the following lifestyle restrictionsduring the study to be eligible for participation:

• Refer to Section 8.6.3, Prohibited Therapies for details regarding prohibited andrestricted therapy during the study
• Agree to follow all requirements that must be met during the study as noted inthe Inclusion and Exclusion Criteria (e.g., contraceptive requirements)

Exclusion Criteria: 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 withinthe 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 forCOVID-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 drugor use of an invasive investigational medical device within 14 days or at least 5half-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 palliativepurposes and the radiation portal covered ≤5% of the bone marrow reserve, thepatient is eligible irrespective of the end date of radiotherapy

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

• Non-muscle invasive bladder cancer treated within the last 24 months that isconsidered completely cured
• Skin cancer (non-melanoma or melanoma) treated within the last 24 months that isconsidered completely cured
• Non-invasive cervical cancer treated within the last 24 months that is consideredcompletely cured
• Localised prostate cancer (N0M0):
• With a Gleason score of ≤6, treated within the last 24 months or untreatedand under surveillance
• With a Gleason score of 3+4 that has been treated more than 6 months priorto full study screening and considered to have a very low risk ofrecurrence, or
• History of localised prostate cancer and receiving androgen deprivationtherapy and considered to have a very low risk of recurrence
• Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinomain situ, or history of localised breast cancer and receiving anti-hormonal agentsand 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 standarddifferential), Waldenström's macroglobulinaemia, POEMS syndrome (polyneuropathy,organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primaryamyloid light-chain amyloidosis
11. Contraindications or known life-threatening allergies, hypersensitivity, orintolerance to any of the study treatments (if known) or any of their excipients,including boron, mannitol, and dimethyl sulfoxide (refer to IB), or local productprescribing information for complete lists of excipients
12. Pregnant or breast-feeding or planning to become pregnant while enrolled in this studyor within 1 year after receiving cilta-cel infusion
13. Plans to father a child while enrolled in this study or within 1 year after receivingcilta-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 allimmunosuppressive medications for 6 weeks without signs of graft-versus-hostdisease. 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 ofmeningeal 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, quantitativeviral levels are necessary to determine the infection status (Appendix 6)
• Hepatitis C infection (defined as anti -HCV antibody positive or HCV-RNApositive) or known to have a history of hepatitis C NOTE: For patients withpositive HCV antibody due to prior resolved disease can be enrolled, only if aconfirmatory HCV RNA test is undetectable. For patients with known history of HCVinfection, confirmation of sustained virologic response is required for studyeligibility, defined as undetectable HCV RNA ≥24 weeks after completion ofantiviral therapy.

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

• Requirement of continuous supplemental oxygen
• Evidence of active viral or bacterial infection, requiring systemic antimicrobialtherapy, 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 toplanned apheresis
• History of clinically significant ventricular arrhythmia or unexplainedsyncope, 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 scanperformed ≤8 weeks before planned apheresis

19. Major operations or surgical procedures within 2 weeks prior to bridging therapy, orhas surgery planned during the study or within 2 weeks after study treatmentadministration Note: patients with planned surgical procedures to be conducted underlocal 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 theplanned treatment, to understand informed consent or any condition for which, in theopinion of the Investigator, participation would not be in the best interest of thepatient (e.g., compromise the well-being) or that could prevent, limit, or confoundthe protocol-specified assessments