Ciltacabtagene Autoleucel in High-Risk Smoldering Multiple Myeloma

Inclusion Criteria:

• Be ≥18 years of age (or the legal age of consent in the jurisdiction in which thestudy is taking place) at the time of informed consent.

• High-risk SMM defined as having 1 of the following 2 criteria: i) High-risk per "Mayo 20-2-20" criteria defined as presence of any ≥2 of the following:

1. Serum M-protein ≥2 gm/dL

2. Involved to uninvolved FLC ratio ≥20

3. BMPC % ≥20% to <40% OR ii) Presence of ≥95% of BMPC with an aberrant phenotypewithin the BMPC compartment and immunoparesis present defined as a reduction of atleast 25% below the lower normal limit for ≥1 uninvolved immunoglobulin isotype (only IgG, IgA and IgM will be considered).

• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1.

• Have an estimated glomerular filtration rate (eGFR), based on the Modified Dietin Renal Disease (MDRD) 4-variable formula or 24-hour urine collection of ≥40mL/min during the screening period.

• Laboratory values obtained <21 days prior to Screening: i) Total bilirubin ≤2.0mg/dL ii) Aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN)iii) Alanine transaminase (ALT) ≤3 x ULN

• Hemoglobin ≥8.0 g/dL (≥5 mmol/L) (without prior red blood cell [RBC]transfusion within 7 days before the laboratory test; recombinant humanerythropoietin use is permitted). For subjects who meet the inclusion criteriaat screening, transfusion of RBCs is permitted after screening as needed tomaintain a hemoglobin level ≥8.0 g/dL.

• Neutrophils ≥1.0 × 109/L (prior growth factor support is permitted but must bewithout support in the 7 days prior to the laboratory test)

• Platelets ≥75 × 109/L (must be without transfusion support in the 7 days priorto the laboratory test)

• Lymphocyte count ≥0.3*109/L

• Participants should be seronegative for human immunodeficiency virus (HIV) orhave controlled disease if seropositive.

• A female participant of childbearing potential must have a negative serumpregnancy test at screening and within 72 hours of the first dose of studytreatment and must agree to further serum or urine pregnancy tests during thestudy.

• A female participant must be either of the following: i) Not of childbearingpotential ii) Of childbearing potential and practicing at least 1 highlyeffective method of contraception throughout the study and through 6 monthsafter the last dose of study treatment. If a female participant becomes ofchildbearing potential after the start of the study, the female participantmust comply with ii).

• A female participant using oral contraceptives should use an additional barriercontraceptive method.

• A female participant must agree not to donate eggs (ova, oocytes) or freeze forfuture use for the purposes of assisted reproduction during the study and for aperiod of 6 months after receiving the cilta-cel infusion. Female participantsshould consider preservation of eggs prior to study treatment as anti-cancertreatments may impair fertility.

• A male participant must wear a condom when engaging in any activity that allowsfor passage of ejaculate to another person during the study and for 1 yearafter receiving the cilta-cel infusion. If the male participant's partner is afemale of childbearing potential, the male participant must use condoms (withor without spermicide) and the female partner of the male participant must alsobe practicing a highly effective method of contraception. A male participantwho is vasectomized must still use a condom (with or without spermicide), butthe partner is not required to use contraception.

• A male participant must agree not to donate sperm for the purposes ofreproduction during the study and for 1 year after receiving the last dose ofstudy treatment. Male participants should consider preservation of sperm priorto study treatment as anti-cancer treatments may impair fertility.

• A male participant must agree not to plan to father a child while enrolled inthis study or within 1 year after the last dose of study treatment.

• Must sign an informed consent form (ICF) indicating that the participantunderstands the purpose of, and procedures required for, the study and iswilling to participate in the study

• An additional ICF will be collected to get participants authorization tocollect the necessary samples for performing the Biological studies indicatedin this protocol.

• Be willing and able to adhere to the lifestyle restrictions specified in thisprotocol.

Exclusion Criteria:

• History of uncontrolled illness, including but not limited to MGUS, standardrisk smoldering myeloma, active myeloma by current IMWG definition, light chainamyloidosis with organ involvement or patients with extramedullary disease.

• Non-muscle-invasive bladder cancer treated within the last 24 months that isconsidered completely cured.

• Skin cancer (nonmelanoma or melanoma) treated within the last 24 months that isconsidered completely cured.

• Noninvasive cervical cancer treated within the last 24 months that isconsidered completely cured.

• Localized prostate cancer (N0M0):i) with a Gleason score ≤6, treated within the last 24 months or untreated andunder surveillance. ii) with a Gleason score of 3+4 that has been treated more than 6 months prior tofull study screening and considered to have a very low risk of recurrence. iii) history of localized prostate cancer and receiving androgen deprivation therapyand considered to have a very low risk of recurrence).

• Adequately treated lobular carcinoma in situ or ductal carcinoma in situ.

• History of localized breast cancer and receiving antihormonal agents andconsidered to have a very low risk of recurrence.

• Known allergies, hypersensitivity, or intolerance to cilta-cel or itsexcipients.

• Participant had major surgery or had significant traumatic injury ≤14 daysprior to Cycle1Day1.

• If any of the following exist at screening, participant will be excludedbecause this trial involves an investigational agent whose genotoxic,mutagenic, and teratogenic effect on the developing fetus and newborn areunknown:i) Pregnant women ii) Nursing women iii) Men or women of childbearing potentialwho are unwilling to employ adequate contraception

• Other comorbidity which would interfere with subject's ability to participatein trial, eg, uncontrolled infection, uncompensated heart, or lung disease.

• Any medical or psychiatric illness that could, in the investigator's opinion,potentially interfere with the completion of treatment according to thisprotocol.

• History of neurodegenerative disease (eg, Parkinson or stroke within 6 months).

• Medical history of treatment for another malignancy <2 years before trialenrollment, other concurrent chemotherapy, or any ancillary therapy consideredinvestigational. Note: Bisphosphonates are considered supportive care ratherthan therapy and are thus allowed while on protocol treatment.

• Known seropositive for or active viral infection with HIV, HBV, hepatitis Cvirus (HCV), or SARS-CoV-2 (Coronavirus Disease 2019 [COVID-19]).i) Participants who are positive for SARS-COV-2 antibody, HIV1 and 2 antibody,hepatitis B core antibody (HBc), or hepatitis B surface antigen (HBsAg) musthave a negative polymerase chain reaction (PCR) result before enrollment. Thosewho are PCR positive will be excluded. ii) Participants who are positive for HIV1 or 2 infections, with undetectable viralload and on stable antiretrovirals, will not be excluded. iii) Participants with past HCV infection need at least 12 months of sustainedvirologic response and be negative for RNA to enter. iv) Patients with a high-risk of HBV reactivation (eg, negative for HBV antigen butpositive for chronic HBV, with or without anti-serum HBV) must be monitored with DNAand ALT/AST).

• Any condition for which, in the opinion of the investigator, participationwould not be in the best interest of the participant (eg, compromise thewell-being) or that could prevent, limit, or confound the protocol-specifiedassessments. NOTE: Investigators must ensure that all study enrollment criteria have been met atscreening. If a participant's clinical status changes (including any availablelaboratory results or receipt of additional medical records) after screening butbefore the first dose of study intervention is given such that the participant nolonger meets all eligibility criteria, then the participant must be excluded fromparticipation in the study.