Phase II Open-Label, Single Arm, Multicenter Study of Ciltacabtagene Autoleucel in High-Risk Smoldering Multiple Myeloma

Prior treatment

• Active malignancies (ie, 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 (nonmelanoma or melanoma) treated within the last 24 months that is considered completely cured. • Noninvasive cervical cancer treated within the last 24 months that is considered completely cured. • Localized prostate cancer (N0M0): • with a Gleason score ≤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 localized 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 localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence. • Malignancy that is considered cured with minimal risk of recurrence
• Participant had major surgery or had significant traumatic injury ≤14 days prior to C1D1
• If any of the following exist at screening, participant will be excluded because this trial involves an investigational agent whose genotoxic, mutagenic, and teratogenic effect on the developing fetus and newborn are unknown: a) Pregnant participants; b)Nursing participants; c) Participants of childbearing potential who are unwilling to employ adequate contraception (per protocol)
• Medical history of treatment for another malignancy <2 years before trial enrollment, other concurrent chemotherapy, or any ancillary therapy considered investigational. Note: Bisphosphonates are considered supportive care rather than therapy and are thus allowed while on protocol treatment

Other illness

• History of uncontrolled illness, including but not limited to MGUS, standard risk smoldering myeloma, active myeloma by current IMWG definition, light chain amyloidosis with organ involvement or patients with extramedullary disease
• Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
• Known allergies, hypersensitivity, or intolerance to cilta-cel or its excipients (refer to the IB).
• Other comorbidity which would interfere with participant's ability to participate in 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 this protocol
• History of neurodegenerative disease (eg, Parkinson or other neurodegenerative disorders) including overt clinical evidence of dementia or altered mental status or; stroke (within 6 months).

Lab values

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

• Be ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.
• A participant of chilbearing potential using oral contraceptives should use an additional barrier contraceptive method (details in Appendix 5).
• A participant with childbearing potential must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the cilta-cel infusion. Participants of childbearing potential should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility.
• A participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for 1 year after receiving the cilta-cel infusion. If the participant’s partner is of childbearing potential, the participant must use condoms (with or without spermicide) and the partner of childbearing potential of the participant must also be practicing a highly effective method of contraception (see Appendix 5). A participant who is vasectomized must still use a condom (with or without spermicide), but the partner is not required to use contraception.
• A participant must agree not to donate sperm for the purposes of reproduction during the study and for 1 year after receiving the last dose of study treatment. Participants should consider preservation of sperm prior to study treatment as anti-cancer treatments may impair fertility.
• A participant must agree not to plan to father a child while enrolled in this study or within 1 year after the last dose of study treatment
• Must sign an informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study
• An additional ICF will be collected to get participants authorization to collect the necessary samples for performing the Biological studies indicated in this protocol
• Be willing and able to adhere to the lifestyle restrictions specified in this protocol
• Not included in other clinical trial or treated with an experimental drug
• High-risk SMM defined as having 1 of the following 2 criteria: 1. High-risk per “Mayo 20-2-20” criteria defined as presence of any ≥2 of the following: a. Serum M-protein ≥2 gm/dL b. Involved to uninvolved FLC ratio ≥20 c. BMPC % ≥20% OR 2. Presence of ≥95% of BMPC with an aberrant phenotype within the BMPC compartment and immunoparesis present defined as a reduction of at least 25% below the lower normal limit for ≥1 uninvolved immunoglobulin isotype (only IgG, IgA and IgM will be considered).
• Have an ECOG performance status of ≤1.
• Have an estimated glomerular filtration rate (eGFR), based on the Modified Diet in Renal Disease (MDRD) 4-variable formula (Appendix 11: Formulas for Estimating Glomerular Filtration Rate Using Modified Diet in Renal Disease Formula (in mL/min)) or 24-hour urine collection of ≥40 mL/min during the screening period
• Laboratory values obtained <21 days prior to Screening: • Total bilirubin ≤2.0 mg/dL • Aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) • Alanine transaminase (ALT) ≤3 x ULN
• Participants should have: • Hemoglobin ≥8.0 g/dL (≥5 mmol/L) (without prior red blood cell [RBC] transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted).* For participants who meet the inclusion criteria at screening, transfusion of RBCs is permitted after screening as needed to maintain a hemoglobin level 8.0 g/dL • Neutrophils ≥1.0 × 109/L (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test) • Platelets ≥75 × 109/L (must be without transfusion support in the 7 days prior to the laboratory test) • Lymphocyte count ≥0.3 × 109/L
• Participants should be seronegative for human immunodeficiency virus (HIV) or have controlled disease if seropositive.
• A participant of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study.
• A participant must be either of the following (as defined in Appendix 5) a. Not of childbearing potential, or b. Of childbearing potential and practicing at least 1 highly effective method of contraception (details in Appendix 5) contraception throughout the study and through 6 months after the last dose of study treatment. Note: If a participant becomes of childbearing potential after the start of the study, the participant must comply with (b.).