CAR- PRISM (PRecision Intervention Smoldering Myeloma)

Inclusion Criteria:

• Age > 18 years.

• High-risk SMM with ≤40% plasma cells in the bone marrow and with high-risk criteriadefined as having 1 of the following 2 criteria:

1. High-risk per "20-2-20" Criteria defined as presence of any two of thefollowing:

• Serum M-protein ≥ 2 gm/dL
• Involved to uninvolved free light chain (FLC) ratio≥ 20
• Bone marrow PC% ≥ 20% to <40%.
• OR total score of 9 using the following scoring system:
• FLC Ratio
• >10-25 = 2
• >25-40 = 3
• > 40 = 5
• Serum M-protein (g/dL)
• >1.5-3 = 3
• >3 = 4
• BMPC%
• >15-20 = 2
• >20-30 = 3
• >30-40 = 5
• >40 = 6
• FISH abnormality (t(4,14), t(14,16), 1q gain, or del13q = 2

2. Presence of ≥10% BMPC and at least one of the following:

• Evolving pattern:

• eMP (≥10% increase in serum M-protein ) over a 6 month period OR;

• Evolving change in hemoglobin (eHb) ≥ 0.5 g/dl decrease over a 12months period OR;

• Progressive Involved light chain increase >10% over a 6 month periodalong with a light chain ration > 8

• Abnormal PC immunophenotype (≥95% of BMPCs are clonal) and reduction of ≥1uninvolved immunoglobulin isotype. (Only IgG; IgA and IgM will beconsidered) High risk cytogenetics defined as presence of t(4;14),t(14;16), t(14;20), 17p deletion, TP53 mutation, 1q21 gain

• No evidence of CRAB criteria* or new criteria of active MM (SLIM-CRAB) whichincluding the following:

• Increased calcium levels: Corrected serum calcium >0.25 mmol/L (>1mg/dL) abovethe upper limit of normal or >2.75 mmol/L (>11mg/dL);

• Renal insufficiency (attributable to myeloma);

• Anemia (Hgb 2g/dL below the lower limit of normal or <10g/dL);

• Bone lesions (lytic lesions or generalized osteoporosis with compressionfractures)

• No evidence of the following new criteria for active MM including thefollowing:

• Bone marrow plasma cells >60%

• Serum involved/uninvolved FLC ratio ≥100

• MRI with more than one focal lesion

• Participants with CRAB criteria that are attributable to conditionsother than the disease under study may be eligible after discussionwith the Sponsor Investigator.

• ECOG Performance Status (PS) 0 or 1 (Appendix 8)

• The following laboratory values obtained < 28 days prior to registration:

• ANC >1000/mL

• PLT >75,000/mL

• Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and if normalpatient is eligible.)

• AST <2.5 x institutional upper limit of normal (ULN)

• ALT <2.5 x institutional upper limit of normal (ULN)

• Estimated creatinine clearance CrCl ≥60 mL/min (Cockcroft Gault equation).

• Voluntary written informed consent before performance of any study-related procedurenot part of normal medical care, with the understanding that consent may bewithdrawn by the subject at any time without prejudice to future medical care.

• Women of childbearing potential must have a negative pregnancy test at screening.

• When a woman is of childbearing potential, the following are required: • Subject must agree to practice a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agreeto remain on a highly effective method of contraception from the time ofsigning the informed consent form (ICF) until 1 year after receiving acilta-cel infusion. Examples of highly effective contraceptives include:

• user-independent methods: 1) implantable progestogen-only hormonecontraception associated with inhibition of ovulation; 2) intrauterinedevice; intrauterine hormone- releasing system; 3) vasectomized partner.

• user-dependent methods: 1) combined (estrogen- and progestogen-containing)hormonal contraception associated with inhibition of ovulation: oral orintravaginal or transdermal; 2) progestogen-only hormone contraceptionassociated with inhibition of ovulation (oral or injectable).

• In addition to the highly effective method of contraception, a man:

• Who is sexually active with a woman of childbearing potential must agreeto use a barrier method of contraception (eg, condom with spermicidalfoam/gel/film/cream/suppository) from the time of signing the ICF until 1year after receiving a cilta-cel infusion.

• Who is sexually active with a woman who is pregnant must use a condom.Women and men must agree not to donate eggs (ova, oocytes) or sperm,respectively, during the study and for 1 year after the last dose of studytreatment.

Note: Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive method.

Exclusion Criteria:

• Prior SMM directed therapy.

• Symptomatic Multiple Myeloma or any evidence of CRAB criteria, including presence ofmyeloma defining events (MDE). Any prior therapy for active Myeloma should also beexcluded. Bisphosphonates are not excluded.

• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapyconsidered investigational. Prior therapy with bisphosphonate is allowed. Priorradiation therapy to a solitary plasmacytoma is allowed but had to be at least 1year prior to enrollment on the trial. Prior clinical trials or therapy forsmoldering MM or MGUS are not allowed per exclusion criteria described above.

• Serious medical or psychiatric illness likely to interfere with participation inthis clinical study.

• Diagnosed or treated for another malignancy within 2 years of enrollment, with theexception of complete resection of basal cell carcinoma or squamous cell carcinomaof the skin, an in-situ malignancy, or low-risk prostate cancer after curativetherapy.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, inflammatory disorders, unstableangina pectoris, cardiac arrhythmia, or psychiatric illness/social situations thatwould limit compliance with study requirements.

• Plans to father a child while enrolled in this study or within 1 year afterreceiving the last dose of study drug.

• Pregnant or breast-feeding or planning to become pregnant while enrolled in thisstudy or within 1 year after receiving the last dose of study drug.

• Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) or SARS-CoV-2 (COVID-19).

• Participants who are seropositive because of hepatitis B virus vaccine areeligible.

• Participants who are positive for SARS-COV-2 antibody, HIV1 and 2 antibody,hepatitis B core antibody or hepatitis B surface antigen must have a negativepolymerase chain reaction (PCR) result before enrollment. Those who are PCRpositive will be excluded.

• Participants who are positive for HIV1 or 2 infections, with undetectable viralload and on stable antiretrovirals, will not be excluded.

• Participants with past HCV infection that have now cleared will not beexcluded.

• Contraindications or life-threatening allergies, hypersensitivity, or intolerance toany study drug or its excipients (refer to Investigator's Brochure and appropriatepackage inserts).

• Prior or concurrent exposure to any of the following:

1. Teclistamab, Belantamab, or any anti-BCMA therapy

2. Investigational vaccine within 4 weeks of study therapy

3. Live, attenuated vaccine within 4 weeks of study therapy.

4. Monoclonal antibody therapy within 21 days except for those unrelated to MMtherapy such as rituximab or other monoclonal antibodies for RA for example.

5. Cytotoxic therapy within 14 days of study therapy

6. PI therapy within 14 days of study therapy

7. IMiD agent therapy within 14 days of study therapy

8. Radiotherapy within 14 days or focal radiation within 7 days of study therapy.

• Known active CNS involvement or exhibits clinical signs of meningeal involvement ofmultiple myeloma. If either is suspected, negative whole brain MRI and lumbarcytology are required.

• Myelodysplastic syndrome or active malignancies (i.e., progressing or requiringtreatment change in the last 24 months). The only allowed exceptions are:

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

2. Skin cancer (non-melanoma or melanoma) treated within the last 24 months thatis considered completely cured.

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

4. Localized prostate cancer (N0M0):

• With a Gleason score of <6, treated within the last 24 months, oruntreated and under surveillance.
• With a Gleason score of 3 or 4 that has been treated > 6months prior tostudy screening and considered to have a very low risk of occurrence, or

5. History of localized prostate cancer and receiving androgen deprivation therapyand considered to have a very low risk of recurrence.

6. Breast cancer: Adequately treated lobular carcinoma in situ or ductal carcinomain situ, or history of localized breast cancer and receiving anti-hormonalagents and considered to have a very low risk of recurrence.

7. Other malignancy that is considered cured with minimal risk of recurrence inthe judgement of the investigator.

• Stroke or seizure within 6 months prior to signing ICF.

• Presence of the following cardiac conditions:

1. New York Heart Association stage III or IV congestive heart failure

2. Myocardial infarction or coronary artery bypass graft ≤6 months

3. History of clinically significant ventricular arrhythmia or unexplainedsyncope, not believed to be vasovagal in nature or due to dehydration

4. History of severe non-ischemic cardiomyopathy

• Major surgery within 2 weeks prior to the start of administration of studytreatment, or will not have fully recovered from surgery, or has major surgeryplanned during the time the participant is expected to be treated in the study orwithin 2 weeks after administration of the last dose of study treatment.

• Concurrent medical or psychiatric condition or disease that is likely to interferewith study procedures or results, or that in the opinion of the investigator wouldconstitute a hazard for participating in this study, such as:

1. Uncontrolled diabetes.

2. Acute diffuse infiltrative pulmonary disease.

3. Evidence of active systemic viral, fungal, or bacterial infection, requiringsystemic antimicrobial therapy.

4. History of inflammatory disorders with the exception of vitiligo, type Idiabetes, and prior autoimmune thyroiditis that is currently euthyroid based onclinical symptoms and laboratory testing. Participants with mild rheumatoidarthritis will not be excluded.

5. Disabling psychiatric conditions (e.g., alcohol or drug abuse), severedementia, or altered mental status.

6. Any other issue that would impair the ability of the participant to receive ortolerate the planned treatment at the investigational site, to understandinformed consent or any condition for which, in the opinion of theinvestigator, participation would not be in the best interest of theparticipant (e.g., compromise the well-being) or that could prevent, limit, orconfound the protocol-specified assessments.

7. History of non-compliance with recommended medical treatments.