Immuno-PRISM (PRecision Intervention Smoldering Myeloma)

Inclusion Criteria:

• Age ≥18 years.

1. High risk SMM defined as having 1 of the following 2 criteria: High risk per "20-2-20" Criteria defined as presence of any two of the following:

-- Serum M spike ≥ 2 gm/dL, Involved to uninvolved free light chain (FLC) ratio≥ 20,Bone marrow Plasma Cell (BMPC) % ≥ 20%

• 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

• Fluorescence In Situ Hybridization (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:

• evolving Monoclonal Protein (eMP) (≥10% increase in MonoclonalProtein/Immunoglobulin (Ig)) within the first 6 months (only if M-protein ≥3g/dl) and/or ≥25% increase in M/Ig within the first 12 months, with a minimumrequired increase of 0.5 g/dl in M-protein and/or 500 mg/dl in Ig.

• Evolving change in hemoglobin (eHb) ≥0.5 g/dl decrease within 12 months ofdiagnosis;

• Progressive involved light chain increase on two successive evaluation

• Abnormal Plasma Cell immunophenotype (≥ 95% of BMPCs are clonal) and reductionof ≥1 uninvolved 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), 17pdeletion, TP53 mutation, 1q21 gain

• Monoclonal light chain excretion of > 200mg/24 hours for those with monoclonallight chain SMM

• No evidence of CRAB criteria* or new criteria of active MM (SLIM-CRAB) which includethe 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 conditions other than thedisease under study may be eligible after discussion with the Sponsor Investigator.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, or 2

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

• Absolute Neutrophil Count (ANC) >1000/mL

• Platelets Count (PLT) >75,000/mL

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

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

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

• Estimated creatinine clearance (CLcr) ≥60 mL/min

• Voluntary written informed consent will be obtained before performance of anystudy-related procedure not part of normal medical care, with the understanding thatconsent may be withdrawn by the subject at any time without prejudice to futuremedical care.

• Females of child-bearing potential* randomized to Lenalidomide must have a negativeserum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by Revlimid Risk Evaluationand Mitigation Strategies (REMS®) and must either commit to continued abstinencefrom heterosexual intercourse or begin TWO acceptable methods of birth control, onehighly effective method and one additional effective method AT THE SAME TIME, atleast 28 days before she starts taking lenalidomide.

• A female of child-bearing potential is a sexually mature female who: has notundergone a hysterectomy (the surgical removal of the uterus) or bilateraloophorectomy (the surgical removal of both ovaries), or has not been naturallypostmenopausal (amenorrhea following cancer therapy does not rule outchildbearing potential) for at least 24 consecutive months (i.e., has hadmenses at any time during the preceding 24 consecutive months)

• A woman must be . A Not of childbearing potential, or b. Of childbearingpotential and Practicing true abstinence; or Have a sole partner who isvasectomized; or Practicing ≥1 highly-effective, user-independent method ofcontraception NOTE: Participant must agree to continue the above throughout thestudy and for 90 days after the last dose of study treatment.

NOTE: If a woman becomes of childbearing potential after start of the study the woman must comply with point (b) as described above.

NOTE: An interaction between hormonal contraception and teclistamab has not been formally studied. Therefore, it is unknown whether teclistamab may reduce the efficacy of the contraception method.

• A woman must agree not to donate eggs (ova, oocytes) or freeze for future use, forthe purposes of assisted reproduction during the study and for 90 days afterreceiving the last dose of study treatment

• A man must wear a condom (with or without spermicidalfoam/gel/film/cream/suppository) when engaging in any activity that allows forpassage of ejaculate to another person during the study and for a minimum of 90 daysafter receiving the last dose of study treatment. If a female partner is ofchildbearing potential, she must also be practicing a highly effective method ofcontraception

• If the male participant is vasectomized, he still must wear a condom (withspermicidal foam/gel/film/cream/suppository), but his female partner is not requiredto use contraception.

• A male participant must agree not to donate sperm for the purpose of reproductionduring the study and for a minimum of 90 days after receiving the last dose of studytreatment.

• Must be willing and able to adhere to the lifestyle restrictions specified in thisprotocol

• All study participants randomized to lenalidomide must be registered into themandatory Revlimid REMS® program and be willing and able to comply with therequirements of the REMS® program.

• Females of child-bearing potential must adhere to the scheduled pregnancy testing asrequired in the Revlimid REMS® program if randomized to lenalidomide

• Men must agree to use a latex condom during sexual contact with a female ofchildbearing potential even if they have had a successful vasectomy

• Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

• Prior SMM directed therapy administered within 6 months of beginning treatment onstudy. To avoid including primary refractory cases to the lenalidomide arm,participants who received a prior lenalidomide-based therapy should have had atleast an Minimal Response (MR) to be considered on this trial.

• Symptomatic Multiple Myeloma or any evidence of CRAB criteria, including presence ofmyeloma defining events (MDE). Any prior therapy for active Myeloma should also beexcluded. Prior therapy for smoldering myeloma is not an exclusion criterion.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 6months prior to enrollment on the trial. Prior clinical trials or therapy forsmoldering MM or Monoclonal Gammopathy of Unknown Significance (MGUS) are allowedper 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

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

• Plans to father a child while enrolled in this study or within 90 days afterreceiving the last dose of study drug.

• Pregnant or breast-feeding or planning to become pregnant while enrolled in thisstudy or within 90 days 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 are eligible.

• 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 PCR positivewill be excluded.

• Contraindications or life-threatening allergies, hypersensitivity, or intolerance toany study drug or its excipients (refer to the teclistamab Investigator's Brochureand appropriate package inserts).

• Prior or concurrent exposure to any of the following:

• Investigational vaccine within 4 weeks

• Live, attenuated vaccine within 4 weeks before randomization.

• Monoclonal antibody therapy within 21 days

• Cytotoxic therapy within 14 days

• PI therapy within 14 days

• IMiD agent therapy within 14 days

• Radiotherapy within 14 days or focal radiation within 7 days

• A maximum cumulative dose of corticosteroids of ≥140 mg of prednisone or equivalentwithin 14-day period before the first dose of study drug (does not includepretreatment medications)

• Known active Central Nervous System (CNS) involvement or exhibits clinical signs ofmeningeal involvement of multiple myeloma. If either is suspected, negative wholebrain MRI and lumbar cytology are required.

• Myelodysplastic syndrome or active malignancies (i.e., progressing or requiringtreatment change in the last 24 months). The only allowed exceptions are: a.Non-muscle invasive bladder cancer treated within the last 24 months that isconsidered completely cured b. Skin cancer (non-melanoma or melanoma) treated withinthe last 24 months that is considered completely cured. c. Noninvasive cervicalcancer treated within the last 24 months that is considered completely cured d.Localized prostate cancer (N0M0): With a Gleason score of ≤6, treated within thelast 24 months, or untreated and under surveillance With a Gleason score of 3+4 thathas been treated >6 months prior to full study screening and considered to have avery low risk of recurrence, or e. History of localized prostate cancer andreceiving androgen deprivation therapy and considered to have a very low risk ofrecurrence. f. Breast cancer: adequately treated lobular carcinoma in situ or ductalcarcinoma in situ, or history of localized breast cancer and receiving antihormonalagents and considered to have a very low risk of recurrence. g. Other malignancythat is considered cured with minimal risk of recurrence

• Stroke or seizure within 6 months prior to signing informed consent form

• Presence of the following cardiac conditions:

-- New York Heart Association stage III or IV congestive heart failure, 2)Myocardial infarction or coronary artery bypass graft ≤6 months prior torandomization,3) History of clinically significant ventricular arrhythmia orunexplained syncope, 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. NOTE:Participants with planned surgical procedures to be conducted under local anesthesiamay participate. Kyphoplasty or vertebroplasty are not considered major surgery. Ifthere is a question whether a procedure is considered a major surgery, theinvestigator must consult with the appropriate sponsor representative and resolveany issues before enrolling a participant in the study.

• 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:

• Uncontrolled diabetes defined by Hemoglobin A1C > 8.5, Acute diffuse infiltrativepulmonary disease, Evidence of active systemic viral, fungal, or bacterialinfection, requiring systemic, antimicrobial therapy, History of autoimmune diseasewith the exception of vitiligo, type I diabetes, and, prior autoimmune thyroiditisthat is currently euthyroid based on clinical symptoms and laboratory testing, .Disabling psychiatric conditions (e.g., alcohol or drug abuse), severe dementia, oraltered mental status, Any other issue that would impair the ability of theparticipant to receive or tolerate the planned treatment at the investigationalsite, to understand informed consent or any condition for which, in the opinion ofthe investigator, participation would not be in the best interest of the participant (e.g., compromise the wellbeing) or that could prevent, limit, or confound theprotocol-specified assessments, History of non-compliance with recommended medicaltreatments