Teclistamab or Talquetamab in Combination with Daratumumab for High-Risk Smoldering Myeloma (REVIVE Study)

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed smoldering multiplemyeloma (SMM) based on the IMWG Criteria10 including:

• Serum M-protein ≥3 g/dL and/or BMPCs≥10 % (but <60%)

• Absence of anemia: hemoglobin >10 g/dL

• Absence of renal failure: serum creatinine <2.0 mg/dL

• Absence of hypercalcemia: Calcium <10.5 mg/dL

• Absence of lytic bone lesion on X-ray, CT, or positron emission tomography (PET)/CT and not more than 1 lesion on whole body MRI (NOTE: At the discretionof the Investigator, whole body CT or PET/CT may replace MRI in patients whohave a contraindication or who are unable to have MRI performed.)

• Involved/uninvolved light chain ratio <100 (unless involved light chain is ≤10mg/dL) NOTE: Anemia, renal failure, and hypercalcemia is allowed if deemedunrelated to multiple myeloma (MM), see organ function criteria in point #5below.

2. Patients must have measurable disease within the past 4 weeks, which is defined byany one of the following:

• Serum monoclonal protein ≥ 0.5 g/dL

• Urine monoclonal protein >200 mg/24 hour

• Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal kappa/lambda serumfree light chain ratio (reference: 0.26-1.65)

• Other measurable disease as defined by the International Myeloma Working Group (IMWG).

• Because the primary endpoint is MRD negativity based on bone marrow analysis, apatient without measurable disease in blood or urine may be enrolled andassessed for MRD negativity. NOTE: In patients who received minimal priortherapy within the allowable range per exclusion criteria 1, patients shouldhave had documented measurable disease within 4 weeks of starting thatrespective therapy if currently unmeasurable.

3. Patients age ≥18 years.

4. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1assessed within the past 45 days. (See Appendix 17.1).

5. Patients must have adequate organ and marrow function ≤45 days as defined below:

• Absolute neutrophil count (ANC) >1.0 K cells/μL; At the discretion of theInvestigator, patients with an ANC of 0.5 K/μL-1.0 K/μL may also be enrolled ifclinically appropriate (eg, patients with a baseline neutropenia that ischronic and/or ethnic neutropenia and that does not cause complications, e.g,no history of chronic infections).

• Platelet count >75 K cells/μL

• Hemoglobin >8 g/dL (transfusions are permissible if the cause of the anemia isother than myeloma)

• Total bilirubin <1.5 X upper limit of normal (ULN). NOTE: Isolated totalbilirubin ≥1.5 X ULN with conjugated [direct] bilirubin <1.5 X ULN is allowedfor those participants with known Gilbert's syndrome.

• Aspartate aminotransferase (AST)/ alanine transaminase (ALT) ≤2.5 X ULN

• ≥30 mL/min based on Modification of Diet in Renal Disease (MDRD) 4-variableFormula calculation (Appendix 17.2) or creatine clearance (CrCl) measured by a 24-hour urine collection. The estimated glomerular filtration rate (eGFR) mayalso be determined by using other widely accepted methods as clinicallyindicated, ie, Cockcroft-Gault method or the chronic kidney disease (CKD)-epidemiology collaboration (EPI) per institutional standards.

6. Patients must have SMM that is categorized as high-risk for progression toMM-related end- organ damage by both clinical and genomic characteristics. Patientsmay be categorized as high risk by the Program for Study and Treatment of MalignantHemopathies (PETHEMA) (immunoparesis and ≥95% aberrant bone marrow plasma cells (aBMPCs) by flow) and/or Mayo Clinic78 (20/2/20) criteria and/or have clonal BMPCs ≥10% with any one or more of the following criteria4:

• Serum M protein ≥3 g/dL

• Immunoglobulin A (IgA) SMM

• Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes

• Serum involved/uninvolved free light chain (FLC) ratio ≥8 (but <100)

• Progressive increase in M-protein level (evolving type of SMM; increase inserum M- protein by ≥25% on 2 successive evaluations within a 6-month period)

• Clonal bone marrow plasma cells (BMPC) 50%-59%

• Abnormal plasma cell (PC) immunophenotype (≥95% of BMPCs are clonal) andreduction of ≥1 uninvolved immunoglobulin isotype(s)

• Chromosomal abnormalities specifically translocation of chromosomes 4 or 14 (t(4;14)) or deletion of the short arm of chromosome 17 del(17p)) or gain ofthe long arm of chromosome 1 (1q gain) found in ≥5% of cells

• Increased circulating PCs (PCs >5 x 106/L and/or >5% PCs per 100 peripheralblood mononuclear cells (PBMCs)

• MRI with diffuse abnormalities or 1 focal lesion, AND/OR PET-CT with focallesion with increased uptake without underlying osteolytic bone destruction.

7. A female participant of childbearing potential must have a negative serum or urinepregnancy test at screening (at or within 45 days of study enrollment) and within 72hours of the start of study treatment (Section 4.7) and must agree to further serumor urine pregnancy tests during the study

8. A female participant must be (as defined in Appendix 17.3):

9. Not of childbearing potential, or

10. Of childbearing potential and practicing at least 1 highly effective method ofcontraception (see Appendix 17.3). NOTE: Participant must agree to continue theabove throughout the study and for 3 months after the last dose of studytreatment. NOTE: If a woman becomes of childbearing potential after start of the study, thewoman must comply with point (b) as described above.

11. 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 3 months after receiving the last dose of study treatment. Femaleparticipants should consider preservation of eggs prior to study treatment, asanti-cancer treatments may impair fertility.

12. A female participant must agree to not breastfeed during the study and for a periodof 5 months after receiving the last dose of study treatment.

13. A male participant must wear a condom when engaging in any activity that allows forpassage of ejaculate to another person during the study and for a period of 3 monthsafter receiving the last dose of study treatment. If the male participant's partneris a female of childbearing potential, the male participant must use condoms (withor without spermicide), and the female partner of the male participant must also bepracticing a highly effective method of contraception (see Appendix 17.3). NOTE: If the male participant is vasectomized, he still must wear a condom (with orwithout spermicidal foam/gel/film/cream/suppository), but his female partner is notrequired to use contraception.

14. A male participant must agree not to donate sperm for the purpose of reproductionduring the study and for period of 3 months after receiving the last dose of studytreatment. Male participants should consider preservation of sperm prior to studytreatment, as anti-cancer treatments may impair fertility.

15. Ability of the patient to understand and the willingness to sign a written informedconsent document.

16. Have any condition that, in the opinion of the Investigator, would compromise thewell-being of the patient or the study or prevent the patient from meeting orperforming study requirements.

17. Must be willing and able to adhere to the lifestyle restrictions specified in thisprotocol (Section 3.3).

Exclusion Criteria:

1. Patients who have received prior systemic therapies for SMM/MM. One prior cycle (4-5weeks) of therapy for SMM is allowed provided that patient undergoes a 4-weekwashout period prior to first dose of study treatment. Treatment withcorticosteroids for other indications is permitted.

2. Patients who are receiving any other investigational agents for any reasons.

3. Patients who receive a live attenuated vaccine within 4 weeks of scheduled studytreatment administration.

4. Contraindication to any concomitant medication, including those medicationsadministered for infusion reaction, antiviral, antibacterial, anticoagulation, tumorlysis, or hydration prophylaxis given prior to therapy.

5. Patient has any of the following:

6. Human immunodeficiency virus (HIV)-positive with 1 or more of the following:

• History of acquired immune deficiency syndrome (AIDS)-defining conditionscluster of differentiation (CD4)count <350 cells/mm3
• Detectable viral load during screening or within 6 months prior toscreening
• Not receiving highly active anti-retroviral therapy
• Had a change in antiretroviral therapy within 6 months of the start ofscreening
• Receiving antiretroviral therapy that may interfere with study treatmentas assessed after discussion with the Medical Monitor

2. Hepatitis B infection (ie, hepatitis B surface antigen (HBsAg) or hepatitis Bvirus (HBV)- DNA positive). Patients with resolved infection (ie, patients whoare HBsAg negative but positive for antibodies to hepatitis B core antigen (anti-HBc) and/or antibodies to hepatitis B surface antigen [anti-HBs]) must bescreened using real-time polymerase chain reaction (PCR) measurement of HBV DNAlevels. Those who are PCR positive will be excluded. In the event the infectionstatus is unclear, quantitative viral levels are necessary to determine theinfection status; see Section 10.3.5.2.1 for further required assessments.EXCEPTION: Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of priorHBV vaccination do not need to be tested for HBV DNA by PCR.

3. Active hepatitis C infection as measured by positive HCV-ribonucleic acid (RNA)testing.Participants with a history of hepatitis C virus (HCV) antibody positivity mustundergo HCV-RNA testing (Section 10.3.5.2.2). If a participant with history ofchronic hepatitis C infection (defined as both HCV antibody and HCV-RNApositive) completed antiviral therapy and has undetectable HCV-RNA 12 weeksfollowing the completion of therapy, the participant is eligible for the study.

4. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is requiredfor participants with known or suspected of having COPD or asthma, andparticipants must be excluded if FEV1 <50% of predicted normal.

5. Moderate or severe persistent asthma within the past 2 years or uncontrolledasthma of any classification. Note that FEV1 testing is required forparticipants with known or suspected asthma, and participants must be excludedif FEV1 <50% of predicted normal.

6. History of allergic reactions attributed to compounds of similar chemical orbiologic composition to the experimental agents used in study.

7. Female patient refuses to discontinue breastfeeding her infant during studytreatment or within 5 months after receiving the last dose of study treatment.

8. Participant plans to father a child while enrolled in this study or within 3 monthsafter the last dose of study treatment.

9. Presence of the following cardiac conditions:

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

11. Myocardial infarction or coronary artery bypass graft ≤6 months prior to studyenrollment

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

13. Uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities

14. Unstable or uncontrolled disease/condition related to or affecting cardiacfunction (eg, unstable angina)

15. Uncontrolled intercurrent illness including but not limited to ongoing or activeinfection, venous thromboembolic disease, hemorrhage, pulmonary fibrosis,pneumonitis, active autoimmune disease or a documented 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, orpsychiatric illness/social situations within 2 weeks that would limit compliancewith study requirements.

16. Active malignancy other than SMM requiring treatment in the past 24 months.Malignancies treated within the past 24 months that are considered cured withminimal risk of recurrence are allowed.

17. Have any condition that, in the opinion of the Investigator, would compromise thewell-being of the patient or the study or prevent the patient from meeting orperforming study requirements.

18. Patients with impaired decision-making capacity will not be enrolled on this trial.