A Study of Dara-RVd and Teclistamab-RVd in People With Multiple Myeloma

Inclusion Criteria:

1. Documented multiple myeloma satisfying the International Myeloma Working Group (IMWG) diagnostic criteria36 (evidence of myeloma defining event attributed tounderlying plasma cell disorder) with measurable disease defined as:

2. Clonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy provenplasmacytoma

3. Measurable disease within the past 4 weeks defined by any of the following:

• IgG myeloma: Serum monoclonal protein ≥ 1.0 g/dL or urine monoclonalprotein ≥ 200 mg/24 hr; or
• IgA, IgM, IgD, IgE multiple myeloma: serum M-protein ≥ 0.5 g/dL or urinemonoclonal protein ≥ 200 mg/24 hr; or
• Light chain multiple myeloma: Involved serum immunoglobulin free lightchain ≥ 10 mg/dL AND abnormal serum free kappa/lambda light chain ratio
• Measurable plasmacytomas seen on imaging (≥ 1 lesion that has a singlediameter ≥ 2 cm). If this is the primary marker of measurable disease,patients will need a biopsy at screening.
• Bone marrow plasma cells ≥ 30% as determined by CD138 immunohistochemistrystaining.

2. Standard risk multiple myeloma - excluding patients with high risk cytogeneticabnormality (HRCA) according to the IMS/IMWG 2024 Consensus Definition:

3. TP53 mutation and/or del(17p) with cancer clonal function (CCF) >20% byanalyses conducted on CD138+ purified cells

4. t(4;14), t(14;16), or t(14;20) co-occurring with +1q (gain/amp 1q) and/ordel(1p)

5. Monoallelic del(1p32) with +1q or biallelic del(1p32)

6. High Beta-2 microglobulin (>5.5 mg/dL) with normal creatinine (<1.2 mg/dL)

7. Newly diagnosed patient considered a candidate for high-dose chemotherapy andautologous stem cell transplant a. For patients who received one complete cycle of Dara-RVd at MSK, patients canenter treatment at cycle 2 at the discretion of treating investigator and PI

8. Age ≥18 years.

9. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

10. Have adequate organ and hematologic function:

11. Hemoglobin ≥ 7.5 g/dL (prior RBC transfusion or recombinant humanerythropoietin use is permitted);

12. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (G-CSF use is permitted);

13. Platelet count ≥ 75 x 109/L

14. Creatinine Clearance ≥ 30 ml/min. CrCl can be measured or estimated usingCockcroft-Gault method, MDRD, or CKD-EPI formula

15. Total bilirubin ≤ 2 x ULN (≤ 3 x ULN if documented Gilbert's syndrome);

16. AST ≤ 2.5 x ULN;

17. ALT ≤ 2.5 x ULN

18. All study participants must be able to tolerate one of the followingthromboprophylaxis strategies: aspirin, low molecular weight heparin or warfarin (coumadin) or alternative anti-coagulant.

19. All study participants must be able to tolerate one of the followingthromboprophylaxis strategies: aspirin, low molecular weight heparin or warfarin (Coumadin), or direct-acting oral anticoagulants (DOACs).

20. All study participants must be registered into the mandatory REMS® program and bewilling and able to comply with the requirements of REMS®, including compliance withcontraception methods (Appendix A).

Exclusion Criteria:

1. Patients who have received > 1 cycle of prior treatment or concurrent systemictherapy for multiple myeloma (excluding corticosteroids or radiation therapy). Forpatients who received one complete cycle of Dara-RVd at MSK, patients can entertreatment at cycle 2 at the discretion of treating investigator and PI

2. Patients with diagnosis of plasma cell leukemia, primary light chain amyloidosis,monoclonal gammopathy of undetermined significance, smoldering multiple myeloma,POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skinchanges), Waldentröm's macroglobulinemia

3. History of another active primary malignancy within 2 years prior to enrollment,except for adequately treated basal cell carcinoma or squamous cell skin cancer orcarcinoma in situ.

4. Significant, uncontrolled comorbid conditions that is likely to interfere with thestudy procedures or results, or that in the opinion of the investigator, wouldconstitute a hazard for participating in the study. Examples include, but are notlimited to

5. 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 suspected of having COPD and participants must be excluded ifFEV1 is < 50% of predicted normal.

6. Moderate or severe persistent asthma within the past 2 years or uncontrolledasthma of any classification. Note that participants who currently havecontrolled intermittent asthma or controlled mild persistent asthma are allowedto participate.

7. Infiltrative pulmonary disease

8. Active autoimmune disease requiring systemic immunosuppressive therapy within 6months before start of study treatment. Exception of vitiligo, type 1 diabetes,and prior autoimmune thyroiditis that is currently euthyroid

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

10. Known history of human immunodeficiency virus (HIV)

11. Seropositive for hepatitis B (defined by a positive test for hepatitis Bsurface antigen [HBsAg]). i. Subjects with resolved infection (i.e., subjects who are HBsAg negative withantibodies to total hepatitis B core antigen [anti-HBc] with or without the presenceof hepatitis B surface antibody [anti-HBs]) must be screened using real-timepolymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.Those who are PCR positive will be excluded. ii. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of HBVvaccination, do not need to be testing for HBV DNA by PCR. h. Seropositive for hepatitis C i. Except in the setting of a sustained virologicresponse [SVR], defined as a viremia at least 12 weeks after completion of antiviraltherapy. i. Clinically significant cardiac disease, including: i. Myocardial infarctionwithin 6 months before enrollment, or unstable or uncontrolled disease/conditionrelated to or affection cardiac function (e.g., unstable angina, congestive heartfailure, New York Heart Association Class III-IV) ii. Uncontrolled cardiacarrhythmia

12. Pregnant or lactating patients

13. Unwilling to give written, informed consent, unwilling to participate, or unable tocomply with the protocol for the duration of the study