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

Eligibility Criteria

• 1. Documented multiple myeloma satisfying the International Myeloma Working Group (IMWG) diagnostic criteria36 (evidence of myeloma defining event attributed to underlying plasma cell disorder) with measurable disease defined as:
• 1. Clonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma
• 2. Measurable disease within the past 4 weeks defined by any of the following:
• * IgG myeloma: Serum monoclonal protein ≥ 1.0 g/dL or urine monoclonal protein ≥ 200 mg/24 hr; or
• * IgA, IgM, IgD, IgE multiple myeloma: serum M-protein ≥ 0.5 g/dL or urine monoclonal protein ≥ 200 mg/24 hr; or
• * Light chain multiple myeloma: Involved serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum free kappa/lambda light chain ratio
• * Measurable plasmacytomas seen on imaging (≥ 1 lesion that has a single diameter ≥ 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 immunohistochemistry staining.
• 2. Standard risk multiple myeloma - excluding patients with high risk cytogenetic abnormality (HRCA) according to the IMS/IMWG 2024 Consensus Definition:
• 1. TP53 mutation and/or del(17p) with cancer clonal function (CCF) \>20% by analyses conducted on CD138+ purified cells
• 2. t(4;14), t(14;16), or t(14;20) co-occurring with +1q (gain/amp 1q) and/or del(1p)
• 3. Monoallelic del(1p32) with +1q or biallelic del(1p32)
• 4. High Beta-2 microglobulin (\>5.5 mg/dL) with normal creatinine (\<1.2 mg/dL)
• 3. Newly diagnosed patient considered a candidate for high-dose chemotherapy and autologous stem cell transplant
• 4. Age ≥18 years.
• 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• 6. Have adequate organ and hematologic function:
• 1. Hemoglobin ≥ 7.5 g/dL (prior RBC transfusion or recombinant human erythropoietin use is permitted);
• 2. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (G-CSF use is permitted);
• 3. Platelet count ≥ 75 x 109/L
• 4. Creatinine Clearance ≥ 30 ml/min. CrCl can be measured or estimated using Cockcroft-Gault method, MDRD, or CKD-EPI formula
• 5. Total bilirubin ≤ 2 x ULN (≤ 3 x ULN if documented Gilbert's syndrome);
• 6. AST ≤ 2.5 x ULN;
• 7. ALT ≤ 2.5 x ULN
• 7. All study participants must be able to tolerate one of the following thromboprophylaxis strategies: aspirin, low molecular weight heparin or warfarin (coumadin) or alternative anti-coagulant.
• 8. All study participants must be able to tolerate one of the following thromboprophylaxis strategies: aspirin, low molecular weight heparin or warfarin (Coumadin), or direct-acting oral anticoagulants (DOACs).
• 9. All study participants must be registered into the mandatory REMS® program and be willing and able to comply with the requirements of REMS®, including compliance with contraception methods (Appendix A).
• 1. Patients who have received \> 1 cycle of prior treatment or concurrent systemic therapy for multiple myeloma (excluding corticosteroids or radiation therapy)
• 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 skin changes), 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 or carcinoma in situ.
• 4. Significant, uncontrolled comorbid conditions that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in the study. Examples include, but are not limited to
• 1. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \< 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is \< 50% of predicted normal.
• 2. Moderate or severe persistent asthma within the past 2 years or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
• 3. Infiltrative pulmonary disease
• 4. Active autoimmune disease requiring systemic immunosuppressive therapy within 6 months before start of study treatment. Exception of vitiligo, type 1 diabetes, and prior autoimmune thyroiditis that is currently euthyroid
• 5. Disabling psychiatric conditions (e.g., alcohol or drug abuse)., severe dementia, or altered mental status
• 6. Known history of human immunodeficiency virus (HIV)
• 7. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen \[HBsAg\]).
• 5. Pregnant or lactating patients
• 6. Unwilling to give written, informed consent, unwilling to participate, or unable to comply with the protocol for the duration of the study