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

Inclusion Criteria

• Documented multiple myeloma satisfying the International Myeloma Working Group (IMWG) diagnostic criteria (evidence of myeloma defining event attributed to underlying plasma cell disorder) with measurable disease defined as: * Clonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma * Measurable disease within the past 4 weeks defined by any of the following: ** Immunoglobulin G (IgG) myeloma: Serum monoclonal protein ≥ 1.0 g/dL or urine monoclonal protein ≥ 200 mg/24 hr; or ** Immunoglobulin A (IgA), immunoglobulin M (IgM), immunoglobulin D (IgD), immunoglobulin E (IgE) multiple myeloma: serum monoclonal immunogloculin (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
• Standard risk multiple myeloma-excluding patients with high risk cytogenetic abnormality (HRCA) according to the International Myeloma Society (IMS)/IMWG 2024 Consensus definition: * TP53 mutation and/or del(17p) with cancer clonal function (CCF) > 20% by analyses conducted on CD138+ purified cells * t(4;14), t(14;16), or t(14;20) co-occurring with +1q (gain/amp 1q) and/or del(1p) * Monoallelic del(1p32) with +1q or biallelic del(1p32) * High beta-2 microglobulin (> 5.5 mg/dL) with normal creatinine (< 1.2 mg/dL)
• Newly diagnosed patient considered a candidate for high-dose chemotherapy and autologous stem cell transplant
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Hemoglobin ≥ 7.5 g/dL (prior bed blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted)
• Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L (granulocyte colony-stimulating factor [G-CSF] use is permitted)
• Platelet count ≥ 75 x 10^9/L
• Creatinine clearance ≥ 30 ml/min. Creatinine clearance (CrCl) can be measured or estimated using Cockcroft-Gault method, Modification of Diet in Renal Disease (MDRD), or Chronic Kidney Disease Epidemiology (CKD-EPI) formula
• Total bilirubin ≤ 2 x upper limit of normal (ULN) (≤ 3 x ULN if documented Gilbert's syndrome)
• Aspartate aminotransferase (AST) ≤ 2.5 x ULN
• Alanine aminotransferase (ALT) ≤ 2.5 x ULN
• 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
• 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)
• All study participants must be registered into the mandatory Risk Evaluation and Mitigation Strategies (REMS®) program and be willing and able to comply with the requirements of REMS®, including compliance with contraception methods

Exclusion Criteria

• Patients who have received > 1 cycle of prior treatment or concurrent systemic therapy for multiple myeloma (excluding corticosteroids or radiation therapy)
• 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
• 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
• 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 * 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 * 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 * Infiltrative pulmonary disease * 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 * Disabling psychiatric conditions (e.g., alcohol or drug abuse), severe dementia, or altered mental status * Known history of human immunodeficiency virus (HIV) * Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]) ** Subjects with resolved infection (i.e., subjects who are HBsAg negative with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence of hepatitis B surface antibody [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded ** EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of HBV vaccination, do not need to be testing for HBV DNA by PCR * Seropositive for hepatitis C ** Except in the setting of a sustained virologic response (SVR), defined as a viremia at least 12 weeks after completion of antiviral therapy * Clinically significant cardiac disease, including: ** Myocardial infarction within 6 months before enrollment, or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association class III-IV) ** Uncontrolled cardiac arrhythmia
• Pregnant or lactating patients
• Unwilling to give written, informed consent, unwilling to participate, or unable to comply with the protocol for the duration of the study