Minimal Residual Disease-Guided Treatment with or Without Autologous Hematopoietic Cell Transplantation and Teclistamab for Patients with Multiple Myeloma, The MASTER-2 Trial

Inclusion Criteria

• Age > 18 years with no upper age limit
• Newly diagnosed multiple myeloma with indication for initiation of therapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• No prior multiple myeloma (MM)-directed therapy except for dexamethasone (up to 160 mg) and/or bortezomib (up to 5.2 mg/m^2) and/or cyclophosphamide up to 1000 mg/m^2 and/or lenalidomide (up to 21 days of therapy) administered for no longer than 4 weeks prior to enrollment (pre induction). If subject received any prior therapy, pretreatment parameters necessary for disease characterization and response assessment must be available.
• Measurable disease meeting at least one of the following criteria (at screening or prior to pre induction): * Serum monoclonal (M) protein ≥ 1.0 g/dl (≥ 0.5 g/dl if IgA, IgD, IgE or IgM multiple myeloma) * ≥ 200 mg of M protein/24 hour (h) in the urine * Difference between affected and unaffected free light chain ≥ 10 mg/dL with abnormal kappa to lambda ratio
• Hemoglobin ≥ 7 g/dL (≥ 4.65 mmol/L; without prior red blood cell (RBC) transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted) (during the screening phase and also at start of administration of study treatment)
• Platelets ≥ 75×10^9/L in participants in whom < 50% of bone marrow nucleated cells are plasma cells and ≥ 50×10^9/L in participants in whom ≥ 50% of bone marrow nucleated cells are plasma cells (without transfusion support or thrombopoietin receptor agonist within 7 days before the laboratory test) (during the screening phase and also at start of administration of study treatment)
• Absolute neutrophil count ≥1.0×10^9/L (prior growth factor support is permitted but must be without support for 7 days for granulocyte colony stimulating factor [G-CSF] or granulocyte macrophage colony stimulating factor [GM-CSF] and for 14 days for pegylated [G-CSF]) (during the screening phase and also at start of administration of study treatment)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN) (during the screening phase and also at start of administration of study treatment)
• Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min based on Modified Diet in Renal Disease Formula calculation or creatine clearance measured by a 24-hour urine collection (during the screening phase and also at start of administration of study treatment)
• Total bilirubin ≤ 2.0 × ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤ 1.5 × ULN is required) (during the screening phase and also at start of administration of study treatment)
• Serum calcium corrected for albumin ≤ 14 mg/dL (≤ 3.5 mmol/L) or free ionized calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L) (during the screening phase and also at start of administration of study treatment)
• A woman of childbearing potential must have a negative highly-sensitive serum pregnancy test at screening and again within 24 hours of the start of study treatment and must agree to further serum or urine pregnancy tests during the study
• A woman must be: * Not of childbearing potential, or * Of childbearing potential and ** Practicing true abstinence; or ** Have a sole partner who is vasectomized; or ** Practicing ≥ 1 highly‑effective, user‑independent method of contraception *** NOTE: Participant must agree to continue the above throughout the study 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 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, for the purposes of assisted reproduction during the study and for 90 days after receiving the last dose of study treatment
• A man must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 90 days after receiving the last dose of study treatment. If a female partner is of childbearing potential, she must also be practicing a highly effective method of contraception * NOTE: If the male participant is vasectomized, he still must wear a condom (with or without spermicidal foam/gel/film/cream/suppository), but his female partner is not required to use contraception
• A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 90 days after receiving the last dose of study treatment
• Must be willing and able to adhere to the lifestyle restrictions specified in this protocol
• Must sign an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study
• All participants must agree to comply with and be enrolled in Revlimid risk evaluation and mitigation strategy (REMS)TM program
• All participants must meet institution-specific criteria for AHCT eligibility as assessed by the investigator
• In line with the higher incidence of MM in Blacks, and to address the historical underrepresentation of ethnical minorities in MM trials, at least 25% of the enrolled patients will be of ethnical minorities

Exclusion Criteria

• Diagnosis of plasma cell leukemia, primary light chain amyloidosis, polyneuropathy, organomegaly, endocrineopathy, monocolnal gammopathy and skin changes (POEMS), or Waldenstrom’s macroglobulinemia
• Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug or its excipients
• Prior or concurrent exposure to any of the following: * Teclistamab or any anti-BCMA therapy * Daratumumab or any anti-CD38 therapy * Targeted therapy, epigenetic therapy, or treatment with an investigational drug or an invasive investigational medical device within 21 days or ≥ 5 half-lives, whichever is less * Investigational vaccine within 4 weeks * Live, attenuated vaccine within 4 weeks before randomization * Radiotherapy within 14 days or focal radiation within 7 days * Gene-modified adoptive cell therapy (eg, chimeric antigen receptor modified T cells, natural killer [NK] cells) within 3 months * Cytotoxic therapy within 14 days * Proteasome inhibitors [PI] therapy within 14 days * Immunomodulary drugs (IMiD) agent therapy within 14 days
• Known active central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required
• Myelodysplastic syndrome or active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than multiple myeloma. The only allowed exceptions are: * Non-muscle invasive bladder cancer treated within the last 24 months that is considered completely cured * Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured * Noninvasive cervical cancer treated within the last 24 months that is considered completely cured * Localized prostate cancer (N0M0): ** With a Gleason score of ≤ 6, treated within the last 24 months, or untreated and under surveillance ** With a Gleason score of 3+4 that has been treated > 6 months prior to full study screening and considered to have a very low risk of recurrence, or * History of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence * Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence * Other malignancy that is considered cured with minimal risk of recurrence
• Stroke or seizure within 6 months prior to signing ICF
• 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 in the study
• Prior allogeneic bone marrow, hematopoietic stem cell or solid organ transplant
• Participant is pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 90 days after the last dose of study treatment
• Participant plans to father a child while enrolled in this study or within 90 days after the last dose of study treatment
• Presence of the following cardiac conditions: * New York Heart Association stage III or IV congestive heart failure * Myocardial infarction or coronary artery bypass graft ≤ 6 months prior to randomization * History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration * History of severe non-ischemic cardiomyopathy
• Any of the following: * Known to be seropositive for human immunodeficiency virus * Hepatitis B infection (ie, Hepatitis B surface antigen [HBsAg] or hepatitis B virus deoxyribonucleic acid [HBV-DNA] positive). In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status * Active hepatitis C infection as measured by positive Hepatitis C virus [HCV]-ribonucleic acid [RNA] testing. Participants with a history of HCV antibody positivity must undergo HCV-RNA testing. If a participant with history of chronic hepatitis C infection (defined as both HCV antibody and HCV-RNA positive) completed antiviral therapy and has undetectable HCV-RNA for at least 12 weeks following the completion of therapy, the participant is eligible for the study
• Major surgery within 2 weeks prior to the start of administration of study treatment, or will not have fully recovered from surgery, or has major surgery planned during the time the participant is expected to be treated in the study or within 2 weeks after administration of the last dose of study treatment * NOTE: Participants with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery. If there is a question whether a procedure is considered a major surgery, the investigator must consult with the appropriate sponsor representative and resolve any issues before enrolling a participant in the study
• Significant neuropathy (grades 3–4, or grade 2 with pain) within 21 days prior to registration
• Contraindication or intolerance to required supportive care medications
• Concurrent medical or psychiatric condition or disease that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study, such as: * Uncontrolled diabetes * Acute diffuse infiltrative pulmonary disease * Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy * History of autoimmune disease with the exception of vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing * Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status * Any other issue that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments * History of non-compliance with recommended medical treatments