Response-Based Dose Reduction of Linvoseltamab in the Treatment of Relapsed, Refractory, or Triple-Class Relapsed/Refractory Multiple Myeloma

Inclusion Criteria:

• Age ≥ 18 years. Myeloma is not seen in the younger age group and safety of B-cellmaturation antigen (BCMA) T-cell engagers (TCE) in this group is not known

• Ability to understand and willingness to sign a written informed consent document.Legally authorized representatives may sign and give informed consent on behalf ofpotential study participants

• Confirmed diagnosis of active multiple myeloma (MM) by International Myeloma WorkingGroup (IMWG) diagnostic criteria

• Patients must have myeloma that is measurable and response evaluable according to 2016 IMWG response criteria. Measurable disease is defined as one of the following,documented ≤ 14 days prior to registration:

• Serum M protein ≥ 1 g/dl

• Urine M protein ≥ 200 mg/24h

• Free light chain (FLC) assay with involved FLC ≥ 10 mg/dl and abnormal FLCratio

• A patient with immunoglobulin A (IgA) MM without measurable M protein may beenrolled if quantitative (quant) IgA level ≥ 400 mg/dl and can be followedlongitudinally

• Plasmacytoma target lesion defined as measurable based on at least 1 softtissue lesion ≥ 2 cm in long axis on CT or PET/CT, if not previously irradiated

• Skin lesions ≥ 2 cm in long axis as measured with a ruler

• Patients with relapsed or refractory myeloma who have received at least 4 priorlines of therapy including proteasome inhibitor (PI), immunomodulatory imide drug (IMiD), and anti-CD38 monoclonal antibody

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

• Adequate organ function (based on testing ≤14 days prior to registration):

• Adequate hematologic function before dosing as measured by:

• Platelet count ≥50 x 10⁹/L. A patient may not have received a platelettransfusion ≤7 days in order to meet this platelet eligibility requirement

• Absolute neutrophil count (ANC) ≥1.0 x 10⁹/L. A patient may not havereceived granulocyte colony stimulating factor (G-CSF) ≤2 days in order tomeet this absolute neutrophil count eligibility requirement

• Hemoglobin ≥8.0 g/dL

• Adequate renal and hepatic function, defined as:

• Total bilirubin ≤1.5 x ULN

• Transaminase (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) ≤2.5 x ULN

• Alkaline phosphatase ≤2.5 x ULN

• Patients with Gilbert syndrome do not need to meet this totalbilirubin requirement provided that the total bilirubin is unchangedfrom the baseline value

• Serum creatinine clearance by Cockcroft-Gault ≥30 mL/min. A patient with acreatinine clearance by Cockcroft-Gault who does not meet eligibilitycriteria may be considered for enrollment per principal investigatordiscretion if a measured creatinine clearance (based on 24-hour urinecollection or other reliable method) is ≥30 mL/min

• Prior treatment with BCMA-targeted antibody-drug conjugates (ADCs) is allowable ifall adverse events (AEs) attributable to these therapies have resolved to grade 1 orlower

• Willing and able to comply with clinic visits and study-related procedures andprovide informed consent signed by study patient

Exclusion Criteria:

• Diagnosis of known plasma cell leukemia, known primary systemic light-chainamyloidosis (excluding myeloma-associated amyloidosis), known Waldenströmmacroglobulinemia (lymphoplasmacytic lymphoma), or known POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

• Patients with known MM brain lesions or meningeal involvement

• History of known neurodegenerative condition, central nervous system (CNS) movementdisorder, or patients with a history of seizure within 12 months prior to studyenrollment

• Continuous systemic corticosteroid treatment with more than 10 mg per day ofprednisone or anti-inflammatory equivalent within 72 hours of start of study drug

• Live or live attenuated vaccines with replicating potential within 28 days prior tofirst study drug administration

• Previous treatment with chimeric antigen receptor (CAR) T therapy or any genetherapy products

• Any infection requiring hospitalization or treatment with intravenous (IV)anti-infectives within 2 weeks of first administration of study drug

• Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B (HBV),or hepatitis C (HCV)

• Known allergy or hypersensitivity to components of linvoseltamab (REGN5458)

• Women of childbearing potential (WOCBP) with a positive serum beta-human chorionicgonadotropin (beta-hCG) pregnancy test are ineligible for this study

• WOCBP are defined as women who are fertile following menarche until becomingpostmenopausal, unless permanently sterile. Post-menopausal state is defined asno menses for 12 months without an alternate medical cause

• Participants who are receiving other investigational agents

• Women of childbearing potential (WCOBP) and men who are unwilling to practice highlyeffective contraception prior to the initial dose/start of the first treatment,during the study, and for at least 6 months after the last dose

• Uncontrolled or concurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements

• Another malignancy in the past 5 years, except for non-melanoma skin cancer that hasundergone potentially curative therapy or in situ cancer, or any other tumor thathas been deemed to be effectively treated with definitive local control and withcurative intent