A Study of Comparing Talquetamab to Belantamab Mafodotin in Participants With Relapsed/Refractory Multiple Myeloma

The purpose of this study is to compare the efficacy of talquetamab versus belantamab mafodotin in terms of overall response rate (ORR) or progression-free survival (PFS).

Multiple myeloma is an incurable, malignant, plasma cell disorder that accounts for approximately 18 percent (%) of hematological malignancies, making it the second most common hematologic malignancy. Talquetamab (also known as JNJ-64407564) is a humanized immunoglobulin G4 (IgG4) bispecific antibody designed to target G Protein-coupled receptor family C group 5 member D (GPRC5D+) cells and cluster of differentiation 3 (CD3) receptor complex on T-cells. Belantamab mafodotin is a humanized B-cell maturation antigen (BCMA)-targeting monoclonal antibody (mAb) conjugated to a cytotoxic agent maleimidocaproyl monomethyl auristatin F (MMAF) which disrupts the microtubule network, leading to cell cycle arrest and apoptosis. This study will investigate the possible improvement of ORR or PFS with talquetamab compared with belantamab mafodotin in participants with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 mAb (alone or in combination), and whose disease is refractory to at least one proteasome inhibitor (PI) and one immunomodulatory drug (IMiD). The study will consists of a screening phase, treatment phase (until confirmed progressive disease, start of subsequent antimyeloma therapy, death, intolerable toxicity, withdrawal of consent, or end of the study, whichever occurs first), and post-treatment follow-up phase (until death, withdrawal of consent, loss to follow-up, or end of the study, whichever occurs first). Safety evaluations will include a review of adverse events, physical examinations, eastern cooperative oncology group (ECOG) performance status, clinical laboratory tests, and vital signs.

Eligibility Criteria:
Inclusion Criteria:

* Documented multiple myeloma as defined by the criteria: a) multiple myeloma according to international myeloma working group (IMWG) diagnostic criteria b) measurable disease at screening, as assessed by central laboratory, defined by any of the following i) serum M-protein level greater than or equal to (\>=) 1.0 gram per deciliter (g/dL) ii) urine M-protein level \>=200 milligram (mg)/24 hours iii) Light chain multiple myeloma without measurable M-protein in the serum or the urine: serum free light chain (sFLC) \>=10 milligram per deciliter (mg/dL) (central laboratory) and abnormal serum immunoglobulin kappa lambda free light chain (FLC) ratio
* Received at least 4 prior antimyeloma therapies including an anti-cluster of differentiation 38 (CD38) monoclonal antibody (mAb) (alone or in combination) and is refractory per IMWG criteria to at least one proteasome inhibitor (PI), and one immunomodulatory drug (IMiD)
* Documented evidence of progressive disease based on investigator's determination of response by IMWG criteria on or after their last regimen
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at screening
* A female participant of childbearing potential must have a negative serum pregnancy test at screening, and must agree to further serum or urine pregnancy tests during the study and within 6 months after receiving the last dose of study treatment

Exclusion Criteria:

* Contraindications or life-threatening known allergies, hypersensitivity, or intolerance to any study drug or its excipients
* Stroke or seizure within 6 months prior to signing informed consent form (ICF)
* Prior or concurrent exposure to belantamab mafodotin
* Current corneal epithelial disease except mild punctate keratopathy
* Known active central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain magnetic resonance imaging (MRI) and lumbar cytology are required