A Study to Investigate the Safety and Efficacy of Belantamab for the Treatment of Multiple Myeloma When Used as Monotherapy and in Combination Treatments

The study consists of two parts: Part 1 The primary purpose of this part aims to evaluate the safety, tolerability, and clinical activity of escalating doses of single agent belantamab in participants with refractory multiple myeloma (RRMM) who have received at least 3 prior therapies (4L+). Part 2 The primary purpose of this part is to evaluate the safety, tolerability, and clinical activity of different dose ratios of belantamab mafodotin in combination with belantamab (delivered as separate drugs) in participants with RRMM who have received at least 3 prior therapies (4L+).


Eligibility Criteria:
Inclusion Criteria:

* Participants at the time of signing the Informed Consent Form (ICF) are at least 18 years old or are of the legal age of consent in the jurisdiction in which the study is taking place.
* Participants who have histologically or cytologically confirmed diagnosis of Multiple Myeloma (MM), as defined by the international myeloma working group (IMWG).

  1. Participants who have received at least 3 prior lines of anti-myeloma treatments, and have already received an immunomodulating agent, a proteasome inhibitor, and an anti-CD38 mAb (unless contraindicated or unavailable) and have confirmed progression on or following the last line of treatment.
* Participants with a history of Autologous stem cell transplant (ASCT) are eligible for study participation provided the following eligibility criteria are met:

  1. transplant was greater than (\>)100 days prior to screening.
  2. no active infection(s)
* Eastern cooperative oncology group-performance status (ECOG-PS) of 0 to 2.
* Measurable disease defined as at least ONE of the following:

  1. Serum M-protein concentration greater than (\>=) 0.5 gram (g)/ deciliter (dL) (\>=5 gram/liter \[g/L\])
  2. Urine M-protein excretion \>=200 mg/24 hours (\>=0.2 g/24 hours)
  3. Serum free light chain (FLC) assay: involved FLC level \>=10 mg/dL (\>=100 milligrams per liter \[mg/L\]) and an abnormal serum FLC ratio (less than \[\<\]0.26 or \>1.65)
* Have adequate organ system function as defined by the laboratory assessments.
* All prior treatment-related toxicities (defined by National Cancer Institute-Common Toxicity Criteria for Adverse Events \[NCI-CTCAE\], v5.0, 2017) must be Grade \<=1 at the time of screening except for alopecia (any grade), neuropathy (Grade \<=2), or endocrinopathy managed with replacement therapy (any grade).
* Participants or Legally authorized representative (LAR) capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

* Diagnosis of primary Amyloid Light chain (AL) Amyloidosis, active Polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes (POEMS) syndrome, primary plasma cell leukemia.
* Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormalities) that could interfere with participant's safety, obtaining informed consent, or compliance with study procedures.
* Participant is exhibiting signs of meningeal or central nervous system involvement with MM.
* Current corneal epithelial disease except nonconfluent Superficial punctate keratitis (SPK).
* Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.
* Presence of malignancies other than disease under study are excluded, except for any other malignancy from which the participant has been disease-free for more than 2 years and, in the opinion of the Principal investigator (PI) and GlaxoSmithKline (GSK) Medical Director, will not affect the evaluation of the effects of this clinical trial treatment on the currently targeted malignancy (MM).
* Evidence of cardiovascular risk
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belantamab / belantamab mafodotin or any of the components of the study treatment. History of severe hypersensitivity to other Monoclonal antibodies (mAbs).
* Active infection requiring antibiotic, antiviral, or antifungal treatment.
* Known Human immunodeficiency virus (HIV) infection, unless the participant can meet specific criteria.
* Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
* Participants with Hepatitis B virus (HBV) or Hepatitis C virus (HCV) will be excluded unless specific criteria can be met
* Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant's safety). Participants with isolated proteinuria resulting from MM are eligible
* Part 1: Refractory to belantamab mafodotin (confirmed PD as per IMWG criteria while on belantamab mafodotin therapy or within 60 days of completing that treatment). Prior belantamab mafodotin is allowed if it was discontinued due to toxicity which subsequently resolved.
* Part 2: Prior belantamab mafodotin therapy is not allowed. Prior treatment with other anti-BCMA directed agents is allowed provided there is at least a 6-month washout period from completion of prior anti-BCMA therapy to start of study therapy.
* Prior radiotherapy within 2 weeks of start of study therapy.
* Plasmapheresis within 7 days prior to the first dose of study drug.
* Prior allogeneic transplant is prohibited.
* Participants who have received prior Chimeric Antigen Receptor T-cell therapy (CAR-T) therapy with lymphodepletion with chemotherapy within 3 months of screening.
* Any major surgery (other than bone-stabilizing surgery) within 2 weeks of first dose or has not recovered fully from surgery.
* Prior treatment with a mAb within 30 days of receiving the first dose of study drugs, or treatment with an investigational agent or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or 5 half-lives of receiving the first dose of study drugs, whichever is longer.
* Part 1: Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including Granulocyte colony stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GMCSF), recombinant erythropoietin) or any thrombopoietin receptor agonists within 2 weeks before the first dose of study drug.
* Participants must not receive live/live attenuated vaccines within 30 days prior to first dose of study treatment or whilst receiving belantamab for at least 70 days following last study treatment.
* Known, current drug or alcohol abuse.
* Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this trial, unless prospective Independent Review Board (IRB) approval (by chair or designee) is allowing exception to this criterion for a specific participant.