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

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) and have progressed on or following the last line of treatment

• Part 1 and Part 2: Participants who have received at least 3 prior lines of anti-myeloma treatments, including any immunomodulatory drug (IMiDs lenalidomide, pomalidomide or thalidomide), a proteasome inhibitor, and an anti-CD38 monoclonal antibodies (mAb) (either in combination or separately).
• Part 3: Have received at least 1 prior line of treatment anti-myeloma treatments, including lenalidomide. Prior anti-CD38-containing regimen is not mandated, however no more than 70% of participants recruited may be anti-CD38 naïve.
• Participants with a history of Autologous stem cell transplant (ASCT) are eligible for study participation provided the following eligibility criteria are met:

• transplant was greater than (>)100 days prior to screening.
• No active bacterial, viral, or fungal infection(s) present
• Eastern cooperative oncology group-performance status (ECOG-PS) of 0 to 2.
• Measurable disease defined as at least ONE of the following:

• Serum M-protein concentration greater than or equal to (>=) 0.5 gram (g)/ deciliter (dL) (>=5 gram/liter [g/L])
• Urine M-protein excretion >=200 milligram (mg)/24 hours (>=0.2 g/24 hours)
• 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 less than or equal to (<=)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) (if applicable per local regulation) capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
• Male Participants (for parts 1b, 2 and 3):
• Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male Participants enrolled in part 1 (and expansion) cohort receiving belantamab monotherapy are not required to use contraception
• Male participants are eligible to participate in parts 2 and 3 if they agree to the following during the intervention period and for at least 6 months after the last dose of study intervention to allow for clearance of any altered sperm:

• Refrain from donating fresh unwashed semen PLUS either:

• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
• Must agree to use contraception/barrier as detailed below
• Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of <1 percent (%) per year when having sexual intercourse with POCBP who is not currently pregnant. Male participants should also use a condom when having sexual intercourse with pregnant females.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

• Is NOT a Participant of child-bearing potential (POCBP) or
• Is a POCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, 30 days prior to treatment start, during the intervention period and for 4 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
• Part 3: Due to pomalidomide being a thalidomide analogue with a risk for embryofetal toxicity and prescribed under a pregnancy prevention/controlled distribution program, POCBP will be eligible if they commit either to abstain continuously from heterosexual sexual intercourse or use two methods of reliable birth control (one method that is highly effective plus an additional barrier method), beginning at least 4 weeks prior to initiating treatment with pomalidomide, during therapy, during dose interruptions and continuing for at least 4 weeks following discontinuation of pomalidomide treatment. Thereafter, POCBP must use one contraceptive method that is highly effective (with a failure rate of less than (<)1% per year) for a further 3 months (total 4 months).
• The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention
• All POCBP must agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.

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.
• Part 3: Active or history of venous or arterial thromboembolism within the past 3 months. Contraindications to or unwilling to undergo protocol-required anti-thrombotic prophylaxis
• 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.
• Part 2: 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). Participants on active surveillance or hormone treatment for non-metastatic prostate cancer are not excluded. Participants on hormone therapy for non-metastatic breast cancer are not excluded
• Evidence of cardiovascular risk including any of the following:

• Evidence of current clinically significant untreated arrhythmias, including, but not limited to, clinically significant Electrocardiogram (ECG) abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree Atrioventricular (AV) block.
• Part 1 dose escalation and Part 2 only: QT interval corrected using Fridericia's formula (QTcF) interval >480 millisecond (msec) (QT interval corrected for heart rate according to Fridericia's formula), and/or hypokalemia, and/or family history of long QT syndrome.
• Part 1 dose expansion and Part 3: Not applicable.
• History of MI, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting or bypass grafting, all within three months of screening.
• Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
• Uncontrolled hypertension
• 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.
• For serology of Hepatitis B surface antigen (HBsAg)+ at screen or within 3 months prior to first dose Japan only: must test Hepatitis B e antigen (HBeAg) and Hepatitis B e antibody (HBeAb). Eligibility verification should be evaluated and agreed with a hepatologist (after they record the approval in the participant medical record).
• 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. Note: Prior treatment with other anti- B-cell maturation antigen (BCMA) directed agents is allowed. Provided there is at least 6-month washout after the last dose of prior anti-BCMA therapy.
• 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 after the last dose of prior anti-BCMA 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 stem cells transplant.
• 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 dose escalation only: 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. This does not apply for Part 1 Expansion Cohort.
• Part 3: Prior belantamab, belantamab mafodotin, and pomalidomide therapy are not allowed. Prior treatment with other anti- BCMA directed agents is allowed provided there is at least 6-month washout after the last dose of prior anti-BCMA therapy.
• 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.
• 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.
• The use of other anti-cancer therapy not specified in this protocol, and any investigational agents other than belantamab and belantamab mafodotin, or any other MM Standard of Care (SoC) agents other than pomalidomide or dexamethasone are explicitly prohibited for the duration of the study.