Study of Single Agent Belantamab Mafodotin Versus Pomalidomide Plus Low-dose Dexamethasone (Pom/Dex) in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM-3)

Inclusion Criteria:

• Capable of giving signed informed consent.
• Participants must be 18 or older, at the time of signing the informed consent. In Republic of Korea, participants must be over 19 years of age inclusive, at the time of signing informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Histologically or cytologically confirmed diagnosis of Multiple myeloma (MM) as defined according to IMWG, and : Has undergone autologous stem cell transplant (SCT), or is considered transplant ineligible; Has received at least 2 prior lines of anti-myeloma treatments, including at least 2 consecutive cycles of both lenalidomide and a proteasome inhibitor (given separately or in combination), and must have documented disease progression on, or within 60 days of, completion of the last treatment or must be non-responsive while on last treatment, where non-responsive is defined as not achieving at least Minimal Response (MR) after 2 complete treatment cycles. In such cases lack of achieving of at least MR must be determined no earlier than at least 4 weeks after the last treatment.
• Has measurable disease with at least one of the following: Serum M-protein >=0.5 gram per deciliter (g/dL) (>=5 gram per Liter); Urine M-protein >=200 mg/24 hours; Serum free light chain (FLC) assay: Involved FLC level >=10 milligram per deciliter (mg/dL) (>=100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65).
• Participants with a history of autologous SCT are eligible for study participation provided the following eligibility criteria are met: Transplant was >100 days prior to initiating study treatment; No active infection(s).
• Adequate organ system functions as defined: Absolute neutrophil count (ANC) >=1.0*10^9/L; Hemoglobin >= 8.0 g/dL; Platelets >= 50x10^9/L; Total bilirubin <=1.5* Upper limit of normal (ULN) (isolated bilirubin >1.5*ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent); ALT <=2.5*ULN; Estimated glomerular filtration rate (eGFR) >=30 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2); Spot urine (albumin/creatinine ratios) <=500 milligram per gram (mg/g) (56 milligram per millimoles [mg/mmol]).
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants are eligible to participate if they agree to the following during the intervention period and until 6 months after the last dose of study intervention to allow for clearance of any altered sperm: Refrain from donating sperm 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 depending on whether they are randomised to Arm 1 (belantamab mafodotin) or Arm 2 (pom/dex), even if they have undergone a successful vasectomy: Agree to use a male condom throughout study treatment including the 6 month follow-up period even if they have undergone a successful vasectomy and a female partner to use an additional highly effective contraceptive method with a failure rate of <1 percent per year when having sexual intercourse with a pregnant woman or a woman of childbearing potential who is not currently pregnant. Four weeks for male participants on Treatment Arm 2 (pom/dex).
• 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 woman of childbearing potential (WOCBP) OR Is a WOCBP and agrees to abide by the following: Arm 1 (belantamab mafodotin): Use a contraceptive method that is highly effective (with a failure rate of <1 percent per year) which includes abstinence, preferably with low user dependency during the intervention period and for 4 months after the last dose of study treatment. Arm 2 (pom/dex): Due to pomalidomide being a thalidomide analogue with risk for embryofetal toxicity and prescribed under a pregnancy prevention/controlled distribution program, WOCBP participants will be eligible if they commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control (one method that is highly effective), beginning 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. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing pomalidomide therapy. And agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should confirm the effectiveness of the contraceptive method(s) ahead of the first dose of study intervention.
• All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events [NCI-CTCAE], version 5.0, 2017) must be <=Grade 1 at the time of enrollment, except for alopecia and Grade 2 peripheral neuropathy.

Exclusion Criteria:

• Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes); active plasma cell leukemia at the time of screening.
• Systemic anti-myeloma therapy or use of an investigational drug within <14 days or 5 half-lives, whichever is shorter, before the first dose of study intervention.
• Prior treatment with an anti-MM monoclonal antibody within 30 days prior to receiving the first dose of study intervention.
• Prior B cell maturation antigen (BCMA)-targeted therapy or prior pomalidomide treatment.
• Plasmapheresis within 7 days prior to the first dose of study intervention.
• Prior allogeneic stem cell transplant. (Participants who have undergone syngeneic transplant will be allowed only if no history of, or currently active, Graft-Versus-Host Disease [GvHD]).
• Any major surgery within the last 4 weeks.
• 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, provided they fulfil criteria as described in inclusion criteria.
• 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.
• History of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
• Evidence of active mucosal or internal bleeding.
• Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. (Stable chronic liver disease [including Gilbert's syndrome or asymptomatic gallstones] or hepatobiliary involvement of malignancy is acceptable if participant otherwise meets entry criteria)
• Participants with previous or concurrent malignancies other than multiple myeloma are excluded, unless the second malignancy has been considered medically stable for at least 2 years. The participant must not be receiving active therapy, other than hormonal therapy for this disease. (Participants with curatively treated non-melanoma skin cancer are allowed without a 2-year restriction).
• Evidence of cardiovascular risk including any of the following: Evidence of current clinically significant uncontrolled arrhythmias including clinically significant electrocardiogram (ECG) abnormalities including 2nd degree (Mobitz Type II) or 3rd degree atrioventricular block; History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 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 mafodotin, pomalidomide, dexamethasone or any of the components of the study intervention.
• Pregnant or lactating female.
• Active infection requiring treatment.
• Known human immunodeficiency virus (HIV), unless the participant can meet all of the following criteria: Established anti-retroviral therapy (ART) for at least 4 weeks and HIV viral load <400 copies/mL; CD4+ T-cell (CD4+) counts ≥350 cells/uL; No history of AIDS-defining opportunistic infections within the last 12 months.(Consideration must be given to ART and prophylactic antimicrobials that may have a drug-drug interaction and/or overlapping toxicities with belantamab mafodotin or other combination products as relevant)
• Participants with Hepatitis B will be excluded unless the following criteria can be met: If the participant is hepatitis B core antibody (HbcAb) positive or hepatitis B surface antigen (HbsAg) negative, then hepatitis B virus (HBV) deoxyribonucleic acid (DNA) should be undectectable at the time of screening; If HbsAg+ at screening or <=3 months prior to first dose of study treatment, then HBV DNA should be undetectable, highly effective antiviral treatment should be started ≥4 weeks prior to first dose of study treatment, exclusion of participants with cirrhosis and participants in Japan must test hepatitis B e antigen (HBeAg) and hepatitis B e antibody (HBeAb ).
• Positive hepatitis C antibody test result or positive hepatitis C Ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment unless the participant can meet the following criteria: Hepatitis C RNA test negative at Screening and successful anti-viral treatment (usually 8 weeks duration) is required, followed by a negative HCV RNA test after a washout period of at least 4 weeks (Hepatitis RNA is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing).
• Participants unable to tolerate thromboembolic prophylaxis.
• Current corneal epithelial disease except for mild punctate keratopathy.