Belantamab MafodotinA Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin in Combination With Standard of Care in Participants With Relapsed-Refractory Multiple Myeloma (RRMM)

Inclusion Criteria:

• Participants are eligible to be included in the study only if all of the following criteria apply:

Applicable to All Arms - BPd, BVd, BKd:

• Male or female, 18 years or older (at the time consent is obtained).
• Have a confirmed diagnosis of Multiple Myeloma (MM) as defined by the International Myeloma Working Group (IMWG) criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of zero to 2.
• Have been previously treated with at least 1, but no more than 2, prior lines of MM therapy and must have documented disease progression during or after their most recent therapy.
• Must have at least 1 aspect of measurable disease, defined as one the following:

1. Urine M-protein excretion ≥200 mg/24 h, or
2. Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L), or
3. Free Light Chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum free light chain ratio (<0.26 or >1.65) only if patient has no measurable urine or serum M spike.

• Patients with a history of Autologous Stem Cell Transplant (ASCT) are eligible for study participation provided the following eligibility criteria are met:

1. ASCT was >100 days prior to the first dose of study medication,
2. No active bacterial, viral, or fungal infection(s) present.

• All prior treatment-related toxicities (defined by National Cancer Institute-Common Terminology Criteria for Adverse Events \[NCI-CTCAE\] v5.0) must be ≤Grade 1 at the time of enrollment, except for alopecia.
• Adequate organ system functions as defined by the laboratory assessments.
• Contraceptive requirements for men and women per local regulations; strict pregnancy prevention for women of childbearing potential (WOCBP), including negative pregnancy tests and use of highly effective contraception.
• Male participants must refrain from sperm donation and must use a condom plus an additional highly effective method of contraception if sexually active with a woman of childbearing potential.

Specific Inclusion Criteria for BPd arm:

• Prior treatment must include a lenalidomide-containing regimen, with lenalidomide administered for at least 2 consecutive cycles.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

Applicable for all (BPd, BVd, BKd):

• Active plasma cell leukemia at Screening.
• Symptomatic amyloidosis, including active Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma proliferative disorder, and Skin changes (POEMS).
• Previous or concurrent invasive malignancy other than MM, except:

1. The disease must be considered medically stable for at least 2 years; or
2. The patient must not be receiving active therapy, other than hormonal therapy for this disease.

• Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to belantamab mafodotin or drugs chemically related to belantamab mafodotin, or any of the components of the study treatment.
• Plasmapheresis within 7 days prior to the first dose of study intervention.
• Patients after prior allogeneic stem cell transplant
• Any major surgery within 4 weeks prior to start of treatment, except for bone stabilizing surgery.
• Evidence of active mucosal or internal bleeding.
• Intolerance or contraindications to anti-viral prophylaxis.
• Current corneal epithelial disease except for mild punctate keratopathy.
• Systemic anti-myeloma therapy (including chemotherapy and systemic steroids); prior treatment with an anti-MM monoclonal antibody drug within 30 days of receiving the first dose of study intervention.
• Presence of active renal condition (infection, requirement for dialysis, or any other condition that could affect participant's safety). Patients with isolated proteinuria resulting from MM are eligible, provided they fulfill certain criteria
• Received prior B-cell maturation antigen (BCMA)-targeted therapy.
• Contact lenses are prohibited while receiving belantamab mafodotin treatment. Use may be restarted after a qualified eye care specialist confirms there are no other contraindications. Bandage contact lenses are permitted during study treatment as directed by the treating eye care specialist.
• HIV infection unless well-controlled, no recent AIDS-defining infections, and adequate CD4+ count.
• Significant liver dysfunction (ALT >2.5x ULN, bilirubin >1.5x ULN, cirrhosis, unstable liver/biliary disease).
• Positive hepatitis B or C markers unless criteria for resolved infection are met.
• Evidence of cardiovascular risk including any of the following: untreated arrhythmias, recent MI/ACS/angioplasty/bypass, NYHA III/IV heart failure, uncontrolled hypertension, QTc prolongation.

Specific Exclusion Criteria for BPd Arm:

• Received prior treatment with or intolerant to pomalidomide.
• Active or history of venous and arterial thromboembolism within the past 3 months.

Specific Exclusion Criteria for BVd Arm:

• Intolerant to bortezomib or refractory to bortezomib (defined as progressive disease during treatment with a bortezomib-containing regimen of 1.3 mg/m² twice weekly or within 60 days of completing that treatment).
• Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain.

Specific Exclusion Criteria for BKd Arm:

• Intolerant to carfilzomib or refractory to carfilzomib (defined as progressive disease during treatment with a carfilzomib-containing regimen or within 60 days of completing that treatment).
• Known history of allergy to captisol (i.e., cyclodextrin derivatives) used to solubilize carfilzomib.
• Left ventricular ejection fraction <40% as assessed by transthoracic echocardiogram.
• Pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrolment.
• Intolerance to hydration due to pre-existing pulmonary or cardiac impairment.
• Known pulmonary hypertension.