The aim of this study is to assess safety, efficacy and pharmacokinetic (PK) parameters with alternative dosing schedules of belantamab mafodotin in combination with bortezomib and dexamethasone compared to the approved dosing regimen in participants with relapsed or refractory multiple myeloma (RRMM) who have received at least 2 prior lines of therapy. The study will further characterize the risk of ocular toxicity and impact on efficacy measures and PK evaluations using alternative and approved dosing regimens.

Inclusion Criteria:

• Is at least 18 years of age or the legal age of consent in the jurisdiction in which the study is taking place at the time of signing the Informed consent form (ICF).

• Has histologically or cytologically confirmed diagnosis of Multiple myeloma (MM), as defined by the IMWG.

• Previously treated with at least 2 prior lines of MM therapy, including a proteasome inhibitor and an immunomodulatory agent.

• Has at least 1 aspect of measurable disease, as assessed by the central laboratory, defined as at least 1 of the following:

  • Urine M-protein excretion >=200 milligrams (mg)/24 hours (>=0.2 grams [g]/24 hours)
  • Serum M-protein concentration >=0.5 grams per deciliter (g/dL) (>=5.0 g/L)
  • Serum free light chain (FLC) assay: involved FLC level >=10 milligrams per deciliter (mg/dL) (>=100 mg/L) and an abnormal serum FLC ratio (less than [<] 0.26 or greater than [>] 1.65).

• Participants with a history of autologous stem cell transplants are eligible for study participation provided the following eligibility criteria are met:

  • Transplant was > 100 days prior to study enrollment
  • No active infection(s)
  • Participant meets the remainder of the eligibility criteria

• All prior treatment-related toxicities (defined by NCI-CTCAE version [v] 6.0) must be Grade less than or equal to (<=)1 at the time of treatment assignment, except for alopecia (any grade), neuropathy (Grade <=2), or endocrinopathy managed with replacement therapy (any grade).

• Is willing to use adequate contraception male and female participants. Contraceptive use by male and female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

  1. Male participants are eligible to participate if they agree to the following during the Treatment Period and for at least 6 months after the last dose of belantamab mafodotin and 5 months after the last dose of bortezomib, whichever is longest, 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), including any activity or passage of ejaculate to another person, 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 a partner who can become pregnant and is not currently pregnant. Male participants should also use a condom when having sexual intercourse with pregnant females

  2. Female participants are eligible to participate if they are not pregnant or breastfeeding, and one of the following conditions applies:

     • Is a Person of non-childbearing potential (PONCBP) OR
     • Is a Person of childbearing potential (POCBP) and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, during the study intervention period and for at 4 months after the last dose of belantamab mafodotin or 8 months after the last dose of bortezomib, whichever is longest, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.
     • A POCBP must have a negative highly sensitive serum pregnancy tests within 72 hours before the first dose of study intervention.
     • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a person with an early undetected pregnancy.

• Is capable of giving signed informed consent.

• Has an Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

• Has adequate organ system functions as defined by the laboratory assessments.

• Participants with a history of Hepatitis B virus (HBV) and/or Hepatitis C virus (HCV) and Human immunodeficiency virus (HIV) exposure are eligible under specific conditions.

Exclusion Criteria:

• Intolerant to bortezomib
• Diagnosis of systemic amyloid light chain amyloidosis, Waldenstrom's disease, polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes (POEMS) or Primary Plasma Cell Leukemia (defined as circulating plasma cells >5%)
• Has previous or concurrent invasive malignancy other than Multiple myeloma (MM), except:

The disease must be considered medically stable for at least 2 years; or

• The participant 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.
  • Evidence of active mucosal or internal bleeding.
  • Active infection requiring treatment
  • Any major surgery within 4 weeks prior to the first dose of study drug. Exception allowed for bone stabilizing surgery after consultation with Medical Monitor.
  • Active or history of venous and arterial thromboembolism within the past 3 months.
  • Contraindications to or unwilling to undergo protocol-required anti-thrombotic prophylaxis.
  • Current corneal epithelial disease except for mild punctate keratopathy
  • Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including laboratory abnormalities) that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures.
  • Participants after prior allogeneic stem cell transplant.
  • Has received prior belantamab mafodotin therapy.
  • Has received treatment with an investigational agent within 14 days or 5 half-lives, whichever is shorter, preceding the first dose of study drug. This includes prior treatment with a monoclonal antibody and any other B-cell maturation antigen (BCMA) targeting-therapy. The only exception is emergency use of a short course of systemic corticosteroids (equivalent to, or less than: dexamethasone 40 mg/day for a maximum of 4 days) before treatment.
  • 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.
  • Plasmapheresis within 7 days prior to the first dose of study treatment. Screening laboratory values must be performed after last plasmapheresis
  • Has received any live vaccine within 30 days of randomization/enrollment. Vaccination against Coronavirus Disease 2019 (COVID-19) using vaccines that are authorized via the appropriate regulatory mechanisms (e.g., Emergency Use Authorization, Conditional Marketing Authorization, or Marketing Authorization Application) are not exclusionary.
  • Is currently enrolled or has participated in any other clinical study involving an investigational drug within 14 days or 5 half-lives (whichever is shorter) preceding the first dose of study intervention.
  • Known Human immunodeficiency virus (HIV) infection, unless the participant can meet all of the following criteria:

• Established anti-retroviral therapy for at least 4 weeks and HIV viral; load <400 copies/milliliter (mL)

• Cluster of differentiation 4 (CD4+) T-cell counts >=350 cells/microliter;

• No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections within the last 12 months.

  • Is pregnant, plan to become pregnant, or breastfeeding.
  • Has an Alanine aminotransferase (ALT) value >2.5 times Upper limit of normal (ULN).
  • Has a total bilirubin value >1.5 times ULN
  • Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice.
  • Has a positive Hepatitis C virus (HCV) antibody test result at screening or within 3 months prior to the first dose of study intervention unless HCV Ribonucleic acid (RNA) is negative, indicating past resolved HCV infection, including participants who have undergone curative treatment.
  • Has a positive HCV RNA test result at screening or within 3 months prior to the first dose of study intervention.
  • Has documented presence of Hepatitis B surface antigen (HBsAg) and/or Hepatitis B virus antibody (HBcAb) at screening or within 3 months prior to the first dose of study intervention unless specific criteria are met.
  • Evidence of cardiovascular risk including any of the following:

• Evidence of current clinically significant untreated arrhythmias, including clinically significant electrocardiogram (ECG) abnormalities including second degree (Mobitz Type II) or third 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 • Has QT interval corrected (QTc) >450 milliseconds (msec) or QTc >480 msec for participants with bundle branch block.

This is an open-label study.