The study aims to evaluate the efficacy and safety of belantamab mafodotin in combination with cyclophosphamide, bortezomib, and dexamethasone in adult participants with newly diagnosed (ND) AL amyloidosis .

Inclusion criteria:

• Participant is at least 18 years of age or the legal age of consent

• Has histologically confirmed newly diagnosed primary AL amyloidosis according to the following criteria:

  • Presence of an amyloid-related systemic syndrome as per consensus guidelines.
  • Positive amyloid staining by Congo red stain with green birefringence on polarized light microscopy in any tissue AND at least 1 of the following tests to confirm amyloid type as AL Characteristic appearance by electron microscopy or confirmatory immunohistochemistry or AL amyloidosis typing by mass spectrometric proteomic analysis of the amyloid deposits or amyloid-typing by immunofluorescence oEvidence of a monoclonal plasma cell proliferative disorder

• Measurable clonal disease as defined by at least 1 of the following:

  • Serum monoclonal protein >=0.5 grams per deciliter (g/dL) by protein electrophoresis (routine serum protein electrophoresis and immunofixation performed at central laboratory),
  • Involved serum FLC >=5.0 milligram per deciliter (mg/dL) with an abnormal kappa:lambda ratio or the difference between involved and uninvolved light chain, FLC concentrations (dFLC) >=5 mg/dL.

• Not considered candidate for high-dose chemotherapy with autologous stem cell transplantation (ASCT) as part of first line of therapy

• Is willing to use adequate contraception.

• Is capable of giving signed informed consent

• Has an Eastern Cooperative Oncology Group performance status of 0, 1 or 2

• Has adequate hematologic, hepatic and renal function

Exclusion criteria:

• Has a previous or current diagnosis of plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes (POEMS) syndrome or symptomatic multiple myeloma (MM), as per International Myeloma Working Group criteria for MM including the presence of lytic bone disease , plasmacytomas, or clonal BM plasma cells >=60%.

• Has Immunoglobulin M (IgM)-related AL amyloidosis.

• Has any form of non-AL amyloidosis, including wild type or mutated (Transthyretin amyloidosis [ATTR]) amyloidosis.

• Has evidence of significant cardiovascular (CV) conditions as specified below:

  • New York Heart Association (NYHA) classification IIIb or IV heart failure.
  • Heart failure that in the opinion of the investigator is caused by ischemic heart disease (e.g., prior myocardial infarction with documented history of cardiac enzyme elevation and electrocardiogram [ECG] changes) or uncorrected valvular disease and not primarily due to AL amyloidosis cardiomyopathy.
  • In-participant admission to a hospital for unstable angina or myocardial infarction within the last 3 months prior to screening or percutaneous cardiac intervention with recent stent within last 3 months prior to screening or coronary artery bypass grafting within the last 3 months prior to screening
  • Participants with current evidence of clinically significant untreated arrhythmia(s), including clinically significant ECG abnormalities including second-degree (Mobitz Type II) or third-degree atrioventricular block.
  • Participants with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker/implantable cardioverter-defibrillator is indicated but not placed (participants who do have a pacemaker/implantable cardioverter-defibrillator are allowed on the study).
  • Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >450 millisecond (msec) or >480 msec for participants with bundle branch block. Participants who have a pacemaker may be included regardless of calculated QTc interval.
  • Supine systolic blood pressure <90 millimeters of mercury (mmHg), or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of >20 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion.
  • Uncontrolled hypertension.

• Has Mayo stage 3B disease

• Has a current corneal epithelial disease except for mild punctate keratopathy.

• Has previous or concurrent malignancies other than AL amyloidosis, except for any other malignancy that has been considered medically stable for at least 2 yearsThe participant must not be receiving active therapy, other than hormonal therapy for this disease.

• Has major surgery within 2 weeks prior to the first dose of study interventions or has not recovered fully from surgery.

• Has any history of prior allogenic or autologous BM transplant or other solid organ transplant.

• Has known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belantamab mafodotin, cyclophosphamide, bortezomib, boron or mannitol

• Has active infection or active bleeding.

• Has intolerance or contraindications to antiviral prophylaxis.

• Has known Human immunodeficiency virus (HIV) infection, 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/milliliter (mL) Cluster of differentiation 4 plus (CD4+) T-cell (CD4+) counts >=350 cells/microliter.
  • No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the last 12 months.

• Has prior therapy for AL amyloidosis or MM, with the exception of 160 milligram (mg) dexamethasone (or equivalent corticosteroid) maximum exposure prior to enrollment.

• Has received any live or live-attenuated vaccine within 30 days prior to first dose of belantamab mafodotin

• Is currently enrolled or has participated in any other clinical study involving an investigational study intervention or any other type of interventional medical research within 28 days before enrollment.

• Has an alanine aminotransferase (ALT) value >2.5*upper limit of normal (ULN) or >3*ULN if hepatic involvement of AL amyloidosis

• Has a total bilirubin value >1.5*ULN

• Has cirrhosis or current unstable liver or biliary disease per investigator assessment Has documented presence of Hepatitis B surface antigen (HBsAg) and/or Hepatitis B core antibody (HBcAb) at screening or within 3 months prior to the first dose of study intervention, unless HBV DNA is undetectable at screening and participant receives antiviral prophylaxis or treatment.

• Has a 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 intervention unless the following criteria are met:

  • RNA test negative.
  • Successful antiviral treatment (usually 8 weeks duration), followed by a negative Hepatitis C virus RNA test after a washout period of at least 4 weeks.

• Chronic hepatitis B infection, with the presence of HBsAg and/or detectable hepatitis B virus deoxyribonucleic acid (HBV DNA), and hepatitis D co-infection, with hepatitis D antibody and/or RNA, within 3 months