Study of Single Agent Belantamab Mafodotin Versus Pomalidomide Plus Low-dose Dexamethasone (Pom/Dex) in Participants With Relapsed/Refractory Multiple Myeloma (RRMM)
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Belantamab mafodotin; Pom/dex (Pomalidomide plus low dose Dexamethasone)
Intervention description: Belantamab mafodotin will be administered.; Pomalidomide and Dexamethasone will be administered.
Intervention MeSH terms: Dexamethasone; Pomalidomide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is an open-label, randomized and multi-center study
Masking: None (Open Label)
Enrollment: 325.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Belantamab mafodotin; Pomalidomide; Dexamethasone; Relapsed/Refractory Multiple Myeloma; Driving Excellence in Approaches to Multiple Myeloma 3 (DREAMM 3)

Summary:

      This open-label, randomized study for evaluating the efficacy and safety of single agent
      belantamab mafodotin when compared to pom/dex in participants with RRMM. Participants will be
      randomized in a 2:1 ratio to receive either single agent belantamab mafodotin or pom/dex.
      Belantamab mafodotin will be administered on Day 1 (D1) at every 3 weeks (Q3W) schedule.
      Pomalidomide will be administered daily on Days 1 to 21 of each 28-day cycle, with
      dexamethasone administered once weekly (Days 1, 8, 15, and 22). Participants in both arms
      will be treated until disease progression, death, unacceptable toxicity, withdrawal of
      consent, and lost to follow-up or end of study, whichever comes first.
    

Eligibility criteria:

        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.