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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase III, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Single Agent Belantamab Mafodotin Compared to Pomalidomide Plus Lowdose Dexamethasone (Pom/Dex) in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM 3)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Belantamab mafodotin
* Drug: Pom/dex (Pomalidomide plus low dose Dexamethasone)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an open-label, randomized and multi-center study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving Belantamab mafodotin<br>Participants will receive belantamab mafodotin single agent dose on Day 1 of Q3W | Drug: Belantamab mafodotin<br>* Belantamab mafodotin will be administered.<br>|
| Active Comparator: Participants receiving pom/dex<br>Participants will receive pomalidomide daily on Days 1 to 21 of each 28-day cycle, with dexamethasone once weekly on Days 1, 8, 15 and 22. | Drug: Pom/dex (Pomalidomide plus low dose Dexamethasone)<br>* Pomalidomide and Dexamethasone will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Based on Investigator-assessed Response as Per International Myeloma Working Group (IMWG) | PFS is time from randomization until earliest date of progressive disease (PD), or death due to any cause per investigator-assessed response per IMWG. PD is ≥25% increase from nadir in any of following: serum M-protein (absolute increase ≥0.5 gram per deciliter [g/dL]),urine M-protein(absolute increase ≥200 mg/24hr),difference between involved/uninvolved FLC levels (absolute increase >10 mg/dL) in patients without measurable serum and urine M-protein levels, or bone marrow plasma-cell percentage irrespective of baseline status (absolute increase ≥10%) in patients without measurable serum and urine M-protein levels and without measurable involved FLC levels; appearance of new lesion,≥50% increase in longest diameter of a lesion previously measured >1cm in short axis, or ≥50% increase from nadir in sum of products of two longest perpendicular diameters of more than 1 lesion; ≥50% increase in circulating plasma cells (minimum of 200 cells/microliter) if this is only measure of disease. | Up to 27 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from randomization until death due to any cause. | 60 months | 
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants with a confirmed partial response (PR) or better per IMWG. | Up to 55 months | 
| Clinical Benefit Rate (CBR) | CBR is defined as the percentage of participants with a confirmed minimal response (MR) or better per IMWG. | Up to 55 months | 
| Duration of Response (DoR) | DoR is defined as the time from first documented evidence of PR or better until progressive disease (PD) per IMWG or death due to PD among participants who achieve confirmed PR or better. | Up to 55 months | 
| Time to Response (TTR) | TTR is defined as the time between the date of randomization and the first documented evidence of response (PR or better) among participants who achieve confirmed PR or better. | Up to 55 months | 
| Time to Progression (TTP) | TTP is defined as the time from the date of randomization until the earliest date of documented PD (per IMWG Response Criteria) or death due to PD. | Up to 55 months | 
| Number of Participants With Adverse Events (AEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. | Up to 55 months | 
| Change From Baseline in Hematology Parameters: Absolute White Blood Cell Count (WBC), Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, and Neutrophils (Giga Cells Per Liter) | Blood samples will be collected for the analysis of hematology parameters. | Baseline and up to 55 months | 
| Change From Baseline in Hematology Parameters: Red Blood Cell (RBC) Count and Reticulocyte Count (Trillion Cells Per Liter) | Blood samples will be collected for the analysis of hematology parameters. | Baseline and up to 55 months | 
| Change From Baseline in Hematology Parameters: Mean Corpuscular Hemoglobin Concentration (MCHC) and Hemoglobin (Grams Per Liter) | Blood samples will be collected for the analysis of hematology parameters. | Baseline and up to 55 months | 
| Change From Baseline in Hematology Parameters: Hematocrit (Proportion of Red Blood Cells in Blood) | Blood samples will be collected for the analysis of hematology parameters. | Baseline and up to 55 months | 
| Change From Baseline in Hematology Parameters: Mean Corpuscular Volume (MCV) [Femtoliter] | Blood samples will be collected for the analysis of hematology parameters. | Baseline and up to 55 months | 
| Change From Baseline in Hematology Parameters: Mean Corpuscular Hemoglobin (MCH) [Picograms] | Blood samples will be collected for the analysis of hematology parameters. | Baseline and up to 55 months | 
| Change From Baseline in Clinical Chemistry Parameters: Alanine Amino Transferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase (CK), Gamma Glutamyl Transferase (GGT), and Lactate Dehydrogenase (LDH) | Blood samples will be collected for the analysis of clinical chemistry parameters like ALT, AST, ALP, CK, GGT, and LDH [International units per Liter | Baseline and up to 55 months | 
| Change From Baseline in Clinical Chemistry Parameters: Calcium, Chloride, Glucose, Potassium, Sodium, Magnesium, Blood Urea Nitrogen (BUN), and Phosphorous (Millimoles Per Liter) | Blood samples will be collected for the analysis of clinical chemistry parameters. | Baseline and up to 55 months | 
| Change From Baseline in Clinical Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin, Uric Acid (Micromoles Per Liter) | Blood samples will be collected for the analysis of clinical chemistry parameters. | Baseline and up to 55 months | 
| Change From Baseline in Clinical Chemistry Parameters: Albumin and Total Protein (Grams Per Liter) | Blood samples will be collected for the analysis of clinical chemistry parameters. | Baseline and up to 55 months | 
| Change From Baseline in Urinalysis Parameter: Specific Gravity (Ratio) | Urine samples will be collected for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. | Baseline and up to 55 months | 
| Change From Baseline in Urinalysis Parameters- Urine Potential of Hydrogen (pH) (Points on a Scale) | Urine samples will be collected for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). | Baseline and up to 55 months | 
| Change From Baseline in Urinalysis Parameter: Glucose (Millimole Per Liter) | Urine samples will be collected for the assessment of urinary glucose. | Baseline and up to 55 months | 
| Change From Baseline in Urinalysis Parameter: Protein (Grams Per Liter) | Urine samples will be collected for the assessment of urinary protein. | Baseline and up to 55 months | 
| Change From Baseline in Urinalysis Parameter: Ketones (Millimoles Per Liter) | Urine samples will be collected for the assessment of urinary ketones. | Baseline and up to 55 months | 
| Change From Baseline in Urinalysis Parameter: Blood (10^9 Cells Per Liter) | Urine samples will be collected for the assessment of urinary blood. | Baseline and up to 55 months | 
| Change From Baseline in Urinalysis Parameter: Creatinine/Albumin Ratio (Ratio) | Urine samples will be collected for the assessment of urinary creatinine/albumin ratio. | Baseline and up to 55 months | 
| Number of Participants With Abnormal Ocular Findings | Participants will be assessed for any abnormal ocular findings. | Up to 55 months | 
| Plasma Concentrations of Belantamab Mafodotin | Blood samples will be collected for the analysis. | Up to 55 months | 
| Plasma Concentrations of Total Monoclonal Antibody (mAb) | Blood samples will be collected for the analysis. | Up to 55 months | 
| Plasma Concentrations of Cys-mc Microtubular Inhibitor Monomethyl Auristatin-F (MMAF) | Blood samples will be collected for the analysis. | Up to 55 months | 
| Number of Participants With Anti-drug Antibody (ADAs) Against Belantamab Mafodotin | Blood samples will be collected for the analysis. | Up to 55 months | 
| Titer of ADAs Against Belantamab Mafodotin | Blood samples will be collected for the analysis. | Up to 55 months | 
| Number of Participants With Symptomatic Adverse Effects Measured by Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) | PRO-CTCAE is a patient-reported outcome measure developed to evaluate symptomatic toxicity in participants on cancer clinical trials. The PRO-CTCAE includes an item library of 124 items representing 78 symptomatic toxicities drawn from the CTCAE. | Up to 55 months | 
| Number of Participants With Symptomatic Adverse Effects Measured by Ocular Surface Disease Index (OSDI) | OSDI is a 12-item questionnaire designed to assesses both the frequency of dry eye symptoms and their impact on vision-related functioning. It is graded on a scale of 0-4, with 0 indicating none of the time, 1 for some of the time, 2 for half of the time, 3 for most of the time and 4 indicating all the time. A higher score represents greater symptoms severity. | Up to 55 months | 
| European Organization for Research and Treatment of Cancer IL52 (EORTC IL52) Score | The EORTC Quality of Life Questionnaire 20-item Multiple Myeloma module (QLQMY20) is a supplement to the QLQ-C30 instrument used in participants with multiple myeloma. For the EORTC IL52, disease symptoms domain of the QLQ-MY20 will be used for bone aches or pain, back pain, hip pain, arm or shoulder pain, chest pain, and pain increasing with activity. The individual component scores in the disease symptom domain are averaged and transformed linearly to a score ranging from 0 to100. A high score for disease symptoms represents a high level of symptomatology or problems. A high score represents a high/healthy level of functioning. | Up to 55 months | 
| Rate of Minimal Residual Disease (MRD) | MRD negativity rate, defined as; the percentage of participants who are MRD negative by Next generation sequencing (NGS) method. | Up to 55 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Belantamab mafodotin, Pomalidomide, Dexamethasone, Relapsed/Refractory Multiple Myeloma, Driving Excellence in Approaches to Multiple Myeloma 3 (DREAMM 3)