Belantamab Mafodotin Plus Pomalidomide and Dexamethasone (Pd) Versus Bortezomib Plus Pd in Relapsed/Refractory Multiple Myeloma

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of belantamab mafodotin in combination with pomalidomide and dexamethasone (Arm A) compared with that of combination of pomalidomide, bortezomib and dexamethasone (Arm B) in participants with relapsed/refractory multiple myeloma (RRMM).

Official Title
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A Phase III, Multicenter, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin in Combination With Pomalidomide and Dexamethasone (B-Pd) Versus Pomalidomide Plus Bortezomib and Dexamethasone (PVd) in Participants With Relapsed/Refractory Multiple Myeloma (DREAMM 8)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Belantamab mafodotin
* Drug: Pomalidomide
* Drug: Dexamethasone
* Drug: Bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent. Male or female, 18 years or older. 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 0 to 2. Have been previously treated with at least 1 prior line of MM therapy including a lenalidomide-containing regimen and must have documented disease progression during or after their most recent therapy. (Participants treated with lenalidomide ≥10 mg daily for at least 2 consecutive cycles are eligible). Must have at least 1 aspect of measurable disease defined as one of the following; Urine M-protein excretion greater than or equal to (≥)200 milligrams (mg) per 24-hour, or Serum M-protein concentration ≥0.5 grams/deciliters (g/dL) (≥5.0 g/liter [L]), or Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum free light chain ratio (less than [<]0.26 or greater than [>]1.65) only if participant has no measurable urine or serum M spike. Have undergone autologous stem cell transplant (ASCT) or are considered transplant ineligible. Participants with a history of ASCT are eligible for study participation provided the following eligibility criteria are met: a. ASCT was >100 days prior to the first dose of study medication. b. 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] version 5.0) must be less than or equal to (≤)Grade 1 at the time of enrolment, except for alopecia. Adequate organ system functions as mentioned in the protocol. Male and female participants agree to abide by protocol-defined contraceptive requirements. Exclusion Criteria: Active plasma cell leukemia, symptomatic amyloidosis or active polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, and skin changes (POEMS) syndrome at the time of screening. Prior allogeneic SCT. Systemic anti-myeloma therapy (including chemotherapy and systemic steroids) within 14 days or five half-lives (whichever is shorter) preceding the first dose of study drug; prior treatment with a monoclonal antibody drug within 30 days of receiving the first dose of study drugs. Plasmapheresis within 7 days prior to the first dose of study drug. Received prior treatment with or intolerant to pomalidomide. Received prior Beta cell maturation antigen (BCMA) targeted therapy. Intolerant to bortezomib or refractory to bortezomib (for example; participant experienced progressive disease during treatment, or within 60 days of completing treatment, with a bortezomib-containing regimen of 1.3 mg/meter square [m^2] twice weekly). Evidence of cardiovascular risk including any of the following; Evidence of current clinically significant untreated arrhythmias, including clinically significant electrocardiogram abnormalities including second degree (Mobitz type II) or third degree atrioventricular (AV) block. Recent history within (3 months of screening) of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting . Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system Uncontrolled hypertension. Any major surgery within the last 4 weeks. Previous or concurrent invasive malignancy other than multiple myeloma, 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. 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. Active infection requiring treatment. Known or active human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C will be excluded unless the protocol-defined criteria are met. Presence of active renal conditions (such as infection, severe renal impairment requiring dialysis or any other condition that could affect participant's safety). Ongoing Grade 2 peripheral neuropathy with pain within 14 days prior to randomization or ≥Grade 3 peripheral neuropathy. 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 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. Pregnant or lactating female.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Belantamab mafodotin plus Pomalidomide and Dexamethasone<br> | Drug: Belantamab mafodotin<br>* Humanized anti-B-cell maturation antigen (BCMA) antibody/drug conjugate will be administered.<br>Drug: Pomalidomide<br>* Immunomodulatory drug (IMiD) will be administered.<br>Drug: Dexamethasone<br>* Synthetic glucocorticoid with anti-tumor activity will be administered.<br>|
| Active Comparator: Arm B: Bortezomib plus Pomalidomide and Dexamethasone<br> | Drug: Pomalidomide<br>* Immunomodulatory drug (IMiD) will be administered.<br>Drug: Dexamethasone<br>* Synthetic glucocorticoid with anti-tumor activity will be administered.<br>Drug: Bortezomib<br>* Proteasome Inhibitor 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) | PFS will be defined as the time from the randomization until the earliest date of progressive disease (PD) based on Independent Review Committee (IRC) assessment per International Myeloma Working Group (IMWG) criteria, or death due to any cause | Up to 84 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DoR) | DoR will be defined as the time from first documented evidence of partial response or better until progressive disease (PD) or death due to any cause. Response will be based on IRC-assessment per IMWG criteria. | Up to 84 months | 
| Minimal residual disease (MRD) negativity rate | MRD negativity rate will be defined as the percentage of participants who achieve MRD negative status (as assessed by next-generation sequencing (NGS) at 10^5 threshold) at least once during the time of confirmed CR or better response, based on IRC assessment per IMWG. | Up to 84 months | 
| Overall survival (OS) | OS will be defined as the interval of time from randomization to the date of death due to any cause. | Up to 84 months | 
| Overall response rate (ORR) | ORR will be defined as the percentage of participants with a confirmed partial response or better (i.e., PR, VGPR, CR, and sCR) based on IRC-assessment per IMWG criteria. | Up to 84 months | 
| Complete response rate (CRR) | CRR will be defined as the percentage of participants with a confirmed complete response or better (i.e., CR and stringent complete respone (sCR) based on IRC-assessment per IMWG criteria. | Up to 84 months | 
| Very good partial response (VGPR) or better rate | VGPR will be the defined as the percentage of participants with a confirmed VGPR or better (i.e., VGPR, CR, and sCR) based on IRC-assessment per IMWG criteria. | Up to 84 months | 
| Time to best response (TTBR) | TTBR will be defined as the interval of time between the date of randomization and the earliest date of achieving best response among participants with a confirmed PR or better based on IRC-assessment per IMWG. | Up to 84 months | 
| Time to response (TTR) | TTR defined as the time between the date of randomization and the first documented evidence of response (PR or better) among participants who achieve a response (i.e., confirmed PR or better) based on IRC-assessment per IMWG. | Up to 84 months | 
| Time to progression (TTP) | TTP defined as the time from randomization until the earliest date of PD based on IRC-assessment per IMWG criteria, or death due to PD. | Up to 84 months | 
| Progression-free survival on subsequent line of therapy (PFS2) | PFS2 defined as time from randomization to disease progression (investigator-assessed response) after initiation of new anti-myeloma therapy or death from any cause, whichever is earlier. If disease progression after new anti-myeloma therapy cannot be measured, a PFS event is defined as the date of discontinuation of new anti-myeloma therapy, or death from any cause, whichever is earlier. | Up to 84 months | 
| Number of participants with adverse events (AEs) and serious adverse events (SAEs) |  | Up to 84 months | 
| Number of participants with clinically significant changes in hematology, clinical chemistry and urinalysis lab parameters |  | Up to 84 months | 
| Number of participants with abnormal ocular findings on ophthalmic examination |  | Up to 84 months | 
| Plasma concentrations of belantamab mafodotin at indicated time points |  | Up to 84 months | 
| Plasma concentrations of monomethyl auristatin-F with a cysteine linker (cys-mcMMAF) at indicated time points |  | Up to 84 months | 
| Maximum observed concentration (Cmax) for pomalidomide |  | Up to 24 hours | 
| Time of Cmax (Tmax) for pomalidomide |  | Up to 24 hours | 
| Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC[0-t]) for pomalidomide |  | Up to 24 hours | 
| Number of participants with positive anti-drug antibodies (ADAs) against belantamab mafodotin |  | Up to 84 months | 
| Titers of ADAs against belantamab mafodotin |  | Up to 84 months | 
| Number of participants with maximum post-baseline changes in patient-reported outcome version of the common terminology criteria for adverse events (PRO-CTCAE) scores for each item attribute | PRO-CTCAE questionnaire assesses side effect symptoms in cancer clinical trial. Impacts of the side effects will be assessed using PRO-CTCAE score. | Baseline and up to 84 months | 
| Change from Baseline in health related quality of life (HRQoL) as measured by European Organization for Research and Treatment of Cancer Quality of life Questionnaire 30-item core module (EORTC QLQ-C30) | EORTC Quality of Life questionnaire QLQ-C30 on a scale of 0-100. Lower scores correlate with worse quality of life and higher scores correlate with better quality of life. | Baseline and up to 84 months | 
| Change from Baseline in HRQoL as measured by EORTC item library 52 (IL52) | EORTC QLQ- 20-item Multiple Myeloma Module (MY20) questionnaire will be referred to as the EORTC IL52. Only disease symptoms domain will be assessed. A high score represents a high level of symptoms or problems. | Baseline and up to 84 months | 
| Change from Baseline in HRQoL as measured by EORTC QLQ-20-item Multiple Myeloma Module (MY20) | EORTC QLQ-MY20 is a questionnaire which will evaluate disease symptoms. In EORTC QLQ-MY20, domain scores will be averaged and will be transformed linearly to a score ranging from 0 to 100. Higher score represents high level of symptomatology or problems. | Baseline and up to 84 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Belantamab Mafodotin, Relapsed/Refractory Multiple Myeloma, Pomalidomide, Dexamethasone, Bortezomib