Phase III Evaluation of Belantamab Mafodotin, Bortezomib, and Dexamethasone Versus Daratumumab, Bortezomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma
- Trial ID
- 2023-510537-28-00
- Protocol
- 207503
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the efficacy of **belantamab mafodotin** in combination with bortezomib and dexamethasone (B-Vd) with that of daratumumab in combination with bortezomib and dexamethasone (D-Vd) in participants with relapsed refractory **multiple myeloma** in terms of progression-free survival. This is clinically relevant as progression-free survival is a critical endpoint in assessing the effectiveness of treatment regimens in prolonging the time patients live without disease progression.
Secondary objectives include:
- Comparing the efficacy of B-Vd with D-Vd in terms of overall survival, duration of response, and minimal residual disease.
- Further assessing the efficacy of B-Vd with D-Vd in terms of other efficacy outcomes.
- Evaluating the safety and tolerability of B-Vd.
- Describing the exposure to belantamab mafodotin when administered in combination with bortezomib and dexamethasone.
- Assessing anti-drug antibodies (ADAs) against belantamab mafodotin.
- Evaluating the safety and tolerability of B-Vd based on self-reported symptomatic adverse effects.
- Evaluating and comparing changes in symptoms and health-related quality of life (HRQOL) as measured by EORTC QLQ-C30 and EORTC IL52.
Participants
The clinical trial involves a total of **338 participants** diagnosed with **Multiple Myeloma**, specifically targeting individuals with relapsed refractory conditions. The study population includes both male and female subjects aged **18 years or older**. Participants were selected based on their confirmed diagnosis of multiple myeloma as per the International Myeloma Working Group (IMWG) criteria and must have experienced disease progression during or after their most recent therapy. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they are fully active or capable of self-care. Lifestyle considerations such as diet and physical activity are not specified, but participants must have adequate organ function and meet specific laboratory criteria. The selection process ensures that all prior treatment-related toxicities are at or below Grade 1, except for alopecia, at the time of enrollment. The trial does not specify any particular lifestyle habits or restrictions beyond the medical and health criteria outlined.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase III study to evaluate the efficacy and safety of two treatment combinations in participants with relapsed/refractory **multiple myeloma**. The trial compares the combination of belantamab mafodotin, bortezomib, and dexamethasone (B-Vd) with the combination of daratumumab, bortezomib, and dexamethasone (D-Vd). The primary objective is to assess progression-free survival, while secondary endpoints include overall survival, duration of response, and minimal residual disease negativity rate, among others. The trial is expected to conclude by June 2026, with recruitment having started in May 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and prior treatment history. The trial will include regular follow-up visits to monitor treatment response and safety, with assessments of laboratory parameters and adverse events. The end-of-study visit will occur upon completion of the treatment period or earlier if the participant experiences disease progression or unacceptable toxicity. The expected length of participant involvement is up to 24 months, although certain conditions, such as significant adverse events or withdrawal of consent, may lead to early termination from the study.
The trial involves the administration of investigational products, including **dexamethasone** in various formulations, with specific dosing regimens and routes of administration. Participants will receive treatment according to the assigned group, with belantamab mafodotin administered intravenously and dexamethasone provided in tablet form for oral use. The study ensures that all products are packaged and labeled for clinical use, adhering to regulatory standards. The trial's design and procedures aim to provide robust data on the comparative efficacy and safety of the treatment regimens in the target population.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments to evaluate their efficacy and safety in participants with relapsed/refractory multiple myeloma. The primary experimental medication is **Belantamab Mafodotin**, a protein-based drug provided as a powder for solution for injection. It is administered intravenously with a maximum daily dose of 15 mg/kg. The treatment period can extend up to 999 days, and the product is specifically packaged and labeled for use in this clinical study.
**Dexamethasone** is used in various formulations as a comparator treatment. It is available in tablet form, with dosages of 2 mg and 8 mg, and is administered orally. The maximum daily dose is 20 mg, with a total dose limit of 1280 mg over a treatment period of 24 days. Additionally, Dexamethasone is available as a solution for injection, administered intravenously, with the same dosing limits and treatment period.
**Daratumumab** is another comparator treatment, provided as a 20 mg/mL concentrate for solution for infusion. It is administered intravenously, with a maximum daily dose of 15 mg/kg. The treatment period for Daratumumab can also extend up to 999 days, and the product is packaged and labeled for clinical study use.
**Bortezomib** is included as a comparator treatment in the form of a 3.5 mg powder for solution for injection. It is administered intravenously, with a maximum daily dose of 1.3 mg/m² and a total dose limit of 41.6 mg/m² over a 24-day treatment period. The product is specifically packaged and labeled for the clinical study.
Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the prescribed treatment regimens. All medications are provided in forms suitable for their respective routes of administration, and the study is conducted in accordance with regulatory standards for clinical trials.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. PFS is defined as the time from the date of randomization until the earliest date of documented disease progression or death due to any cause. This endpoint will provide a direct measure of the treatment's ability to delay disease progression in participants with relapsed/refractory multiple myeloma.
Secondary efficacy endpoints include **Overall Survival (OS)**, which measures the time from randomization until death from any cause, and **Duration of Response (DoR)**, defined as the time from first documented evidence of partial response (PR) or better until progressive disease or death. Additional secondary endpoints are the **Minimal Residual Disease (MRD) negativity rate**, **Complete Response Rate (CRR)**, **Overall Response Rate (ORR)**, **Clinical Benefit Rate (CBR)**, **Time to Response (TTR)**, **Time to Progression (TTP)**, and **PFS2**. These endpoints will be evaluated using next-generation sequencing, clinical assessments, and laboratory tests to provide a comprehensive understanding of the treatment's efficacy.
Data collection for these endpoints will occur at specified intervals throughout the trial, with analysis conducted using validated statistical methods to ensure accuracy and reliability. The trial will also monitor the incidence of adverse events and changes in laboratory parameters to assess safety alongside efficacy. The study is designed to provide robust data on the efficacy of the treatment combinations in the target population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Capable of giving signed informed consent as described in protocol section 10.1.3 which includes compliance with the requirements and restrictions listed in the informed consent form and in the protocol.
- Male or female, 18 years or older (at the time consent is obtained)
- Confirmed diagnosis of multiple myeloma as defined by the IMWG criteria [Rajkumar, 2014].
- Previously treated with at least 1 prior line of multiple myeloma therapy, and must have documented disease progression during or after their most recent therapy. "
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
- Participants with a history of autologous SCT are eligible for study participation provided the following are met: a. Autologous stem cell transplant was >100 days prior to initiating study treatment, and b. No active bacterial, viral, or fungal infection(s) present."
- Must have at least ONE aspect of measurable disease, defined as one the following: a. Urine M-protein excretion ≥200 mg/24h, or b. Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L), or c. Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum free light chain ratio (<0.26 or >1.65). "
- All prior treatment-related toxicities, defined by NCI-CTCAE v5.0, must be ≤ Grade 1 at the time of enrollment, except for alopecia."
- Adequate organ system functions as defined by the following laboratory assessments: Absolute Neutrophil Count: ≥1.0 x 10^9/L Hemoglobin: ≥ 8.0g/dL Platelets: ≥75x109^/L Total bilirubin: ≤1.5xULN; (Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%) Alanine aminotransferase: ≤2.5xULN eGFR: ≥30 mL/min/1.73 m2 Urine dipstick for protein: Negative/trace [if ≥1+, only eligible if confirmed ≤500 mg/g (56 mg/mmol) by albumin/creatinine ratio (spot urine from first void)] OR Albumin/creatinine ratio (from spot urine): ≤500 mg/g (56 mg/mmol) "
- Female Participants: Contraceptive use by women should be consistent with local regulations regarding contraception for those participating in clinical studies. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies: Is not a woman of childbearing potential OR Is a woman of childbearing potential and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency during the intervention period and for 4 months after the last dose of belantamab mafodotin, 3 months from the last dose of daratumumab, and 7 months from the last dose of bortezomib, whichever is longer, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. Women of childbearing potential must have a negative highly sensitive serum pregnancy test within 72 hours of dosing on C1D1. Additional requirements for pregnancy testing during and after study intervention are provided in Section 10.3 and the SoA of the protocol. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. "
- Male Participants: Contraceptive use by men 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 from the time of first dose of study until 6 months after the last dose of belantamab mafodotin, and 4 months from the last dose of bortezomib, 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 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% per year when having sexual intercourse with a woman of child bearing potential (including pregnant females)"
Exclusion Criteria
- Intolerant to daratumumab
- Prior allogenic stem cell transplant. Participants who have undergone syngeneic transplant are allowed only if no history of GvHD"
- 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 all inclusion criteria are met "
- Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures "
- 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, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice. NOTE: stable non-cirrhotic chronic liver disease(including Gilbert’s syndrome or asymptomatic gallstones) is acceptable provided all inclusion criteria are met"
- Any major surgery within 4 weeks prior to the first dose of study drug. Exception allowed for bone stabilizing surgery in consultation with medical monitor"
- Refractory to daratumumab or any other anti-CD38 therapy (defined as progressive disease during treatment with anti-CD38 therapy, or within 60 days of completing that treatment) "
- Intolerant to bortezomib, or refractory to bortezomib (defined as progressive disease during treatment with a bortezomib-containing regimen of 1.3 mg/m2 twice weekly, or within 60 days of completing that treatment). Participants with progressive disease during treatment with a weekly bortezomib regimen are allowed."
- Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain
- Prior treatment with anti-BCMA therapy"
- Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drugs, or treatment with an investigational agent or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or 5 half-lives of receiving the first dose of study drugs, whichever is shorter"
- Plasmapheresis within 7 days prior to the first dose of study drug"
- Has received radiotherapy to a large pelvic area. Bridging radiotherapy is allowed. NOTE: Disease assessment should be repeated if RT is done prior to first dose of study drug within screening window"
- Previous or concurrent malignancies other than multiple myeloma, 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. NOTE: Participants with curatively treated non-melanoma skin cancer are allowed without a 2-year restriction"
- Evidence of cardiovascular risk including any of the following: a. Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities including second degree (Mobitz Type II) or third degree atrioventricular (AV) block b. History of myocardial infarction, acute coronary syndromes, coronary angioplasty, or stenting or bypass grafting within 3 months of Screening c. Class III or IV heart failure as defined by the New York Heart Association functional classification system d. Uncontrolled hypertension "
- Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belantamab mafodotin, daratumumab, bortezomib, boron or mannitol or any components of the study treatment"
- Active infection requiring treatment"
- Known 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/mL • CD4+ T-cell (CD4+) counts ≥350 cells/uL • No history of AIDS-defining opportunistic infections within the last 12 months Note: 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 (see protocol Section 6.5.2) "
- Patients with Hepatitis B unless the following criteria can be met: Serology: HBcAb+, HbsAg-: At Screening: • HBV DNA undetectable During the study: • Monitoring per protocol (Table 18) • Antiviral treatment instituted if HBV DNA becomes detectable Serology: HBsAg+ at screen or within 3 months prior to first dose: • HBV DNA undetectable at Screening • Highly effective antiviral treatment started at least 4 weeks prior to first dose of study treatment • Baseline imaging per protocol at Screening • Participants with cirrhosis at Screening are excluded During the study: • Antiviral treatment maintained throughout study treatment • Monitoring and management per protocol (Table 18)"
- Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment unless the participant can meet the following criteria: • RNA test negative • 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. "
- Current corneal epithelial disease except for mild punctate keratopathy "
- Intolerance or contraindications to anti-viral prophylaxis."
- Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukaemia at the time of screening."
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 28 May 2020 | 13 |
 Czechia | Recruiting | 28 May 2020 | 15 |
 France | Recruiting | 28 May 2020 | 24 |
 Germany | Not Yet Recruiting | 28 May 2020 | 27 |
 Greece | Not Recruiting | 28 May 2020 | 14 |
 Italy | Not Recruiting | 28 May 2020 | 27 |
 The Netherlands | Not Recruiting | 28 May 2020 | — |
 Poland | Not Recruiting | 28 May 2020 | 39 |
 Spain | Not Recruiting | 28 May 2020 | 33 |
| Netherlands | — | — | 11 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Dexamethasone 2mg Tablets | Comparator | TABLETS | ORAL USE | 20 | 24 | PRD6599963 |
Dexamethason 8 mg JENAPHARM® | Comparator | TABLET | ORAL USE | 20 | 24 | PRD988427 |
Dexa 8 mg inject JENAPHARM Injektionslösung | Comparator | INJEKTIONSLÖSUNG | INTRAVENOUS SLOW BOLUS INJECTION | 20 | 24 | PRD989395 |
Dexamethason 8 mg GALEN®
Tabletten | Comparator | TABLETTEN | ORAL USE | 20 | 24 | PRD808394 |
VELCADE 3.5 mg powder for solution for injection | Comparator | POWDER FOR SOLUTION FOR INJECTION | INTRAVENOUS USE | 1.3 | 24 | PRD703624 |
Dexamethasone Tablets BP 2.0mg | Comparator | TABLETS | ORAL USE | 20 | 24 | PRD3570594 |
DARZALEX 20 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 15 | 999 | PRD4091122 |
Dexa-ratiopharm® 8 mg Injektionslösung | Comparator | INJEKTIONSLÖSUNG | INTRAVENOUS USE | 20 | 24 | PRD599887 |