Phase 2 Study of Belantamab Mafodotin and Mezigdomide in Patients with Relapsed/Refractory Multiple Myeloma Following BCMA-Targeting CAR-T or Bispecific Antibody Therapy

Trial ID: 2025-520976-25-00
Protocol: 24CH294
Sponsor: Centre Hospitalier Universitaire De Saint Etienne

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Diseases & Conditions

Plasma cell myeloma

Objectives

The primary objective of this study is to determine the median progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma who have previously received BCMA-targeting CAR-T cells and/or bispecific antibodies, following treatment with belantamab mafodotin and mezigdomide in combination with dexamethasone. 5

Secondary objectives include the evaluation of:

Overall response rate (ORR), including the percentage of patients achieving complete response (CR), partial response (PR), or very good partial response (VGPR).
Time to response (TTR), duration of response (DOR), overall survival (OS), time to progression (TTP), time to next treatment (TNT), and time-to-treatment failure (TTF).
Safety and tolerability assessments, specifically the rate of adverse events related to the therapy, with a focus on ocular safety, the management of ocular events, and changes in the Ocular Surface Disease Index (OSDI).
Investigation of biological mechanisms of response and resistance through biobank-related objectives.

Participants

The sponsor did not provide information regarding the total number of participants. The study population consists of adults aged 18 years and older of both sexes diagnosed with relapsed/refractory multiple myeloma. Eligible individuals must have a histologically or cytologically confirmed diagnosis according to IMWG criteria and must demonstrate documented presence of BCMA. Participants are required to have measurable disease, defined by specific serum or urine protein levels or abnormal serum free light chain ratios. The population includes individuals who are quadruple-class exposed or refractory, having failed at least three prior lines of therapy, including previous treatment with BCMA-targeting CAR-T cells and/or bispecific antibodies. Inclusion requires an ECOG performance status of 0, 1, or 2, adequate organ function, and a life expectancy of at least 6 months. Specific requirements regarding contraception and pregnancy testing are mandated for female participants, while male participants must adhere to specific sperm donation and contraceptive restrictions. Participants must not have active infections and must have controlled prior treatment-related toxicities as defined by NCI-CTCAE.

Plans and Procedures

This multicenter, phase 2 study incorporates a phase Ib safety run to evaluate the efficacy and safety of belantamab mafodotin and mezigdomide in combination with dexamethasone. The trial is designed for patients with relapsed multiple myeloma who have previously received BCMA-targeting CAR-T cells or bispecific antibodies. The primary objective is to determine the median progression-free survival. The study methodology includes a screening visit to assess eligibility based on criteria such as measurable disease, quadruple-class exposure, and adequate organ function. Participants will receive belantamab mafodotin via intravenous infusion and mezigdomide via oral use. Clinical monitoring includes the assessment of overall response rate, overall survival, and time to progression. Safety evaluations will specifically monitor for adverse events, including ocular toxicity using the Ocular Surface Disease Index. The total study duration is estimated to extend until 2031. Participant involvement may be subject to early termination based on clinical progression, death, or treatment-limiting toxicity.

Treatment

Belantamab mafodotin is an experimental medication administered as a powder for solution for injection. The substance is delivered via intravenous infusion at a dosage of 1.90 mg/kg. This study investigates its efficacy in patients with relapsed multiple myeloma.

Mezigdomide, also identified as CC-92480, is an experimental capsule administered for oral use at a dose of 1 mg. This agent is evaluated in combination with belantamab mafodotin and dexamethasone to determine progression-free survival.

Efficacy

The primary efficacy endpoint is the median progression-free survival, defined as the duration from the treatment initiation date to the occurrence of either progressive disease or death. Progressive disease is evaluated based on the International Myeloma Working Group (IMWG) response criteria.

Secondary efficacy parameters include:

Overall response rate (ORR), encompassing complete response (CR), very good partial response (VGPR), or partial response (PR).
The percentage of subjects achieving VGPR or better, CR, VGPR, PR, or progressive disease (PD).
Time to response, measured from treatment initiation to the date of the first response.
Response duration, measured from treatment initiation to the date of first progression.
Overall survival (OS), measured from treatment initiation to the date of death.
Time to progression (TTP), defined as the interval from treatment initiation to the date of objective tumor progression.
Time to next treatment (TNT), defined as the interval from treatment initiation to the start of subsequent therapy.
Time to treatment failure (TTF), defined as the interval from treatment initiation to therapy discontinuation due to any cause, including death, progression, or toxicity.
Exploratory endpoints related to the biobank.

Safety and tolerability assessments include the monitoring of adverse events using the Common Terminology Criteria for Adverse Events (CTCAE), with a specific focus on ocular events and corneal safety. The Ocular Surface Disease Index (OSDI) is utilized for ocular assessment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participant must be 18 years of age inclusive at the time of signing the Informed Consent Form (ICF)
Participant has a histologically or cytologically confirmed diagnosis of MM as defined by IMWG criteria (Rajkumar 2016)
Participant has Eastern Cooperative Oncology Group (ECOG) performance status of score of 0, 1, or 2
Participant is considered transplant ineligible or for participants with a history of autologous stem cell transplant (ASCT), ASCT was >100 days before initiating study treatment
Participant has measurable disease with at least one of the following criteria: • Serum M protein >0.5 g/dL (>5 g/L), or • Urine M protein >200 mg/24h, or • Serum free light chain (FLC) assay: Involved FLC level >5 mg/dL (>50 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65)
Participant is quadruple-class exposed or refractory (anti-CD38 antibody (e.g., daratumumab, isatuximab) alone or in combination, immunomodulatory agent (e.g., lenalidomide, pomalidomide), a proteasome inhibitor (e.g., bortezomib, ixazomib, carfilzomib) and BCMA-directed CAR-T cells and/or anti-BCMA bispecific antibodies) and has failed at least 3 prior lines of anti-myeloma therapies
Documented presence of BCMA
No active bacterial, viral, or fungal infection(s).
All prior treatment related toxicities (defined by the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version 5.0) must be Grade ≤1 at the time of enrollment, except for alopecia and Grade 2 peripheral neuropathy
Participant must have adequate organ function at minimum, defined in Table 2 “adequate organ function”. More restrictive parameters are also acceptable if needed
Life expectancy of at least 6 months, in the opinion of the investigator
Sex and Contraceptive/Barrier Requirements
Participants must adhere to contraceptive guidelines on contraception methods in clinical studies to minimize the risk of pregnancy
Signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
Participant affiliated to or a beneficiary of a social security category
Female Participants : 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) as defined in Appendix 7, or - Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency (as described in Appendix 7 Contraception Guidance) during the intervention period and for at least 4 months after the last dose of study intervention, 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. - A WOCBP must have a negative highly sensitive serum pregnancy test within 72 hours before the first dose (Cycle 1 Day 1) of study treatment and agree to use a highly effective method of contraception during the study and for 4 months after the last dose of belamaf and for 3 months after mezigdomide. Additional requirements for pregnancy testing during and after study treatment are provided in the Schedule of Activities (SoA) (Appendix 1). - 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 Male participants are eligible to participate if they agree to the following during the intervention period and for 6 months after the last dose of study treatment 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: - 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, as when having sexual intercourse with a WOCBP (including pregnant females).

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Exclusion Criteria

Prior treatment with an anti BCMA targeted therapy within 90 days of receiving the first dose of study drugs, or treatment with an investigational agent or approved systemic anti-myeloma thrapy (including systemic steroids) within 14 days or 5 half-lives of receiving the first dose of study drugs
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 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, hypoalbuminemia, esophageal or gastric varices, persistent jaundice
Evidence of cardiovascular risk including any of the following: • Evidence of current clinically significant untreated arrhythmias, including clinically significant electrocardiogram abnormalities such as second degree (Mobitz Type II) or third degree atrioventricular (AV) 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 functional classification system (see Appendix 8). • Uncontrolled hypertension.
Participant has malignancies other than the disease under study are excluded, except for any other malignancy from which the participant has been disease free for >5 years with the exception of the following noninvasive malignancies: basal or squamous cell skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological findings of prostate cancer (T1a or T1b using the tumor, nodes, and metastases clinical staging system), or prostate cancer that is curative
Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belamaf or mezigdomide or any other components of the study treatment
Active infection requiring antibiotic, antiviral, or antifungal therapy
Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma-proliferative disorder, skin changes) or active plasma cell leukemia at the time of screening
Current corneal epithelial disease except mild punctuate keratopathy
Contact lenses are not allowed for participants while they are receiving belamaf treatment. Contact lens use may be restarted after discontinuation of belamaf treatment, provided the eye-care specialist confirms there are no other contraindications
A known immediate or delayed hypersensitivity or idiosyncratic reaction to drugs chemically related to belamaf, or mezigdomide or any of the components of the study treatment
Patients have to use strong CYP3A4/5 modulators
Participant is a pregnant or lactating female
Participants with known HIV infection are excluded, unless the following criteria are met: • Established antiretroviral therapy (ART) for at least 4 weeks and HIV viral load <400 copies/mL • CD4+ T-cell (CD4+) counts ≥350 cells/µL • No history of AIDS-defining opportunistic infections within the last 12 months
Patients with a presence of hepatitis B surface antigen (HbsAg) or hepatitis B core antibody (HbcAb) at screening or within 3 months before first dose of study treatment should be excluded unless the following criteria described below are met: • Also note that the presence of hepatitis B surface antibody (HBsAb) indicating previous vaccination will not exclude a participant. • Patients with hepatitis B virus (HBV) will be excluded unless the following criteria (Table 3) can be met:
Participants with a positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months before first dose of study treatment are excluded unless the following conditions are met: • Participants with a positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained. • Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months before first dose of study treatment unless the participant can meet the following criteria : • RNA test negative • Successful antiviral treatment (usually 8 weeks duration) is required, followed by a negative HCV RNA test after a washout period of at least 4 weeks
Prior treatment with an antibody-drug conjugate
Prior treatment with mezigdomide
Prior allogenic stem cell transplant
Any major surgery within 4 weeks before the first dose of study drug (or 2 weeks if clinically stable)
Has received a live or attenuated vaccine within 30 days before the first dose of study treatment
Participant has received plasmapheresis ≤7 days before the first dose of study treatment
Presence of active renal condition (infection, requirement for dialysis, or any other condition that could affect participant’s safety).
Patient under guardianship or conservatorship
Patients with insufficient proficiency in French to understand the study information