This is a phase 1/2, open label, single-center study designed to assess the safety and preliminary clinical activity of different belantamab mafodotin doses in combination with daratumumab, pomalidomide, and dexamethasone (DPd) in patients with Relapsed/ Refractory Multiple Myeloma (RRMM) previously treated with one line of therapy who are lenalidomide refractory. This will be a 2-Part study. Part 1 will evaluate the safety of belantamab mafodotin in combination with DPd in 2 cohorts and determine the Recommended Phase 2 Dose (RP2D). In the dose expansion phase (Part 2) an expansion cohort will be treated with the RP2D. The expansion cohort will randomize participants (1:1) in two groups to evaluate two alternate dose modification guidelines for corneal AEs. Part 2 will further evaluate the safety and assess the preliminary clinical activity of the belantamab mafodotin RP2D in combination with DPd. Overall, approximately 48 participants will be enrolled in the study. Participant follow-up will continue up to 3 years after the last participant is randomized. The estimated accrual period will be 12 months corresponding to an approximate total study duration of 4 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
48
Blmf will be available as 100 mg/vial in single-use vial for reconstitution, supplied as lyophilized powder. Blmf will be delivered as IV solution over at least 30 minutes
Daratumumab will be administered with subcutaneous injections. On days where Blmf is given together with daratumumab, daratumumab should be performed first.
Pomalidomide will be administered per os.
Dexamethasone will be administered intravenously or per os.
Part 1: Dose-Limiting Toxicity (DLT)
The number (percent) of participants with DLTs using the DLT evaluable population.
Time frame: Up to 28 days
Part 1 and 2: Adverse Events (AEs) and Serious adverse events (SAEs)
The number (percent) of participants with AEs and SAEs using the DLT evaluable and Safety populations.
Time frame: Up to 4 years
Part 1 and 2: Ocular Toxicity
The number (percent) of participants with Grade ≥2 ocular toxicity per Keratopathy Visual Acuity (KVA) scale.
Time frame: Up to 4 years
Part 2: Overall Response Rate (ORR)
ORR as per IMWG by Investigator assessment; defined as the percentage of participants with a confirmed partial response (PR), very good partial response (VGPR), complete response (CR) or stringent CR (sCR) (For the 'intention to treat' (ITT) population).
Time frame: Up to 4 years
Part 1 and 2: Cumulative dose of belantamab mafodotin
Cumulative belantamab mafodotin dose of (DLT evaluable population, safety population) administered in combination with daratumumab, pomalidomide and dexamethasone, i.e., the total dose of belantamab mafodotin that was administered.
Time frame: Up to 4 years
Part 1: Overall Response Rate (ORR)
ORR and 95% CI as per IMWG by Investigator Assessment (ITT population); ORR is defined as the percentage of participants with a confirmed PR, VGPR, CR or sCR.
Time frame: Up to 4 years
Part 1: Very good partial response (VGPR)
VGPR+ and 95% CI as per IMWG by Investigator Assessment (ITT population);ORR is defined as the percentage of participants with a confirmed VGPR, CR or sCR.
Time frame: Up to 4 years
Part 1 and 2: Time to response (TTR)
TTR as per IMWG by Investigator Assessment (ITT population). TTR is defined as the time (in months) between the date of randomization and the first evidence of confirmed response (PR or better) for participants who achieve a response (i.e., confirmed PR or better).
Time frame: Up to 4 years
Part 1 and 2: Duration of Response
DoR as per IMWG by Investigator Assessment (ITT population). DoR is defined as the time (months) from first evidence of confirmed PR or better until the earliest date of: documented disease progression (PD) per IMWG response criteria; or death due to PD among participants who achieved a response of PR or better. For alive and progression-free participants, data will be censored at the date of initiation of the subsequent line of treatment or at the last date of follow-up that the participant was known to be alive and progression-free.
Time frame: Up to 4 years
Part 1 and 2: Complete Response Rate (CRR)
CRR as per IMWG by Investigator Assessment (ITT population). CRR is defined as the percentage of participants with a confirmed CR or sCR. The denominator will be the total number of participants in each population and group respectively.
Time frame: Up to 4 years
Part 1 and 2: Minimal Residual Disease (MRD) negative rate
MRD negativity rate (ITT population); defined as the number (percent) of participants who achieve MRD negativity (at or below the threshold of 10-5), assessed via NGF in participants with CR or better response. The denominator will be the total number of participants in each population group respectively.
Time frame: Up to 4 years
Part 1 and 2: Very Good Partial Response (VGPR) or better
VGPR or better as per IMWG by Investigator Assessment (ITT population). VGPR or better rate is defined as the percentage of participants with a confirmed VGPR, CR or sCR. The denominator will be the total number of participants in each population, and group respectively.
Time frame: Up to 4 years
Part 1 and 2: Progression Free Survival (PFS)
PFS as per IMWG by Investigator Assessment (ITT population, Safety population). PFS is defined as the time (in months) from randomization until the earliest date of documented PD per IMWG, or death due to any cause. For participants who neither progress nor die, the PFS will be censored at the date of their last adequate disease assessment. For participants who start a new anti-myeloma treatment, PFS will be censored at the date of the last adequate assessment before the start of the new treatment. For a randomized participant who does not have any post-baseline disease assessments and who has not died, PFS will be censored at the randomization date.
Time frame: Up to 4 years
Part 1 and 2: Overall Survival (OS)
OS (ITT population, Safety population). OS is defined as the time from first dose/randomization until death due to any cause. If a participant is not known to have died, survival time will be censored at the date of last contact ("last known date alive").
Time frame: Up to 4 years
Part 1 and 2: Abnormal ocular findings
Number (percent) of participants with abnormal ocular findings (on ophthalmic exam) (DLT evaluable population, Safety population).
Time frame: Up to 4 years
Part 1 and 2: Pharmacokinetics Analysis (PK population)
Concentration-time data: linear and semi-logistic unique profiles of concentration-time and the mean and median profiles (as applicable) will be graphically represented for belantamab mafodotin. Belantamab mafodotin concentrations will be presented for each participant and summarized (as applicable) at each PK timepoint.
Time frame: Up to 4 years
Part 2: Number of Ocular Symptoms and Related Impact
Number of participants with within-participant meaningful change in ocular symptoms and related impacts as measured by the Vision Related Anamnestic Tool.
Time frame: Up to 4 years
Part 2: Proportion of Ocular Symptoms and Related Impact
Proportion of participants with within-participant meaningful change in ocular symptoms and related impacts as measured by the Vision Related Anamnestic Tool.
Time frame: Up to 4 years
Part 1 and 2: Frequency of KVA Events
No statistical comparison will be made between the 2 groups.
Time frame: Up to 4 years
Part 1 and 2: Proportion of KVA Events
No statistical comparison will be made between the 2 groups.
Time frame: Up to 4 years
Part 1 and 2: Frequency of Dose holds
No statistical comparison will be made between the 2 groups.
Time frame: Up to 4 years
Part 1 and 2: Proportion of Dose holds
No statistical comparison will be made between the 2 groups.
Time frame: Up to 4 years
Part 1 and 2: Frequency of Worst Post-Baseline BCVA
No statistical comparison will be made between the 2 groups.
Time frame: Up to 4 years
Part 1 and 2: Proportion of Worst Post-Baseline BCVA
No statistical comparison will be made between the 2 groups.
Time frame: Up to 4 years
Part 1 and 2: Frequency of Grade 4 corneal findings
No statistical comparison will be made between the 2 groups.
Time frame: Up to 4 years
Part 1 and 2: Proportion of Grade 4 corneal findings
No statistical comparison will be made between the 2 groups.
Time frame: Up to 4 years
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