BLENREP Powder for concentrate for solution for infusion Ref.[50842] Active ingredients: Belantamab mafodotin
Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: GlaxoSmithKline Trading Services Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland, D24 YK11
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, and antibody drug conjugates
ATC code: L01FX15
Mechanism of action
Belantamab mafodotin is a humanised IgG1 kappa monoclonal antibody conjugated with a cytotoxic agent, mcMMAF. Belantamab mafodotin binds to cell surface BCMA and is rapidly internalised. Once inside the tumour cell, the cytotoxic agent (cys-mcMMAF) is released disrupting the microtubule network, leading to cell cycle arrest and apoptosis. The antibody also enhances recruitment and activation of immune effector cells, killing tumour cells by antibody-dependent cellular cytotoxicity and phagocytosis. Apoptosis induced by belantamab mafodotin is accompanied by markers of immunogenic cell death, which may contribute to an adaptive immune response to tumour cells.
Pharmacodynamic effects
Cardiac electrophysiology
Belantamab mafodotin or cys-mcMMAF had no meaningful QTc prolongation (> 10 ms) at doses of up to 3.4 mg/kg once every 3 weeks.
Immunogenicity
Anti-drug antibodies (ADA) were rarely detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.
Clinical efficacy and safety
DREAMM-7: belantamab mafodotin in combination with bortezomib and dexamethasone
The efficacy and safety of belantamab mafodotin in combination with bortezomib and dexamethasone (BVd) were investigated in a multicentre, randomised (1:1), open-label, Phase 3 study conducted in patients with multiple myeloma (MM) who had relapsed following treatment with at least one prior line of therapy.
In the BVd arm (N=243), patients received belantamab mafodotin 2.5 mg/kg by intravenous infusion every 3 weeks on day 1 of each cycle; bortezomib 1.3 mg/m² (subcutaneously) on days 1, 4, 8, and 11 of cycles 1 to 8 (21-day cycles); and dexamethasone 20 mg (intravenous infusion or orally) on the day of and the day after bortezomib treatment. In the daratumumab, bortezomib, and dexamethasone (DVd) arm (N=251), patients received daratumumab 16 mg/kg (IV) in 21-day cycles: every week for cycles 1 to 3 and every 3 weeks for cycles 4 to 8. Dexamethasone and bortezomib schedules were the same in both arms. Treatment continued in both arms until disease progression, death, unacceptable toxicity, withdrawal of consent, or study end. Patients were stratified by the Revised International Staging System (R-ISS), prior exposure to bortezomib, and the number of prior lines of therapy.
The key eligibility criteria for the study were having a confirmed diagnosis of MM as defined by International Myeloma Working Group (IMWG) criteria, having previously been treated with at least 1 prior line of MM therapy, and having had documented disease progression during or after their most recent therapy. Patients were excluded if they were intolerant to bortezomib, refractory to twice weekly bortezomib, previously treated with BCMA-targeted therapy, had ongoing ≥ Grade 2 peripheral neuropathy or neuropathic pain, or had current corneal epithelial disease except for mild punctate keratopathy.
The primary efficacy outcome measure was progression-free survival (PFS) as evaluated by a blinded Independent Review Committee (IRC) based on the IMWG criteria for MM.
A total of 494 patients were evaluated for efficacy in DREAMM-7. Baseline demographics and characteristics were similar across both arms including: median age: 65 years (36% aged 65-74 years and 14% aged 75 years or older); 55% male, 45% female; 83% White, 12% Asian, 4% Black, < 1% mixed race; R-ISS stage at screening I (41%), II (53%), III (5%); 28% high cytogenetics risk, median number of 1 prior line of therapy; 8% with extramedullary disease (EMD) present; and of those who received treatment (N=488), Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 (48%), 1 (48%), or 2 (4%). In the BVd arm, 90% of patients received prior proteasome inhibitor therapy (bortezomib, carfilzomib, ixazomib), 81% of patients received prior immunomodulator therapy (lenalidomide, thalidomide, pomalidomide), and 67% of patients previously received autologous stem cell transplantation (ASCT). There were 9% of patients refractory to proteasome inhibitor therapy and 39% of patients refractory to immunomodulator therapy. In the DVd arm, 86% of patients received prior proteasome inhibitor therapy (bortezomib, carfilzomib, ixazomib), 86% of patients received prior immunomodulator therapy (lenalidomide, thalidomide, pomalidomide), and 69% of patients previously received autologous stem cell transplantation (ASCT). Ten percent of patients refractory to proteasome inhibitor therapy and 41% of patients refractory to immunomodulator therapy.
Patients treated with belantamab mafodotin in combination with bortezomib and dexamethasone had a statistically significant improvement in PFS, overall survival (OS), and minimal residual disease (MRD) negativity rate compared with daratumumab, bortezomib, and dexamethasone. Efficacy results at the time of the first interim analysis (data cut-off 2 October 2023), except OS where data is presented from the second interim analysis data cut-off (7 October 2024) are presented in Table 6 and Figures 1 and 2.
Table 6. Efficacy results in DREAMM-7:
| Belantamab mafodotin plus bortezomib and dexamethasone (BVd)a N=243 | Daratumumab plus bortezomib and dexamethasone (DVd)a N=251 | |
|---|---|---|
| Primary endpoint | ||
| Progression-free survival (PFS)b | ||
| Number (%) of patients with event | 91 (37) | 158 (63) |
| Median in months (95% CI)c | 36.6 (28.4, NR) | 13.4 (11.1, 17.5) |
| Hazard ratio (95% CI)d | 0.41 (0.31, 0.53) | |
| p-valuee | <0.00001 | |
| Secondary endpoints | ||
| Overall survival (OS) | ||
| Number (%) of patients with event | 68 (28) | 103 (41) |
| Median in months (95% CI)c | NR (NR, NR) | NR (41, NR) |
| Hazard ratio (95% CI)d | 0.58 (0.43, 0.79) | |
| p-value | 0.00023 | |
| Minimal residual disease (MRD) negativity rateb,f,g | ||
| Percent of patients, (95% CI) | 24.7 (19.4, 30.6) | 9.6 (6.2, 13.9) |
| p-valueh | <0.00001 | |
CI = Confidence interval; NR = Not reached.
a Efficacy data is based on the intent-to-treat (ITT) population.
b Response was based on IRC per IMWG criteria.
c By Brookmeyer and Crowley method.
d Based on stratified Cox regression model.
e One-sided p-value based on stratified log-rank test.
f For patients with a complete response or better.
g Assessed by Next Generation Sequencing (NGS) at 10-5 threshold.
h Two-sided p-value based on stratified Cochran-Mantel-Haenszel test.
Figure 1. Kaplan-Meier curve of progression-free survival per IRC in DREAMM-7:
Figure 2. Kaplan-Meier curve of overall survival in DREAMM-7:
DREAMM-8: belantamab mafodotin in combination with pomalidomide and dexamethasone
The efficacy and safety of belantamab mafodotin in combination with pomalidomide and dexamethasone (BPd) were investigated in a multicentre, randomised (1:1), open-label, Phase 3 study conducted in patients with multiple myeloma (MM) who had relapsed following treatment with at least one prior line of therapy, including lenalidomide.
In the BPd arm (N=155), patients received belantamab mafodotin 2.5 mg/kg by intravenous infusion once on day 1 in cycle 1 (28-day cycle) followed by belantamab mafodotin 1.9 mg/kg by intravenous infusion every 4 weeks on day 1 of cycle 2 onwards (28-day cycles); pomalidomide 4 mg (orally [PO]) administered on days 1 to 21; and dexamethasone 40 mg PO on days 1, 8, 15, and 22 in all cycles (28-day cycles). In the pomalidomide, bortezomib, and dexamethasone (PVd) arm (N=147), pomalidomide 4 mg PO was administered every 3 weeks on days 1 to 14 in all cycles (21-day cycles); bortezomib 1.3 mg/m² was administered subcutaneously on days 1, 4, 8, and 11 in cycles 1 to 8, and on days 1 and 8 in cycle ≥ 9 (21-day cycles). Dexamethasone 20 mg PO was administered on the day of and the day after bortezomib. The dose level of dexamethasone in each arm was reduced by half in patients aged 75 years and older. Treatment in both arms continued until disease progression, unacceptable toxicity, withdrawal of consent, initiation of another anticancer therapy, or end of study/death. Patients were stratified by the number of prior lines of treatment, prior exposure to bortezomib, prior anti-CD38 treatment, and International Staging System (ISS) status.
The key eligibility criteria included having confirmed diagnosis of MM as defined by IMWG criteria, having previously been treated with at least 1 prior line of MM therapy, including lenalidomide, and having had documented disease progression during or after their most recent therapy. Patients were excluded if they received prior treatment with or intolerant to pomalidomide, were previously treated with BCMA-targeted therapy, or had current corneal disease except for mild punctate keratopathy.
The primary efficacy outcome measure was PFS as evaluated by a blinded IRC based on the IMWG criteria for MM.
A total of 302 patients were evaluated for efficacy in DREAMM-8. Baseline demographics and characteristics were similar across both arms including: median age: 67 years (43% aged 65-74 years and 18% aged 75 years or older); 60% male, 40% female; 86% White, 12% Asian, < 1% Native Hawaiian or other Pacific Islander, < 1% mixed race; ISS stage at screening I (59%), II (26%), III (15%); 33% high cytogenetic risk, median number of 1 prior line of therapy; 10% with EMD present; and of those who received treatment (N=295), ECOG PS 0 (55%), 1 (42%), or 2 (3%). In the BPd arm, 100% of patients received prior immunomodulator therapy (lenalidomide, thalidomide), 90% of patients received prior proteasome inhibitor therapy (bortezomib, carfilzomib, ixazomib), 25% of patients received prior anti-CD38 therapy (daratumumab, isatuximab), and 64% of patients previously received ASCT. There were 82% of patients refractory to immunomodulator therapy, 26% of patients refractory to proteasome inhibitor therapy, and 23% of patients refractory to anti-CD38 therapy. In the PVd arm, 100% of patients received prior immunomodulator therapy (lenalidomide, thalidomide), 93% of patients received prior proteasome inhibitor therapy (bortezomib, carfilzomib, ixazomib), 29% of patients received prior anti-CD38 therapy (daratumumab, isatuximab, anti-CD38), and 56% of patients previously received ASCT. There were 76% of patients refractory to immunomodulator therapy, 24% of patients refractory to proteasome inhibitor therapy, and 24% of patients refractory to anti-CD38 therapy.
Patients treated with belantamab mafodotin in combination with pomalidomide and dexamethasone had a statistically significant improvement in PFS in the overall population compared with pomalidomide, bortezomib and dexamethasone. Efficacy results at the time of the first interim analysis (data cut-off 29 January 2024) are presented in Table 7 and Figures 3 and 4.
Table 7. Efficacy results in DREAMM-8:
| Belantamab mafodotin plus pomalidomide and dexamethasone (BPd)a N=155 | Pomalidomide plus bortezomib and dexamethasone (PVd)a N=147 | |
|---|---|---|
| Primary endpoint | ||
| Progression-free survival (PFS)b | ||
| Number (%) of patients with event | 62 (40) | 80 (54) |
| Median in months (95% CI)c,d,e | NR (20.6, NR) | 12.7 (9.1, 18.5) |
| Hazard ratio (95% CI)f | 0.52 (0.37, 0.73) | |
| p-valueg | <0.001 | |
| Secondary endpointsh | ||
| Overall survival (OS) | ||
| Number (%) of patients with event | 49 (32) | 56 (38) |
| Median in months (95% CI)c | NR (33, NR) | NR (25.2, NR) |
| Hazard ratio (95% CI)f | 0.77 (0.53, 1.14) | |
| Minimal residual disease (MRD) negativity rateb,i,j | ||
| Percent of patients (95% CI) | 23.9 (17.4, 31.4) | 4.8 (1.9, 9.6) |
CI = Confidence interval; NR = Not reached.
a Efficacy data is based on the intent-to-treat (ITT) population.
b Response was based on IRC per IMWG criteria.
c By Brookmeyer and Crowley method.
d Median follow-up of 21.8 months.
e At the time of the data cut-off (29 JAN 2024).
f Based on stratified Cox regression model.
g One-sided p-value based on stratified log-rank test.
h Results have not reached statistical significance.
i For patients with a complete response or better.
j Assessed by NGS at 10-5 threshold.
Figure 3. Kaplan-Meier curve of progression-free survival per IRC in DREAMM-8:
Figure 4. Kaplan-Meier curve of overall survival in DREAMM-8:
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Blenrep in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use).
5.2. Pharmacokinetic properties
Absorption
Maximum concentration for belantamab mafodotin ADC occurred at or shortly after the end of infusion while cys-mcMMAF concentrations peaked ~24 hours after dosing.
Table 8 describes the pharmacokinetics of belantamab mafodotin for 2.5 mg/kg doses on cycle 1 Day 1 at the end of the first 3-week interval.
Table 8. Belantamab mafodotin pharmacokinetics at the end of the first 3-week intervala:
| AUCb | Cavg21 | Cmax | Ctau | |
|---|---|---|---|---|
| ADC (%) | 3 950 mcg•h/mL (30.6) | 7.83 mcg/mL (30.6) | 43.7 mcg/mL (22.1) | 2.03 mcg/mL (62.5) |
| cys-mcMMAF (%) | 94.2 ng•h/mL (42.3) | 0.243 ng/mL (42.4) | 0.976 ng/mL (45.3) | – |
ADC = antibody drug conjugate; AUC = Area under the curve; Cavg21 = belantamab mafodotin average concentration over 21 days; Cmax = maximum plasma concentration; Ctau = concentration at the end of a dosing interval.
a Data presented as geometric mean (%CV), based on population PK models.
b AUC for ADC is AUC(0-21days) and AUC(0-7days) for cys-mcMMAF.
Accumulation of belantamab mafodotin (ADC) was minimal to moderate (the ratio from cycle 3 to cycle 1 was 1.13 for Cmax and 1.58 for AUC) and accumulation of cys-mcMMAF was negligible as observed in clinical trials with a every 3 weeks dosing regimen.
Distribution
In vitro, cys-mcMMAF exhibited low protein binding, (70% unbound at a concentration of 5 ng/mL) in human plasma in a concentration-dependent manner.
Based on the population PK analysis, the geometric mean (geometric CV%) for steady-state volume of distribution of belantamab mafodotin was 10.8 L (22%).
Biotransformation
The monoclonal antibody portion of belantamab mafodotin is expected to undergo proteolysis to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Cys-mcMMAF had limited metabolic clearance in human hepatic S9 fraction incubation studies.
Drug interactions
In vitro studies demonstrated that cys-mcMMAF is not an inhibitor, an inducer, or a sensitive substrate of cytochrome P450 enzymes, but is a substrate of organic anion transporting polypeptide (OATP)1B1 and OATP1B3, multidrug resistance-associated protein (MRP)1, MRP2, MRP3, bile salt export pump (BSEP), and a possible substrate of P-glycoprotein (P-gp). Clinically relevant drug-drug interactions with inhibitors or inducers of these enzymes and transporters are not expected.
Elimination
Based on the population PK analysis from patients treated with belantamab mafodotin monotherapy or in combination with other medicinal products, the geometric mean (geometric CV%) belantamab mafodotin (ADC) initial systemic clearance (CL) was 0.901 L/day (40%), and the elimination half- life was 13 days (26%). Following treatment, steady-state CL was 0.605 L/day (43%) or approximately 33% lower than initial systemic CL with an elimination half-life of 17 days (31%).
The fraction of intact cys-mcMMAF excreted in urine was not substantial (approximately 18% of the dose) after cycle 1 dose, with no evidence of other MMAF-related metabolites.
Linearity/non-linearity
Belantamab mafodotin exhibits dose-proportional pharmacokinetics over the recommended dose range with a reduction in clearance over time.
Special populations
Elderly
Based on a population of patients aged 32 to 89 years, age was not a significant covariate in population pharmacokinetics analyses.
Renal impairment
In patients with severe renal impairment (eGFR 15-29 mL/min, n=8), belantamab mafodotin Cmax decreased by 23% and AUC(0-tau) decreased by 16% compared with patients with normal renal function or mild renal impairment (eGFR ≥ 60 mL/min, n=8). For cys-mcMMAF, Cmax and AUC(0-168h) decreased by 56% and 44%, respectively compared to patients with normal renal function or mild renal impairment. Renal function (eGFR 12-150 mL/min) was not a significant covariate in population pharmacokinetic analyses that included patients with normal renal function, mild (eGFR 60-89 mL/min), moderate (eGFR 30-59 mL/min), or severe renal impairment (eGFR < 30 mL/min not requiring dialysis). No impact on belantamab mafodotin PK was observed for patients with end stage renal disease (eGFR < 15 mL/min requiring dialysis, n=5).
Belantamab mafodotin is not expected to be removed via dialysis due to its molecular size. While free cys-mcMMAF may be removed via dialysis, cys-mcMMAF systemic exposure is very low and has not been shown to be associated with efficacy or safety based on exposure-response analysis.
Hepatic impairment
No formal studies have been conducted in patients with hepatic impairment. Hepatic function as per the National Cancer Institute Organ Dysfunction Working Group classification, was not a significant covariate in population pharmacokinetic analyses that included patients with normal hepatic function, mild (total bilirubin > ULN to ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN with AST > ULN) or moderate hepatic impairment (total bilirubin > 1.5 x ULN to ≤ 3 × ULN and any AST). Limited data are available for patients with moderate (n=5) or severe hepatic impairment (n=1, total bilirubin > 3 × ULN and any AST) in the population pharmacokinetic analyses.
Body weight
Body weight (37 to 170 kg) was a significant covariate in population pharmacokinetic analyses, but this effect will be adjusted by the weight-proportional dosing regimen (see section 4.2).
5.3. Preclinical safety data
Animal toxicology and/or pharmacology
In non-clinical trials, the principal adverse findings (directly related to belantamab mafodotin) in the rat and monkey, at similar exposures to the recommended clinical dose of 2.5 mg/kg, were elevated liver enzymes sometimes associated with hepatocellular necrosis at ≥10 and ≥3 mg/kg, respectively, and increases in alveolar macrophages associated with eosinophilic material in the lungs at ≥3 mg/kg (rat only). Most findings in animals were related to the cytotoxic drug conjugate, the histopathological changes observed in the testes and lungs, were not reversible in rats.
Single cell necrosis in the corneal epithelium and/or increased mitoses of corneal epithelial cells was observed in rat and rabbit. Inflammation of the corneal stroma correlating with superficial haze and vascularisation was observed in rabbits. Belantamab mafodotin was taken up into cells throughout the body by a mechanism unrelated to BCMA receptor expression on the cell membrane.
Carcinogenesis/mutagenesis
Belantamab mafodotin was genotoxic in an in vitro micronucleus screening assay in human lymphocytes, consistent with the pharmacological effect of cys-mcMMAF-mediated disruption of microtubules causing aneuploidy.
No carcinogenicity or definitive genotoxicity studies have been conducted with belantamab mafodotin.
Reproductive toxicology
No animal studies have been performed to evaluate the potential effects of belantamab mafodotin on reproduction or development. The mechanism of action is to kill rapidly dividing cells which would affect a developing embryo which has rapidly dividing cells. There is also a potential risk of heritable changes via aneuploidy in female germ cells.
Effects on male and female reproductive organs have been observed in animals at doses of ≥10 mg/kg, which is approximately 4 times the exposure of the clinical dose. Luteinised nonovulatory follicles were seen in the ovaries of rats after 3 weekly doses. Findings in male reproductive organs that were adverse and progressed following repeat dosing in rat, included marked degeneration/atrophy of seminiferous tubules that generally did not reverse following dosing cessation.
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