Blenrep
belantamab mafodotin
Species
MonkeyRatRabbit
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (monkey the only relevant species; rat and rabbit for payload/ocular toxicity)
“The only pharmacologically relevant species able to capture on-target BCMA-related toxicities for belantamab mafodotin is the cynomolgus monkey. To capture any non-specific toxicities related to the payload (MMAF), general toxicology and ocular toxicology studies were conducted in the Wistar Han rat and New Zealand White Rabbit.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 30Source ↗
Why that species
Monkey BCMA binding affinity within 2-fold of human (Biacore)
“Binding of belantamab mafodotin to human and monkey BCMA has been demonstrated using Biacore and the affinity shown to be within 2-fold”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 33Source ↗
Surrogate molecule
No surrogate; ADC tested, plus payload cys-mcMMAF and unconjugated antibody GSK2857914 separately
“Selected evaluations were conducted with cys-mcMMAF, the active cytotoxic moiety, and GSK2857914, the parent, unconjugated afucosylated anti-BCMA antibody, to further characterize the overall nonclinical profile of belantamab mafodotin.”
Tissue cross-reactivity
Conducted with human tissues; antigen-specific staining in human spleen
“Additionally, tissue cross-reactivity studies showed antigen-specific staining of belantamab mafodotin in human spleen.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 33Source ↗
Species: general tox
Rat and cynomolgus monkey (plus rabbit for ocular findings)
“Repeat dose toxicity evaluation was conducted for belantamab mafodotin, cys-mcMMAF and GSK2857914 in rats and cynomolgus monkeys, and in rabbits focusing on the ocular findings.”
Species: DART
Not conducted (ICH S9): cytotoxic ADC expected to be embryo/fetotoxic and teratogenic
“Reproductive and developmental studies have not been conducted since cytotoxic drugs such as belantamab mafodotin which target rapidly dividing cells, particularly in the bone marrow, are expected to be embryo/ fetotoxic and teratogenic. This position is consistent with ICH S9 guidance.”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted to support the development of belantamab mafodotin.”
Surrogate used in
No surrogate used; payload cys-mcMMAF and unconjugated antibody GSK2857914 tested separately
“Selected evaluations were conducted with cys-mcMMAF, the active cytotoxic moiety, and GSK2857914, the parent, unconjugated afucosylated anti-BCMA antibody, to further characterize the overall nonclinical profile of belantamab mafodotin.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Monkeys were dosed in GLP-compliant repeat-dose general toxicology studies for 3 or 13 weeks with IV bolus doses of 0, 1, 3, or 10 mg/kg belantamab mafodotin, with 12-week recovery periods.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 31Source ↗
Longest repeat-dose study and recovery
13-week rat (IV q3w) and monkey (IV weekly) GLP studies, each with 12-week recovery
“The 3-week and 13-week rat studies utilized weekly and every 3 weeks (q3w) dosing regimens, respectively. Monkeys were dosed in GLP-compliant repeat-dose general toxicology studies for 3 or 13 weeks with IV bolus doses of 0, 1, 3, or 10 mg/kg belantamab mafodotin, with 12-week recovery periods.”
Pivotal GLP studies
GLP IV: rat 3-week (weekly) and 13-week (q3w); monkey 3- and 13-week (weekly); 12-week recovery
“The 3-week and 13-week rat studies utilized weekly and every 3 weeks (q3w) dosing regimens, respectively. Monkeys were dosed in GLP-compliant repeat-dose general toxicology studies for 3 or 13 weeks with IV bolus doses of 0, 1, 3, or 10 mg/kg belantamab mafodotin, with 12-week recovery periods.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 31Source ↗
Route in tox
Intravenous (rat 10-minute infusion; monkey IV bolus)
“rats were dosed for 3 or 13 weeks with intravenous (IV) doses (10-minute infusion) of 0, 3, 10, or 30 mg/kg belantamab mafodotin”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 30Source ↗
Skipped studiesopen answer page →
Genotoxicity
No definitive ADC studies (expected genotoxic); ADC positive in in vitro human lymphocyte micronucleus screen; cys-mcMMAF Ames negative
“Definitive genetic toxicology studies with belantamab mafodotin have not been conducted as it would be expected to be genotoxic based on its mechanism of action. Belantamab mafodotin was genotoxic in an in vitro micronucleus screening assay in human lymphocytes.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 65Source ↗
Genotox: what was tested
ADC: in vitro human lymphocyte micronucleus positive (non-GLP); payload cys-mcMMAF: Ames, mouse lymphoma, rat micronucleus negative
“Belantamab mafodotin was genotoxic in an in vitro micronucleus screening assay in human lymphocytes. Genotoxicity assessments of cys-mcMMAF showed it was not mutagenic in the Ames test or genotoxic in the in vitro mouse lymphoma assay”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 65Source ↗
Carcinogenicity
Not conducted (ICH S9, S6(R1))
“The absence of carcinogenicity studies is accepted in line with the ICH S9 and S6(R1) guidelines.”
Why no carcinogenicity study
Not conducted; absence accepted under ICH S9 and S6(R1)
“The absence of carcinogenicity studies is accepted in line with the ICH S9 and S6(R1) guidelines.”
Reproductive & developmental
Not conducted (ICH S9): cytotoxic/genotoxic ADC expected embryo-fetotoxic and teratogenic
“Reproductive and developmental studies were not conducted since cytotoxic (i.e. genotoxic) drugs such as belantamab mafodotin which target rapidly dividing cells, are expected to be embryo/feto toxic and teratogenic. This position is consistent with the ICH S9 guidance.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 31Source ↗
Fertility study
Not conducted; repeat-dose rat studies indicate potential for impaired male and female fertility
“Fertility studies have not been conducted with belantamab mafodotin. Results of repeat-dose toxicity studies with intravenous administration of belantamab mafodotin in rats indicate the potential for impaired male and female reproductive function and fertility.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 66Source ↗
Embryo-fetal study
Not conducted (ICH S9); cytotoxic (genotoxic) ADC expected to be embryo/feto toxic and teratogenic
“Reproductive and developmental studies were not conducted since cytotoxic (i.e. genotoxic) drugs such as belantamab mafodotin which target rapidly dividing cells, are expected to be embryo/feto toxic and teratogenic. This position is consistent with the ICH S9 guidance.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 31Source ↗
Pre- and postnatal study
Not conducted
“No embryo-fetal or pre/ postnatal development studies have been conducted to support the development of belantamab mafodotin.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 67Source ↗
Why reproductive studies were limited
Cytotoxic (genotoxic) ADC targeting rapidly dividing cells expected to be embryo/feto toxic and teratogenic (ICH S9)
“Reproductive and developmental studies were not conducted since cytotoxic (i.e. genotoxic) drugs such as belantamab mafodotin which target rapidly dividing cells, are expected to be embryo/feto toxic and teratogenic. This position is consistent with the ICH S9 guidance.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 31Source ↗
Juvenile toxicity
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Phototoxicity
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Safety pharmacology
Incorporated into GLP rat and monkey repeat-dose studies; cys-mcMMAF hERG assay negative
“No stand-alone safety pharmacology studies were conducted, and safety pharmacology assessments were incorporated into the GLP-compliant general toxicology studies in Wistar Han rats and cynomolgus monkeys.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 30Source ↗
Genotox: Ames
Payload cys-mcMMAF: Ames negative
“Genotoxicity assessments of cys-mcMMAF showed it was not mutagenic in the Ames test or genotoxic in the in vitro mouse lymphoma assay”
Genotox: in vitro mammalian
ADC positive in non-GLP in vitro micronucleus screen in human lymphocytes
“In a non-GLP study, belantamab mafodotin was genotoxic in an in vitro micronucleus screening assay in human lymphocytes, with a statistically significant increase in the number of micronucleated binucleate cells that exceeded the laboratory control range.”
Genotox: in vivo
Payload cys-mcMMAF negative in rat bone marrow micronucleus, attributed to low cell permeability of MMAF
“Although cys-mcMMAF was not genotoxic in the rat bone marrow micronucleus assay, this is considered to reflect the low cell permeability of MMAF (due to its charged C terminal phenylalanine), because freely permeable MMAE was genotoxic in this assay”
Carcinogenicity model
Not conducted (ICH S9, S6(R1))
“The absence of carcinogenicity studies is accepted in line with the ICH S9 and S6(R1) guidelines.”
Carcinogenicity timing
Not required: no carcinogenicity studies (ICH S9, S6(R1))
“The absence of carcinogenicity studies is accepted in line with the ICH S9 and S6(R1) guidelines.”
hERG / QT
cys-mcMMAF: no effect on hERG current up to 100 µM
“Cys-mcMMAF had no detectable effect on ionic currents in human embryonic kidney (HEK)293 cells stably expressing hERG channels at concentrations up to 100”
First doseopen answer page →
First-in-human starting dose
Rationale not stated; first-in-human DREAMM-1 escalated from 0.03 to 4.6 mg/kg Q3W
“The FTIH study DREAMM-1 evaluated dose levels from 0.03 to 4.6 mg/kg Q3W and selected 3.4 mg/kg Q3W based on emerging efficacy, safety, and pharmacokinetic data for evaluation in Part 2 of the study.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 91Source ↗
NOAEL / key findings
Monkey HNSTD 3 mg/kg; kidney (dose-limiting), liver, lung, testes, bone marrow, cornea (rat), inflammation
“The highest non-severe toxic dose in monkeys was 3 mg/kg and the highest dose tested exceeded the clinical dose by 3.8 and 2.5 -fold (ADC and mAb respectively).”
Risksopen answer page →
Immune & cytokine safety
Antibody induced IFN-γ, TNF-α (NK cells) and IL-8 (monocytes) release; ADA/immune complex disease in monkeys
“Other toxicity studies showed GSK2857914 to cause cytokine release, with IFN-γ and TNF-α produced predominantly by the NK cells, and IL-8 by monocytes.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 32Source ↗
Biodistribution & persistence
Rat: ADC in liver, kidney, ocular connective tissue, lacrimal/harderian glands and eyelid muscle
“Belantamab mafodotin could be detected in the liver, kidney, connective tissue of the eyes and eyelids, lacrimal and harderian glands, and muscle of the eyelids in rats.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 30Source ↗
Modality-specific risk
MMAF-driven corneal toxicity via non-specific (macropinocytosis) uptake; also nephrotoxicity and pro-inflammatory responses
“The data support the involvement of non-specific macropinocytosis as a mechanism of cellular uptake to the eye and indicate that the ocular adverse effects observed in rats result from unspecific uptake leading to microtubulin inhibition and apoptosis due to the cys-mcMMAF moiety.”
Free payload and catabolites (animal PK)
Deconjugated cys-mcMMAF measured in animals: less than 3% of total conjugated MMAF; ADC and antibody levels comparable
“Plasma concentrations were overall comparable between belantamab mafodotin and the antibody, GSK2857914, and there was less than 3% of deconjugated cys-mcMMAF when compared to the total conjugated MMAF.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 30Source ↗
Anti-drug antibodies: animals
13-week monkey: 21 of 36 ADA-positive, 12 of 36 with circulating immune complexes
“Across all dose levels, 21of 36 monkeys tested positive for ADA, 12 of 36 monkeys were positive for circulating immune complexes CIC”
Anti-drug antibodies: patients
Post-dose ADA in 2/274 participants; no obvious effect on safety, efficacy or PK
“post-belantamab mafodotin antibody responses to date have been both low in incidence (2/274 participants) and with no obvious effects on the safety, efficacy, pharmacokinetics, or pharmacodynamics of belantamab mafodotin.”
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
3-week weekly-dosing monkey toxicology study (IND-enabling)
“The FDA notes that the 3-week (IND-enabling) and 13-week toxicology st udies conducted in monkeys with weekly dosing for belantamab mafodotin had comparable t oxicities and exposures.”
First-in-human starting dose
Rationale not stated; first-in-human DREAMM-1 escalated from 0.03 to 4.6 mg/kg Q3W
“The FTIH study DREAMM-1 evaluated dose levels from 0.03 to 4.6 mg/kg Q3W and selected 3.4 mg/kg Q3W based on emerging efficacy, safety, and pharmacokinetic data for evaluation in Part 2 of the study.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 91Source ↗
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat (IV q3w) and monkey (IV weekly) GLP studies, each with 12-week recovery
“The 3-week and 13-week rat studies utilized weekly and every 3 weeks (q3w) dosing regimens, respectively. Monkeys were dosed in GLP-compliant repeat-dose general toxicology studies for 3 or 13 weeks with IV bolus doses of 0, 1, 3, or 10 mg/kg belantamab mafodotin, with 12-week recovery periods.”
Pivotal GLP studies
GLP IV: rat 3-week (weekly) and 13-week (q3w); monkey 3- and 13-week (weekly); 12-week recovery
“The 3-week and 13-week rat studies utilized weekly and every 3 weeks (q3w) dosing regimens, respectively. Monkeys were dosed in GLP-compliant repeat-dose general toxicology studies for 3 or 13 weeks with IV bolus doses of 0, 1, 3, or 10 mg/kg belantamab mafodotin, with 12-week recovery periods.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 31Source ↗
DART package
Species: DART
Not conducted (ICH S9): cytotoxic ADC expected to be embryo/fetotoxic and teratogenic
“Reproductive and developmental studies have not been conducted since cytotoxic drugs such as belantamab mafodotin which target rapidly dividing cells, particularly in the bone marrow, are expected to be embryo/ fetotoxic and teratogenic. This position is consistent with ICH S9 guidance.”
Reproductive & developmental
Not conducted (ICH S9): cytotoxic/genotoxic ADC expected embryo-fetotoxic and teratogenic
“Reproductive and developmental studies were not conducted since cytotoxic (i.e. genotoxic) drugs such as belantamab mafodotin which target rapidly dividing cells, are expected to be embryo/feto toxic and teratogenic. This position is consistent with the ICH S9 guidance.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 31Source ↗
PPND / ePPND: when
No PPND study: cytotoxic (genotoxic) ADC expected to be embryo/fetotoxic and teratogenic (ICH S9)
“Reproductive and developmental studies were not conducted since cytotoxic (i.e. genotoxic) drugs such as belantamab mafodotin which target rapidly dividing cells, are expected to be embryo/feto toxic and teratogenic. This position is consistent with the ICH S9 guidance.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted to support the development of belantamab mafodotin.”
Carcinogenicity model
Not conducted (ICH S9, S6(R1))
“The absence of carcinogenicity studies is accepted in line with the ICH S9 and S6(R1) guidelines.”
Carcinogenicity timing
Not required: no carcinogenicity studies (ICH S9, S6(R1))
“The absence of carcinogenicity studies is accepted in line with the ICH S9 and S6(R1) guidelines.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey mid-dose ADC AUC approximately equal to human exposure at 2.5 mg/kg (no margin)
“Although ADA formation was evident in monkey studies, the exposures were generally maintained at low and mid-dose animals and were approximately at the same level in mid-dose animals as the recommended human dose of 2.5 mg/kg, based on ADC area under concentration curve (AUC).”
NOAEL / key findings
Monkey HNSTD 3 mg/kg; kidney (dose-limiting), liver, lung, testes, bone marrow, cornea (rat), inflammation
“The highest non-severe toxic dose in monkeys was 3 mg/kg and the highest dose tested exceeded the clinical dose by 3.8 and 2.5 -fold (ADC and mAb respectively).”
Efficacy evidenceopen answer page →
Efficacy evidence
Human MM xenografts (NCI-H929, OPM-2, MM1Sluc) and EL4-hBCMA syngeneic mouse model
“Belantamab mafodotin induced durable tumour growth regression in xenograft mice models bearing human multiple myeloma NCI-H929, OPM-2, and MM1Sluc cells, and dependently on the presence of CD8+ T-cells in immune-competent syngeneic mouse expressing human BCMA (EL4-hBCMA).”
Why that model
No binding to mouse or rat BCMA, so efficacy relied on human MM xenografts and human-BCMA-expressing mouse tumour
“Supporting the selection of cynomolgus monkey as a species for toxicological evaluation, comparable affinity to monkey BCMA (Kd 0.7 nM at 25°C and 8.4 nM at 37°C) was shown, and no binding to mouse or rat BCMA.”
Reviewer's view of the efficacy data
FDA: EL4-hBCMA syngeneic model limited; predictive value for human disease uncertain
“This model has several limitations in that it is a mouse lymphoma cell line expressing human BCMA and its predictive value for human disease is uncertain.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No fertility, embryo-fetal or pre/postnatal development studies
Why: Cytotoxic (genotoxic) ADC targeting rapidly dividing cells expected to be embryo/fetotoxic and teratogenic; consistent with ICH S9 · Within the guideline · Pharmacology or kinetics
“Reproductive and developmental studies were not conducted since cytotoxic (i.e. genotoxic) drugs such as belantamab mafodotin which target rapidly dividing cells, are expected to be embryo/feto toxic and teratogenic. This position is consistent with the ICH S9 guidance.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 31Source ↗
“FDA concurs that belantamab mafodotin is anticipated to be embryo/feto toxic and teratogenic based on the mechanism of action belantamab mafodotin, which targets rapidly dividing cells, and the fact that the payload (MMAF) conjugated to belantamab mafodotin is aneugenic.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 67Source ↗
GenotoxicityCriticised but acceptedBeyond the letter
No definitive genotoxicity studies with the ADC; only a non-GLP in vitro micronucleus screen plus payload battery
Why: Expected genotoxic by mechanism; FDA judged the conducted studies sufficient for labeling given the drug class and indication · Class precedent · Pharmacology or kinetics
“Definitive genetic toxicology studies with belantamab mafodotin have not been conducted as it would be expected to be genotoxic based on its mechanism of action. Belantamab mafodotin was genotoxic in an in vitro micronucleus screening assay in human lymphocytes.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 65Source ↗
“FDA disagrees with the Applicant's statement that the genetic toxicology studies are not applicable, but agrees with the Applicant that the data indicate that MMAF is genotoxic based on an aneugenic mechanism and that the genetic toxicology studies conducted, given the class of drug and the proposed indication, are sufficient to communicate a genotoxic risk in the product labeling.”
✓ VerifiedFDA multi-discipline review (BLA 761158, 2020 accelerated approval (withdrawn 2023; approved again Oct 2025)), p. 65Source ↗
Safety marginVerdict not stated
No exposure margin: monkey mid-dose ADC AUC approximately equal to human exposure at 2.5 mg/kg
“Although ADA formation was evident in monkey studies, the exposures were generally maintained at low and mid-dose animals and were approximately at the same level in mid-dose animals as the recommended human dose of 2.5 mg/kg, based on ADC area under concentration curve (AUC).”
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