In August 2020, the US Food and Drug Administration (FDA) approved a new therapy for the treatment of multiple myeloma. Belantamab mafodotin-blmf, marketed under the brand name Blenrep by GlaxoSmithKline, is a B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with refractory or relapsed multiple myeloma who have previously received at least 4 therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. The indication was approved through an accelerated pathway based on response rate; continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Belantamab mafodotin-blmf is an antibody-drug conjugate (ADC) comprising an afucosylated immunoglobulin G1 antibody component, a protease-resistant maleimidocaproyl linker, and a small molecule microtubule inhibitor, monomethyl auristatin F (MMAF). Upon binding to BCMA (a protein expressed on B lymphocytes as well as multiple myeloma cells) through its antibody component, the ADC is internalized and MMAF is released via proteolytic cleavage. Once MMAF is released intracellularly, disruption of the microtubule network occurs, leading to cell cycle arrest and apoptosis
The approval of Blenrep was based on the DREAMM-2 study (ClinicalTrials.gov Identifier: NCT03525678), which evaluated the safety and efficacy of the treatment in 218 adult patients with relapsed or refractory multiple myeloma who had previously received at least 3 prior therapies.
Safety and efficacy results were only reported for patients who received the recommended dose of Blenrep (2.5 mg/kg). Results of the study revealed a clinically meaningful overall response rate with Blenrep. The median time to first response was 1.4 months (95% CI, 1.0-1.6), and 73% of responders had a response duration of ≥6 months.
Efficacy of Blenrep
Safety Findings of the DREAMM-2 Study
Immunogenicity analysis of Blenrep revealed that <1% of patients (2/274) tested positive for anti-belantamab mafodotin-blmf antibodies after treatment. No conclusions regarding a potential effect of immunogenicity on pharmacokinetics, efficacy, or safety can be currently drawn due to the limited number of patients with anti-belantamab mafodotin-blmf antibodies.
Dosage and Administration
Blenrep is available in 100-mg single-dose vials for reconstitution and further dilution and is intended for intravenous infusion. The recommended dosage of Blenrep is 2.5 mg/kg of actual body weight administered via intravenous infusion over approximately 30 minutes once every 3 weeks until progression of disease or unacceptable toxicity.
The recommended dose reduction of Blenrep due to an adverse reaction is 1.9 mg/kg intravenously once every 3 weeks. Blenrep should be discontinued in patients who are not able to tolerate a dose of 1.9 mg/kg.
Blenrep Dose Modifications for Adverse Reactions
Contraindications, Warnings, Precautions, and Adverse Reactions
There are no contraindications to the use of Blenrep. The most common adverse reactions associated with treatment include keratopathy, decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, fatigue, and laboratory abnormalities. Details of adverse reactions are presented above in the Safety Findings of the DREAMM-2 Study table.
The prescribing information for Blenrep includes a Boxed Warning regarding the risk of ocular toxicity. Ocular adverse reactions including keratopathy (76%), visual acuity changes (55%), blurred vision (27%), and dry eye (19%) were reported by 77% of the pooled safety population in the DREAMM-2 study.
The majority of cases of keratopathy were grade 2 or 3 per the Keratopathy and Visual Acuity (KVA) scale (22% and 45%, respectively), and most events developed within the first 2 treatment cycles (cumulative incidence by cycle 2: 65%). After a median follow-up of 6.2 months, 39% of patients with grade 2 to 4 keratopathy recovered to grade 1 or lower. Of the 61% of patients with ongoing keratopathy, 28% were still receiving treatment with Blenrep and 9% were in follow-up; in 24%, follow-up ended due to death, withdrawal from the study, or patients being lost to follow-up. Median time to resolution of keratopathy was reported to be 2 months (range: 11 days to 8.3 months).
Visual acuity changes occurred in 55% of the pooled safety population: 19% had a clinically significant decrease in visual acuity of worse than 20/40 in their better-seeing eye and 1.4% had a clinically significant decrease in visual acuity of 20/200 or worse in their better-seeing eye. Resolution of visual acuity changes occurred in 88% of patients who experienced decreased visual acuity of worse than 20/40 (median time to resolution: 22 days; range: 7 days to 4.2 months) and in 100% of patients who experienced decreased visual acuity of 20/200 or worse (median duration: 22 days; range: 15 to 22 days).
Ophthalmic examinations should be performed at baseline (within 3 weeks prior to first dose), before each subsequent dose, and immediately if a patient is experiencing worsening of symptoms. Follow-up examinations should be conducted ≥1 week after the last dose and within 2 weeks of the next dose
Blenrep is only available through the Blenrep Risk Evaluation and Mitigation Strategy (REMS) program due to the risk of ocular toxicity.
Of the 69% of patients who experienced thrombocytopenia in the DREAMM-2 study, 13% were considered grade 2, 10% were considered grade 3, and 17% were considered grade 4. Median time to onset of the first event was reported to be 26.5 days. Thrombocytopenia resulted in 9% of patients having to reduce their Blenrep dose, 2.8% of patients interrupting treatment, and 0.5% of patients discontinuing therapy altogether.
Complete blood cell counts should be performed at baseline as well as during therapy when clinically indicated. Blenrep should be withheld and/or the dose should be reduced based on the severity of a patient’s symptoms.
Infusion-related reactions were reported by 18% of patients in the DREAMM-2 study, with 1.8% of these reactions being grade 3. Patients undergoing treatment with Blenrep should be monitored for infusion-related reactions. For grade 2 or 3 reactions, the infusion should be interrupted and supportive care should be given. The infusion should be resumed at a lower rate once symptoms have resolved and premedication should be administered for all subsequent infusions. For life-threatening infusion-related reactions, Blenrep should be discontinued and emergency care should be provided.
Because it contains a genotoxic compound and targets actively dividing cells, Blenrep can cause fetal harm when administered to a pregnant woman. Pregnant women should be counseled on this potential risk. Females of reproductive potential should be advised to use effective contraception during treatment and for 4 months after their last dose of Blenrep. Males with female partners of reproductive potential should also be advised to use effective contraception during treatment and for 6 months after their last dose of Blenrep.
In vitro studies determined that cys-mcMMAF is a substrate of organic anion transporting polypeptide (OATP)1B1, OATP1B3, multidrug resistance-associated protein (MRP)1, MRP2, MRP3, bile salt export pump (BSEP), and possibly P-glycoprotein (P-gp).
Considerations for Specific Populations
Due to the potential of Blenrep causing fetal harm, it is recommended that females of reproductive potential take a pregnancy test prior to initiating treatment. Additionally, it is recommended that effective contraception be used during treatment with Blenrep and for 4 months after the last dose for females and for 6 months after the last dose for males with a female partner of reproductive potential. Additionally, male and female patients should be advised that Blenrep may impair fertility. According to animal study findings, these effects were reversible in female rats but were irreversible in male rats.
Although there are no data available on its use in pregnant women, Blenrep can theoretically cause fetal harm based on its mechanism of action. Blenrep not only contains a genotoxic compound and targets actively dividing cells, but it also has the potential of being transmitted from mother to fetus by crossing the placenta. Based on the existing evidence, pregnant women should be counseled on the potential of Blenrep to cause embryotoxicity and teratogenicity.
No data currently exist on the presence of Blenrep in breast milk, the potential of serious adverse reactions in a breastfed child, or its effect on milk production. Women should be counseled to avoid breastfeeding during treatment and for 3 months after receiving their last dose of Blenrep.
Efficacy and safety of Blenrep have not been established in pediatric patients. Moreover, there was an insufficient number of geriatric patients in the DREAMM-2 study to determine whether the efficacy and safety of Blenrep differ compared with those of younger patients.
No dose adjustment is recommended for patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-89 mL/min/1.73m2) or in those with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN or total bilirubin 1 to ≤ 1.5 x ULN and any AST). For patients with severe renal impairment (eGFR 15-29 mL/min/1.73m2) or end-stage renal disease (eGFR <15 mL/min/1.73m2) with or without dialysis, or in patients with moderate or severe hepatic impairment (total bilirubin >1.5 x ULN and any AST), a recommended dosage has not been established.
- Blenrep is approved for adults with relapsed/refractory multiple myeloma who have received at least 4 prior therapies.
- The product is available only through the Blenrep REMS.
- Ocular toxicity has been reported in clinical trials; monitoring for this adverse reaction is necessary, and patients should be counseled about the risk.
- Dose/infusion modification may be necessary due to adverse reactions (ie, corneal adverse reactions, thrombocytopenia, infusion-related reactions).
1. Blenrep [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2020.
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Reviewed September 2020