FDA Approves BLENREP (Belantamab Mafodotin-blmf)

FDA Approves BLENREP (Belantamab Mafodotin-blmf) for Adult Patients with Relapsed or Refractory Multiple Myeloma who Have Received at Least 4 Prior Therapies Including an Anti-CD38 Monoclonal Antibody, a Proteasome Inhibitor, and an Immunomodulatory Agent

On August 5, 2020, the U.S. Food and Drug Administration (FDA) approved BLENREP (belantamab mafodotin-blmf) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The recommended dosage of BLENREP is 2.5 mg/kg of actual body weight given as an intravenous infusion over approximately 30 minutes once every 3 weeks until disease progression or unacceptable toxicity. 

There is a boxed warning regarding ocular toxicity. BLENREP caused changes in the corneal epithelium resulting in changes in vision, including severe vision loss and corneal ulcer, and symptoms, such as blurred vision and dry eyes. Conduct ophthalmic exams at baseline, prior to each dose, and promptly for worsening symptoms. Withhold BLENREP until improvement and resume, or permanently discontinue, based on severity. BLENREP is available only through a restricted program, called the BLENREP REMS. Advise patients to use preservative-free lubricant eye drops and avoid contact lenses unless directed by an ophthalmologist. 

Additional information regarding dosage and administration as well as warnings and precautions about ocular toxicity, thrombocytopenia, infusion-related reactions, and embryo-fetal toxicity can be found in the full prescribing information linked below. 

BLENREP can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with BLENREP and for 4 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BLENREP and for 6 months after the last dose.  

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

MOA: Belantamab mafodotin-blmf is a B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate. 

General PK: Belantamab mafodotin-blmf mean (%CV) AUC and C_max was 4,666 mcg.h/mL (46%) and 42 mcg/mL (26%), respectively at Cycle 1. Belantamab mafodotin-blmf exhibited dose-proportional pharmacokinetics, with a gradual decrease in clearance over time. The time to reach steady state was approximately 70 days. Accumulation of belantamab mafodotin-blmf was approximately 70%. 

Distribution: The mean (%CV) steady-state volume of distribution of belantamab mafodotin-blmf was 11 L (15%).

Elimination: Total plasma clearance (mean [CV%]) of belantamab mafodotin-blmf was approximately 22% lower at steady state (0.7 L/day [50%]) than after the first dose (0.9 L/day [42%]). The terminal phase half-life of belantamab mafodotin-blmf was 12 days after the first dose and 14 days at steady state.

Metabolism: Belantamab mafodotin-blmf is expected to be metabolized into small peptides and individual amino acids by catabolic pathways.

PD: Higher belantamab mafodotin-blmf exposure was associated with higher incidence of some adverse reactions (e.g., Grade ≥ 2 corneal toxicity). No exposure-response relationship for efficacy was observed at doses of 2.5 mg/kg or 3.4 mg/kg (1.4 times of the approved recommended dose) after accounting for the effect of baseline disease-related characteristics, such as soluble BCMA, IgG, and ß2-microglobulin.

Immunogenicity: Due to the limited number of patients with antibodies against belantamab mafodotin-blmf, no conclusions can be drawn concerning a potential effect of immunogenicity on pharmacokinetics, efficacy, or safety.

Use in Specific Populations

No clinically significant differences in the pharmacokinetics of belantamab mafodotin-blmf were observed based on age (34 to 89 years), sex, race (White vs. Black), body weight (42 to 130 kg), mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m², by MDRD), or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to ≤ 1.5 x ULN and any AST).

The effects of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²) or ESRD with eGFR < 15 mL/min/1.73 m² not on dialysis or requiring dialysis, or moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and any AST) on the pharmacokinetics of belantamab mafodotin-blmf are unknown.

Efficacy and Safety

Efficacy of BLENREP was demonstrated in an open-label, multicenter study in patients who had relapsed or refractory multiple myeloma, had previously received 3 or more prior therapies, including an anti-CD38 monoclonal antibody, and were refractory to an immunomodulatory agent and a proteasome inhibitor. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (≥ 20%) are keratopathy (corneal epithelium change on eye exam), decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, and fatigue. The most common grade 3 or 4 laboratory abnormalities (≥ 5%) are platelets decreased, lymphocytes decreased, hemoglobin decreased, neutrophils decreased, creatinine increased, and gamma-glutamyl transferase increased.

Full prescribing information is available at https://go.usa.gov/xfvCC.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at https://updates.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.

We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to ocp@fda.hhs.gov.