BLENREP Powder for solution for injection Ref.[9941] Active ingredients: Belantamab mafodotin

Exposure-Response Relationships

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 the recommended dose) after accounting for the effect of baseline disease-related characteristics, such as soluble BCMA, IgG, and ß₂-microglobulin.

Cardiac Electrophysiology

Belantamab mafodotin-blmf had no large QT_c prolongation (>10 ms) at the recommended dosage of 2.5 mg/kg once every 3 weeks.

Belantamab mafodotin-blmf exhibited dose-proportional pharmacokinetics, with a gradual decrease in clearance over time; the time to reach steady state was ~70 days. After a planned infusion duration of 0.5 hours, maximum belantamab mafodotin-blmf plasma concentrations occurred at or shortly after the end of the infusion. Accumulation of belantamab mafodotin-blmf was ~70% with a dosing regimen of every 3 weeks.

The pharmacokinetics of belantamab mafodotin-blmf after a dose of 2.5 mg/kg in Cycle 1 are shown in Table 5.

Table 5. Belantamab Mafodotin-blmf Pharmacokinetics at Cycle 1 in Patients Who Received a Dose of 2.5 mg/kg:

AUC = Area under curve over the dosing interval; C_max = Maximum observed plasma concentration; t_max = Time of C_max; C_trough = Observed plasma concentration prior to next dose.
Data presented as geometric mean (%CV), except t_max, which is presented as median (minimum, maximum).

Distribution

The mean 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

The monoclonal antibody portion of belantamab mafodotin-blmf is expected to be metabolized into small peptides and individual amino acids by catabolic pathways. In vitro, cys-mcMMAF is mainly hydrolyzed and dehydrated to a cyclized isomeric form of cys-mcMMAF.

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/1.73m²), 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.

Drug Interaction Studies

In Vitro Studies

Transporter Systems: Cys‑mcMMAF 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).

Carcinogenicity studies have not been conducted with belantamab mafodotin-blmf.

Belantamab mafodotin-blmf was genotoxic in an in vitro micronucleus assay in human lymphocytes through an aneugenic mechanism. These results are consistent with the pharmacological effect of MMAF binding to tubulin causing microtubule depolymerization resulting in spindle disorganization during cell division. Cys-mcMMAF was not mutagenic in the bacterial reverse mutation assay (Ames test), the L5178Y mouse lymphoma forward mutation assay, or the in vivo rat bone marrow micronucleus assay.

Fertility studies have not been conducted with belantamab mafodotin-blmf. Results of repeat-dose toxicity studies with intravenous administration of belantamab mafodotin-blmf in rats indicate the potential for impaired male and female reproductive function and fertility. In rats, weekly dosing for 3 weeks at doses ≥10 mg/kg (approximately 4 times the exposure at the maximum recommended human dose [MRHD] of 2.5 mg/kg based on the AUC of belantamab mafodotin-blmf) resulted in degeneration and atrophy of seminiferous tubules in the testes and luteinized nonovulatory follicles in the ovaries. Findings in females were reversible; findings in the testes were not reversible at the end of the 12-week recovery period with weekly dosing or when given every 3 weeks for 13 weeks at doses ≥10 mg/kg. In male monkeys, the highest dose tested of 10 mg/kg (approximately 4 times the exposure at the MRHD based on AUC of belantamab mafodotin-blmf) given weekly for 13 weeks resulted in seminiferous tubules degeneration in the testes that was fully reversed following the 12-week recovery period.

Increased mitoses of corneal epithelial cells with bilateral single-cell necrosis were observed following intravenous administration of belantamab mafodotin-blmf in rats and rabbits.

14.1 Relapsed or Refractory Multiple Myeloma

The efficacy of BLENREP was evaluated in DREAMM-2, an open-label, multicenter study (NCT 03525678). Eligible patients 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. Patients had measurable disease by International Myeloma Working Group (IMWG) criteria. Patients with corneal epithelial disease, except mild punctate keratopathy, at baseline were excluded from the study. Patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73m²) at baseline were also eligible for the study. Patients received either BLENREP 2.5 mg/kg or 3.4 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate as evaluated by an Independent Review Committee (IRC) based on the IMWG Uniform Response Criteria for Multiple Myeloma. Only the results of the recommended dosage of 2.5 mg/kg are described below.

A total of 97 patients received BLENREP at a dose of 2.5 mg/kg administered intravenously once every 3 weeks. The median age was 65 years (range: 39 to 85 years), 53% were male, 74% were White, and 16% were Black. Most patients (77%) were International Staging System (ISS) Stage II or III, 87% had received prior autologous stem cell transplantation (ASCT), and 16% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. High-risk cytogenetic factors (presence of t[4;14], t[14;16] and 17p13del) were present in 27% of patients. The median number of prior lines of therapy was 7 (range: 3 to 21).

Efficacy results are summarized in Table 6. The median time to first response was 1.4 months (95% CI: 1.0, 1.6). Seventy-three percent of responders had a duration of response ≥6 months.

Table 6. Efficacy in DREAMM-2:

^a NR = Not reached