Blenrep

1 INDICATIONS AND USAGE BLENREP is indicated in combination with bortezomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least two prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. BLENREP, a B‑cell maturation antigen (BCMA)‑directed antibody and microtubule inhibitor conjugate, is indicated in combination with bortezomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least two prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. ( 1 )

2 DOSAGE AND ADMINISTRATION • The recommended dosage of BLENREP, in combination with bortezomib and dexamethasone, is 2.5 mg/kg as an intravenous infusion over 30 minutes once every 3 weeks for 8 cycles, followed by BLENREP 2.5 mg/kg every 3 weeks as a single agent. ( 2.2 ) • See Full Prescribing Information for instructions on preparation and administration. ( 2.4 ) 2.1 Important Safety Information Ophthalmic exams, including slit lamp exam and assessment of best‑corrected visual acuity (BCVA), should be conducted by an eye care professional, such as an ophthalmologist or optometrist. Conduct ophthalmic exams at baseline, before each dose of BLENREP, promptly for new or worsening symptoms, and as clinically indicated [see Warnings and Precautions ( 5.1 )]. Counsel patients to promptly inform their healthcare provider of any ocular symptoms. Advise patients to use preservative‑free artificial tears at least 4 times a day starting with the first infusion and continuing until end of treatment, and to avoid wearing contact lenses for the duration of therapy. Bandage contact lenses may be used under the direction of an eye care professional [see Warnings and Precautions ( 5.1 )]. 2.2 Recommended Dosage The recommended dosage for BLENREP is 2.5 mg/kg of actual body weight once every 3 weeks in combination with bortezomib and dexamethasone (BVd) for the first 8 cycles, followed by BLENREP 2.5 mg/kg of actual body weight once every 3 weeks as a single agent until disease progression or unacceptable toxicity. For dosing instructions of agents administered in combination with BLENREP, see Clinical Studies ( 14 ) and respective Prescribing Information, as appropriate. BLENREP is administered as an intravenous infusion over approximately 30 minutes. 2.3 Dosage Modifications for Adverse Reactions In the BVd arm of the clinical study, 98% of patients required a dosage modification for any component of treatment for an adverse reaction, including 87% who required a dosage modification of BLENREP [see Clinical Studies ( 14 )] . Eighty-three percent of patients required a dosage modification of BLENREP for ocular toxicity based on ophthalmic exam findings or other ocular adverse reactions as defined by the Common Terminology Criteria for Adverse Events (CTCAE) [see Adverse Reactions ( 6.1 )] . There were high rates of dosage modifications in early treatment cycles. By Cycle 3, 53% of patients had a dosage interruption or reduction, 7% had discontinued treatment, and only 40% received the planned dose of BLENREP. The recommended dosage modifications for ocular toxicity based on ophthalmic exam findings are provided in Tables 1 and 2. Ophthalmic exam findings include both corneal exam findings and change in BCVA as assessed by an eye care professional. The overall grade of ophthalmic exam findings is based on the worst finding in the worst affected eye, based on either corneal exam finding or a change in BCVA. Corneal exam findings may or may not be accompanied by changes in BCVA or ocular symptoms. • Do not re‑escalate the dose of BLENREP after a dosage reduction is made for ocular toxicity based on ophthalmic exam findings. • In the clinical study, 67% of patients required a dosage interruption of BLENREP for ocular toxicity that lasted longer than 3 weeks (time between doses, median: 5.7 weeks [range: 3 to 31 weeks]). The recommended dosage modifications for other adverse reactions, including dosage modifications for ocular adverse reactions based on the CTCAE, are provided in Table 3 . Table 1. Recommended Dosage Reductions of BLENREP for Adverse Reactions a Reduced Dosage Level 2 is specific to dosage reductions due to ocular toxicity based on ophthalmic exam findings. BLENREP Reduced Dosage Level 1 1.9 mg/kg every 3 weeks Reduced Dosage Level 2 a 1.9 mg/kg every 8 weeks Table 2. Recommended Dosage Modifications for Ocular Toxicity Based on Ophthalmic Exam Findings a BCVA = best‑corrected visual acuity. a Mild superficial keratopathy (docu…

5 WARNINGS AND PRECAUTIONS • Thrombocytopenia: Monitor complete blood counts at baseline and periodically during treatment. Withhold or reduce the dosage based on severity. ( 2.3 , 5.3 ) • Embryo‑fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 ) 5.1 Ocular Toxicity BLENREP causes ocular toxicity, defined as changes in the corneal epithelium and changes in BCVA based on ophthalmic exam (including slit lamp exam), or other ocular adverse reactions as defined by the CTCAE [see Adverse Reactions ( 6.1 )] . In DREAMM-7, ocular toxicity occurred in 92% of patients, including Grade 3 or 4 in 77% of patients. The most common ocular toxicities (>25%) were reduction in BCVA (89%) and corneal exam findings (86%) based on ophthalmic exam findings, blurred vision (66%), dry eye (51%), photophobia (47%), foreign body sensation in eyes (44%), eye irritation (43%), and eye pain (33%) [see Adverse Reactions ( 6.1 )] . Ocular toxicity based on ophthalmic exam findings was reported as Grade 2 in 9% of patients, Grade 3 in 56% of patients, and Grade 4 in 21% of patients. The median time to onset of the first Grade 2 to 4 ophthalmic exam findings was 43 days (range: 15 to 611 days). The median duration of all Grade 2 to 4 ophthalmic exam findings was 85 days (range: 5 to 813 days). Patients experienced a median of 3 episodes (range: 1 to 11 episodes) of ocular toxicity based on ophthalmic exam findings. Of the patients with Grade 2 to 4 ophthalmic exam findings, 42% had improvement of the last event to Grade 1 or better; 22% had resolution of the last event based on return to baseline or normal ophthalmic exam findings. The most commonly reported corneal exam findings included superficial punctate keratopathy, microcyst-like deposits, epithelial changes, and haze. Cases of corneal ulcer, including cases with infection, have been reported and should be managed promptly by an eye care professional [see Adverse Reactions ( 6.1 )] . A reduction in BCVA to 20/50 or worse in at least one eye occurred in 69% of patients, including 29% who experienced a change in BCVA to 20/100 or worse, and 12% who experienced a change in BCVA to 20/200 or worse. Of the patients with reduced BCVA to 20/50 or worse in at least one eye, 61% had resolution of the last event to baseline or better. Of the patients with reduced BCVA to 20/100 or worse, 57% had resolution of the last event. Of the patients with reduced BCVA to 20/200 or worse, 48% had resolution of the last event. Ophthalmic exams (including slit lamp exam and BCVA assessment) should be conducted by an eye care professional, such as an ophthalmologist or optometrist, at baseline, before each dose of BLENREP, promptly for new or worsening symptoms, and as clinically indicated. Perform baseline exam within 4 weeks prior to the first dose. Perform each follow-up exam within 10 days prior to the next planned dose. All effort should be made to schedule the exam as close to BLENREP dosing as possible. Withhold BLENREP until improvement in both corneal exam findings and change in BCVA to Grade 1 or less and resume at same or reduced dose or permanently discontinue based on severity [see Dosage and Administration ( 2.1 , 2.3 )]. Counsel patients to promptly inform their healthcare provider of any ocular symptoms. Counsel patients to use preservative‑free artificial tears at least 4 times a day starting with the first infusion and continuing until the end of treatment, and to avoid wearing contact lenses for the duration of therapy. Bandage contact lenses may be used under the direction of an eye care professional [see Dosage and Administration ( 2.1 )]. Changes in visual acuity may be associated with difficulty for driving and reading. Counsel patients to use caution when driving or operating machinery. BLENREP is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and …

4 CONTRAINDICATIONS None. None. ( 4 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, BLENREP can cause fetal harm when administered to a pregnant woman, because it contains a genotoxic compound (the microtubule inhibitor, MMAF) and it targets actively dividing cells [see Clinical Pharmacology ( 12.1 ), Nonclinical Toxicology ( 13.1 )] . Human immunoglobulin G (IgG) is known to cross the placenta; therefore, belantamab mafodotin-blmf has the potential to be transmitted from the mother to the developing fetus. There are no available data on the use of BLENREP in pregnant women to evaluate for drug-associated risk. No animal reproduction studies were conducted with BLENREP. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data: Animal reproductive or developmental toxicity studies were not conducted with belantamab mafodotin‑blmf. The cytotoxic component of BLENREP, mcMMAF, disrupts microtubule function, is genotoxic, and can be toxic to rapidly dividing cells, suggesting it has the potential to cause embryo‑fetal toxicity.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Ocular Toxicity [see Warnings and Precautions ( 5.1 )] • Thrombocytopenia [see Warnings and Precautions ( 5.3 )] The most common adverse reactions (≥20%) with BLENREP in combination with bortezomib and dexamethasone are reduction in best-corrected visual acuity (BCVA), corneal exam findings, blurred vision, dry eye, photophobia, foreign body sensation in eyes, eye irritation, upper respiratory tract infection, hepatotoxicity, eye pain, diarrhea, fatigue, pneumonia, cataract, and COVID-19. The most common Grade 3 or 4 (≥10%) laboratory abnormalities are decreased platelets, decreased lymphocytes, decreased neutrophils, increased gamma-glutamyl transferase, decreased white blood cells, and decreased hemoglobin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory Multiple Myeloma in Combination with Bortezomib and Dexamethasone The safety of BLENREP with bortezomib and dexamethasone (n = 242) compared with daratumumab with bortezomib and dexamethasone (n = 246) was evaluated in DREAMM‑7 in patients with relapsed or refractory multiple myeloma who received at least one prior line of therapy [see Clinical Studies ( 14 )] . Patients received BLENREP 2.5 mg/kg of actual body weight once every 3 weeks in combination with bortezomib and dexamethasone (BVd) for the first 8 cycles, followed by BLENREP as a single agent or daratumumab in combination with bortezomib and dexamethasone (DVd) for the first 8 cycles, followed by daratumumab as a single agent. Among patients who received BLENREP, 69% were exposed for 6 months or longer and 55% were exposed for greater than one year. The safety of BLENREP in combination with bortezomib and dexamethasone in patients who received only one prior line of therapy (n = 125) has not been established. Serious adverse reactions occurred in 50% of patients who received BVd. Serious adverse reactions in ≥2% of patients included pneumonia (18%), pyrexia (5%), thrombocytopenia (5%), COVID-19 (5%), upper respiratory tract infection (4%), sepsis (4%), second primary malignancy (3%), and anemia (2%). Fatal adverse reactions occurred in 10% of patients who received BVd. Fatal adverse reactions which occurred in >1 patient included pneumonia (4%), sepsis (2%), COVID-19 (1%), respiratory failure (<1%), and intracranial hemorrhage (<1%). Permanent discontinuation of BLENREP due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of BLENREP in ≥3% of patients included ocular toxicity (9%) and pneumonia (4%). Dosage interruptions of BLENREP due to an adverse reaction occurred in 78% of patients. Adverse reactions which required dosage interruption of BLENREP in ≥3% of patients included ocular toxicity based on ophthalmic exam findings (74%), blurred vision (32%), upper respiratory tract infection (20%), dry eye (14%), photophobia (14%), pneumonia (14%), eye irritation (13%), COVID-19 (12%), foreign body sensation in eyes (12%), eye pain (10%), thrombocytopenia (9%), visual impairment (7%), cataract (5%), diarrhea (4%), and neutropenia (4%). Dosage reductions of BLENREP due to an adverse reaction occurred in 36% of patients. Adverse reactions which required dosage reductions for BLENREP in ≥3% of patients included ocular toxicity based on ophthalmic exam findings (30%), thrombocytopenia (14%), and blurred vision (10%). The most common adverse reactions (≥20%) were reduction in BCVA, corneal exam findings, blurred vision, dry eye, photophobia…