Version May 2024
GlaxoSmithKline has initiated the process for voluntary withdrawal of the Biologic License Application for 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. The confirmatory randomized DREAMM-3 phase 3 trial of belantamab mafodotin monotherapy versus PomDex (pomalidomide and dexamethasone) in patients with relapsed or refractory multiple myeloma did not meet its primary end point of superior progression-free survival. GlaxoSmithKline has stopped new patient enrollment into the Blenrep REMS. To ensure patients who are currently deriving clinical benefit continue to have access to Blenrep, GlaxoSmithKline will be opening a compassionate use program.
Further information may be found at https://www.blenrep.com/content/dam/cf-pharma/dsa-blenrepv3/en_US/pdf/Blenrep-(belantamab-mafodotin-blmf)DearHCPLetterNov2022.pdf.
Belantamab mafodotin 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 belantamab mafodotin until improvement and resume, or permanently discontinue, based on severity.
Because of the risk of ocular toxicity, belantamab mafodotin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BLENREP REMS.
Note: Perform ophthalmic examinations (visual acuity and slit lamp) at baseline, prior to each dose, and promptly for worsening ocular symptoms. Baseline examinations should be done within 3 weeks prior to the first dose; perform subsequent examinations at least 1 week after the previous dose and within 2 weeks prior to the next dose. Patients should use preservative-free lubricant eye drops at least 4 times a day, starting with the initial infusion and continuing until the end of therapy, and avoid contact lenses unless otherwise directed.
Multiple myeloma, relapsed/refractory: IV: 2.5 mg/kg (based on actual body weight) once every 3 weeks until disease progression or unacceptable toxicity (Ref).
Note: A confirmatory phase 3 trial in patients with relapsed or refractory multiple myeloma comparing belantamab mafodotin to pomalidimide and dexamethasone did not demonstrate a clinical benefit for belantamab mafodotin; due to the trial results, the manufacturer is voluntarily withdrawing belantamab mafodotin from the market.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Renal function may be estimated by the Modification of Diet in Renal Disease (MDRD) equation.
eGFR 30 to 89 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 15 to 29 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (has not been established).
End-stage renal disease, not on dialysis or requiring dialysis (eGFR <15 mL/minute/1.73 m2): There are no dosage adjustments provided in the manufacturer's labeling (has not been established).
Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to ≤1.5 times ULN and any AST): No dosage adjustment necessary.
Moderate or severe impairment (total bilirubin >1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been established).
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full, weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref). Note: Belantamab mafodotin dosing is based on actual body weight (according to the prescribing information).
|
Dose reduction level |
Belantamab mafodotin dose reduction schedule |
|---|---|
|
Usual (initial dose) |
2.5 mg/kg once every 3 weeks |
|
First |
1.9 mg/kg once every 3 weeks |
|
If unable to tolerate 1.9 mg/kg once every 3 weeks, discontinue belantamab mafodotin. | |
For corneal adverse reactions, determine the recommended dosage modification based on the worst finding in the worst affected eye; worst finding should be based on either a corneal examination finding or a change in visual acuity per the Keratopathy and Visual Acuity (KVA) scale.
|
Corneal adverse reaction (per KVA scale) |
Recommended dosage modification | |
|---|---|---|
|
aChanges in visual acuity due to treatment-related corneal findings. | ||
|
Grade 1 |
Corneal examination finding(s): Mild superficial keratopathy (documented worsening from baseline), with or without symptoms. Change in best corrected visual acuity (BCVA)a: Decline from baseline of 1 line on Snellen Visual Acuity. |
Continue belantamab mafodotin at the current dose. |
|
Grade 2 |
Corneal examination finding(s): Moderate superficial keratopathy with or without patchy microcyst-like deposits, subepithelial haze (peripheral), or a new peripheral stromal opacity. Change in BCVAa: Decline from baseline of 2 or 3 lines on Snellen Visual Acuity and not worse than 20/200. |
Withhold belantamab mafodotin until improvement in both corneal examination findings and change in BCVA to ≤ grade 1, then resume at the same dose. |
|
Grade 3 |
Corneal examination finding(s): Severe superficial keratopathy with or without diffuse microcyst-like deposits, subepithelial haze (central), or a new central stromal opacity. Change in BCVAa: Decline from baseline by >3 lines on Snellen Visual Acuity and not worse than 20/2000. |
Withhold belantamab mafodotin until improvement in both corneal examination findings and change in BCVA to ≤ grade 1, then resume at a reduced dose. |
|
Grade 4 |
Corneal examination finding(s): Corneal epithelial defect such as corneal ulcers. Change in BCVAa: Snellen Visual Acuity worse than 20/200. |
Consider permanent discontinuation. If continuing treatment, withhold belantamab mafodotin until improvement in both corneal examination findings and change in BCVA to ≤ grade 1, then resume at a reduced dose. |
|
Other Adverse Reactions | ||
|
Adverse reaction |
Severity |
Recommended dosage modifications |
|
Thrombocytopenia |
Platelets 25,000/mm3 to <50,000/mm3 |
Consider withholding belantamab mafodotin and/or reducing the dose. |
|
Platelets <25,000/mm3 |
Withhold belantamab mafodotin until platelet count improves to ≤ grade 3. Consider resuming at a reduced dose. | |
|
Infusion-related reactions |
Grade 2 (moderate) or grade 3 (severe) |
Interrupt belantamab mafodotin infusion and provide supportive care. Once symptoms resolve, resume at a lower infusion rate (reduce the infusion rate by at least 50%). Administer premedication for all subsequent infusions. |
|
Grade 4 (life threatening) |
Permanently discontinue belantamab mafodotin and provide emergency care. | |
|
Other adverse reactions |
Grade 3 |
Withhold belantamab mafodotin until improvement to ≤ grade 1. Consider resuming at a reduced dose. |
|
Grade 4 |
Consider permanent belantamab mafodotin discontinuation. If continuing treatment, withhold belantamab mafodotin until improvement to ≤ grade 1 and resume at a reduced dose. | |
Refer to adult dosing.
Thrombocytopenia occurred in the majority of patients. Grade 2, 3, and 4 events were common. Thrombocytopenia may warrant dose reduction and/or therapy interruption or discontinuation, depending on severity. Grade 3 to 4 bleeding events have also been reported in a small percentage of patients, including rare cases of fatal cerebral hemorrhage. Lymphocytopenia, decreased hemoglobin, and decreased neutrophils have also been commonly reported.
Mechanism: Exact mechanism is unknown, but it has been suggested that thrombocytopenia is the result of apoptosis of megakaryocyte progenitor cells induced by the nonspecific uptake of the antibody drug conjugate (Ref).
Onset: Thrombocytopenia: Intermediate; median time to onset of the first thrombocytopenic events was ~27 days.
Infusion-related reaction occurred commonly during therapy. Reactions are usually grade 1 or 2, but severe events may occur (Ref). Treatment interruption or permanent discontinuation may be warranted, depending on severity.
Onset: Rapid; most often occurred with the first infusion, though reactions have occurred with the second infusion (Ref).
Belantamab mafodotin may cause changes in the corneal epithelium leading to ocular toxicity, including severe vision loss and corneal ulcer (ulcerative keratitis and infective keratitis). Commonly reported ocular events include blurred vision, dry eye syndrome, epithelial keratopathy and clinically significant decreased visual acuity. Approximately one-third of patients had both ocular symptoms and visual acuity changes. Driving and reading may be difficult due to visual acuity changes; use caution when driving or operating machinery. Other less frequently reported ocular events include eye irritation and photophobia. Ocular events commonly lead to permanent discontinuation or dose interruptions (Ref). Secondary cataracts, requiring surgical removal, and increased intraocular pressure have also been reported postmarketing (Ref).
Mechanism: Exact mechanism of corneal events unknown but may be related to nonspecific uptake of the antibody-drug conjugate into actively dividing basal corneal epithelial cells (Ref). Belantamab mafodotin enters the cornea via the vascularized region of the limbus or the tear film, becomes internalized by these corneal epithelial cells, thereby initiating apoptosis (Ref).
Onset: Varied; most keratopathy events developed within the first 2 treatment cycles. The median time to onset of corneal epithelium changes has been reported as 37 days with a median time to resolution of 86.5 days for the first event, including those with and without dosage modifications (Ref). In patients with decreased visual acuity, median time to resolution was 22 days (range: 7 days to 4.2 months).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Endocrine & metabolic: Decreased serum albumin (43%), decreased serum potassium (20%), decreased serum sodium (21%), increased gamma-glutamyl transferase (25%), increased serum glucose (38%)
Gastrointestinal: Constipation (13%), decreased appetite (12%), diarrhea (13%; grades 3/4: 1%), nausea (24%)
Hematologic & oncologic: Decreased hemoglobin (32%; grades 3/4: 18%), decreased neutrophils (28%; grades 3/4: 9%), lymphocytopenia (49%; grades 3/4: 22%), thrombocytopenia (62%; grades 3/4: 21%)
Hepatic: Increased serum alkaline phosphatase (26%), increased serum aspartate aminotransferase (57%)
Nervous system: Fatigue (≤20%)
Neuromuscular & skeletal: Arthralgia (12%), asthenia (≤20%), back pain (11%), increased creatine phosphokinase in blood specimen (22%)
Ophthalmic: Decreased visual acuity [53%], dry eye syndrome [14%], epithelial keratopathy [71%]), ocular toxicity (including blurred vision [22%]
Renal: Increased serum creatinine (28%)
Respiratory: Upper respiratory tract infection (11%)
Miscellaneous: Fever (22%), infusion related reaction (21%; severe infusion related reaction: 3%)
1% to 10%:
Endocrine & metabolic: Albuminuria (<10%), hypercalcemia (4%)
Gastrointestinal: Vomiting (<10%)
Infection: Sepsis (4%)
Ophthalmic: Eye irritation (<10%), keratitis (infective keratitis and ulcerative keratitis: <10%), photophobia (<10%)
Renal: Renal insufficiency (4%)
Respiratory: Pneumonia (7%)
<1%: Immunologic: Antibody development
Frequency not defined:
Ophthalmic: Corneal ulcer, severe vision loss
Respiratory: Pneumonitis
Postmarketing: Ophthalmic: Increased intraocular pressure (Warcel 2020), secondary cataract (Warcel 2020)
There are no contraindications listed in the manufacturer's labeling.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Blenrep: Belantamab mafodotin-blmf 100 mg (1 ea) [contains edetate (edta) disodium dihydrate, polysorbate 80]
No
Solution (reconstituted) (Blenrep Intravenous)
100 mg (per each): $10,591.76
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
For patients receiving belantamab mafodotin prior to the market withdrawal, continued access will be available via a compassionate use program; compassionate use enrollment information will be provided directly to prescribers enrolled in the REMS program. Belantamab mafodotin will continue to be available while patients are being transitioned to the compassionate use program.
IV: Infuse over ~30 minutes using an infusion set made of PVC or polyolefin. Although not required, a polyethersulfone-based filter (0.2 micron) may be used. Do not administer with any other medications. If refrigerated, allow the diluted solution to equilibrate to room temperature prior to administration; solution must be infused within 6 hours after removal from refrigeration (including infusion time). Monitor for infusion-related reactions.
Hazardous agent (NIOSH [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761158s006lbl.pdf#page=22, must be dispensed with this medication.
Multiple myeloma, relapsed or refractory: Treatment of relapsed or refractory multiple myeloma in adults who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
Note: A confirmatory phase 3 trial in patients with relapsed or refractory multiple myeloma comparing belantamab mafodotin to pomalidimide and dexamethasone did not demonstrate a clinical benefit for belantamab mafodotin; due to the trial results, the manufacturer is voluntarily withdrawing belantamab mafodotin from the market.
Belantamab mafodotin may be confused with belimumab, belinostat, blinatumomab, brentuximab vedotin, burosumab, enfortumab vedotin.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of OATP1B1/1B3 (SLCO1B1/1B3)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Evaluate pregnancy status prior to use in patients who could become pregnant. Patients who could become pregnant should use effective contraception during therapy and for 4 months after the last belantamab mafodotin dose. Patients with partners who could become pregnant should use effective contraception during therapy and for 6 months after the last belantamab mafodotin dose.
Based on the mechanism of action, in utero exposure to belantamab mafodotin may cause fetal harm.
It is not known if belantamab mafodotin is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 3 months after the last belantamab mafodotin dose.
CBC at baseline and during treatment as clinically necessary. Evaluate pregnancy status prior to therapy initiation in females of reproductive potential. Perform ophthalmic examinations (visual acuity and slit lamp) at baseline, prior to each dose, and promptly for worsening ocular symptoms; baseline examinations should be done within 3 weeks prior to the first dose; perform subsequent examinations at least 1 week after the previous dose and within 2 weeks prior to the next dose. Monitor for bleeding events and for signs/symptoms of infusion-related reaction.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Belantamab mafodotin is an afucosylated, humanized antibody-drug conjugate directed against B-cell maturation antigen (BCMA); BCMA is expressed on multiple myeloma cells but is mostly absent on naive and memory B cells (Lonial 2020). The antibody is conjugated by a protease-resistant maleimidocaproyl linker to microtubule-disrupting monomethyl auristatin F (MMAF). After binding to BCMA, belantamab mafodotin is internalized and MMAF is released via proteolytic cleavage, resulting in cell cycle arrest and apoptosis. In addition to MMAF-induced apoptosis, belantamab mafodotin causes tumor cell lysis through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.
Onset: Median time to first response: 1.4 months.
Duration: Most patients had a duration of response of ≥6 months.
Distribution: Vdss: 11 L.
Metabolism: The monoclonal antibody is expected to be metabolized into small peptides and individual amino acids by catabolic pathways.
Half-life elimination: 14 days (at steady state); 12 days (after first dose).
Time to peak: Shortly after the end of the infusion.
Excretion: Clearance: 0.7 L/day (at steady state).
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