Linvoseltamab-gcpt
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]
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Black Box Warning
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CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITY, INCLUDING IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
See full prescribing information for complete Boxed Warning.
* Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving LYNOZYFIC. Initiate treatment with LYNOZYFIC step-up dosing to reduce the risk of CRS. Manage CRS, withhold LYNOZYFIC until CRS resolves, and modify the next dose or permanently discontinue based on severity
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Overview
Linvoseltamab-gcpt is a bispecific B-cell maturation antigen (BCMA)‑directed CD3 T-cell engager that is FDA approved for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti‑CD38 monoclonal antibody.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include are musculoskeletal pain, cytokine release syndrome, cough, upper respiratory tract infection, diarrhea, fatigue, pneumonia, nausea, headache, and dyspnea..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
FDA-labeled Indications
- LYNOZYFIC is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
- This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Recommended Dosage
- The recommended dosage for LYNOZYFIC is presented in Table 1. In patients who experience CRS, ICANS, or neurologic adverse reactions, refer to Tables 3, 4, and 5, respectively, for recommendations regarding administration of the next LYNOZYFIC dose.
- Continue treatment until disease progression or unacceptable toxicity. The recommended dosing schedule for LYNOZYFIC is provided in Table.
- The recommended dosage of LYNOZYFIC is step-up doses of 5 mg, 25 mg, and 200 mg, followed by 200 mg weekly for 10 doses, followed by 200 mg biweekly (every 2 weeks). In patients who have achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of 200 mg, decrease the dosing frequency to 200 mg every 4 weeks.
Recommended Pretreatment Medications
- Administer the following pre-treatment medications before each dose of the LYNOZYFIC step-up dosing schedule, which includes step-up dose 1, step-up dose 2, and the first treatment dose, the second treatment dose, and if indicated, subsequent treatment doses (as mentioned in the table), to reduce the risk of CRS and/or IRR:
1. acetaminophen (or equivalent) 650 mg to 1,000 mg orally 30 to 60 minutes prior to infusion 2. diphenhydramine (or equivalent) 25 mg orally or intravenously 30 to 60 minutes prior to infusion 3. dexamethasone (or equivalent) intravenously 1 to 3 hours prior to infusion
40 mg dexamethasone (or equivalent) before step-up dose 1, step-up dose 2, and the first full treatment dose. Once a treatment dose of LYNOZYFIC is tolerated without CRS and/or IRR with 40 mg dexamethasone (or equivalent), administer 10 mg dexamethasone (or equivalent) prior to the subsequent LYNOZYFIC treatment dose.
- Pre-treatment medications may be discontinued once a treatment dose of LYNOZYFIC is tolerated without CRS and/or IRR following pre-treatment with 10 mg dexamethasone (or equivalent), acetaminophen (or equivalent), and diphenhydramine (or equivalent) as described.
Restarting LYNOZFIC After Dosage Delay
Dose delay table LYNOZFIC
Dosage Forms and Strengths
LYNOZYFIC is a clear to slightly opalescent, colorless to pale yellow solution, available as:
Injection: 5 mg/2.5 mL (2 mg/mL) single-dose vial Injection: 200 mg/10 mL (20 mg/mL) single-dose vial
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Linvoseltamab-gcpt in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Linvoseltamab-gcpt in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Linvoseltamab-gcpt FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Linvoseltamab-gcpt in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Linvoseltamab-gcpt in pediatric patients.
Contraindications
None
Warnings
|
CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITY, INCLUDING IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
See full prescribing information for complete Boxed Warning.
* Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving LYNOZYFIC. Initiate treatment with LYNOZYFIC step-up dosing to reduce the risk of CRS. Manage CRS, withhold LYNOZYFIC until CRS resolves, and modify the next dose or permanently discontinue based on severity
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Cytokine Release Syndrome (CRS)
- LYNOZYFIC can cause cytokine release syndrome (CRS), which can be serious or life-threatening.
- In LINKER-MM1, CRS occurred in 46% (54/117) of patients who received LYNOZYFIC at the recommended dose, with Grade 1 CRS occurring in 35% (41/117) of patients, Grade 2 in 10% (12/117), and Grade 3 in 0.9% (1/117). Thirty-eight percent (45/117) of patients had CRS following step-up dose 1, including 1 patient who experienced Grade 3 CRS; 8% (9/117) had an initial CRS event following a subsequent dose. Seventeen percent (19/113) of patients developed CRS after step-up dose 2, 10% (11/111) developed CRS after the first full 200 mg dose of LYNOZYFIC, and 3.6% (4/110) developed CRS after the second full dose.
- Recurrent CRS occurred in 20% (23/117) of patients. The median time to onset of CRS from the end of infusion was 11 (range: -1 to 184) hours after the most recent dose with a median duration of 15 (range: 1 to 76) hours.
- Clinical signs and symptoms of CRS included, but were not limited to pyrexia, chills, hypoxia, tachycardia, and hypotension.
- Administer pretreatment medications and initiate therapy according to LYNOZYFIC step-up dosing to reduce the incidence and severity of CRS.
- Monitor patients for signs and symptoms of CRS after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur.
- At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold LYNOZYFIC until CRS resolves and modify the next dose or permanently discontinue LYNOZYFIC based on severity.
Infusion Related Reactions
- Infusion-related reactions (IRR) may be clinically indistinguishable from manifestations of CRS. In the patients who were treated with the recommended step-up dosing regimen and pretreatment medications, the rate of IRR was 9% [11/117 including Grade 2 IRR (4.3%) and Grade 3 IRR (1.7%)]. For IRR, interrupt or slow the rate of infusion or permanently discontinue LYNOZYFIC based on severity of reaction.
- LYNOZYFIC is available only through a restricted program under a REMS.
Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome
- LYNOZYFIC can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS).
- In LINKER-MM1, neurologic toxicity occurred in 54% of patients, with Grade 3 or 4 neurologic toxicity occurring in 8%, at the recommended dose. Neurologic toxicities included ICANS, depressed level of consciousness, encephalopathy, and toxic encephalopathy.
- ICANS occurred in 8% of patients who received LYNOZYFIC with the recommended dosing regimen, including Grade 3 events in 2.6%. Most patients experienced ICANS following step-up dose 1 (5%). Two patients (1.8%) experienced initial ICANS following step-up dose 2 and one patient developed the first occurrence of ICANS following a subsequent full dose of LYNOZYFIC. Recurrent ICANS occurred in one patient. The median time to onset of ICANS was 1 (range: 1 to 4) day after the most recent dose with a median duration of 2 (range: 1 to 11) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.
- The most common clinical signs and symptoms of ICANS are confusion, depressed level of consciousness, and lethargy.
- Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient; provide supportive therapy and consider further management per current practice guidelines.
- Withhold LYNOZYFIC until ICANS resolves and modify the next dose or permanently discontinue LYNOZYFIC based on severity. Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time.
- Due to the potential for neurologic toxicity, including ICANS, patients receiving LYNOZYFIC are at risk of confusion and depressed consciousness. Advise patients to refrain from driving, or operating heavy or potentially dangerous machinery, for 48 hours after completion of each of the step-up doses and in the event of new onset of any neurological symptoms, until symptoms resolve.
- LYNOZYFIC is available only through a restricted program under a REMS.
LYNOZYFIC REMS
- LYNOZYFIC is available only through a restricted program under a REMS called the LYNOZYFIC REMS because of the risks of CRS and neurologic toxicity, including ICANS.
- Notable requirements of the LYNOZYFIC REMS include the following:
Prescribers must be certified with the program by enrolling and completing training. Prescribers must counsel patients receiving LYNOZYFIC about the risk of CRS and neurologic toxicity, including ICANS, and provide patients with LYNOZYFIC Patient Wallet Card. Pharmacies and healthcare settings that dispense LYNOZYFIC must be certified with the LYNOZYFIC REMS program and must verify prescribers are certified through the LYNOZYFIC REMS program. Wholesalers and distributors must only distribute LYNOZYFIC to certified pharmacies or healthcare settings.
- Further information about the LYNOZYFIC REMS program is available at lynozyficREMS.com or by telephone at 1-855-212-6391.
Infections
- LYNOZYFIC can cause serious, life-threatening, or fatal infections.
- In patients who received LYNOZYFIC at the recommended dose in LINKER-MM1, serious infections, including opportunistic infections, occurred in 42% of patients, with Grade 3 or 4 infections in 38% and fatal infections in 4%. The most common serious infection reported (≥10%) were pneumonia and sepsis. Two cases of progressive multifocal leukoencephalopathy (PML) occurred in patients receiving LYNOZYFIC.
- Monitor patients for signs and symptoms of infection and immunoglobulin levels prior to and during treatment with LYNOZYFIC and treat appropriately. Administer prophylactic antimicrobials, antibiotics, antifungals, antivirals, vaccines, and subcutaneous or intravenous immunoglobulin (IVIG) according to guidelines, including prophylaxis for PJP and herpesviruses.
- Withhold LYNOZYFIC or consider permanent discontinuation of LYNOZYFIC based on severity of the infection.
Neutropenia
- LYNOZYFIC can cause neutropenia and febrile neutropenia.
- In patients who received LYNOZYFIC at the recommended dose in LINKER-MM1, decreased neutrophil count occurred in 62% of patients with Grade 3 or 4 decreased neutrophil count in 47%. Febrile neutropenia occurred in 8% of patients.
- Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local guidelines. Monitor patients with neutropenia for signs of infection. Withhold LYNOZYFIC based on severity.
Hepatotoxicity
- LYNOZYFIC can cause hepatotoxicity.
- In LINKER-MM1, elevated ALT occurred in 46% of patients, with Grade 3 or 4 ALT elevation occurring in 6%; elevated AST occurred in 61% of patients, with Grade 3 or 4 AST elevation occurring in 10% of patients who received the recommended dose. Grade 3 or 4 total bilirubin elevations occurred in 1.7% of patients. Liver enzyme elevation can occur with or without concurrent CRS.
- Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold LYNOZYFIC or consider permanent discontinuation of LYNOZYFIC based on severity.
Embryo-Fetal Toxicity
- Based on its mechanism of action, LYNOZYFIC may cause fetal harm when administered to a pregnant woman.
- Advise pregnant women of the potential risk to the fetus.
- Advise females of reproductive potential to use effective contraception during treatment with LYNOZYFIC and for 3 months after the last dose.
Adverse Reactions
Clinical Trials Experience
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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Relapsed or Refractory Multiple Myeloma'
- The safety of LYNOZYFIC was evaluated in LINKER-MM1.
- Patients (n=117) received LYNOZYFIC as step-up doses of 5 mg on Day 1 and 25 mg on Day 8, and the first treatment dose of 200 mg on Day 15. Patients then received 200 mg intravenously once weekly from Week 4 to Week 13, followed by 200 mg every 2 weeks from Week 14. In the Phase 2 portion of the study, patients who achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of 200 mg were able to receive every 4-week dosing. The median duration of treatment was 47 weeks (range 1, 151); 55% of patients were exposed for 9 months or longer and 36% were exposed for 1 year or longer.
- The median age of patients who received LYNOZYFIC was 70 years (range: 37 to 91 years); 55% were male; 71% were White, 17% were Black or African American, and 9% were Asian.
- Serious adverse reactions occurred in 74% of patients who received LYNOZYFIC. Serious adverse reactions that occurred in >5% of patients included cytokine release syndrome (27%), pneumonia (13%), COVID-19 (7%), and acute kidney injury (5%). Fatal adverse reactions occurred in 7% of patients, and included sepsis (3.4%), chronic kidney disease (0.9%), pneumonia (0.9%), tumor lysis syndrome (0.9%), and encephalopathy (0.9%).
- Permanent discontinuation of LYNOZYFIC due to adverse reactions occurred in 16% of patients. Adverse reactions leading to discontinuation that occurred in at least 2 patients included sepsis, pneumonia, and encephalopathy.
- Dosage interruptions or delays of LYNOZYFIC due to adverse reactions occurred in 74% of patients. Adverse reactions which required a dosage interruption or delay in >10% of patients included neutropenia (29%), upper respiratory tract infection (18%), pneumonia (15%), and COVID-19 infection (11%).
- The most common adverse reactions (≥20%) were musculoskeletal pain, cytokine release syndrome, cough, upper respiratory tract infection, diarrhea, fatigue, pneumonia, nausea, headache, and dyspnea.
- The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased lymphocyte count, decreased neutrophil count, decreased hemoglobin, and decreased white blood cell count.
- Clinically significant adverse reactions that occurred in <10% of patients treated with LYNOZYFIC included IRR, motor dysfunction, febrile neutropenia, ICANS, CMV infection, and PML.
Management of Adverse Reactions
- Cytokine Release Syndrome
Identify CRS based on clinical presentation. Evaluate and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold LYNOZYFIC until CRS resolves. CRS should be managed according to the recommendations in Table 3 and per current practice guidelines. Supportive therapy for CRS should be administered, which may include intensive care for severe or life-threatening CRS.
- Neurologic Toxicity, including ICANS
At the first sign of suspected neurologic toxicity, including ICANS, withhold LYNOZYFIC and consider consultation with neurologist and other specialists for further evaluation and management. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care for severe or life-threatening ICANS. Manage per current practice guidelines.
Postmarketing Experience
There is limited information regarding Linvoseltamab-gcpt Postmarketing Experience in the drug label.
Drug Interactions
Effects of LYNOZYFIC on Other Drugs
Certain CYP substrates
- Monitor for toxicity unless otherwise recommended in the Prescribing Information of certain CYP substrates where minimal changes in the concentration may lead to serious adverse reactions when used concomitantly with LYNOZYFIC.
- Linvoseltamab-gcpt causes the release of cytokines that may suppress cytochrome P450 (CYP) enzyme activity.
- Concomitant use with LYNOZYFIC increases CYP substrate exposure which may increase the risk of adverse reactions related to these substrates.
- Increased CYP substrate exposure is more likely to occur from initiation of the LYNOZYFIC step-up dosing schedule up to 14 days after the first 200 mg dose, and during and after CRS.
Use in Specific Populations
Pregnancy
Risk Summary
- Based on the mechanism of action, LYNOZYFIC may cause fetal harm when administered to a pregnant woman.
- There are no available data on the use of LYNOZYFIC in pregnant women to evaluate for a drug associated risk. No animal reproductive or developmental toxicity studies have been conducted with LYNOZYFIC.
- Linvoseltamab-gcpt causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on the finding of B-cell depletion in non-pregnant animals, linvoseltamab-gcpt can cause B-cell lymphocytopenia in infants exposed to linvoseltamab-gcpt in-utero. * Human immunoglobulin (IgG) is known to cross the placenta after the first trimester of pregnancy; therefore, linvoseltamab-gcpt has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus.
- LYNOZYFIC is associated with hypogammaglobulinemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with LYNOZYFIC should be considered.
- 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Linvoseltamab-gcpt in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Linvoseltamab-gcpt during labor and delivery.
Nursing Mothers
Risk Summary
- There are no data on the presence of linvoseltamab-gcpt in human milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk.
- Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with LYNOZYFIC and for 3 months after the last dose.
Pediatric Use
The safety and effectiveness of LYNOZYFIC have not been established in pediatric patients.
Geriatic Use
- Of the 117 patients with relapsed or refractory multiple myeloma who received LYNOZYFIC, 42 (36%) of patients were 65 to 74 years of age and 31 (26%) were 75 years of age and older.
- No overall differences in safety or effectiveness were observed in patients 65 years of age and older, including patients 75 years of age and older, when compared with younger patients.
Gender
There is no FDA guidance on the use of Linvoseltamab-gcpt with respect to specific gender populations.
Race
There is no FDA guidance on the use of Linvoseltamab-gcpt with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Linvoseltamab-gcpt in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Linvoseltamab-gcpt in patients with hepatic impairment.
Females of Reproductive Potential and Males
LYNOZYFIC may cause fetal harm when administered to a pregnant woman.
- Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating treatment with LYNOZYFIC.
- Contraception
Females Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of LYNOZYFIC.
Immunocompromised Patients
There is no FDA guidance one the use of Linvoseltamab-gcpt in patients who are immunocompromised.
Administration and Monitoring
Administration
Preparation
- Use aseptic technique to prepare LYNOZYFIC. Each vial is intended for one time use only. Do not shake.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- LYNOZYFIC is a clear to slightly opalescent, colorless to pale yellow solution.
- Discard the vial if the solution is cloudy, discolored, or contains particulate matter.
- Determine the dose, total volume of LYNOZYFIC solution, and the number of LYNOZYFIC vials needed.
Dilution
- Withdraw the desired dose from the vial of LYNOZYFIC and transfer into an intravenous infusion bag [polyvinyl chloride (PVC) or polyolefin (PO)] of 0.9% Sodium Chloride Injection, as mentioned in the table below. Discard any unused portion left in the vial.
- Mix diluted solution by gentle inversion. Do not shake the solution.
Dilution LYNOZYFIC Tbale
Diluted LYNOZYFIC Storage
- Use diluted LYNOZYFIC immediately. If not used immediately, store the solution:
at room temperature up to 25°C (77°F) for no more than 8 hours from preparation to the start of the infusion. Or under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 48 hours from preparation to the start of the infusion.
- Do not freeze.
- Do not shake.
Administration
- Administer as an intravenous infusion only.
- Connect the prepared intravenous infusion bag containing the final LYNOZYFIC solution to intravenous tubing constructed of PVC, polyethylene (PE)-lined PVC, or polyurethane (PU).
- Use of a 0.2-micron to 5-micron polyethersulfone (PES) filter is required.
Prime with LYNOZYFIC to the end of the intravenous tubing.
- Do not mix LYNOZYFIC with other drugs or concurrently administer other drugs through the same intravenous line.
- Upon completion of LYNOZYFIC infusion, flush the infusion line with an adequate volume of sterile 0.9% Sodium Chloride Injection to ensure that the entire contents of the infusion bag are administered.
- Total infusion time should include flushing of the infusion line.
Monitoring
There is limited information regarding Linvoseltamab-gcpt Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Linvoseltamab-gcpt and IV administrations.
Overdosage
There is limited information regarding Linvoseltamab-gcpt overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Linvoseltamab-gcpt Pharmacology in the drug label.
Mechanism of Action
- Linvoseltamab-gcpt is a bispecific T-cell engaging antibody that binds to the CD3 receptor expressed on the surface of T-cells and B-cell maturation antigen (BCMA) expressed on the surface of multiple myeloma cells and some healthy B-lineage cells.
- In vitro, linvoseltamab-gcpt activated T-cells, caused the release of various proinflammatory cytokines, and resulted in the lysis of multiple myeloma cells. * Linvoseltamab-gcpt had anti-tumor activity in mouse models of multiple myeloma.
Structure
Linvoseltamab-gcpt, a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, is a recombinant human immunoglobulin (Ig)G4 antibody. Linvoseltamab-gcpt is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture. The molecular weight of linvoseltamab-gcpt is approximately 146 kDa.
Pharmacodynamics
- The 200 mg once weekly dosing regimen was associated with better objective response rate and complete response rate when compared to the 50 mg once weekly (0.25 times the recommended dosage) dosing regimen in patients with relapsed or refractory multiple myeloma.
- Linvoseltamab-gcpt exposure-response relationships have not been fully characterized.
Effect on Circulating Cytokines
- Transient elevation of circulating cytokines (IL-2, IL-6, and IFN-γ) was primarily observed during the step-up dose regimen and the first full 200 mg dose.
- The highest elevation of cytokines was generally observed 4 hours after each infusion and generally returned to baseline prior to the next dose.
- Limited cytokine release was observed following subsequent doses.
Pharmacokinetics
- Pharmacokinetic (PK) parameters were evaluated at the recommended dosage in patients with relapsed or refractory multiple myeloma and are presented as geometric mean (CV%) unless otherwise specified.
- Linvoseltamab-gcpt Ctrough increased more than proportionally over a dose range of 96 mg to 800 mg (0.48 to 4 times the recommended full dose). Linvoseltamab-gcpt maximum concentration (127 mg/L [51%]) is achieved after the first dose of the every-2-weeks dosing regimen (i.e., the 12th dose of 200 mg).
- Distribution
Linvoseltamab-gcpt volume of distribution (Vd) is 7.05 L (33.6%).
- Elimination
Linvoseltamab-gcpt clearance is 0.68 L/day (52.2%) at baseline and 0.43 L/day (83.8%) at steady state. Linvoseltamab-gcpt clearance decreases over time because its elimination is mediated by two parallel processes: a linear, non-saturable catabolic process and a nonlinear, saturable target-mediated pathway. Patients who discontinue linvoseltamab-gcpt are expected to have a 97% reduction from Cmax at a median (5th to 95th percentile) time of 77.7 (18 to 154) days after last dose.
- Metabolism
Linvoseltamab-gcpt is expected to be metabolized into small peptides by catabolic pathways.
- Specific Populations
No clinically significant differences in the pharmacokinetics of linvoseltamab-gcpt were observed based on age (37 to 91 years), weight (44 to 172 kg), sex, race (White, Asian, or Black), ethnicity (Hispanic/Latino or not Hispanic/Latino), mild to moderate renal impairment (creatinine clearance [CrCL] 30 to 89 mL/min, by Cockcroft-Gault [C-G] equation), or mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST). The effect of severe renal impairment (CrCL 15 to 29 mL/min), end-stage renal disease (CrCL less than 15 mL/min), and moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN with any AST) on the pharmacokinetics of linvoseltamab-gcpt is unknown.
Immunogenecity
- The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.
- Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the study described below with the incidence of anti-drug antibodies in other studies, including those of linvoseltamab-gcpt.
- During treatment in LINKER-MM1 (evaluated through 30 months) [see Clinical Studies (14)], 1% (2/192) of LYNOZYFIC-treated patients developed anti-linvoseltamab-gcpt antibodies.
- Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of linvoseltamab products is unknown.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenicity or genotoxicity studies have been conducted with linvoseltamab-gcpt.
- No animal studies have been performed to evaluate the effects of linvoseltamab-gcpt on fertility.
Clinical Studies
Relapsed or Refractory Multiple Myeloma
- The efficacy of LYNOZYFIC was evaluated in patients with relapsed or refractory multiple myeloma in an open-label, multi-center, multi-cohort study: LINKER-MM1 (NCT03761108).
- The study included patients who had previously received at least 3 prior therapies, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 antibody.
- The study included patients with Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 and adequate baseline hematologic (absolute neutrophil count > 1 × 109/L, platelet count > 50 × 109/L, hemoglobin level >8 g/dL), renal (CrCL > 30 mL/min), and hepatic (AST and ALT ≤ 2.5 × ULN, total bilirubin ≤ 1.5 × ULN, alkaline phosphatase ≤ 2.5 × ULN) function.
- The study excluded patients with known multiple myeloma brain lesions or meningeal involvement, history of a neurodegenerative condition, history of seizure within 12 months prior to study enrollment, active infection, a history of an allogeneic or autologous stem cell transplantation within 12 weeks, prior BCMA-directed bispecific antibody therapy, prior bispecific T-cell engaging therapy, or prior BCMA CAR-T cell therapy.
- Patients received a step-up dose of 5 mg on Day 1, 25 mg on Day 8, and the first treatment dose of 200 mg on Day 15 of LYNOZYFIC by intravenous infusion.
- Then, patients received 200 mg of LYNOZYFIC weekly from Week 4 to Week 13, followed by 200 mg every other week thereafter.
- After at least 24 weeks, the Phase 2 patients who achieved a very good partial response (VGPR) or greater received 200 mg of LYNOZYFIC every 4 weeks.
- Patients were treated until disease progression or unacceptable toxicity.
- The efficacy population included 80 patients who had received at least four prior lines of therapy. The median age was 71 (range: 37 to 83) years with 30% of patients 75 years or older; 64% were male and 36% were female; 69% were White, 14% were Black or African American, 13% were Asian, and 2.5% were Hispanic/Latino.
- The International Staging System (ISS) at study entry was Stage I in 39%, Stage II in 36%, and Stage III in 19%. High-risk cytogenetics (presence of del(17p), t(4;14) and t(14;16)) were present in 40% of patients. Eighteen percent of patients had extramedullary disease at baseline.
- The median number of prior lines of therapy was 5 (range: 4 to 13); 83% of patients were refractory to the last line of therapy.
- Sixty-five percent of patients received prior stem cell transplantation.
- Seventy-nine percent of patients were triple-class refractory (refractory to a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody). Thirteen percent of patients were previously treated with a BCMA antibody-drug conjugate.
- Efficacy was established based on objective response rate (ORR) as determined by blinded independent review committee (IRC), as measured using the International Myeloma Working Group (IMWG) criteria.
- The median time to first response was 0.95 months (range: 0.5 to 6 months). With a median follow-up of 11.3 months among responders, the estimated duration of response (DOR) rate was 89% (95% CI: 77, 95) at 9 months and 72% (95% CI: 54, 84) at 12 months.
Efficacy table
How Supplied
LYNOZYFIC (linvoseltamab-gcpt) injection is a clear to slightly opalescent, colorless to pale yellow solution in a single-dose vial. It is supplied as provided in Table:
Storage
- Store unopened vial in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.
- Do not freeze or shake.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Cytokine Release Syndrome (CRS)
- Advise patients that they should be hospitalized for 24 hours after administration of the first and second step-up doses of LYNOZYFIC.
- Inform patients of the risk of CRS, and discuss the signs and symptoms associated with CRS, including fever, chills, hypoxia, tachycardia, and hypotension.
- Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.
Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome
- Discuss the signs and symptoms associated with neurologic toxicity, including ICANS, including confusion, depressed level of consciousness, and lethargy.
- Advise patients to immediately contact their healthcare provider if they experience any signs or symptoms of neurologic toxicity.
- Advise patients to refrain from driving, or operating heavy or potentially dangerous machinery, for 48 hours after completion of each of the step-up doses or if they experience new onset of neurologic toxicity symptoms until the symptoms resolve.
LYNOZYFIC REMS
- LYNOZYFIC is available only through a restricted program called the LYNOZYFIC REMS.
- Inform patients that they will be given a Patient Wallet Card that they should carry with them at all times and show to all of their healthcare providers.
- This card describes symptoms of CRS and neurologic toxicity, including ICANS which, if experienced, should prompt the patient to seek immediate medical attention.
Infections
- Advise patients of the risk of serious infections. Instruct patients to immediately report infection-related signs or symptoms of infection (e.g., fever, chills, weakness).
Neutropenia Discuss the signs and symptoms associated with neutropenia and febrile neutropenia.
Hepatotoxicity Advise patients that liver enzymes elevations may occur and that they should report symptoms that may indicate liver toxicity, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
Embryo-Fetal Toxicity
- Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
- Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant.
- Advise females of reproductive potential to use effective contraception during treatment with LYNOZYFIC and for 3 months after the last dose.
Lactation Advise women not to breastfeed during treatment with LYNOZYFIC and for 3 months after the last dose
Precautions with Alcohol
Alcohol-Linvoseltamab-gcpt interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
LYNOZYFIC™ (lin-oh-ZI-fik)
Look-Alike Drug Names
There is limited information regarding Linvoseltamab-gcpt Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.