Linvoseltamab-gcpt (Monograph)

Brand name: Lynozyfic
Drug class: Antineoplastic Agents

Introduction

Linvoseltamab-gcpt, a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, is an antineoplastic agent.

Uses for Linvoseltamab-gcpt

Linvoseltamab-gcpt has the following uses:

Linvoseltamab-gcpt 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).

Linvoseltamab-gcpt Dosage and Administration

General

Linvoseltamab-gcpt is available in the following dosage form(s) and strength(s):

Injection:

• 5 mg/2.5 mL (2 mg/mL) single-dose vial

• 200 mg/10 mL (20 mg/mL) single-dose vial

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Premedicate to reduce the risk of CRS and infusion-related reactions (IRR).

• Administer only as an IV infusion after dilution in 0.9% sodium chloride injection.

• Administer by a healthcare provider with immediate access to emergency equipment and appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS), infusion-related reactions (IRR), and neurologic toxicity, including ICANS.

• The recommended dosage of linvoseltamab-gcpt is presented in the table below. Weekly doses should be at least 5 days apart. Biweekly doses should be at least 10 days apart. Every 4-week doses should be at least 24 days apart.

• Patients should be hospitalized for 24 hours after administration of the first step-up dose and for 24 hours after administration of the second step-up dose.

• See Full Prescribing Information for instructions on preparation and administration, and dosage modification recommendations for adverse effects.

Cautions for Linvoseltamab-gcpt

Contraindications

None.

Warnings/Precautions

Cytokine Release Syndrome (CRS)

Linvoseltamab-gcpt can cause cytokine release syndrome (CRS), which can be serious or life-threatening.

In the LINKER-MM1 study, CRS occurred in 46% (54/117) of patients who received linvoseltamab-gcpt 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 linvoseltamab-gcpt, 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 linvoseltamab-gcpt 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 linvoseltamab-gcpt until CRS resolves and modify the next dose or permanently discontinue linvoseltamab-gcpt 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 linvoseltamab-gcpt based on severity of reaction.

Linvoseltamab-gcpt is available only through a restricted program under a REMS.

Neurologic Toxicity, Including Immune Effector Cell-associated Neurotoxicity Syndrome

Linvoseltamab-gcpt 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 linvoseltamab-gcpt 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 linvoseltamab-gcpt. 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 linvoseltamab-gcpt until ICANS resolves and modify the next dose or permanently discontinue linvoseltamab-gcpt 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 linvoseltamab-gcpt 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.

Linvoseltamab-gcpt REMS

Linvoseltamab-gcpt is available only through a restricted program under a REMS called the linvoseltamab-gcpt REMS because of the risks of CRS and neurologic toxicity, including ICANS.

Notable requirements of the linvoseltamab-gcpt REMS include the following:

• Prescribers must be certified with the program by enrolling and completing training.

• Prescribers must counsel patients receiving linvoseltamab-gcpt about the risk of CRS and neurologic toxicity, including ICANS, and provide patients with linvoseltamab-gcpt Patient Wallet Card.

• Pharmacies and healthcare settings that dispense linvoseltamab-gcpt must be certified with the linvoseltamab-gcpt REMS program and must verify prescribers are certified through the linvoseltamab-gcpt REMS program.

• Wholesalers and distributors must only distribute linvoseltamab-gcpt to certified pharmacies or healthcare settings.

Further information about the linvoseltamab-gcpt REMS program is available at [Web] or by telephone at 1-855-212-6391.

Infections

Linvoseltamab-gcpt can cause serious, life-threatening, or fatal infections.

In patients who received linvoseltamab-gcpt 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 linvoseltamab-gcpt.

Monitor patients for signs and symptoms of infection and immunoglobulin levels prior to and during treatment with linvoseltamab-gcpt and treat appropriately. Administer prophylactic antimicrobials, antibiotics, antifungals, antivirals, vaccines, and subcutaneous or IV immunoglobulin (IVIG) according to guidelines, including prophylaxis for PJP and herpes viruses.

Withhold linvoseltamab-gcpt or consider permanent discontinuation of linvoseltamab-gcpt based on severity of the infection.

Neutropenia

Linvoseltamab-gcpt can cause neutropenia and febrile neutropenia.

In patients who received linvoseltamab-gcpt 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 linvoseltamab-gcpt based on severity.

Hepatotoxicity

Linvoseltamab-gcpt 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 linvoseltamab-gcpt or consider permanent discontinuation of linvoseltamab-gcpt based on severity.

Embryo-fetal Toxicity

Based on its mechanism of action, linvoseltamab-gcpt 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 linvoseltamab-gcpt and for 3 months after the last dose.

Specific Populations

Pregnancy

Based on the mechanism of action, linvoseltamab-gcpt may cause fetal harm when administered to a pregnant woman. There are no available data on the use of linvoseltamab-gcpt in pregnant women to evaluate for a drug associated risk. No animal reproductive or developmental toxicity studies have been conducted with linvoseltamab-gcpt.

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.

Linvoseltamab-gcpt is associated with hypogammaglobulinemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with linvoseltamab-gcpt 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.

Lactation

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 linvoseltamab-gcpt and for 3 months after the last dose.

Females and Males of Reproductive Potential

Linvoseltamab-gcpt may cause fetal harm when administered to a pregnant woman.

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with linvoseltamab-gcpt.

Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of linvoseltamab-gcpt.

Pediatric Use

The safety and effectiveness of linvoseltamab-gcpt have not been established in pediatric patients.

Geriatric Use

Of the 117 patients with relapsed or refractory multiple myeloma who received linvoseltamab-gcpt, 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.

Common Adverse Effects

The most common adverse reactions (≥20%) are musculoskeletal pain, cytokine release syndrome, cough, upper respiratory tract infection, diarrhea, fatigue, pneumonia, nausea, headache, and dyspnea.

The most common Grade 3 or 4 laboratory abnormalities (≥30%) are decreased lymphocyte count, decreased neutrophil count, decreased hemoglobin, and decreased white blood cell count.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

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.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Advise patients that they should be hospitalized for 24 hours after administration of the first and second step-up doses of linvoseltamab-gcpt.

• 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.

• Linvoseltamab-gcpt is available only through a restricted program called the linvoseltamab-gcpt 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.

• 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).

• Discuss the signs and symptoms associated with neutropenia and febrile neutropenia.

• 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.

• 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 linvoseltamab-gcpt and for 3 months after the last dose.

• Advise women not to breastfeed during treatment with linvoseltamab-gcpt and for 3 months after the last dose.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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