linvoseltamab

LIN-voe-SEL-ta-mab

Therapeutic Classification: antineoplastics

Pharmacologic Classification: T-cell engagers, monoclonal antibodies

High Alert

Relapsed or refractory multiple myeloma in patients who have received ≥4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Acts as a T-cell engager, binding to the CD3 receptor expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of multiple myeloma cells, resulting in facilitated lysis of malignant cells.

Therapeutic effects:

Slowed progression of multiple myeloma.

Absorption: IV administration results in complete bioavailability.

Distribution: Minimally distributed to tissues.

Metabolism/Excretion: Metabolized into small peptides by catabolic pathways.

Half-Life: Unknown.

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
IV	rapid	end of infusion	unknown

Contraindicated in:

OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: edema, hypertension

Derm: rash

EENT: nasal congestion

F and E: hypophosphatemia

GI: ↓appetite, ↑liver enzymes, constipation, diarrhea, nausea, vomiting, hyperbilirubinemia

GU: ↑serum creatinine

Hemat: anemia, leukopenia, lymphopenia, neutropenia, thrombocytopenia

MS: pain

Neuro: ↓consciousness, encephalopathy, fatigue, headache, IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME (ICANS), insomnia, peripheral neuropathy, confusion, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Resp: cough, dyspnea

Misc: cytokine release syndrome (CRS), fever, hypogammaglobulinemia, INFECTION, INFUSION-RELATED REACTIONS

Drug-drug:

May suppress activity of CYP450 drug-metabolizing enzymes (especially within 14 days after 1st dose and during/after onset of cytokine release syndrome); careful monitoring of CYP450 substrates is recommended.

IV (Adults ): Day 1 (step-up dose 1): 5 mg as a single dose; Day 8 (step-up dose 2): 25 mg as a single dose; Day 15 (1st treatment dose): 200 mg as a single dose; Weekly dosing schedule: 200 mg administered 1 wk after 1st treatment dose and then once weekly from Wk 4 to Wk 13 (total of 10 treatment doses); Biweekly dosing schedule: 200 mg starting at Wk 14 and then every 2 wk. For patients who have achieved and maintained a very good partial response or better at Wk 24 AND have received ≥17 doses of 200 mg, administer 200 mg every 4 wk starting at Wk 24 or after. Continue until disease progression or unacceptable toxicity.

Solution for injection: 2 mg/mL; 20 mg/mL

Monitor for signs/symptoms of CRS (pyrexia, chills, hypoxia, tachycardia, hypotension) after infusion. If Grade 1 CRS (temperature ≥100.4ºF) occurs, hold therapy and treat as indicated until resolved; resume per restarting recommendations. If Grade 2 CRS (temperature ≥100.4ºF with fluid responsive hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen) occurs, hold therapy and treat as indicated until resolved; resume per dose delay restarting recommendations and consider ↓ infusion rate up to 50% (no more than 6 hr total). ↑ infusion rate on subsequent infusions if tolerated; monitor near health care facility or hospitalize for 24 hr following this dose. If Grade 3 CRS (temperature ≥100.4ºF with hypotension requiring vasopressor [with or without vasopressin] and/or hypoxia requiring high-flow oxygen) occurs, hold therapy and treat as indicated until resolved; resume per dose delay restarting recommendations and consider ↓ infusion rate up to 50% (no more than 6 hr total). Hospitalize for 24 hr following this dose; if tolerated, continue with next recommended dose; if that full dose is tolerated, ↑ infusion rate to rate prior to adverse reaction. If Grade 4 CRS (temperature ≥100.4ºF with hypotension requiring multiple vasopressors [without vasopressin] and/or hypoxia requiring oxygen delivery through continuous or bilevel positive pressure or intubation) occurs, or Grade 3 CRS recurs, permanently discontinue linvoseltamab and treat as indicated.
Monitor for infusion-related reactions, which may be clinically indistinguishable from manifestations of CRS. If Grade 2 reaction occurs, hold therapy and treat as indicated; may resume dose (total time not to exceed 6 hr) if resolved to Grade ≤1. Consider ↓ infusion rate up to 50% when resuming; if tolerated, rate may be ↑ with subsequent doses. If Grade 3 reaction occurs, hold therapy and treat as indicated; resume if resolved to Grade ≤1 per dose delay restarting recommendations and ↓ infusion rate up to 50% (no more than 6 hr total). If tolerated, continue with next dose of the dose delay recommendation at ↓ infusion rate. May ↑ rate as tolerated. If Grade 3 recurs or Grade 4 reaction occurs, permanently discontinue linvoseltamab and treat as indicated.
Monitor for signs/symptoms of neurologic toxicity, including encephalopathy. If Grade 2 or Grade 3 neurologic reaction (excluding ICANS) occurs, hold therapy until resolved to Grade ≤1; resume according to dose delay recommendation. If Grade 3 recurs or Grade 4 neurologic reaction (excluding ICANS) occurs, permanently discontinue linvoseltamab and treat as indicated.
Monitor for signs/symptoms of ICANS (confusion, ↓ consciousness, lethargy). At 1st suspected sign of ICANS or other neurologic toxicity, consider consulting neurology and other specialties and rule out other causes of neurologic symptoms. Treat as indicated including need for intensive care. If Grade 1 ICANS (ICE score 7–9 or awakens spontaneously) occurs, hold therapy until resolved or at baseline, and treat as per current practice guidelines ; consider providing nonsedating seizure prophylaxis. If Grade 2 ICANS (ICE score 3–6 or awakens to voice) occurs, hold therapy until resolved or at baseline; treat as per Grade 1 and with dexamethasone 10 mg IV every 6 hr continuing until resolved to Grade ≤1; then taper. Monitor near health care facility or hospitalize for 24 hr following next dose. If Grade 3 ICANS (ICE score 0–2 or awakens only to tactile stimulus; or any clinical seizure that resolves rapidly, or nonconvulsive seizure on EEG that resolves with intervention; or ↑ intracranial pressure or focal edema on neuroimaging) occurs, hold therapy until resolved or at baseline; treat as per Grade 2 and resume per dose delay restarting recommendations, hospitalizing for 24 hr following this dose. If tolerated, continue with next dose per restarting recommendations. If Grade 3 ICANS recurs or Grade 4 ICANS (ICE score 0 or arouses to vigorous/repetitive tactile stimuli, or stupor/coma; or life-threatening seizure >5 min, or repetitive clinical or electrical seizures without return to baseline; or deep focal motor weakness; or ↑ intracranial pressure/cerebral edema) occurs, permanently discontinue linvoseltamab and treat as per initial Grade 3.
Monitor for signs/symptoms of infection. Administer prophylactic antimicrobials, vaccines, and IV immunoglobulin as guidelines indicate, including prophylaxis for Pneumocystis jiroveci pneumonia and herpes viruses. If Grades 2 or 3 active infection occurs, hold therapy until resolved to Grade ≤1 and resume per dose delay restarting recommendations. If Grade 4 infection occurs, hold therapy until resolved to Grade ≤1 and resume per dose delay restarting recommendations or consider permanent discontinuation of linvoseltamab.

Lab Test Considerations:

Verify negative pregnancy test prior to initiating therapy.
Monitor immunoglobulin levels prior to and during therapy.
Monitor AST/ALT and bilirubin at baseline and during therapy as indicated. If AST/ALT >5 times upper limit of normal (ULN) associated with CRS Grade ≤3 occurs, hold therapy until CRS resolved and AST/ALT <3 times ULN (if baseline normal) or 1.5–3 times baseline (if baseline abnormal) and treat as indicated. No dose change if CRS symptoms resolved and transaminases trend toward baseline within 7 days; if this does not occur, see infusion rate information by CRS Grade and ↓ the dose as follows: if last dose was 5 mg, administer 2.5 mg; if last dose was 25 mg, restart step-up dosing from 5 mg; if last dose was 200 mg, refer to dose delay restarting recommendations based on time since last dose.
Monitor CBC at baseline and periodically during therapy. If platelets <50,000/mcL with bleeding or <25,000/mcL occurs, hold until ≥25,000/mcL and no evidence of bleeding. If ANC <1 × 10⁹/L with Grade ≥2 infection or <0.5 × 10⁹/L occurs, hold therapy until ≥0.5 × 10⁹/L. If febrile neutropenia occurs, hold therapy until >1 × 10⁹/L and fever resolved. If hemoglobin <8 g/dL occurs, hold therapy until ≥8 g/dL. For each adverse reaction above, resume linvoseltamab per dose delay restarting recommendations.

REMS: Linvoseltamab is available only through the LYNOZYFIC REMS. Pharmacies and health care settings that dispense must be certified and verify prescriber certification through the REMS program. For information, call or go to: 1-855-212-6391; lynozyficREMS.com.
Pretreatment: Administer the following medications or equivalents before step-up doses 1 and 2, 1st and 2nd treatment doses, and as indicated for subsequent doses to ↓ risk of CRS and infusion-related reaction. Give acetaminophen 650–1000 mg PO and diphenhydramine 25 mg PO/IV 30–60 min prior to infusion. Also give dexamethasone 40 mg IV 1–3 hr before step-up dose 1 and 2 and before 1st full treatment dose. Once therapy is tolerated without CRS or infusion-related reaction, administer dexamethasone 10 mg IV before subsequent doses.
Immediate access to emergency equipment and appropriate medical support to manage severe reactions during infusion must be available.
Patient must be hospitalized for 24 hr after infusion of step-up dose 1 and for 24 hr after step-up dose 2.
Restarting after Dose Delay: If last dose was 5 mg with ≤14 day delay, administer 25 mg for next dose; if >14 days delay, restart step-up dosing from 5 mg. If last dose was 25 mg with ≤14 day delay, administer 200 mg for next dose; if >14–≤28 days delay, restart step-up dosing from 25 mg; if >28 days delay, restart step-up dosing from 5 mg. If last dose was 200 mg with ≤49 day delay, administer 200 mg for next dose, if >49 days delay, restart step-up dosing from 5 mg. Consider benefit-risk of restarting if delay >30 days.

IV Administration:

Intermittent Infusion: Diluent: Withdraw the amount of solution for dose needed from vial, as indicated, and transfer into a polyvinyl chloride (PVC) or polyolefin-only infusion bag of 0.9% NaCl according to the following directions: for 2.5-mg dose, add 1.25 mL solution from a 5-mg/2.5 mL vial to 50 mL of 0.9% NaCl; for 5-mg dose, add 2.5 mL from a 5-mg/2.5 mL vial to 50 or 100 mL of 0.9% NaCl; for 25-mg dose, add 12.5 mL from a 5-mg/2.5 mL vial to 50 or 100 mL of 0.9% NaCl; for 200-mg dose, add 10 mL from a 200-mg/10 mL vial to 50 or 100 mL of 0.9% NaCl. Mix by gentle inversion; do not shake. Solution is clear to slightly opalescent, colorless to pale yellow. Discard if cloudy, discolored, or contains particulates. If not used immediately, store at room temperature 8 hr or refrigerate 48 hr from dilution to infusion start. Do not freeze. Administer through PVC, polyethylene-lined PVC, or polyurethane tubing with a 0.2- to 5-micron polyethersulfone filter. Prime entire line with diluted solution. Once infusion is complete, flush line with 0.9% NaCl to ensure that the entire contents of infusion bag are administered. Include flush in total infusion time. Rate: Infuse step-up doses 1 and 2 and 1st treatment dose over 4 hr; infuse 2nd treatment dose over 1 hr and subsequent weekly, biweekly, and every-4-wk doses over 30 min.
Y-Site Incompatibility: Do not administer other drugs through same IV line.

Explain purpose and side effects of medication. Advise patient to read Patient Information before starting therapy.
Inform patient that they must be counseled about risk of CRS and neurologic toxicity, including ICANS, and provided with LYNOZYFIC Patient Wallet Card. Advise patient to immediate notify health care provider if signs/symptoms of CRS or neurologic toxicity occur.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other medications.
Advise patient to refrain from driving or operating heavy or potentially dangerous machinery for 48 hr after each step-up dose and in the event of new onset of any neurological symptoms until resolved.
Advise patient of the risk for neutropenia and serious infections and to immediately notify health care provider if fever, chills, or other signs of infection occur.
Inform patient of risk for hepatotoxicity and to notify health care provider if fatigue, anorexia, right upper abdominal pain, dark urine, or jaundice occur.
Rep: May cause fetal harm. Advise women of reproductive potential to notify health care provider if pregnancy is planned or suspected or if breastfeeding. Advise women of reproductive potential to use effective contraception and not to breastfeed during therapy and for 3 mo after last dose.

Slowed progression of multiple myeloma.

Lynozyfic

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