Linvoseltamab

Linvoseltamab is a recombinant human immunoglobulin G4 (IgG4)-based bispecific antibody produced in Chinese hamster ovary cells. One arm binds CD3, a T-cell antigen of the T-cell receptor complex; the other binds B-cell maturation antigen (BCMA), which is found on malignant multiple myeloma B-lineage cells and on late-stage B cells and plasma cells.

Mechanism of Action

• T-cell redirection: binding both targets at once forms a synapse between the T cell and the BCMA-expressing cell. The T cell is activated and mounts a polyclonal cytotoxic response that lyses the target cells, including malignant myeloma cells.
• Independent of antigen presentation: the effect does not depend on T-cell receptor specificity or on MHC class I molecules on antigen-presenting cells.
• Cytokine release: circulating IL-2, IL-6 and interferon-gamma rise transiently, mainly during step-up dosing and the first 200 mg dose. The peak is generally 4 hours after each infusion, and levels return to baseline before the next dose; release is limited after later doses (see Special Instructions).
• Immunogenicity: anti-linvoseltamab antibodies appeared during treatment in 1.0% (2 of 192) of patients in the LINKER-MM1 study, followed for up to 30 months, with no evidence of an effect on pharmacokinetics or safety; data are still limited.

Pharmacokinetics

• Exposure: given intravenously; pharmacokinetics were characterised across 1 mg to 800 mg. At the 200 mg dose, model-based geometric mean peak levels (Cmax) were 124 mg/L at Week 14 of weekly dosing, 97.9 mg/L at Week 24 of every-other-week dosing and 64.8 mg/L at Week 48 of every-4-week dosing; trough levels fell over the same periods from 61.8 to 30.2 to 6.3 mg/L.
• Distribution: volume of distribution at steady state about 7.05 L.
• Metabolism: expected to be broken down into small peptides by catabolic pathways.
• Elimination: two parallel processes, a linear non-saturable catabolic pathway and a non-linear, saturable target-mediated pathway. After the last 200 mg dose, the median time to fall to the lower limit of quantification (0.078 mg/L) was 20.1 weeks after weekly dosing, 18.9 weeks after every-other-week dosing and 15.6 weeks after every-4-week dosing.
• Special populations: no clinically relevant difference in exposure by age (37–91 years), sex or race (White, Asian, Black), or between normal kidney function and mild, moderate or severe renal impairment (CrCL 15 mL/min or more). It has not been studied in moderate or severe hepatic impairment.

Linvoseltamab is indicated as monotherapy for adults with relapsed and refractory multiple myeloma who:

• have received at least 3 prior therapies, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody, and
• have demonstrated disease progression on the last therapy.

There is no relevant use in children for the treatment of multiple myeloma.

• Hypersensitivity to linvoseltamab or to any of the excipients.

The most frequent reactions were musculoskeletal pain (52%), cytokine release syndrome (46%), neutropenia (43%), cough (42%), diarrhoea (39%), anaemia (38%), fatigue (36%), pneumonia (32%) and upper respiratory tract infection (30%). Serious reactions occurred in 75% of patients; the most frequent were cytokine release syndrome (27%), pneumonia (13%), COVID-19 (7%) and acute kidney injury (5%). Permanent discontinuation because of reactions occurred in 19% of patients, most often for COVID-19 pneumonia, Pneumocystis jirovecii pneumonia and pseudomonal sepsis (1.7% each). The frequencies below come from 117 patients with relapsed or refractory multiple myeloma who received the recommended step-up and full doses (median exposure 53 weeks).

Very common (≥1/10): pneumonia, COVID-19, upper respiratory tract infection, urinary tract infection, neutropenia, thrombocytopenia, anaemia, lymphopenia, cytokine release syndrome, hypogammaglobulinaemia, decreased appetite, hyperuricaemia, hypophosphataemia, insomnia, encephalopathy (excluding ICANS), musculoskeletal pain, pain, motor dysfunction, headache, hypertension, cough, dyspnoea, nasal congestion, diarrhoea, constipation, nausea, vomiting, rash, oedema, pyrexia, fatigue, chills, increased blood creatinine and weight loss.

Common (≥1/100 to <1/10): sepsis, cytomegalovirus infection, febrile neutropenia, immune effector cell-associated neurotoxicity syndrome (ICANS), increased transaminases and infusion-related reactions.

Uncommon (≥1/1,000 to <1/100): progressive multifocal leukoencephalopathy.

The important serious reactions are cytokine release syndrome, ICANS and other neurological toxicity, serious or fatal infections (including progressive multifocal leukoencephalopathy), neutropenia and hypogammaglobulinaemia.

No drug interaction studies have been done. The transient rise in cytokines may suppress CYP450 enzyme activity. The risk of interaction is highest during step-up dosing and the first full 200 mg dose in patients taking CYP450 substrates. Monitor for toxicity, or for the concentrations, of medicines that are CYP substrates where small changes in concentration may cause serious reactions (for example ciclosporin, phenytoin, sirolimus and warfarin).

Treatment must be started and supervised by physicians experienced in treating multiple myeloma. Linvoseltamab must be given by a healthcare professional with immediate access to emergency equipment and appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS), infusion-related reactions (IRR) or immune effector cell-associated neurotoxicity syndrome (ICANS). Before treatment, check a complete blood count, rule out any active infection, and rule out pregnancy in women of childbearing potential. It is for intravenous use only, through a dedicated infusion line, and a 0.2-micron to 5-micron polyethersulfone (PES) filter is recommended. It must not be given as an intravenous push or bolus.

Pretreatment and Prophylaxis

Pretreatment medicines reduce the risk of CRS and IRR and are given until two full doses have been tolerated without CRS or IRR:

• Step-up doses and the first 200 mg dose: dexamethasone 40 mg intravenously 1 to 3 hours before the infusion; an antihistamine (for example diphenhydramine 25 mg orally or intravenously) and paracetamol (for example 500 to 1,000 mg orally), both 30 to 60 minutes before.
• Second 200 mg dose: the same antihistamine and paracetamol, with dexamethasone 40 mg intravenously in patients who had CRS or IRR with the previous infusion, or 10 mg intravenously in those who did not.
• Later 200 mg doses: if CRS or IRR occurred with the previous infusion, repeat the pretreatment used for the second 200 mg dose. Once a 200 mg dose is tolerated without CRS or IRR, step dexamethasone down from 40 mg to 10 mg; if the previous dose used 10 mg, stop all pretreatment.
• Prophylaxis: treatment per local guidelines against Pneumocystis jirovecii pneumonia and herpes simplex and zoster viruses is recommended for all patients; antimicrobial and antiviral prophylaxis, including against cytomegalovirus, should be considered per local guidelines.

Recommended Dose

• Step-up schedule: Week 1 Day 1, 5 mg (step-up dose 1); Week 2 Day 1, 25 mg (step-up dose 2); Week 3 Day 1, the first full dose of 200 mg.
• Weekly: 200 mg from Week 4 to Week 13 (10 doses).
• Every 2 weeks: 200 mg at Week 14 and every 2 weeks thereafter.
• Every 4 weeks: for patients who have had at least 17 doses of 200 mg and a confirmed response of very good partial response or better (IMWG criteria) at or after Week 24, 200 mg at Week 24 or after and every 4 weeks thereafter. Patients who have not reached this response at Week 24 continue every 2 weeks.
• Weekly doses must be at least 5 days apart, and each dose is given only if the previous one was tolerated. Treatment continues until disease progression or unacceptable toxicity.

Infusion Time and Monitoring

• Infusion: step-up doses 1 and 2 and the first full dose are given over 4 hours. If the first full dose is tolerated, the next full dose can run over 1 hour and later full doses over 30 minutes.
• First step-up dose: all patients are monitored for CRS, IRR and ICANS during the infusion and for 24 hours after it, and are told to stay with a caregiver close to the qualified treatment centre for those 24 hours.
• Second step-up dose: if CRS, IRR, a neurologic reaction or any grade 2 or higher event occurred with the first step-up dose, the patient is monitored during the infusion and for 24 hours after it, and stays with a caregiver close to the treatment centre for those 24 hours. The 24-hour stay with a caregiver also applies after a later dose if grade 2 CRS or ICANS occurred with the previous one.
• Grade 3 events: after a first grade 3 CRS or ICANS event, the patient is hospitalised for 24 hours after the next dose.

Management of Cytokine Release Syndrome

If CRS is suspected, treat other causes of fever, hypoxia and hypotension, withhold linvoseltamab until CRS resolves, and give supportive care (intensive care for severe or life-threatening CRS).

• Grade 1 (fever 38 °C or above): withhold; supportive care; consider anticytokine therapy and/or corticosteroids.
• Grade 2 (fever with hypotension that responds to fluids and/or hypoxia needing low-flow oxygen): withhold; if there is no improvement within 4 hours, give anticytokine therapy; give corticosteroids if organs are affected.
• Grade 3 (hypotension needing a vasopressor and/or hypoxia needing high-flow oxygen): withhold; supportive care including intensive care, anticytokine therapy and corticosteroids; stop permanently if grade 3 CRS recurs with later infusions.
• Grade 4 (multiple vasopressors and/or oxygen under positive pressure): stop permanently and manage as grade 3.
• AST or ALT above 5 times ULN with CRS (grade 3 or less): withhold until CRS resolves and AST/ALT fall below 3 times ULN (normal baseline) or to 1.5 to 3 times baseline (abnormal baseline).
• The SmPC gives tocilizumab 8 mg/kg over 1 hour (maximum 800 mg) and dexamethasone 20 mg a day in divided doses, or equivalent, as examples.

Management of ICANS

At the first sign, withhold linvoseltamab, consider consulting a neurologist and other specialists, rule out other causes and give supportive care (intensive care if severe or life-threatening). Consider non-sedating anti-seizure medicines for seizure prophylaxis.

• Grade 1 (ICE score 7–9, or awakens spontaneously): withhold until neurologic symptoms resolve or return to baseline.
• Grade 2 (ICE score 3–6, or awakens to voice): withhold; dexamethasone 10 mg intravenously every 6 hours until grade 1 or lower, then taper.
• Grade 3 (ICE score 0–2, awakens only to touch, seizures that stop rapidly, or focal oedema on imaging): withhold until symptoms resolve or return to baseline; consider neurology evaluation; dexamethasone as for grade 2; stop permanently for recurrent grade 3.
• Grade 4 (unarousable, stupor or coma, prolonged or repeated seizures, deep focal motor weakness, or raised intracranial pressure or cerebral oedema): stop permanently; consider neurology evaluation; dexamethasone as for grade 2.
• ICE is the Immune Effector Cell-Associated Encephalopathy assessment.

Management of Other Reactions

• Infusion-related reactions: grade 2, stop the infusion and treat; the remaining infusion may resume at grade 1 or baseline (total infusion time not over 6 hours). Grade 3, stop and treat; may resume at grade 1 or baseline; stop permanently if grade 3 recurs. Grade 4, stop permanently.
• Other neurologic events (not ICANS): grade 2 or 3, withhold until grade 1 or baseline; grade 4, consider permanent discontinuation.
• Infections: grade 3, withhold in active infection until it improves to grade 1 or less; grade 4, consider permanent discontinuation.
• Other non-haematologic reactions: grade 3, withhold until grade 1 or baseline; grade 4, consider permanent discontinuation.
• Blood counts: withhold for platelets below 50,000/µL with bleeding or below 25,000/µL (until 25,000/µL or higher and no bleeding); for neutrophils below 1.0 × 10⁹/L with a grade 2 or higher infection, or below 0.5 × 10⁹/L (until 0.5 × 10⁹/L or higher and the infection is grade 1 or less); and for febrile neutropenia (until neutrophils exceed 1.0 × 10⁹/L and fever resolves).
• Restarting: after a reaction, the restart dose depends on the last dose given, the type and grade of the reaction and the days since that dose (SmPC Table 6). Doses must be at least 5 days apart, must not exceed the recommended doses, and pretreatment is repeated.

Missed Doses

If a dose is missed for a reason not covered above, give it as soon as possible, with pretreatment, as follows:

• Last dose 5 mg: 14 days or less, give 25 mg; more than 14 days, restart step-up dosing from 5 mg.
• Last dose 25 mg: 14 days or less, give 200 mg; over 14 and up to 28 days, restart step-up from 25 mg; over 28 days, restart from 5 mg.
• Last dose 200 mg: 49 days or less, give 200 mg; over 49 days, restart step-up from 5 mg.
• Consider the benefit and risk of restarting in patients who need a delay of more than 30 days.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild (CrCL ≥60 to <90 mL/min), moderate (≥30 to <60 mL/min) or severe (≥15 to <30 mL/min) impairment.
• Hepatic impairment: no adjustment in mild impairment (total bilirubin above ULN to 1.5 times ULN, or AST above ULN). It has not been studied in moderate or severe impairment, and no dose can be recommended.
• Children and adolescents: no relevant use in multiple myeloma.

Traceability

To improve the traceability of biological medicines, the name and batch number of the product given must be clearly recorded.

Cytokine Release Syndrome

CRS can be serious or life-threatening. Signs include fever, chills, hypoxia, tachycardia and hypotension. The pretreatment medicines and the step-up schedule reduce the risk. All patients are monitored for CRS during and after infusion and told to seek medical attention immediately if signs or symptoms occur. At the first sign, the patient is evaluated at once for hospitalisation, managed according to current practice guidelines with supportive care, and linvoseltamab is withheld until CRS resolves; the next dose is then modified, or treatment is stopped, according to severity.

Infusion-Related Reactions

IRR can be clinically indistinguishable from CRS. Interrupt or slow the infusion, or stop permanently, according to severity.

Neurotoxicity Including ICANS

ICANS has been reported. Signs may include aphasia, cerebral oedema, confusion, depressed level of consciousness, disorientation, encephalopathy and seizure. All patients are monitored for ICANS during treatment and told to seek medical attention immediately if signs or symptoms occur at any time. At the first sign, the patient is evaluated at once and given supportive care, and linvoseltamab is withheld until ICANS resolves, after which the next dose is modified or treatment is stopped according to severity. Patients are at risk of confusion and depressed consciousness and must not drive or operate heavy or potentially dangerous machinery for 24 hours after each step-up dose, or when any new neurological symptom appears, until it resolves.

Infections

Serious, life-threatening and fatal infections have been reported, and progressive multifocal leukoencephalopathy has occurred. Do not start treatment in patients with active infection. Monitor for signs of infection before and during treatment, give prophylaxis per local guidelines (Pneumocystis jirovecii pneumonia, herpes simplex and zoster, and cytomegalovirus as appropriate), and vaccinate against seasonal influenza, COVID-19, Haemophilus influenzae and pneumococcus per local guidelines. Withhold, or consider stopping, according to severity.

Hypogammaglobulinaemia

Check immunoglobulin levels before and during treatment. Subcutaneous or intravenous immunoglobulin may be considered if IgG falls below 400 mg/dL, with infection precautions and antimicrobial prophylaxis per local guidelines.

Neutropenia

Check a complete blood count at baseline and periodically. Give supportive care per local guidelines, monitor patients with neutropenia for signs of infection, and withhold according to severity.

Vaccines

The immune response to vaccines may be reduced. The safety of live viral vaccines during or after treatment has not been studied; give them only at least 4 weeks before treatment starts or after immune recovery following treatment.

Patient Card

The prescriber must discuss the risks of treatment with the patient. Patients receive a Patient Card, carry it at all times and show it to every healthcare professional. It describes the common signs and symptoms of CRS and ICANS, when to seek immediate medical attention, monitoring instructions and the prescribing physician’s contact details.

Pregnancy, Breastfeeding and Fertility

• Pregnancy and contraception: check pregnancy status before treatment. Patients of childbearing potential should use effective contraception during treatment and for at least 5 months after the last dose. There are no data in pregnant women and no animal reproductive studies. T-cell activation and cytokine release may compromise a pregnancy, and human IgG crosses the placenta, so linvoseltamab may cause foetal harm, including B-cell and plasma cell lymphocytopenia. It is not recommended in pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: there is no information on its presence in human milk, but human IgG can be secreted in milk. Stop breastfeeding during treatment and for at least 5 months after the last dose.
• Fertility: there are no human data.

Polysorbate 80

The medicine contains polysorbate 80 (1 mg/mL), which may cause allergic reactions.

Effect on Driving

Linvoseltamab has a major influence on the ability to drive and use machines because of the risk of ICANS (see Neurotoxicity Including ICANS).

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. Cold-chain handling applies to transport and supply. For storage after dilution, see Shelf Life. Supplied as a single vial per pack: 2.5 mL of concentrate in a 5 mL Type 1 clear glass vial (5 mg), or 10 mL in a 20 mL Type 1 clear glass vial (200 mg).

• Unopened vial: 30 months.
• Diluted infusion solution: give immediately once prepared. Chemical and physical in-use stability has been shown for up to 8 hours at room temperature (20–25 °C) or up to 48 hours at 2–8 °C, from preparation to the start of the infusion. From a microbiological point of view it should be used immediately; otherwise in-use times and conditions are the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless dilution took place in controlled and validated aseptic conditions. Protect the infusion solution from light during storage.

Prescription only (Rx): a medicinal product subject to restricted medical prescription (Annex II B), started and supervised by a physician experienced in treating multiple myeloma. It is given as an intravenous infusion by a healthcare professional with emergency equipment at hand, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions at 2–8 °C.