Linvoseltamab

Transient elevation of cytokines may suppress CYP450 enzyme activities. The highest risk of drug interaction is during the step-up dosing regimen and the first full 200 mg dose in patients who are receiving concomitant CYP450 substrates. Monitor for toxicity or concentrations of medicinal products that are CYP substrates where minimal changes in concentration may lead to serious adverse reactions (e.g., cyclosporine, phenytoin, sirolimus, and warfarin).

Linvoseltamab has not been studied in patients with moderate (total bilirubin > 1.5 to 3 × ULN, any AST) or severe (total bilirubin > 3 to 10 × ULN, any AST) hepatic impairment. No dose recommendations can be made for patients with moderate or severe hepatic impairment.

Treatment should not be initiated in patients with active infections. Patients should be monitored for signs and symptoms of infection prior to and during treatment with linvoseltamab and treated appropriately. Prophylactic treatment per local institutional guidelines for Pneumocystis jirovecii pneumonia (PJP) and herpes simplex and zoster viruses is recommended for all patients. Prophylactic antimicrobials and anti-virals, including prophylaxis against CMV, should be administered according to local institutional guidelines. Vaccination for seasonal influenza, COVID-19, Haemophilus influenza, and Pneumococcus should be administered for all patients according to local institutional guidelines.

There are no available data on the use of linvoseltamab in pregnant women. No animal reproductive or developmental toxicity studies have been conducted with linvoseltamab. Linvoseltamab causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, linvoseltamab has the potential to be transferred from the pregnant woman to the developing foetus. Linvoseltamab is not recommended during pregnancy and in women of childbearing potential not using contraception. Based on its mechanism of action, linvoseltamab may cause foetal harm, including B-cell and plasma cell lymphocytopenia, when administered to a pregnant patient.

There is no information regarding the presence of linvoseltamab in human milk, the effects on the breastfed infant, or the effects on milk production. It is known that human IgG can be secreted in human milk. Breastfeeding should be discontinued during treatment with linvoseltamab and for at least 5 months after the last dose due to the potential risk for serious adverse reactions in the breastfed child.

Women of childbearing potential/Contraception

Pregnancy status for patients of childbearing potential should be verified prior to starting treatment with linvoseltamab.

Patients of childbearing potential should use effective contraception during treatment with linvoseltamab and for at least 5 months after the last dose.

Fertility

No human data on the effect of linvoseltamab on fertility are available.

Linvoseltamab has major influence on the ability to drive and use machines.

Due to the potential for ICANS, patients receiving linvoseltamab are at risk of confusion and depressed consciousness. Patients should be instructed to refrain from driving, or operating heavy or potentially dangerous machinery, for 24 hours after completion of each of the step-up treatment doses and in the event of new onset of any neurological symptoms, until symptoms resolve.

Summary of safety profile

The most frequent adverse 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 adverse reactions occurred in 75% of patients who received linvoseltamab. The most frequent serious adverse reactions were cytokine release syndrome (27%), pneumonia (13%), COVID-19 (7%), and acute kidney injury (5%).

Permanent discontinuation of linvoseltamab due to adverse reactions occurred in 19% of patients. The most frequent adverse reactions leading to discontinuation were COVID-19 pneumonia (1.7%), Pneumocystis jirovecii pneumonia (1.7%), and pseudomonal sepsis (1.7%).

Tabulated list of adverse reactions

The safety population described includes 117 patients with relapsed or refractory multiple myeloma who received linvoseltamab at the recommended step-up treatment and full treatment dose. Unless otherwise stated, the frequencies of adverse reactions in the table below are based on all-cause adverse event frequencies identified in 117 patients exposed to linvoseltamab during a median duration of 53 weeks (range 1, 167) in the clinical study.

Adverse reactions observed during the clinical study are listed below by MedDRA system organ class classification and by frequency. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse reactions occurring in patients with multiple myeloma treated with linvoseltamab:

^a Pneumonia includes atypical pneumonia, COVID-19 pneumonia, haemophilus infection,
influenza, metapneumovirus infection, PJP, pneumonia, pneumonia cytomegaloviral, pneumonia fungal, pneumonia influenzal, and pneumonia viral.
^b Upper respiratory tract infection includes acute sinusitis, bronchitis, nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, rhinovirus infection, sinobronchitis, sinusitis, upper respiratory tract infection, and viral upper respiratory tract infection.
^c Urinary tract infection includes cystitis, escherichia urinary tract infection, klebsiella urinary tract infection, urinary tract infection, urinary tract infection bacterial, and urinary tract infection enterococcal, and urinary tract infection staphylococcal.
^d Sepsis includes sepsis, septic shock, pseudomonal sepsis, streptococcal sepsis, escherichia sepsis, and haemophilus sepsis.
^e CMV infection includes cytomegalovirus infection reactivation, cytomegalovirus infection, and cytomegalovirus viraemia and excludes pneumonia cytomegaloviral.
^f Encephalopathy includes agitation, amnesia, aphasia, cognitive disorder, confusional state, delirium, depressed level of consciousness, encephalopathy, memory impairment, mental status changes, mood altered, somnolence, toxic encephalopathy, and excludes ICANS.
^g Pain includes ear pain, flank pain, groin pain, oropharyngeal pain, pain, and toothache.
^h Motor dysfunction includes dysarthria, dysphonia, gait disturbance, muscle spasm, muscular weakness, and tremor.
ⁱ Headache includes headache and migraine.
^j ICANS is based on adjudicated ICANS which were reported with the terms ICANS, depressed level of consciousness, encephalopathy, and toxic encephalopathy.
^k Rash includes dermatitis acneiform, dermatitis contact, drug eruption, erythema, rash, rash erythematous, rash maculo-papular, rash pruritic, and stasis dermatitis.
^l Oedema includes face oedema, lip oedema, localised oedema, oedema, and oedema peripheral.
^m Fatigue includes fatigue, lethargy, and malaise.
ⁿ Infusion related reactions related to IVIG administration are not included.

Description of selected adverse reactions

Cytokine release syndrome

CRS occurred in 46% of patients who received linvoseltamab at the recommended dose, with Grade 1 CRS occurring in 35% of patients, Grade 2 in 10%, and Grade 3 in 0.9%. Thirty-eight percent of all patients had CRS following step-up treatment dose 1; 8% of all patients had an initial CRS event following a subsequent dose. Seventeen percent of patients receiving step-up treatment dose 2 developed CRS after step-up treatment dose 2, 10% of patients receiving the first full treatment dose developed CRS after the first full treatment dose of linvoseltamab, and 3.6% of patients that received the second full treatment dose developed CRS after the second full treatment dose. The Grade 3 case of CRS was reported after the first step-up treatment dose. Nine patients experienced Grade 2 CRS after receiving either step-up treatment dose 1 or step-up treatment dose 2, and three patients experienced Grade 2 CRS with a dose after step-up treatment dose 2. Recurrent CRS occurred in 20% of patients. CRS resolved in all patients, and the median time to onset of CRS from the end of infusion was 11 (range: -1.1 to 184) hours after the most recent dose with a median duration of 16 (range: 1 to 96) hours.

Clinical signs and symptoms of CRS included, but were not limited to, pyrexia, chills, hypoxia, tachycardia, and hypotension.

In the clinical study, 19% of patients received tocilizumab and 11% received corticosteroids for the management of CRS.

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 medicinal products, the rate of IRR was 9%, including 4.3% Grade 2 IRR and 1.7% Grade 3 IRR. If IRR is suspected, patients should be managed according to the recommendations.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

ICANS occurred in 8% of patients who received linvoseltamab with the recommended dosing regimen, including Grade 3 events in 2.6% of patients. Most patients experienced ICANS following step-up treatment dose 1 (5%). 1.8% of patients experienced initial ICANS following step-up treatment dose 2 and 0.9% of patients developed the first occurrence of ICANS following a subsequent full treatment dose of linvoseltamab. Recurrent ICANS occurred in 0.9% of patients. ICANS resolved in all patients except one who withdrew consent to follow-up. 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. All ICANS occurred in patients concurrent with or after resolution of CRS or IRR.

Infections

Serious infections occurred in 43% of patients who received linvoseltamab at the recommended dose, with Grade 3 or 4 infections occurring in 36%. Infections that were fatal within 30 days of the last dose occurred in 4% of patients. Serious opportunistic infections occurred in 6% of patients. Two cases of progressive multifocal leukoencephalopathy (PML) occurred in patients receiving linvoseltamab; both cases had a fatal outcome.

Neutropenia

Neutropenia (including neutrophil count decreased) occurred in 43% of patients who received linvoseltamab at the recommended dose in the clinical study, including 42% Grade 3-4 events. The median time to onset of neutropenia was 73 days (range: 0 to 421 days). Seventy-four percent of patients who had neutropenia received treatment with G-CSF. Febrile neutropenia occurred in 8% of patients.