Teclistamab

Teclistamab is a full-size, humanised bispecific antibody of the IgG4 type, produced in Chinese hamster ovary cells by recombinant DNA technology. One binding arm recognises the CD3 receptor on T cells and the other recognises B-cell maturation antigen (BCMA), a receptor of the tumour necrosis factor family found on malignant myeloma cells, late-stage B cells and plasma cells. By linking the two cell types it turns the patient’s own T cells against the myeloma.

Mechanism of Action

• T-cell redirection: teclistamab draws CD3-positive T cells into close contact with BCMA-positive cells. The T cells are activated and kill the target cell by releasing perforin and granzymes stored in their secretory vesicles.
• Independent of antigen presentation: the effect does not depend on T-cell receptor specificity or on MHC class I molecules on antigen-presenting cells.
• Role of BCMA: BCMA signalling supports the survival, maturation and proliferation of B-lineage cells. Myeloma cells express it widely and depend on it for survival, which makes it a suitable target.
• Pharmacodynamic effects: within the first month of treatment T cells are activated and redistributed, B cells fall and serum cytokines (including interleukin-6, interleukin-10 and soluble interleukin-2 receptor) rise. The same cytokine release underlies cytokine release syndrome, which step-up dosing is designed to reduce.
• Soluble BCMA: in most responders soluble BCMA falls within a month, and the fall is greater in patients with deeper responses.
• Immunogenicity: anti-drug antibodies were very rarely detected, with no evidence that they affect pharmacokinetics, efficacy or safety.

Pharmacokinetics

• Absorption: after subcutaneous injection the mean bioavailability is 72%. The median time to peak concentration is 139 hours (range 19–168) after the first weekly treatment dose and 72 hours (range 24–168) after the 13th. Exposure rises roughly in proportion to dose between 0.08 and 3 mg/kg, and about 90% of steady-state exposure is reached after 12 weekly doses.
• Accumulation: between the first and 13th weekly 1.5 mg/kg dose, Cmax rises 4.2-fold, Ctrough 4.1-fold and Cavg 5.3-fold. At steady state on weekly dosing the geometric mean Cmax is 23.8 µg/mL and Ctrough 21.1 µg/mL. The pharmacokinetics are consistent whether teclistamab is given alone or with daratumumab.
• Distribution: the mean volume of distribution is 5.63 L (coefficient of variation 29%).
• Metabolism: like other antibodies, teclistamab is cleared by normal protein breakdown into small peptides and amino acids rather than by liver enzymes.
• Elimination: clearance falls with time on treatment, by a mean of 40.8% from the start to the 13th weekly dose, when the geometric mean clearance is 0.472 L/day. Modelling in patients who stop after the 13th dose predicts a 50% fall from peak concentration about 15 days after the peak and a 97% fall about 69 days after it (median values).
• Special populations: no dose adjustment is needed for older age, for mild or moderate renal impairment, or for mild hepatic impairment.

Teclistamab is used in adults with multiple myeloma:

• In combination with daratumumab: relapsed or refractory multiple myeloma in patients who have received at least one prior therapy.
• As monotherapy: relapsed and refractory multiple myeloma in patients who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody, and who have shown disease progression on the last therapy.

• Hypersensitivity to teclistamab or to any of the excipients.

The most frequent reactions of any grade are hypogammaglobulinaemia, neutropenia, cytokine release syndrome, upper respiratory tract infection, musculoskeletal pain, diarrhoea, anaemia, cough, fatigue and injection site reaction. Serious reactions occurred in 65% of patients, most often pneumonia (22%), COVID-19 (14%), cytokine release syndrome (11%), upper respiratory tract infection (7%) and sepsis (6%). The frequencies below come from 739 adults with multiple myeloma (456 given teclistamab alone and 283 given it with daratumumab) and from reports after marketing.

Very common (≥1/10): upper respiratory tract infection, pneumonia, COVID-19, urinary tract infection, neutropenia, anaemia, thrombocytopenia, lymphopenia, leukopenia, hypogammaglobulinaemia, cytokine release syndrome, hypokalaemia, decreased appetite, headache, peripheral neuropathy, haemorrhage, hypertension, cough, dyspnoea, diarrhoea, nausea, constipation, vomiting, abdominal pain, musculoskeletal pain, injection site reaction, fatigue, pyrexia, pain, oedema, raised transaminases, decreased weight.

Common (≥1/100 to <1/10): sepsis, cellulitis, febrile neutropenia, hypophosphataemia, hyponatraemia, hyperkalaemia, hyperamylasaemia, encephalopathy, immune effector cell-associated neurotoxicity syndrome (ICANS), hypotension, hypoxia, muscle spasms, raised gamma-glutamyltransferase, raised lipase.

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

Not known: tumour flare (reported after marketing).

Serious reactions of note: cytokine release syndrome occurred in 65% of patients and 27% had more than one event. Most events were grade 1 (47%) or grade 2 (17%), began during the step-up doses, started a median of 2 days after the latest dose and lasted a median of 2 days; fever (65%), hypotension (13%), hypoxia (8%), chills (6%) and headache (4%) were the usual signs. ICANS occurred in 2.7% of patients (grade 3 or 4 in 0.2%), most often as a confusional state or dysgraphia, 1 to 11 days after a dose. Serious infections occurred in 46% of patients and fatal infections in 7%. Grade 3 or 4 blood-count falls and infections were frequent, for example neutropenia (65%), lymphopenia (24%), anaemia (23%), thrombocytopenia (17%) and pneumonia (24%).

No interaction studies have been performed with teclistamab. The SmPC gives the following precautions.

• CYP450 substrates with a narrow therapeutic index (for example ciclosporin): the cytokines released at the start of treatment could suppress CYP450 enzymes. The risk is highest from the start of the step-up schedule up to 7 days after the first treatment dose, and during a cytokine release syndrome event. In that period toxicity or drug concentrations should be monitored, and the dose of the other medicine adjusted as needed.
• Myeloid growth factors: granulocyte macrophage-colony stimulating factor (GM-CSF) in particular may worsen cytokine release syndrome and should be avoided during an episode.

Treatment must be started and supervised by a physician experienced in treating multiple myeloma. Teclistamab is given by subcutaneous injection only, by a healthcare professional, with trained medical personnel and appropriate equipment on hand to manage severe reactions, including cytokine release syndrome. The dose is based on actual body weight (the SmPC lists weight-based dose volumes in section 6.6). Treatment continues until disease progression or unacceptable toxicity.

Step-Up Dosing and Pre-Treatment Medicines

• Step-up dosing starts every course of treatment, to reduce the frequency and severity of cytokine release syndrome. Not following the recommended doses or schedule, including after a dose delay, may increase the frequency and severity of mechanism-related reactions, particularly cytokine release syndrome.
• Pre-treatment medicines, 1 to 3 hours before each dose in the step-up schedule: a corticosteroid (oral or intravenous dexamethasone 16 mg), an antihistamine (oral or intravenous diphenhydramine 50 mg, or equivalent) and an antipyretic (oral or intravenous paracetamol 650 to 1,000 mg, or equivalent). They may also be needed before later doses in patients who repeat step-up doses after a delay or who had cytokine release syndrome after the previous dose.
• Monitoring: patients are told to stay within reach of a healthcare facility and are monitored for signs and symptoms daily for 48 hours after every dose in the step-up schedule.
• Active infection: the step-up schedule must not be given to a patient with an active infection.

Monotherapy Schedule

Doses are per kilogram of actual body weight, by subcutaneous injection.

• Day 1: step-up dose 1, 0.06 mg/kg.
• Day 3: step-up dose 2, 0.3 mg/kg (may be given 2 to 7 days after step-up dose 1).
• Day 5: first treatment dose, 1.5 mg/kg (may be given 2 to 7 days after step-up dose 2).
• One week after the first treatment dose and weekly thereafter: 1.5 mg/kg once weekly, with at least 5 days between doses.
• Reduced frequency: in patients with a complete response or better lasting at least 6 months, 1.5 mg/kg every two weeks may be considered.

Schedule With Daratumumab

For patients with at least one prior therapy, teclistamab is combined with subcutaneous daratumumab. Daratumumab is dosed as in its own SmPC for monotherapy, except that dexamethasone (or equivalent) premedication is not given after the teclistamab step-up schedule.

• Day 1: daratumumab only.
• Day 2: step-up dose 1, 0.06 mg/kg, at least 20 hours after daratumumab.
• Day 4: step-up dose 2, 0.3 mg/kg (2 to 7 days after step-up dose 1).
• Day 8: first treatment dose, 1.5 mg/kg (2 to 7 days after step-up dose 2).
• Weeks 3 to 8: 1.5 mg/kg weekly, with at least 5 days between doses.
• Weeks 9 to 24: 3 mg/kg every two weeks, with at least 12 days between doses.
• Week 25 onwards: 3 mg/kg every four weeks.
• Timing: teclistamab is given at least 3 hours after daratumumab for the first treatment dose and at least 15 minutes after it thereafter.

Restarting After a Dose Delay

If a dose is delayed, treatment resumes as below and pre-treatment medicines are given before the dose.

• After step-up dose 1: a delay of more than 1 week means restarting at step-up dose 1.
• After step-up dose 2: a delay of 8 to 28 days means repeating step-up dose 2 and continuing the schedule; more than 28 days means restarting at step-up dose 1.
• After any treatment dose: a delay of 8 to 63 days (up to 9 weeks) means continuing at the last treatment dose and schedule; 64 to 112 days (more than 9 and up to 16 weeks) means restarting at step-up dose 2; more than 112 days (over 16 weeks) means restarting at step-up dose 1.

Dose Adjustments for Side Effects

Dose reductions are not recommended for monotherapy. In combination with daratumumab, teclistamab is not reduced during step-up dosing or the first 1.5 mg/kg treatment dose; the SmPC describes how to manage toxicity in later doses, and daratumumab dose changes follow its own SmPC. Doses are instead delayed or stopped:

• Cytokine release syndrome: withhold until it resolves. After grade 2 or a first grade 3 episode lasting under 48 hours, give pre-treatment medicines before the next dose and monitor daily for 48 hours after it. Stop permanently for grade 4, or for grade 3 that recurs or lasts more than 48 hours.
• ICANS: withhold until it resolves. After grade 2 or a first grade 3 event, monitor daily for 48 hours after the next dose. Stop permanently for grade 4 or recurrent grade 3.
• Infections: withhold further treatment doses for grade 3 or 4 infection until there is no evidence of active infection.
• Blood counts: withhold if neutrophils fall below 0.5 × 10⁹/L (until 0.5 × 10⁹/L or higher), in febrile neutropenia (until neutrophils reach 1.0 × 10⁹/L and the fever resolves), or if haemoglobin falls below 8 g/dL (until 8 g/dL or higher). For platelets, withhold below 25,000/µL, or at 25,000–50,000/µL with bleeding, until 25,000/µL or higher with no bleeding; in combination therapy the threshold is 50,000/µL.
• Other reactions: for other grade 3 or 4 reactions, withhold until they improve to grade 2 or better.

Special Populations

• Children and adolescents: there is no relevant use in the treatment of multiple myeloma.
• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment; the SmPC gives no recommendation for severe impairment.
• Hepatic impairment: no adjustment in mild impairment; the SmPC gives no recommendation for moderate or severe impairment.

Cytokine Release Syndrome

Cytokine release syndrome (CRS), including life-threatening or fatal reactions, may occur. Signs and symptoms include fever, hypoxia, chills, hypotension, tachycardia, headache and raised liver enzymes. Potentially life-threatening complications include cardiac dysfunction, adult respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure and disseminated intravascular coagulation.

• Prevention: step-up dosing, and pre-treatment medicines (corticosteroid, antihistamine, antipyretic) before each step-up dose. Patients who had CRS after the previous dose receive pre-treatment medicines again before the next dose.
• Monitoring: patients remain within reach of a healthcare facility and are monitored daily for 48 hours after any dose in the step-up schedule, and after a dose given following grade 2 or higher CRS.
• Management: patients should seek medical attention at the first sign and are evaluated at once for hospitalisation. Other causes of fever, hypoxia and hypotension are looked for. Supportive care, tocilizumab and/or corticosteroids are given according to severity, and laboratory tests for coagulation, blood counts and lung, heart, kidney and liver function may be needed.
• Avoid: myeloid growth factors, especially GM-CSF, which may worsen CRS symptoms.

Neurologic Toxicity Including ICANS

Immune effector cell-associated neurotoxicity syndrome (ICANS) can occur together with CRS, after CRS has resolved, or without CRS. Headache, encephalopathy (for example confusional state, memory impairment, somnolence or depressed consciousness) and peripheral neuropathy also occur. Teclistamab is withheld or stopped according to the grade of ICANS (see Dose Adjustments for Side Effects). Patients should report any new neurological symptom, and should avoid driving and operating machinery as described under Effect on Driving.

Infections and Low Immunoglobulin Levels

Serious infections, including fatal ones, are common. Pneumonia, COVID-19 and upper respiratory tract infections are the most frequent, and sepsis and progressive multifocal leukoencephalopathy have been reported. Hypogammaglobulinaemia occurs in about three quarters of patients and adds to the risk. The step-up schedule is not started in a patient with an active infection; it may go ahead once the infection has resolved. Section 4.4 of the SmPC sets out the recommended prophylactic anti-infective therapy.

Low Blood Counts

Neutropenia, thrombocytopenia, anaemia and lymphopenia are very common, and febrile neutropenia occurs. Blood counts guide when doses are withheld (see Dose Adjustments for Side Effects).

Traceability

Because teclistamab is a biological medicine, the name and batch number of each administered product must be clearly recorded.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy test and contraception: pregnancy status in women of child-bearing potential should be verified before starting. Women of child-bearing potential should use effective contraception during treatment and for five months after the final dose. In clinical studies, male patients with a female partner of child-bearing potential used effective contraception during treatment and for three months after the last dose.
• Pregnancy: no data are available. Human IgG crosses the placenta after the first trimester, so teclistamab may reach the foetus. It is not recommended in pregnancy. Because it is associated with hypogammaglobulinaemia, immunoglobulin levels in newborns of treated mothers should be considered for assessment.
• Breastfeeding: it is not known whether teclistamab passes into milk. Patients should not breastfeed during treatment and for at least five months after the last dose.
• Fertility: there are no data on fertility, and animal studies of fertility have not been done.

Polysorbate 20

Polysorbate 20 is the excipient with a known effect: each 3 mL vial contains 1.2 mg and each 1.7 mL vial 0.68 mg (0.4 mg/mL).

Effect on Driving

Teclistamab has a major influence on the ability to drive and use machines. Because of the potential for ICANS, patients are at risk of a depressed level of consciousness. They should avoid driving and operating heavy or potentially dangerous machinery during, and for 48 hours after completing, the step-up dosing schedule, and if any new neurological symptoms occur.

Store the vials in a refrigerator at 2–8 °C, in the original carton to protect them from light. Do not freeze. Keep the cold chain unbroken from dispatch to the hospital pharmacy.

After a vial has been opened, including in prepared syringes, chemical and physical stability has been shown for 8 days at 2–8 °C and for 24 hours at ambient temperature (15–30 °C). From a microbiological point of view the product should be used immediately. If it is not, in-use times and conditions are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C, unless preparation took place under controlled and validated aseptic conditions.

2 years for the unopened vial. After opening, see Storage Conditions. Do not use after the expiry date on the pack.

Prescription only (Rx), under restricted medical prescription (Annex II B): treatment is started and supervised by a physician experienced in treating multiple myeloma. Teclistamab is injected by a healthcare professional with trained personnel and equipment to manage severe reactions such as cytokine release syndrome, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.