Teclistamab: Effect in Multiple Myeloma

Teclistamab (trade name Tecvayli) is a bispecific T cell activating antibody approved in the EU since August 2022. It simultaneously binds to B Cell Maturation Antigen (BCMA) on myeloma cells and to CD3 on T lymphocytes. In this way, it forces the body's own T cells to directly attack malignant plasma cells. Teclistamab is among the most modern therapies for multiple myeloma and is used in heavily pretreated patients who have undergone multiple previous lines of therapy.

This drug class has significantly expanded the treatment spectrum for patients with relapsed or refractory multiple myeloma in recent years. In studies, response rates of approximately 60 percent were achieved in heavily pretreated patients, a remarkable result in this late line. Application occurs exclusively in specialized centers of hemato-oncology, because characteristic and severe side effects such as Cytokine Release Syndrome (CRS) and neurological symptoms require intensive monitoring.

Mechanism of Action

Teclistamab is a bispecific antibody with two binding sites. One binding site selectively binds to BCMA, a surface receptor expressed on plasma cells and particularly on malignant myeloma cells. The second binding site binds to CD3, a component of the T cell receptor complex on T lymphocytes. Through simultaneous binding to both cell types, T cells are brought directly to the myeloma cell and activated. The T cells release granzyme B and perforin and destroy the myeloma cell.

Unlike monoclonal anti-CD38 antibodies such as daratumumab, bispecific antibodies actively utilize the body's own T cell system. This targeted T cell activation leads to strong cytotoxic effects, but also to systemic cytokine release that causes Cytokine Release Syndrome. Gradual dose escalation (step-up phase) reduces the risk of severe CRS episodes.

Pharmacokinetically, teclistamab shows a half-life of approximately 11 days. The substance is injected subcutaneously and gradually increased to higher doses, then given weekly. Dose reduction to every two weeks is possible after 6 months of sustained remission.

Indications

• Relapsed or refractory multiple myeloma in adults who have previously received at least three lines of therapy including an immunomodulator, a proteasome inhibitor, and an anti-CD38 antibody and show disease progression under the last therapy
• Patients with ECOG performance status 0 or 1 without severe cardiac, pulmonary, or neurological comorbidities who can tolerate intensive therapy
• Bridge function before allogeneic stem cell transplantation in specific constellations
• Off-label or within clinical trials in earlier lines of therapy to evaluate efficacy in first-line constellations

Teclistamab is not approved for first-line therapy. Broad application outside specialized centers is not possible due to complex monitoring requirements.

Dosage and Administration

Step-up phase: Day 1: 0.06 mg per kg body weight subcutaneously, Day 4: 0.3 mg per kg, Day 7: 1.5 mg per kg.

Maintenance therapy: 1.5 mg per kg body weight subcutaneously once weekly. After 6 months of sustained remission, reduce to 1.5 mg per kg every two weeks.

Premedication: 30 to 60 minutes before each step-up dose and the first dose after step-up: glucocorticoid (dexamethasone 16 mg or methylprednisolone 80 mg), H1 antihistamine, paracetamol. Thereafter, premedication only as needed.

Hospitalization: During the step-up phase and at the first maintenance dose, inpatient admission for 48 hours to monitor CRS risk. Later doses can be administered on an outpatient basis if no relevant side effects have occurred.

Renal insufficiency and hepatic insufficiency: Generally no dose adjustment required because no relevant renal or hepatic elimination occurs.

Duration of therapy: Until disease progression or unacceptable toxicity. Long-term therapy over several years is possible as long as efficacy and tolerability are maintained.

Side Effects

Very common: Cytokine Release Syndrome (CRS) with fever, chills, hypotension, hypoxia, especially during the step-up phase. Hypogammaglobulinemia with increased susceptibility to infection. Neutropenia, thrombocytopenia, anemia.

Common: Fatigue, nausea, diarrhea, injection site reactions, increased infection rate (especially respiratory tract infections, pneumonia, opportunistic infections).

Characteristic immune-mediated side effects: Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) with confusion, speech disorders, tremor, seizures, or altered consciousness. Immediate therapy with glucocorticoids is necessary.

Rare but relevant: Severe or life-threatening infections (CMV reactivation, pneumocystosis, invasive fungal infections), pneumonitis, hepatotoxicity, severe skin reactions.

CRS classification: Grade 1 (fever without hypotension or hypoxia), Grade 2 (fever with hypotension responsive to volume administration or hypoxia responsive to oxygen mask), Grade 3 (hypotension requiring a vasopressor or hypoxia requiring high-dose oxygen), Grade 4 (life-threatening). Therapy according to grade with tocilizumab as IL-6 antagonist and glucocorticoids.

Drug Interactions

• Other immunotherapies (CAR T cells, other bispecific antibodies): Combination only in clinical trials because risks are unclear.
• Live vaccines: Contraindicated during therapy and for several months afterward due to immunosuppression.
• Glucocorticoids: Established in premedication and CRS therapy, long-term co-medication increases infection risk.
• Tocilizumab: IL-6 antagonist as specific CRS therapy.
• Antibiotics and antifungals prophylactically: With prolonged therapy in at-risk patients to prevent opportunistic infections.
• Pharmacokinetic interactions via CYP: Not relevant because teclistamab is not metabolized via CYP. Indirectly, CRS can reduce CYP activity, so other medications may show temporarily elevated levels.

Special Precautions

Pregnancy: Teclistamab is contraindicated in pregnancy because monoclonal antibodies can cross the placenta. Women of childbearing age require reliable contraception during therapy and for at least 5 months afterward. Breast-feeding: Breast-feeding during therapy is not recommended.

Before starting therapy: Comprehensive diagnostics with bone marrow aspiration, imaging, blood count, immunoglobulin levels, hepatitis B and C status, HIV, tuberculosis screening. Counseling about CRS, ICANS, infection risk, and warning signs.

Step-up phase: Inpatient admission with continuous monitoring. CRS typically occurs 1 to 3 days after each step-up dose. Immediate therapy with tocilizumab and glucocorticoids upon occurrence.

Infection prophylaxis: Pneumocystosis prophylaxis with trimethoprim-sulfamethoxazole or dapsone, antiviral prophylaxis against HSV and VZV, CMV monitoring if indicated. IVIG substitution for clinically relevant hypogammaglobulinemia.

Emergency card: Patients receive an emergency card with information about ongoing therapy. When admitted to an emergency department at an unfamiliar hospital, treating physicians can immediately assess the CRS risk and treat appropriately.

Follow-up monitoring: Regular determination of blood count, immunoglobulins, disease markers such as serum free light chains, and imaging. Immediate reevaluation if clinical deterioration occurs.

Fitness to drive: Do not drive during step-up phase and when signs of neurological toxicity are present. Otherwise, individual assessment in stable phase.

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Frequently Asked Questions

Sources

• EMA, Tecvayli (Teclistamab) EPAR
• Gelbe Liste, Teclistamab Active Substance Profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Oncological Guidelines
• ESMO, European Society for Medical Oncology