TECVAYLI (teclistamab-cqyv)

What Is Tecvayli?

Tecvayli™ (also known as teclistamab-cqyv, the generic drug name), is the first in a drug class of bispecific antibodies approved by the U.S. Food and Drug Administration (FDA) to treat myeloma.

How Does Tecvayli Work?

Tecvayli is an immunotherapy, a treatment that enhances a patient’s own immune system to attack their myeloma cells. Tecvayli is a bispecific antibody (also called “bispecific therapy”). A bispecific antibody is a laboratory-made monoclonal antibody that uses dual-binding (“bi”) action to kill the targeted myeloma cells.

Tecvayli has two “arms.” One of those arms binds to the myeloma cell surface by adhering to the B-cell maturation antigen (BCMA). The other arm binds to a local T cell by its CD3 antigen. Tecvayli binds to both the myeloma cell and the T cell. As a result, it brings the myeloma cell and T cell together. Also, it activates the T cell to release cytotoxic granules to destroy the myeloma cell.

How Does Tecvayli Differ from CAR T-cell Therapy?

Tecvayli differs from CAR T-cell therapy in that there is no need to collect the patient’s T cells. Instead, Tecvayli engages the patient’s T cells directly after injection. Not having to collect, engineer, and manufacture T cells over the course of several weeks shortens the time-to-treatment for the myeloma patient. The “off-the-shelf” availability of Tecvayli makes it easier to access treatment.

When Should Tecvayli Be Used as a Treatment?

Tecvayli is FDA-approved for patients with relapsed or refractory myeloma (RRMM) who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

How Has Tecvayli Been Used in Clinical Trials?

MajesTEC-1 clinical trial

The safety of Tecvayli was evaluated in the MajesTEC-1 clinical trial with adult patients with RRMM. Patients received step-up doses of 0.06 mg/kg and 0.3 mg/kg of Tecvayli followed by 1.5 mg/kg of Tecvayli, given by a subcutaneous (SQ) injection once-weekly.

The MajesTEC-3 clinical trial of patients with RRMM is studying Tecvayli in combination with

Darzalex® (daratumumab) vs. Darzalex, Pomalyst® (pomalidomide), and dexamethasone [DPd]; or
Darzalex, Velcade® (bortezomib), and dexamethasone [DVd].

Tecvayli is also being studied in several other clinical trials as part of different combination therapies, at different doses, and in earlier disease settings.

Demographics of participants in the MajesTEC-1 clinical trial

The median age of patients of 64 years (range of 33 to 84 years)
58% were male.
81% were white.
13% were Black.
2% were Asian.

How Should Tecvayli Be Administered, Dosed, and Scheduled?

When Tecvayli is injected, there is a risk that the patient’s immune system may react in a way that causes a cytokine release syndrome (CRS). For this reason, patients begin Tecvayli at a lower dose. The patient’s immune system will likely be able to tolerate a lower dose better.

At the discretion of the treating doctor, the patient may be admitted to hospital for 48 hours after the administration of each “step-up” dose of Tecvayli. Alternatively, the individual may be monitored on an outpatient basis for CRS and the risk of neurologic toxicity.

The recommended dosing schedule for Tecvayli is provided in the following table. The two step-up doses of Tecvayli are 0.06 mg/kg then 0.3 mg/kg. The regular once-weekly treatment dose is 1.5 mg/kg given until disease progression or unacceptable side effects. Prior to each dose of the Tecvayli step-up dosing schedule, patients are given pretreatment medications. The step-up dosing schedules includes step-up dose 1, step-up dose 2, and the first treatment dose.

Table 1

Dosing Schedule	Day	Dose	Dose
Step-Up Dosing Schedule	1	Step-up Dose 1	0.06 mg/kg
Step-Up Dosing Schedule	4^b	Step-up Dose 2	0.03 mg/kg
Step-Up Dosing Schedule	7^c	First treatment dose	1.5 mg/kg
Weekly Dosing Schedule	One week after first treatment dose and weekly thereafter	Subsequent treatment doses	1.5 mg/kg weekly

a. See Table 2 for recommendations on restarting Tecvayli after dose delays.
b. Step-up dose 2 may be given between 2 to 4 days after step-up dose 1 and may be given
up to 7 days after step-up dose 1 to allow for resolution of side effects.
c. First treatment dose may be given between 2 to 4 days after step-up dose 2 and may be given
up to 7 days after step-up dose 2 to allow for resolution of side effects.

Table 2

Last dose administered	Duration of delay from the last dose	Recommendations
Step-up 1 dose	More than 7 days	Restart Tecvayli step-up dosing schedule at step-up dose 1 (0.06 mg/kg)^a.
Step-up 2 dose	8 days to 28 days	Repeat step-up dose 2 (0.3 mg/kg)^a and continue Tecvayli step-up dosing schedule.
Step-up 2 dose	More than 28 days^b	Restart Tecvayli step-up dosing schedule at step-up dose 1 (0.06 mg/kg)^a.
Any treatment dose	8 days to 28 days	Continue Tecvayli weekly dosing schedule at treatment (1.5 mg/kg).^a
Any treatment dose	More than 28 days^b	Restart Tecvayli step-up dosing schedule at step-up dose 1 (0.06 mg/kg).^a

What Warnings and Precautions Should Patients Who Undergo Tecvayli Therapy Be Aware Of?

The most common side effects occurring in 20% or more patients treated with Tecvayli in the MajesTEC-1 clinical trial were the following:

fever
cytokine release syndrome (CRS)
musculoskeletal pain
injection site reaction, fatigue
upper respiratory tract infection
nausea
headache
pneumonia
diarrhea

The most common severe laboratory abnormalities occurring in 20% or more patients treated with Tecvayli are the following:

decreased lymphocytes
decreased neutrophils
decreased white blood cells
decreased hemoglobin
decreased platelets

a. Pretreatment medications are given prior to Tecvayli dose and monitor patients accordingly.

b. Discuss with your doctor the benefit-risk of restarting Tecvayli if you require a dose delay of more than
28 days due to a side effect.

How Is Tecvayli Made Available to Patients?

Tecvayli is available only through a Risk Evaluation and Mitigation Strategy (REMS) restricted program. The FDA requires a REMS program if a specific drug or treatment has serious safety concerns. REMS programs support the use of such drugs or treatments and help ensure that the potential benefits outweigh the risks.

What Is Cytokine Release Syndrome (CRS)?

In patients with myeloma, cytokines are proteins that are produced in the bone marrow. These cytokines then circulate in the bloodstream. As the do so, they stimulate or inhibit the growth and/or activity of other cells.

CRS is a potentially fatal, uncontrolled immune reaction. During this reaction, cytokines become highly elevated and trigger an overwhelming immune system response. A “cytokine storm” can seriously damage body tissues and organs.

Occurrences of CRS in the MajesTEC-1 clinical trial

CRS occurred in 72% of patients who received Tecvayli at the recommended dose, with

Grade 1 CRS occurring in 50% of patients,
Grade 2 in 21%, and
Grade 3 in 0.6%.

Most patients experienced CRS following step-up dose 1, step-up dose 2, or the first treatment dose.

After subsequent doses of Tecvayli, less than 3% of study patients developed CRS.

The median time to onset of CRS was 2 days (range of 1 to 6 days), after the most recent dose. In these patients, the median duration of the CRS was days (range of 1 to 9 days).

Clinical signs and symptoms of CRS included, but were not limited to:

fever
hypoxia
chills
hypotension
sinus tachycardia
headache
elevated liver enzymes

What Are Neurological Toxicities That Can Occur with Tecvayli?

Immune effector cell-associated neurotoxicity syndrome (ICANS) has occurred in patients following treatment with Tecvayli. ICANS often correlates with CRS. Yet, it can also occur in the absence of CRS. After treatment with Tecvayli, ICANS can occur before, during, or after CRS onset, or after CRS resolution.

ICANS may be severe, life-threatening, or fatal. Symptoms of neurologic side effects include but are not limited to

confusion
disorientation
loss of consciousness
seizures
tremor
slower movements
changes in personality
depression
tingling and numbness of hands and feet
leg and arm weakness
facial numbness
difficulty speaking, reading, or writing.

Neurologic toxicity in the MajesTEC-1 clinical trial

In the MajesTEC-1 clinical trial, neurologic toxicity occurred in 57% of patients who received Tecvayli at the recommended dose, with Grade 3 or 4 neurologic toxicity occurring in 2.4% of patients.

The most frequent neurologic toxicities were the following:

headache (25%),
motor dysfunction (16%)
sensory neuropathy (15%)
encephalopathy (13%)

With longer follow-up of patients who received Tecvayli, Grade 4 seizure occurred in 1 patient and fatal Guillain-Barré syndrome (GBS) occurred in 1 patient.

ICANS was reported in 6% of patients who received Tecvayli at the recommended dose.

Recurrent ICANS occurred in 1.8% of patients.

Most patients experienced ICANS following step-up dose 1 (1.2%), step-up dose 2 (0.6%), or the initial treatment dose (1.8%).

Less than 3% of patients developed first occurrence of ICANS following subsequent doses of Tecvayli.

The median time to onset of ICANS was 4 days (range of 2 to 8 days) after the most recent dose. The median duration of 3 days (range of 1 to 20 days).

Hepatotoxicity and Tecvyali

Tecvayli can cause hepatotoxicity. Drug-induced hepatotoxicity is an injury to the liver or an impairment of the liver function caused by exposure to a specific compound.

In the MajesTEC-1 clinical trial, the following occurred:

1 fatal case of hepatic failure.
Elevation of the liver enzyme aspartate aminotransferase (AST) occurred in 34% of patients, with Grade 3 or 4 elevations in 1.2%.
Elevated alanine aminotransferase (ALT) occurred in 28% of patients, with Grade 3 or 4 elevations in 1.8%. Elevated total bilirubin occurred in 6% of patients with Grade 3 or 4 elevations in 0.6%.
Liver enzyme elevation can occur with or without concurrent CRS.