Tecvayli™ (teclistamab-cqyv) is a new bispecific antibody that was recently approved by the U.S. Food and Drug Administration (FDA) on October 25th “for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM), who previously received four or more prior lines of therapy, including a proteasome inhibitor, immunomodulatory drug and anti-CD38 monoclonal antibody,” states Johnson & Johnson’s press release.

This is the first bispecific antibody to receive FDA approval and the third immune therapy to be directed against the B-cell maturation antigen (BCMA) on the surface of myeloma cells after belantamab (an antibody drug conjugate) and chimeric antigen receptor (CAR) T-cell therapies, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel).

Teclistamab is an antibody with two arms—one links to the BCMA antigen on the myeloma and the other, to T cells in the surrounding micro-environment via a CD3 receptor on the T cells thus, giving this bispecific antibody its unique mechanism of action. The linked and activated T cells release cytotoxic granules which combine with the direct BCMA linkage effect to destroy the myeloma cells.

 

Overall Findings from the MajesTEC-1 Trial

Responses 

The overall response rate was 63% (104/165) with 58.8 % having Very Good Partial Response (VGPR) or better and 39.4% achieving Complete Response (CR) or better. What was perhaps most impressive was that after 12 months, approximately 70% of patients maintained their responses. Responses usually occur within 1-2 months.

Side Effects

The major issues which impact a typical patient’s journey with Tecvayli are related to potential toxicities, side effects, and the logistics of treatment administration. 

Most patients develop low blood counts which improve over time. In addition, most patients develop low grade cytokine release syndrome (CRS) consisting of fever and low blood pressure. About half the patients require being treated with a specific antibody treatment called tocilizumab (often called toci). 

About 6% of patients developed immune effector cell-associated neurotoxicity syndrome (ICANS) which included a seizure in one patient. Another patient experienced a neurological syndrome called Guillain-Barre in the MajesTEC-1 study.

To minimize toxicities and to ensure maximum safety, patients are typically hospitalized for 1-2 weeks at the start of treatment.

Initial In-Hospital Step-Up Dose Schedule

All doses of teclistamab are given by subcutaneous injection. To reduce the likelihood of CRS or ICANS, the typical patient is admitted to the hospital for what is called an initial step-up dose schedule:

Day 1: First dose is a reduced dose of 0.06 mg/kg 
At least 48 hours after first dose: Second dose is 0.3 mg/kg
At least 48 hours after second dose: Third dose is 1.5 mg/kg, which is a full dose
At least 48 hours after third dose: Patient can be discharged

Note that each dose may be delayed if significant CRS and/or ICANS occur. 

Treatment with intravenous fluids and/or tocilizumab (as noted above) for CRS may be needed.  There is definitely a learning curve in terms how to best manage this step-up period. Centers involved with prior trials will be more well-versed. New sites will need time to activate with the required Risk Evaluation and Mitigation Strategy (REMS) to get set up.

Follow-up Treatment and Supportive Care

A week after the third dose (the first full dose), patients can resume weekly dosing starting with the full dose of 1.5 mg/kg. Any CRS and/or ICANS would have been resolved at this point. However, low blood count usually continues for the first 2 months which may leave patients feeling tired or fatigued.

Teclistamab suppresses the immune system which is needed to fight infection. In the MajesTEC-1 study, 76% of patients developed infection with 44% developing serious infections (including pneumonia at 18%) and 18% developing COVID-19. Unusual brain infection also occurred including progressive multifocal leukoencephalopathy (PML) and fungal pneumocystis pneumonia (PCP).

Some key measures to prevent infection:

• Make sure that there is no Hepatitis B
• Consider an anti-virus treatment with acyclovir, for example, to prevent shingles or herpes outbreaks
• Consider using the antibiotic Bactrim (trimethoprim and sulfamethoxazole) to prevent fungal infection
• Make sure that the patient is up to date with COVID-19 vaccinations and the pre-exposure prophylaxis monoclonal antibody, Evusheld™
• Use of intravenous gamma globulin (IVIg) may need to be considered for infection control

Along the way, blood transfusions and Granulocyte-colony stimulating factor (G-CSF) or filgrastim shots to boost white cell levels may be required. Obviously, best practices for monitoring possible infections are essential to rapidly address and treat infections.

Big Picture Questions

It’s possible that as a patient’s experience with teclistamab grows, it may become safer to take treatments without needing to go to the hospital. However, right now (and most likely in the foreseeable future) getting in-hospital treatments would still be the safest and highly recommended approach.

Spacing out doses over time definitely helps with recovery and minimizes toxicities. Restarting therapy when complications have resolved has also been possible.

Longer-term maintenance may end up being 2-4 weeks of dosing. Clearly, studies looking at shorter fixed durations of therapy will be helpful to guide best ongoing strategies.

Teclistamab will definitely become more available as an off-the-shelf option versus current CAR T approaches which require a break of 4-6 weeks with bridging therapy and uncertain waits at even the top and most active centers. 

This is very good news for patients in desperate need of a back-up option to achieve response. Costs of ongoing therapy and supportive care may emerge as issues over time, but hopefully, will not be prohibitive.

The Bottom Line 

The future is bright in the ever-evolving field of immune therapies, with teclistamab as a really important and exciting new option. 

Other bispecifics (even trispecifics) are moving through clinical trials and will undoubtedly provide additional options, along with antibodies against new targets such as GPRC5D (G protein–coupled receptor, class C, group 5, member D), FCRH5 (Fc receptor-homolog 5) and newer CAR T-cell therapies with faster manufacturing and new targets. 

Staying well-informed on new and excellent treatment options is key to ensure best outcomes for every patient. 

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