Behind the FDA Approval: Teclistamab for R/R Multiple Myeloma

Alfred L. Garfall, MD

The phase 1/2 MajesTEC-1 trial (NCT03145181; NCT04557098) of teclistamab-cqyv (Tecvayli) demonstrated high rates of deep and durable responses in patients with triple-class-exposed relapsed/refractory (R/R) multiple myeloma, leading to FDA approval of the agent.

In the single-arm, open-label, multicenter MajesTEC-1 trial, patients with with R/R multiple myeloma who have received 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody were enrolled. Inclusion in the trial was open to patients aged 18 years and older with progressive, measurable disease at screening, and an ECOG score of 0 or 1.

Findings revealed treatment with teclistamab elicited an objective response rate (ORR) of 61.8% (95% CI, 52.1%-70.9%). The median time to first response was 1.2 months (range 0.2-5.5 months).

Then, the estimated duration of response (DOR) at a median follow-up of 7.4 months for patients administered teclistamab was 90.6% at 6 months (95% CI, 80.3%-95.7%) and 66.5% (95% CI, 38.8%-83.9%) at 9 months. Further, the median DOR was not estimable (NE; 95% CI, 9.0-NE).

Seventy patients (42.4%) continued to receive treatment as of March 16, 2022. The median duration of treatment was 8.5 months (range, 0.2-24.4). Ninety-eight patients (59.4%) were given at least 6 months of teclistamab, and 79 patients (47.9%) were administered at least 9 months of treatment. The median relative dose intensity for all treatment cycles, including step-up doses, was 93.7%.

Regarding safety, each of the 165 patients reported having an adverse event (AE) with a grade 3/4 AEs seen in 156 patients (94.5%). The most common AEs reported were cytokine release syndrome (CRS; 72.1%), neutropenia (70.9%), anemia (52.1%), and thrombocytopenia (40.0%). Grade 3 CRS was observed in 0.6% of patients and there was no grade 4 CRS reported. Grade 3/4 neutropenia was seen in 64.2% of patients, anemia was grade 3 or 4 in 37.0%, and thrombocytopenia was grade 3 or 4 in 21.2%.

Additionally, 76.4% of patients had infections with grade 3/4 reported in 44.8% of patients. There were 24 patients (14.5%) who had neurotoxic events, including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%), all of which were grade 1-2. One patient had a dose reduction during cycle 21 because of recurrent neutropenia, and 104 patients (63.0%) skipped a dose due to AEs.

“Overall, this was very promising in terms of being able to get that same type of immune activation that you get with chimeric antigen receptor [CAR] T cells, but with a simpler process, a more readily available process, and maybe even a slightly safer process,” said Alfred L. Garfall, MD, MS, in an interview with Targeted Oncology™.

In the interview, Garfall, assistant professor of Medicine at Abramson Cancer Center at Penn Medicine in Philadelphia, Pennsylvania, discussed the FDA approval of teclistamab, the MajesTEC-1 trial, and how this information should be used in the future.

Can you discuss teclistamab and its mechanism of action?

Garfall: This is a drug in the class of drugs called bispecific antibodies or more specifically, T cells engaging bispecific antibodies. These are antibodies that have 2 target specificities. One target is a target on the cancer cell and in this case, BCMA or B-cell maturation antigen, which is a cell surface target on multiple myeloma cells. There are many therapies being developed [for this specificity], CAR T cells, antibodies, drug conjugates, etc. Teclistamab is 1 of the number of CD3-engaging, anti-BCMA, bispecific antibodies in development for multiple myeloma and it is the first to be FDA approved. There are other bispecific antibodies in development for other diseases like diffuse large B-cell lymphoma.

It's a very promising class of therapies because it was able to trigger the activation of T cells against the malignancy with a similar strength as you get with CAR T-cell therapy, but it's much simpler to administer compared to CAR T-cell therapies. With CAR T-cell therapy, you have to collect T cells from the patients, those T cells have to go through a patient specific manufacturing process and be re-infused. In the case of teclistamab, it's a subcutaneous injection. You get similar types of activation of T cells against cancer, in this case with multiple myeloma, as you do with CAR T cells, but with the simplicity of the subcutaneous injection.

You also get the same types of toxicity profile as with CAR T cells, but I think in the case of teclistamab and most of the other bispecific antibodies, because you introduce the dosing gradually, we have to be careful about these comparisons. It seems to be that the toxicity, in terms of cytokine release syndrome and neurologic toxicity with bispecific antibodies, may be a bit milder compared with what you can get with CAR T cells in some cases. Overall, this was very promising in terms of being able to get that same type of immune activation that you get with CAR T cells, but with a simpler process, a more readily available process, and maybe even a slightly safer process.

Can you discuss the MajesTEC-1 trial and data that this approval was based upon?

There was a phase 1 and phase 2 study. The phase 1 study was a classic dose-escalation study that began with intravenous dosing and then transitioned to subcutaneous dosing. It made its way through several different dosing cohorts until they settled on a recommended phase 2 dose of 1500 µg/kg given weekly. Then that transition to a phase 2 study, and I believe the approval is based on a little over 100 patients who were treated at that recommended phase 2 schedule of 1500 µg/kg once per week, with 2 what we call step-up or priming doses or 2 smaller doses given within the first week of therapy, and then continuing at that 1.5 mg/kg dose weekly.

Results from that trial showed an overall response rate of about 60% in a heavily pretreated population. The patients had been refractory to the major standard drug classes in multiple myeloma. What was impressive is that among the patients who responded, the responses tended to be quite durable. In the study that was published, the median estimated duration of response and response rates are very impressive with a drug given just a single agent and not a combination therapy in this relapsed/refractory setting.

Can you explain some of the toxicities seen in the study? How will this affect the use of teclistamab in your practice?

The main adverse events that were demonstrated were the expected ones of cytokine release syndrome, a febrile reaction that can occur as the immune system is activated by the drug and that's similar to what has been seen with CAR T-cell therapy in multiple myeloma and other diseases. What was reassuring about the profile of teclicstimab, and many of the other bispecific antibodies in development for multiple myeloma, is that cytokine release syndrome tends to be low-grade and manageable in most patients. Likewise, the neurologic toxicity, which has been a problem, and some have risk of immune effector cell-associated neurotoxicity syndrome [ICANS]. There was some risk of ICANS with teclictsmab, but the cases that occurred were generally low-grade, manageable, and reversible.

The other toxicity that became apparent with prolonged dosing of the medication is risk of infection. A fair number of patients on teclicstimab studies had infections, including some high-grade infections and some opportunistic infections like pneumocystis pneumonia, or progressive multifocal leukoencephalopathy, that potentially fatal brain infection caused by the John Cunningham virus. All multiple myeloma therapies, especially in patients with advanced disease, come with some risk of immunosuppression, but we think the immune suppression is a little more serious with teclicstimab rather than with standard multiple myeloma therapy.

We participated in the clinical trials with teclicstimab and most of our patients had to start receiving intravenous immunoglobulin [IgG] to replace the IgG levels because it induces a very stringent depletion of plasma cells, including normal plasma cells, and that induces a hypogammaglobulinemia that we decided for most of our patients on the study to preventatively give intravenous immunoglobulin. I mentioned that there are a fair number of high-grade toxic infections, including some opportunistic infections. Patients who got COVID-19 on this trial, especially in the earlier days of COVID-19, with some of the earlier variants had unfortunately died of COVID 19 on the studies. Multiple myeloma patients in general fared poorly with COVID-19, even on standard therapy. This highlights that infections are a real problem with this therapy, as with many myeloma therapies, but this therapy may have a bit higher risk of infection.

It's important for patients to undergo some standard prophylaxis measures. When we start using the medication here, we'll be giving patients prophylaxis against pneumocystis pneumonia with drugs like Bactrim [Trimethoprim; Sulfamethoxazole] or atovaquone [Mepron]. At least in our practice, I think we'll be giving patients intravenous immunoglobulin as their immunoglobulin levels drop low for patients who are res,ponding and we anticipate they will be on the drug for a long time.

What are the implications for teclistamab in clinical practice?

The current FDA approval was for patients with quite advanced disease. The approval is for patients with 4 or more prior lines of therapy, so similar with what's contained in the approvals for belantamab mafodotin [Blenrep], the antibody drug conjugate that targets BCMA, and then the 2 CAR T-cell products that target BCMA. It is a big boost to the number of agents that we have available for patients with the most advanced disease, and it offers potential advantages over some of the other drugs approved in that setting. I always have to be careful making comparisons between clinical trials that were all single arm in terms of response rates, but I would say [teclistamab] is comparable in the response rates with those other agents.

It offers some advantages over other agents. Compared with CAR T cells, it's a bit more accessible to many patients in parts of the country or around the world who are not at centers that are set up to give CAR T-cell therapy. Right now, with CAR T-cell products, there's a little bit of a waiting, a supply in demand mismatch, so it's tough for many patients to gain access to manufacturing slots for CAR T cells and many patients have multiple myeloma that's becoming more aggressive and the wait to get a manufacturing slot and process itself. This offers an option with comparable efficacy without those logistical barriers and waiting periods. It's a big improvement to the armamentarium of therapies that we have for patients in that line of therapy.

For patients who continue long-term on the medication, it is very impressive that they have a very good quality of life. Typically, at this line of therapy, we're thinking about combination therapies of standard agents that even though in isolation are well tolerated, maybe at first they're well tolerated, we see cumulative toxicity in terms of adverse events or steroid adverse events from steroid intensive regimens. Patients who want teclistamab will be getting it at weekly subcutaneous injections without steroids. In my experience, patients who respond and get through those initial months where there's a risk of cytokine release syndrome, neurotoxicity, and some inflammation as the immune system is activated against the myeloma, once patients get into the course of therapy a couple of months, their quality of life is very good. It had patients on the trial who would come in, sit around for brief blood testing at their subcutaneous injection, and leave with minimal adverse events in terms of symptoms and things like infections that we have to be careful about day to day. But it is pretty good for patients taking this medication long-term. That compares favorably with blinatumomab.

What advice do you have for community oncologists who want to learn more about this approval?

The 1 barrier for community oncologists may be that it is approved with a REMS program that will require them and their teams to be trained for the management of cytokine release syndrome, neurologic toxicity, and the infection risks. I believe the prescribing information says the patient should be hospitalized for the first couple of doses, so community oncologists will have to be connected with a hospital that is able to administer the drug and have staff that are trained to manage those toxicities as that may be a little bit of a barrier to start.

I do think that's a barrier that can be overcome. In my experience managing patients for toxicities, it's rare that the toxicities were high-grade. I do think community oncologists connected with good hospitals will be able to start the medication. I imagine in the early days though, community oncologists that have referral relationships with academic centers that are CAR T-cell centers which might be their first experience with the medications, referring patients to academic centers, to maybe get started on the medication. Once patients are through that early period of toxicity, maybe transitioning administration of the medication for the long-term from the academic center to the community center. Once patients get beyond that first month or so, some of those toxicities may pose barriers to administration where you have to have inpatient management in place. Some of those barriers don't exist for the ongoing treatment beyond those initial couple of months, so the first exposure that community oncologists have may be handing patients or receiving patients back from an academic center who want to be started on the medication to continue therapy.

I hope with time that this is an accessible medication, even for the initial dosing and that hospitals connected with community oncology practices will be able to manage the cytokine release syndrome and neurologic toxicity. With CAR T cells, I think it's manageable as well, but there are with CAR T cells, a higher risk and a less predictable pattern where there's a fair amount of high-grade toxicity. I think the toxicity with the gradual step-up dosing with teclistamab and other bispecific antibodies like it will be a bit more approachable for community centers. I hope that they're able to get comfortable with that, because I think it would be great to have these types of therapies widely accessible to patients.