Teclistamab Demonstrates Exciting Efficacy in Relapsed or Refractory Multiple Myeloma

The bispecific antibody teclistamab-cqyv (Tecvayli) showed promising efficacy and safety in patients with relapsed/refractory multiple myeloma (MM) with a well-tolerated safety profile in data from the phase 1/2 MajesTEC-1 trial (NCT04557098). These results led to the October 2022 FDA approval of the B-cell maturation antigen (BCMA)-directed, CD3 T-cell engager, for adult patients with relapsed or refractory MM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

The approval was based on 110 patients among whom the overall response rate was 61.8% (95% CI, 52.1%-70.9%) with a complete response rate of 28.2%. The estimated duration of response rate at 6 and 9 months was 90.6% (95% CI, 80.3%95.7%) and 66.5% (95% CI, 38.8%-83.9%), respectively.²

“Teclistamab is a highly effective therapy for relapsed/refractory MM that rivals the efficacy of [chimeric antigen receptor] CAR T-cell therapy, but ultimately is a lot simpler to administer and will be more readily available than CAR T-cell therapies,” Alfred L. Garfall, MD, said.

In an interview with OncologyLive^®, Garfall, director of autologous hematopoietic stem cell transplantation and an assistant professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, discussed the durability of responses teclistamab elicited and how it will change the treatment regimen for relapsed/refractory MM.

How can teclistamab address unmet needs in this patient population?

Despite all the progress with new MM therapies that have been developed over the past [couple of] decades, unfortunately most patients are expected to relapse. We need new therapies to address the needs of patients who are progressing despite all the best currently available therapies.

What is impressive about teclistamab is the high response rate as a single agent in patients who have become refractory to the most commonly available therapies for MM. In the patient population studied in a pivotal trial, approximately 65% of patients responded to teclistamab and those responses tended to be very durable [with a] median duration of response of approximately 18 months. That is quite impressive.

What are some adverse effects clinicians should be aware of when prescribing teclistamab?

Among the therapies that we give on an ongoing basis for MM, there are some specific toxicities in the early week or two of teclistamab therapy. For patients who respond and handle those toxicities as most patients do, there is very little cumulative toxicity. Compared with the typical therapies that are being given to patients in this advanced setting, which often entail multiple agents being given continuously over a long period …typically once [the patients] get through the initial couple of weeks, they have very good quality of life on teclistamab with very little cumulative toxicity.

Despite receiving it continuously in many cases for several years, patients usually continue to feel well with very little toxicity that affects quality of life. There are some toxicities to be aware of as patients are exposed to it over time; the main things are immune suppression and risk of infection. In my experience, this is such a breath of fresh air for patients who have been on myeloma therapy continuously for years with sophisticated agents that are much better than chemotherapy but still take their toll after [months] of continuous exposure.

What makes the mechanism of action of teclistamab unique?

We are used to conventional monoclonal antibody therapies for cancer having a single specificity for target on the surface of the cancer cell and binds to that target. A T-cell–engaging bispecific antibody such as teclistamab has 1 arm binding to a cell surface target on the surface of the MM cell, in this case BCMA, but with the other arm it binds to a T cell, CD3. By having that dual specificity, the drug can bring together a myeloma cell and a T cell and force T-cell recognition of the myeloma cell, activating the T cell.

This is a mechanism that was first exploited with a drug called blinatumomab [Blincyto], which is an anti-CD19/CD3-bispecific T-cell engager approved for treatment of acute lymphoblastic leukemia. Teclistamab is the first bispecific antibody approved that exploits [this] mechanism of action but does so in the format of a full-length antibody. That means that it has a much longer half-life and so it can be given with intermittent dosing, as opposed to the requirement for continuous intravenous infusion, which is the case for the prior generation of bispecific T-cell engagers, such as blinatumomab.

What stood out about MajesTEC-1?

With almost any MM therapy you are concerned about immunosuppressive effects, and...this drug does have some immunosuppressive effects. Almost all patients who were on it for [an extended time] develop low IgG, which is expected from the effect of the drug on normal plasma cells. Patients treated at our center have all received intravenous immunoglobulin if they’ve been on the drug for long enough to develop low immunoglobulin levels.

It was also clear in MajesTEC-1 that there may be an increased risk of opportunistic infections. There was some pneumocystis pneumonia that was seen on the study and as a result we have started giving our patients pneumocystis prophylaxis. There was even a case of progressive multifocal leukoencephalopathy. These infections often occurred in patients who had been on the drug for a [long time] whose myeloma was under very good control, suggesting that there is an immune suppressive effect of teclistamab. Now, the benefit for these patients was clear in terms of their control over myeloma and many of these infections can be [potentially] prevented with measures such as pneumocystis prophylaxis.

How do you see this agent fitting into the current treatment paradigm for MM?

Teclistamab is going to be a workhorse for us and patients with heavily relapsed/ refractory disease, in line with its FDA approval. [With] the availability to give it quickly and the excellent safety and efficacy profile, it will be the therapy of choice for many patients in those late lines of therapy. This will be easier for centers to use compared with the complexity of CAR T-cell therapies, even if [those] are a bit more potent.

There is also potential with teclistamab fixed-duration therapy, especially if it is used earlier [during] MM therapy. So far in the clinical trials, it has been given [via] continuous dosing, but we have all had patients who have had to stop it for one reason or another, often for infection. In those patients, at least my experience is that they seldom progress after it stopped even for many months. That raises the possibility that patients could receive fixed courses of this drug, especially earlier on in MM therapy and get the best of both worlds—the upside of its potent antimyeloma activity without the downside of infection risks that may come with long-term exposure.

References

1. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed January 11, 2023. https://www.fda.gov/drugs
2. Tecvayli. Prescribing information. Janssen Biotech Inc; 2022. Accessed January 11, 2023. https://www.accessdata.fda.gov