Teclistamab Approval Adds to Bucket of Relapsed/Refractory Multiple Myeloma Options

The addition of bispecific antibodies like teclistamab (Tecvayli) to the treatment armamentarium of late relapsed/refractory multiple myeloma provides an option for a patient population who has already progressed on several existing therapies, according to Amandeep Godara, MBBS. 

Teclistamab was granted accelerated approval by the FDA on October 25, 2022, for adult patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy. This was based on findings from the phase 1/2 MajesTEC-1 trial (NCT04557098), which showed that the agent elicited an objective response rate of 61.8% (95% CI, 52.1%-70.9%). The estimated duration of response was 90.6% (95% CI, 80.3%-95.7%) at 6 months and 66.5% (38.8%-83.9%) at 9 months.¹

The agent not only exhibits comparable efficacy with CAR T-cell therapies, but is simpler to administer and more widely available, notes Godara, a medical oncologist at Huntsman Cancer Institute and assistant professor in the Division of Hematology and Hematologic Malignancies at the University of Utah in Salt Lake City. Its use both alone and in combination with current regimens is therefore of great interest for current investigations, he noted.

“The current lineup of therapies in clinical development is going to change how we treat multiple myeloma in [the next] few years,” Godara said in an interview with OncLive^®. “By providing these options for our patients, we are [expanding] therapeutic options for patients who might not have other SOC therapies available when they relapse.”

In the interview, Godara expanded on the advantages and limitations of teclistamab monotherapy in patients with late-relapsed myeloma, discussed the best use of bispecific antibodies and CAR T-cell therapy in this population, and highlighted ongoing efforts to mitigate the impact of treatment-related toxicities and improve accessibility across the paradigm. 

OncLive: What advantages does single-agent teclistamab provide for patients with late relapsed multiple myeloma compared with CAR T-cell therapy?

Godara: Teclistamab is the first bispecific antibody approval in multiple myeloma. Similar to CAR T-cell therapy, it is currently approved for patients who have had 4 prior lines of therapy, including a proteasome inhibitor, immunomodulatory drugs, and an anti-CD38 antibody.

The advantage of teclistamab is that it's available off the shelf. CAR T-cell therapy [is associated with] significant manufacturing time and [sometimes] manufacturing failure, which could delay treatment availability for patients. Those disadvantages are not a problem here with a bispecific antibody, because the antibodies are preprepared.

What benefits were seen with teclistamab in the relapsed population as evidenced in the MajesTEC-1 trial?

The MajesTEC-1 trial looked at teclistamab in over 100 relapsed/refractory patients who had at least 5 prior lines of therapy. We saw that this therapy could be started quickly, [and elicit] either very good partial responses or complete responses in most patients. [However,] there are certain caveats to using bispecific antibodies.

What is important to note about the toxicity profile of bispecific antibodies?

Just like CAR T-cell therapy, bispecific antibodies can cause cytokine release syndrome [CRS]; they can also cause immune effector cell-associated neurotoxicity syndrome [ICANS]. The rate of these toxicities is also like what we see with CAR T-cell therapy. When a patient is started on teclistamab, a step-up dosing schedule [is employed] to mitigate the risk of CRS and neurotoxicity. At our institution, step-up dosing is currently done in the hospital. Patients are hospitalized for 48 hours and monitored for CRS and ICANS so that we can promptly make any interventions if [adverse effects (AEs)] occur.

What patient factors are important to consider when selecting between a CAR T-cell therapy and bispecific antibody in this space?

Deciding [between] CAR T-cell therapy or a treatment [with a] bispecific antibody [depends on if] a patient's relapse is aggressive. If it is an aggressive relapse, and we don't have any other effective treatments to control the disease, a bispecific antibody could be useful. [This is] because we can start [treatment] promptly and [obtain] responses within a short period of time after starting treatment. If we are considering CAR T-cell therapy for aggressive relapse, we might have to [use] bridging therapies to control the disease and [account] for the manufacturing delay.

The other thing to consider in terms of toxicities for bispecific antibodies is the infection [rate]. Generally, these infections occur 1 to 2 months after the therapy has been started. Opportunistic infections like pneumocystis pneumonia or cytomegalovirus were rarely seen in patients with multiple myeloma but occur at higher rates with the use of bispecific antibodies. To minimize the risk of infections and [treatment-related] discontinuation or delays, we are taking intensive supportive care measures for these patients. These include using anti-microbials and giving prophylactic intravenous immunoglobulin [IVIG].

[Overall,] the risk of infection in approved or developing bispecific antibodies is [relatively high] and is increased when [these] therapies are combined with other myeloma drugs like daratumumab or lenalidomide. Before we use bispecific antibodies [as a standard] treatment for multiple myeloma, we must [learn] how to manage these toxicities, [including] the risk for infections.

What research is addressing toxicity concerns?

There are clinical trials focused on how to best mitigate these toxicities. At the 2022 ASH Annual Meeting, we saw an update on the use of prophylactic tocilizumab (Actemra) with the bispecific antibody cevostamab. [This agent] targets the FcRH5 receptor on the myeloma cell, and the CD3 receptor on a T-cell. The incidence of CRS was drastically reduced with tocilizumab compared [with] patients who did not. Using prophylactic tocilizumab could mitigate the risk for CRS or ICANS, and [could] help [some] patients avoid hospitalization.

Another study [of fixed-duration] cevostamab was presented at ASH 2022. Based on currently available data, therapies like cevostamab must be used indefinitely to maintain a response. This study looked at a fixed 12-month duration of bispecific antibody treatment in multiple myeloma to see if the risk of toxicity would be mitigated in these patients. Given that many [patients experience] deep responses after receiving a bispecific antibody, the trial [also aimed] to see if a [patient's] response could be maintained even in the absence of a bispecific antibody.

The response rate in these patients was anywhere from 36% to 56%, and the risk of infection was around 40% to 45%. This is on the lower end of the risk of infections that we have seen with the other bispecific antibodies. Most patients who completed 12 months of treatment continued to be in remission at the trial's last follow-up. Patients who discontinued therapy due to intolerance or toxicities [also] continue to [show] a 9-month median duration of response. This tells us that we could use a fixed-duration [schedule] to still achieve good responses with bispecific antibodies [while] mitigating associated long-term toxicities.

How could this type of research improve future treatments in relapsed multiple myeloma?

We're entering a new era for therapies in multiple myeloma. The current lineup of therapies in clinical development is going to change how we treat [patients with] multiple myeloma in [the next] few years. We are [especially focused on] patients who are triple- or penta- refractory and relapse after they have received the anti-CD38 antibody, proteasome inhibitors, or immunomodulatory drugs. My suggestion would be to refer these patients to centers [that can safely monitor] CAR T-cell therapy or bispecific antibodies, or [enroll them in] new clinical trials.

Currently, our patients who are relapsing don't have any available SOC therapies. At Huntsman Cancer Institute, we have several clinical trials that [aim] to [make] these new innovations in multiple myeloma [more accessible] to our patients. [These will look at] bispecific antibodies, CAR T-cell therapies, and bispecific antibodies in combination with the other myeloma drugs.

Editor’s Note: Dr. Godara reports serving in a consulting or advisory role for X4 Pharma

Reference:

1. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed January 11, 2023. https://www.fda.gov/drugs