Teclistamab Provides a Superior Response for Patients with R/R Multiple Myeloma

CASE

• A 63-year-old man who was diagnosed 8 years ago with multiple myeloma (IgGκ).
• He presented with penta-refractory disease progression; he had received 4 prior lines of therapy that included autologous stem cell transplant, 2 proteasome inhibitors (PIs), 2 immunomodulatory drugs (IMiDs), and 1 anti-CD38 antibody.
• He lives in a rural community.
• Medical history includes hypertension controlled with lisinopril.
• ECOG performance status: 1
• He asked about chimeric antigen receptor (CAR) T-cell therapy, but after counseling, he opted to pursue an alternative therapeutic due to the length of waiting lists at accessible institutions.

Targeted Oncology^TM: Please discuss the evidence for efficacy of teclistamab in patients with relapsed/refractory multiple myeloma (R/R MM).

Approval for teclistamab was supported by the data from MajesTEC-1 [NCT04557098], a...single-arm, multicohort, open-label [phase 1/2] study.¹ In this trial, 110 patients [are currently under] study. These are patients with advanced myeloma on this treatment [for whom] this compound showed efficacy.

Rafael Fonseca, MD

Director of Innovation and Transformational Relationships

Mayo Clinic

Scottsdale, AZ

[Early results] have already been published in the New England Journal of Medicine, with the schedule for administration is starting with step-up doses of 0.06 mg/kg and then 0.3 mg/kg; then they will go up to 1.5 mg/kg.

The drug was administered on a weekly schedule and was given subcutaneously. That’s how this trial was designed, with the primary end point being overall response rate [ORR], and then secondary end points included duration of response [DOR], very good partial response [VGPR], complete response [CR], time to response [TTR], progression-free survival [PFS], and overall survival [OS].

The demographics of the patients are representative [of patients with] myeloma, with a median age of 64.7. We have 15% of patients [older than 75 years], which we can talk about more because one of the interesting things about bispecifics—and CAR T-cell therapies, for that matter—is that there may be fewer limitations when it comes down to age [in determining] who may be a candidate for these types of therapies. [For a patient with] refractory status, [they noted] about 30% of the patients were triple class refractory to 5 drugs.

The drug works rapidly, as [there was] a median TTR of 1.2 months, and the median DOR for these patients was 18.4 months [95% CI, 14.9-not estimable].1 If you look at comparative data, save for real-world evidence, [from] some of the studies...out there for patients [with disease this advanced], most of the patients will have a median DOR somewhere between 6 and 9 months. Teclistamab is clearly superior. The PFS is 11.3 months [95% CI, 8.8-17.1], and that includes responders and nonresponders, and without maturity, the OS is at 18.3 months [95% CI, 15.1-not estimable].

For ORR, it’s interesting that there’s less of a gradient than what we see sometimes with chemotherapy.1 We see ORR reported at 63% [95% CI, 55.2%-70.4%]. Most patients responded quite deeply. We have a significant fraction of patients who had very deep responses, so the CR rate was close to 40%. VGPR was better, in close to 60% of patients, which is interesting in that it’s a little bit more dichotomous.

This is not a completely accurate comparison, but in many ways, I think of the outcomes that we are seeing in some other trials with CAR T-cell therapies and bispecifics and a little bit what you see with allogeneic stem cell transplant approaches, which are more binomial. There’s that first space, but then some of the patient do better and can do well.

What are the safety considerations for teclistamab in patients with R/R MM?

All patients experienced some adverse events [AEs].1 Most of them were not serious AEs, but patients commonly expressed hematologic toxicity, so neutropenia, anemia, those things, of course. One of the things to highlight is infections. Infections were seen in many patients, and I think this is one of the things that we feel the need to better understand and [know] how to mitigate and prevent. Grade 3/4 [infections] were [present in] up to 44% of patients. Likewise, hypogammaglobulinemia was seen in a large fraction of patients, at 75%.

It’s important to recognize that this trial [was ongoing during the peak of COVID-19]. So there were 12 COVID-19–related deaths, but there were other ones [with complications] like pneumonia, hepatic failure, and progressive multifocal leukoencephalopathy.¹ So these are things that we need to monitor closely as we go forward. My hope would be that as we’ve learned to monitor things like infections in the setting of transplant and other CAR T-cell therapies, perhaps preventive strategies could work here as well.

What should clinicians know in regard to cytokine release syndrome (CRS) with this therapy?

CRS was seen in 72% of the patients, but only one patient had a grade 3 or 4 [CRS].¹ As more physicians are learning how to use this and the strategies to do prophylaxis with some of the agents—[which] is not mentioned...in the package insert—potentially physicians are going to start doing things like that.² We’re hoping that it’s going to be more palatable for more widespread use.

The package insert comes with a reference to CRS as well as to ICANS [immune effector cell–associated neurotoxicity syndrome].² The CRS [occurred] in 72% of patients, with grade 3 in only 0.6%. Neurologic toxicity at grade 3/4 was only in 2.6%, and ICANS was reported in 6%. There are a number of AEs that have been seen with regard to neurologic toxicity: headaches, some motor dysfunction, and sensory neuropathy as well—this gets confusing because there are patients who have prior exposure to bortezomib [Velcade]—and then encephalopathy in a fraction of our patients.

There are some practical considerations regarding the dosing and the CRS- and neurotoxicity-preventive strategies.² A lot of what is being done includes step-up dosing for the medications. We have the step-up doses, as I mentioned, in the package insert: 0.06 mg/kg, 0.3 mg/kg, and 1.5 mg/kg. The hope is that you’re in the first phase of administration of some of those drugs. This will alleviate some of the risk associated with CRS. This drug is not the only one.

There are recommendations regarding premedication, [including] how to administer it and the use of corticosteroids, [histamine] H1 receptor antagonists, [and] antipyretics.² Because of the risk of CRS and neurologic toxicity, it is recommended that patients be hospitalized for 48 hours after the administration of all the doses [on] its step-up dosing schedule.

I don’t think this is as clear because of a number of things, including reimbursement....It doesn’t come as a mandate that it must happen, so you might see different hospitals and oncology groups manage this in different ways. Particularly, I suspect not all of them require hospitalization of patients.

^REFERENCES

^{1. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478}

^{2. Tecvayli. Prescribing information. Janssen Biotech Inc; 2022. Accessed December 15, 2022. https://bit.ly/3ZUOubU}