MajesTEC-1 and Teclistamab in Patients with Relapsed-Refractory (R/R) Multiple Myeloma

Dr Shaji Kumar reviews key efficacy and safety outcomes of the updated data from MajesTEC-1, evaluating teclistamab in patients with R/R multiple myeloma.


Shaji Kumar, MD: The activity we have seen with the bispecific antibodies is quite good. Bispecific antibodies are not something new in the cancer space. They have been around for awhile, but teclistamab represents the first bispecific antibody that has been approved for the treatment of multiple myeloma. As a class, the bispecific antibodies all work in a similar fashion. They are, as the name describes, bispecific, so the antibody has specificity both for CD3 that is on the T cell and a tumor antigen, which, in the case of teclistamab, is a B-cell maturation antigen. However, it can be different, such as FcRH5 for cevostamab or GPRC5D for talquetamab. Essentially, the antibody brings the tumor cells in close proximity with the immune cells, leading to an immune synapse formation and even tumor cell death.

The activity with the bispecific antibodies across the board with all these, including teclistamab and others that are in clinical trials, are promising response rates of upward of 60% in patients who are quite refractory to the available therapies. Given all the other options we may have available—the bispecific antibodies and, in this case, teclistamab—make good sense as the next line of treatment.

The MajesTEC-1 trial [NCT04557098] is the pivotal trial that led to the approval of teclistamab for the management of multiple myeloma. This included a phase 1 portion that first identified the recommended phase 2 dose of teclistamab given as a single agent. That was 1.5 mg/kg subcutaneously, weekly, with increased doses of 0.06 and 0.3 mg/kg. In MajesTEC-1, a fairly large number of patients were enrolled on that study, and the overall response rate was 62%. That included nearly 60% of the patients who have eGFR [estimated glomerular filtration rate] and almost a third of the patients who achieved a complete response or better. A significant proportion of the patients who achieved a complete response also were emerging negative in their assessment.

MajesTEC-1 was a phase 1/phase 2 study that looked at, first, the identification of the recommended phase 2 dose 4 teclistamab, followed by a phase 2 study that explored the first tolerated dose in these patients. There were 40 patients who were enrolled in the phase 1 study, which eventually determined that the recommended phase 2 dose is 1.5 mg/kg given subcutaneously. The phase 2 portion of the study at the recommended phase 2 dose enrolled a total of 125 patients.

This was a fairly heavily pretreated group of patients, with a median age of 64. Many of these patients had extramedullary disease, almost 17%, and almost a quarter of these patients were highly cytogenetic. These patients had many prior lines of therapy. There was a median of 5 prior lines of therapy, with almost three-quarters of the patients having had 4 or more lines of therapy. Most of the patients, 82%, had a prior transplant, including a few with allogeneic stem cell transplants. All these patients were triple-class exposed, and almost 75% of the patients were triple-class refractory. The overall response rate was 63%, and that included 59% of the patients who have eGFR or better and almost 40% of the patients who are in complete response. The minimal residual disease negativity rate at the 10–5 cutoff was 27% in the intent-to-treat patient population.

When you look at the overall response across different patient subgroups, you can see it benefited all patients, including some who were high risk, even though the response rates were lower in those who were International Staging System stage 3 compared with those who were stage 1. In addition, there was not as much benefit seen in patients who had extramedullary plasmacytomas, which continue to be a challenge in relapsed disease. When you look at the responses, they were quite durable. Again, we don’t have median progression-free survival for this cohort, but we have patients who have been on therapy for over 2 years at this point in time. When you look at the duration of response, the median was approximately 18 months, and the 12-month event-free rate was approximately 68%. When you look at this cohort of patients who are in complete response or better, the median duration of response was even longer for those groups of patients.

The median overall survival for this group of patients was 18.3 months. In terms of toxicity, the drug was fairly well tolerated. Cytokine release syndrome [CRS] was the most common toxicity encountered, and it was seen in approximately 72% of the patients. Thankfully, most of it was grade 1 or 2 and was managed with steroids and other supportive parameters in most patients, with some needing teclistamab, as well. The hematological toxicity—again, neutropenia was the most common, seen in approximately 70% of the patients, followed by thrombocytopenia, lymphopenia, and anemia. There was some gastrointestinal toxicity, injection site reactions, cough, and headache that were reported in several patients.

One of the adverse effects that clearly needs more review is the infection that was seen in these patients. Nearly three-quarters of the patients had infections, with nearly half of the patients having a grade 3 or 4 infection. There were also 19 deaths due to adverse events—almost 12 COVID-19–related deaths. Clearly, the infection is something we need to be very cognizant of as patients are getting started on teclistamab.

One-third of the patients ended up receiving teclistamab, but others were able to be managed with other measures. The median time to onset of CRS was approximately 2 days, and it lasted for anywhere from 1 to 9 days in these patients. Neurotoxicity was seen, but the overall rate was fairly low—mostly grade 1 or 2. Overall, there were 5 patients, with a total of 9 events. Most of this occurred concurrently with CRS, and all of them were fully resolved. MajesTEC-1 demonstrates the value of teclistamab in a heavily pretreated patient population, such as our patient whom we just talked about.

Transcript edited for clarity.

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