Teclistamab, Daratumumab, Pomalidomide Is Feasible in Multiple Myeloma

Anita D'Souza, MD

According to safety and efficacy data from the MajesTEC-2 (NCT04722146) and TRIMM‑2 (NCT04108195) trials, the combination of teclistamab-cqyv (Tecvayli), daratumumab (Darzalex), and pomalidomide (Pomalyst) was feasible, leading to promising efficacy in patients with multiple myeloma.¹

In MajesTEC-2 (n = 17) and TRIMM-2 (n = 10), patients were enrolled and given the combination. At the data cutoffs of April 9, 2024, for the TRIMM-2 study and April 15, 2024, for MajesTEC-2, the median follow-up was 25.8 months (range, 0.5-39.6) and the median treatment duration of teclistamab, daratumumab, and pomalidomide was 12.0 months (range, 0.5-33.9).

According to findings presented at the 2024 American Society of Hematology (ASH) Annual Meeting, the overall response rate among patients was 88.5%, the very good partial response or better rate was 84.6%, and the complete response or better rate was 61.5%. The median time to first response was 0.95 months (range, 0.9-1.9). Further, the median duration of response was non-estimable (NE; 12.2 months-NE), and the median progression-free survival was 26.5 months (11.2-NE).

For safety, any-grade adverse events (AEs) seen in at least 50% of patients included neutropenia (77.8%), cough (59.3%), and cytokine release syndrome (CRS; 55.6%). AEs that were seen in at least 15% of patients and deemed grade 3 or 4 consisted of neutropenia (77.8%), lymphopenia (22.2%), anemia (18.5%), COVID-19 pneumonia (18.5%), and pneumonia (18.5%). One case of ICANS was observed;it was grade 1and was resolved. Twenty-five patients had infections, 63% of which were grade 3 or 4. The most common were upper respiratory infection (44.4%), pneumonia (29.6%), sinusitis (29.6%), and COVID-19 infection (25.9%).

Three patients discontinued treatment due to their AEs. Seven deaths were linked to the study, including 1 from progressive disease and 6 from infections. All of the infections that were fatal occurred prior to the initiation of an intensified infection prophylaxis plan, which included increased emphasis on recommendations for IVIg supplementation. Once that was implemented, there were no additional fatal infections.

Microscopic, photorealistic image of myeloma cells - Generated with Adobe Firefly

In an interview with Targeted Oncology^TM, Anita D'Souza, MD, professor of medicine at the Medical College of Wisconsin, discussed the results from the MajesTEC-2 and TRIMM-2 trials and what the implications are for oncologists and patients with multiple myeloma.

Targeted Oncology: What did you present at ASH this year?

D'Souza: The ASH abstract that covered the MajesTEC-2 and TRIMM-2 data was a very specific cohort of patients on these 2 trials who were treated with the combination of teclistamab, daratumumab, and pomalidomide. This was a pooled analysis of patients who received this triple-drug combination across these 2 trials. These trials had enrolled patients between 2020 and 2021, so we had a longer follow-up for patients—combined, it was a little over 2 years, slightly longer for the TRIMM-2 patients and a bit shorter for the MajesTEC-2 patients.

For MajesTEC-2, these were [patients with] myeloma who had received 1 to 3 prior lines of therapy. For TRIMM-2, these were patients who had 3 or more prior lines of therapy. So definitely a more heavily pretreated patient population for TRIMM-2 compared with the MajesTEC-2 cohort. We had a total of 27 patients who received this triple-drug combination—17 from MajesTEC-2 and 10 from TRIMM-2.

What were the results?

What we saw in the baseline characteristics among these 27 patients—just as expected based on the eligibility criteria—was that patients from TRIMM-2 had more prior lines of therapy, with a median of 4 compared to 1 in the MajesTEC-2 cohort. They also had higher prior exposure to anti-CD38 monoclonal antibodies, as well as prior pomalidomide. Many of them were refractory to these drugs, and more patients in TRIMM-2 had extramedullary disease.

What we saw was that the 3-drug combination had a very high overall response rate at upwards of 85%. Even taking into account patients who had prior daratumumab exposure, the response rates were over 75%, including a very high rate of complete response or better. Among the patients who had a response, we saw that these responses were very durable as well. So, patients who derived benefit from the combination were able to maintain that benefit for a period of time.

However, along with that good response rate, we also saw that there were lots of infections, and many patients had hypogammaglobulinemia, which is something we expect with exposure to BCMA-directed therapies. Given the timing of the study—2020 to 2021, during the height of the COVID-19 pandemic—we did see a lot of infections, including COVID. This was also the time when we were just beginning to understand how to use these drugs, so immunoglobulin replacement was not something that was mandated. We saw a very high prevalence of hypogammaglobulinemia, defined as an IgG level of less than 400 mg per deciliter.

What we saw was that there were 6 patients who died during treatment due to infections. Four of these deaths were from COVID-19 pneumonia, 1 from another unspecified pneumonia, and 1 patient from monobacteremia. Four of these 6 patients who died from infection had hypogammaglobulinemia prior to the onset of infection and were not receiving immunoglobulin replacement. So, I think what this tells us is that this combination is effective, but you have to administer it carefully. You have to monitor IgG levels and replace them if the levels are low. Once immunoglobulin replacement was strongly recommended—starting around 2023, as we learned the power but also the risks of these therapies—we began mandating immunoglobulin replacement. Since doing that, there have been no further infection-related deaths.

How do you think this combination will impact the relapsed/refractory multiple myeloma treatment landscape?

I think it is yet to be seen. One of the limitations is that this is a small cohort, and it is a pooled analysis across 2 patient populations. One of the things we always think about is: If there is a higher risk of infection, is it one of the particular drugs that you could withdraw and still see a good response? That type of question is something our analysis is unable to answer because we just don't have the number of patients. Also, a similar comparison between the two studies is challenging because they had different eligibility criteria and different kinds of patients.

Now, we also have to put this in the context that teclistamab combined with daratumumab and lenalidomide is being studied as first-line therapy or for earlier relapse. So, I think we will have to wait for all that data to play out to understand where this fits in. But I think it gives an option—a combination like this, where you're combining a bispecific antibody with a monoclonal antibody and adding an immunomodulatory drug, makes a lot of sense immunologically. And now, practically, we can show it is feasible. As long as you are doing it with careful infection mitigation strategies, it is also safe to use.

Are there any next steps or ongoing research similar to this?

There are a number of studies trying different immunomodulatory drugs. I think the focus currently is on the lenalidomide combination with teclistamab and daratumumab. I think time will tell whether pomalidomide will be studied further. We need to wait to see how the teclistamab/daratumumab/lenalidomide combination in newly diagnosed myeloma plays out. There is also going to be a cooperative group study where these combinations will be explored. So, it is too early to say how the pomalidomide combination will come into play. Initially, we were all a little concerned about the infectious complications. To see that by using immunoglobulin replacement, you can mitigate this risk to a big extent is certainly reassuring.

REFERENCE:

1. D'Souza A, Costa LJ, San-Miguel JF, et al. Teclistamab, daratumumab, and pomalidomide in patients with relapsed/refractory multiple myeloma: results from the Majestec-2 cohort a and Trimm‑2 studies. Blood. 2024;144(suppl 1):495. doi:10.1182/blood-2024-200181