Teclistamab in combination with subcutaneous daratumumab and lenalidomide shows promising results in patients with multiple myeloma

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Published: 12 Dec 2022
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Dr Emma Searle - University of Manchester, Manchester, UK

Dr Emma Searle speaks to ecancer about the results from one cohort of MajesTEC-2, a phase1b, multicohort study looking at teclistamab in combination with subcutaneous daratumumab and lenalidomide in patients with multiple myeloma.

She explains that this was a non-randomised trial where all patients received the same combination and, as a phase1b trial, the primary endpoints intended to determine the safety and tolerability of this combination.

Dr Searle reports that there were no safety signals beyond what was expected and that the overall response rate from the mature data was a promising 100%.

This is a first in combination study of a bispecific antibody called teclistamab along with standard of care agents in the form of daratumumab and lenalidomide. It was a non-randomised, phase Ib trial that treated patients with relapse multiple myeloma. The data that I’m presenting here at ASH is just for one cohort of this trial, and that was conducted in patients who have received one to three lines of therapy including an IMiD and a proteasome inhibitor previously.

What was the methodology used in the study?

It was a non-randomised phase Ib trial, so all the patients received the same combination and there was no placebo or control arm. The patients were treated with two different doses so we started off treating with 0.72mg/kg weekly after initial step-up dosing period, and as the trial went on, we moved to 1.5mg/kg weekly, and then those patients that were treated at the higher dosing level were then moved to fortnightly dosing with a 3mg/kg dose. The daratumumab was given, as per usual, at 1800mg subcut following the approved dosing schedule, and the lenalidomide was given at a dose of 25mg for 21 days out of every 28 day cycle.

What were the key findings?

The findings, obviously this was a phase Ib trial, so the primary endpoints really were about understanding the safety and side effect profile of this combination, with key secondary endpoints being the overall response rate, time to response, and response duration. The key findings so far, it’s early data, are that there are no safety signals beyond those that we are already aware of for the individual agents. We did see cytokine release syndrome as we expected to from the data that we saw in MajesTEC-1, the phase I study of this agent. We did see that cytokine release syndrome is a very frequent event with the majority of patients experiencing it, but all but one patient experienced it during cycle one. The cytokine release syndrome was very manageable, patients were treated with tocilizumab for all grade 2 events and grade 1 events at investigator discretion; there were no grade 3 or 4 cytokine release syndrome events and no ICANS seen. We did see a high infection rate occurring in patients, as is often seen in combination myeloma studies. Fortunately, most of these infections were of low grade, though unfortunately we did lose two patients in this dosing cohort to infection - one to COVID-19 and one to multi-organ failure secondary to sepsis. So being vigilant for infection, using prophylactic measures, and early treatment is going to be very important.

The overall response rate was very high, so the pooled data from both dosing treatment cohorts showed an overall response rate of 93%, but actually if we break that down and we look at the more mature data from the 0.72mg/kg dosing cohort, the overall response rate was 100%, which is obviously a hugely exciting finding. The patients in that cohort had a medium follow-up of around about 11 months.

The patients in the higher dosing cohort where the data is less mature, so the patients have got a median duration of treatment of around about 6 months, had a lower response rate at the point of data cut-off, but it was still 90%. If we look at the trends for the patients across the whole study, we see that responses tend to deepen over time, so I would anticipate that in that high dosing cohort we probably will see response rates going up.

In the pooled data for the trial at the point of data cut-off 83% of patients remained on study. Three patients had progressed after the 32 initially treated; two patients had died, one from COVID and one from sepsis, as I already mentioned. But these responses, it’s very early data, but they look to be deep and durable. The CR or better rate is 55% and the VGPR or better rate is over 90%, so it’s a very potent combination. There are side effects that we all need to, as we come to use these treatments in the future, we all need to be aware of and vigilant for, but the activity level of the combination is high.

What does the future look like for this trial?

Obviously we were all excited by the MajesTEC-1 data, the response rate as monotherapy in multiply relapsed patients was very high at 63%. In combination in patients who are not as heavily treated we’re seeing even higher response rates, between 90-100%, depending on the maturity of the data. I think it absolutely justifies the comparison with standard of care in a phase III randomised trial, and this is planned in MajesTEC-7, which will compare teclistamab, daratumumab, and lenalidomide against daratumumab lenalidomide dexamethasone in newly diagnosed patients unfit for autologous stem cell transplant, or in those patients where autologous stem cell transplant is not planned as part of their initial therapy. So I think that will be a really interesting trial to see how this novel immune-based triplet compares to a well understood standard of care option.