EHA 2025 | RedirecTT-1: the safety and efficacy of talquetamab and teclistamab in R/R multiple myeloma with EMD

Extramedullary disease is a real problem in patients with multiple myeloma. Patients who develop true extramedullary disease were the plasma cytoma is developing not in contiguity with the bone lesions. It could be in different organs of tissue but these are truly extramedullary. And these, whether they are diagnosed at the time of initial myeloma diagnosis or they develop subsequently at the time of relapse, is usually associated with very poor outcomes. In fact, many of the treatments, including some of the novel immunotherapies like CAR-T and bispecific antibodies by itself, often give responses higher than what we have seen in the past, but they often tend not to be very durable as these lesions, which are biologically very complex, often break through these treatments. So the RedirectTT-1 trial, the phase one original study had looked at the safety and efficacy of talquetamab and teclistamab used in combination in patients with relapsed myeloma. So among those 94 patients, there were 18 patients who had extramedullary disease and had responses that we had not previously observed with a response rate of about 61% among that 18 patients. So that led to the interest in trying to explore the combination of TEC and TAL in patients with extramedullary disease. So this was a phase two trial that was a cohort within the RedirectTT-1 trial that only enrolled patients with true extramedullary disease. So they had to have at least one lesion that was non-contiguous to bone, at least two centimeters in size. But these patients did not need to have a secretory or measurable disease by paraprotein that we typically require for many of the myeloma studies. So in fact, almost 40% of the patients did not have any measurable disease by protein in this particular cohort. So this is truly patients with an unmet need, both in terms of the fact that they had extramedullary disease, but also the fact that they are often not included in clinical trials for the lack of paraprotein. So we enrolled a total of 90 patients on this trial. The profile is very similar to that, what we typically see in the context of relapsed disease. Most of these patients, all these patients are triple class exposed. Many of them were penta drug exposed. Almost 30% of these patients had seen a prior bispecific antibody or a BCMA targeted therapy or a CAR-T. And most importantly these patients, responses were assessed very uniformly using a central imaging with PET or MRI or both. So these patients were treated with a step-up dosing there were three step-up dosing for teclistamab as well as talquetamab and then patients would get the full dose. And the full dose was given every two weeks for four cycles. And then patients could go to every month if they had a VGPR. Or after six cycles, everybody could go to once a month. With this approach, we saw that the overall response rate was about 80% in this patient population with extramedullary disease. The median progression-free survival was about 15.4 months for the entire cohort. And the median duration of response was a little over 13 months. Again, the follow-up is only about 13 to 14 months at this point in time. But what we saw was that the majority of the patients, almost two-thirds of them, still continue on therapy at this point at the latest data cutoff. And the overall discontinuation rate was fairly low because of adverse events. In terms of the adverse events itself, again, the toxicity profile was no different than what we have seen with bispecific antibodies in general, and particularly with teclistamab and talquetamab. So we did see common hematological toxicity, very similar to what we have seen with bispecific antibodies in general. Of particular importance is the fact that we did not see any new toxicities associated with the combination. We did see cytokine release syndrome in about 70 to 80% of the patients, mostly grade 1 or 2. We did see ICANS in about 12%, mostly grade 1 or 2. And most of this happened during the step-up dosing with the first dose. And there were 10 deaths on treatment or in the trial. Five of them were related to infections. At least three or four of them were in the context of hypergammaglobulinemia or disease progression. And we also had five non-infectious deaths that only one of them happened in the ICANS and was considered related to therapy. So all in all the results suggest that the combination of teclistamab and talquetamab is providing a response rate a depth of response and a durability of response that we typically have not seen in the context of extramedullary disease and certainly seems to reflect a step forward. Obviously you know how will this play out in the clinical practice and what will a trispecific antibody like the one that was presented at ASCO be an alternate approach for these patients. But nevertheless, I think this is another set of evidence showing that we are making progress in this disease.

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