ASH 2025 | Phase Ib/II study of sonrotoclax with carfilzomib & dexamethasone in t(11;14) RRMM

At this ASH meeting, I had the privilege of presenting the initial result of the Phase Ib/II study of sonrotoclax in combination with carfilzomib and dexamethasone for patients with relapsed refractory myeloma carrying the 11;14 translocation. Now around 15 to 20% of patients with myeloma have the 11;14 translocation. And this cytogenetic abnormality is important because it predicts for sensitivity to BCL2 inhibitors such as venetoclax. Sonrotoclax is a second generation BCL2 inhibitor that is more potent than venetoclax. And we previously presented data from our BGB-105 study demonstrating that sonrotoclax and dexamethasone was quite effective for heavily pre-treated patients with 11;14 translocation. And so we now present the early result of another arm in that study, this time exploring sonrotoclax in combination with carfilzomib and dexamethasone. And the rationale for this combination is that both carfilzomib and dexamethasone can potentiate BCL2 dependence within the myeloma cells and in a sense, sensitise the myeloma cells to sonrotoclax. So in this study, we enrolled 22 patients in the dose escalation part one. And these patients were quite heavily pretreated. They had a median of four and up to eight prior lines of therapy. And the vast majority of them were triple class exposed or refractory. And we explored different dosing combinations of sonrotoclax and carfilzomib, and the data that was presented here at ASH came from three of these dosing cohorts consisting of sonrotoclax, 320 milligrams or 640 milligrams orally, daily, in a 28-day cycle, together with carfilzomib, either 56 milligrams per meter squared or 70 milligrams per meter squared on days 1, 8, and 15 in a 28-day cycle, and dexamethasone orally weekly, and treatment was until disease progression. We observed quite a favourable safety profile. The overall haematological adverse events occurred in just over half of all patients, but the grade 3 and 4 neutropenia, thrombocytopenia and anaemia were each quite modest, only in 14%, 23% and 18% of patients respectively. Infections of all grade occurred in just over half of patients but only 23% of patients had grade three or four infections and the nature of these infections were quite variable and importantly there were no signal for opportunistic infections. From an efficacy perspective, the results were quite encouraging in that we saw an overall response rate of 86% with a CR or better of 38%. And after a median follow-up of 10.4 months, the median duration of response was not reached, and the median progression-free survival was not reached. So all in all, these preliminary data would suggest that the combination of sonrotoclax, carfilzomib and dexamethasone is highly deliverable, it’s safe, and with very robust response in a group of patients with 11;14 translocation who continue to have ongoing unmet need, partly because this population tend to respond less well to the traditional IMiDs proteasome inhibitors and anti-CD38 monoclonal antibodies. And so we’re now moving one step closer towards providing effective and precision-based medicine for this group of biologically distinct patients.

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