EHA 2023 | Integrating BCMA-targeted agents in earlier lines of therapy for R/R multiple myeloma
Rakesh Popat, BSc, MBBS, MRCP, FRCPath, PhD, University College London Hospitals NHS Foundation Trust, London, UK, comments on the possibility of introducing BCMA-targeted regimens earlier in the treatment of patients with multiple myeloma. Dr Popat explains that data has shown that treatments are more effective in earlier lines of therapy (LOT) and clinical trials including KarMMa-3 (NCT03651128) and CARTITUDE-4 (NCT04181827) have shown the efficacy and improved tolerability of CAR-T therapy in earlier LOT. Dr Popat also comments on treatment sequencing, explaining the mechanisms of resistance to T-cell engagers and antibody-drug conjugates. This interview took place at the 28th Congress of the European Hematology Association (EHA) 2023 in Frankfurt, Germany.
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Transcript (edited for clarity)
We are seeing a number of BCMA-targeted treatments coming through and we already have two CAR-T cell products licensed, namely cilta-cel and ide-cel, and one bispecific BCMA antibody, teclistamab. But these are all licensed for patients who are multiple relapsed, typically in the fourth/fifth line and beyond setting and they’re triple class exposed. What we do know historically from other myeloma treatments is that if you move into earlier lines of therapy, then these treatments are better...
We are seeing a number of BCMA-targeted treatments coming through and we already have two CAR-T cell products licensed, namely cilta-cel and ide-cel, and one bispecific BCMA antibody, teclistamab. But these are all licensed for patients who are multiple relapsed, typically in the fourth/fifth line and beyond setting and they’re triple class exposed. What we do know historically from other myeloma treatments is that if you move into earlier lines of therapy, then these treatments are better. And we’re already seeing early data from bispecific T-cell engagers at early lines of therapy and we’re seeing improved responsiveness. What’s interesting is that we’ve recently seen CAR-T data from KarMMa-3 and CARTITUDE-4 for patients one to three, or two to four prior lines of therapy, and again, we’re seeing very good efficacy results. But I think more importantly, the safety signals are better because we’re able to treat a more sensitive type of disease and we have lower rates of CRS and ICANS.
We are also seeing the same with antibody-drug conjugate belantamab mafodotin, with combination data with pomalidomide, with the ability to reduce the dosing schedule to Q8. Once you do that, you see a median progression-free survival of 21 months with pomalidomide and much lower levels of ocular toxicity. So there is very exciting data moving all of this forward.
But the challenge that then occurs is: how best should we sequence this? Because we now have antibody-drug conjugate combinations with bispecifics and CAR-T cells, and what we’re looking at is the impact of doing this. With belantamab, what’s interesting is that you don’t tend to get BCMA loss – the mechanisms of resistance are different. However, with more immune-based treatments, we do see BCMA loss at about 8 to 10%. But on top of that you probably get some mutations in the binding site, and the quantification of that we still don’t know, but it’s going to be higher than that 8 to 10%. And then finally, with the immune-based regimens, you get T-cell exhaustion.
So putting it all together, what we can’t do is move from a T-cell engagement to a CAR-T cell, there’s some concerns about the fitness of the T-cells moving forward with that. But we may be able to sequence antibody-drug conjugates and the immune-based therapies. However, the data that’s emerging is that you do need to leave a treatment-free interval between these two agents of at least six months.
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