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ESC 2026 | Emerging approaches being explored for AL amyloidosis
Ronald Witteles, MD, Stanford University, Stanford, CA, comments on the current therapeutic landscape for light chain (AL) amyloidosis, highlighting the significant progress made in lowering light chain levels and directly targeting clonal plasma cells, notably with the approval of daratumumab. Dr Witteles also emphasizes his enthusiasm for the potential of bispecific antibodies and CAR-T therapy for AL amyloidosis following positive early data. This interview took place during the 2026 European Society of Cardiology (ESC) Congress in Munich, Germany.
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Transcript
So once again, for light chain amyloidosis, it’s sort of similar to TTR. There are two ways we can think about it. Ways of knocking down the production of the pathologic clonal light chain, and then this question around depleters. So let me start on the clearly more successful side, which is the former. So the therapeutic landscape for AL amyloidosis has completely changed over the last couple of decades, and therefore outcomes have completely changed because we now have so many effective agents to lower light chain levels to kill the clonal plasma cells that drive the disease...
So once again, for light chain amyloidosis, it’s sort of similar to TTR. There are two ways we can think about it. Ways of knocking down the production of the pathologic clonal light chain, and then this question around depleters. So let me start on the clearly more successful side, which is the former. So the therapeutic landscape for AL amyloidosis has completely changed over the last couple of decades, and therefore outcomes have completely changed because we now have so many effective agents to lower light chain levels to kill the clonal plasma cells that drive the disease. The biggest one, the biggest frame shift was when daratumumab was tested and approved for AL amyloidosis. It doesn’t work for everybody, but it had a huge increase in hematologic response for patients. Now, I would say I am very excited about bispecific antibodies and CAR-T therapy for AL amyloidosis. We’re still in the early days of it, but the early data and my early clinical experience has been exceedingly positive. And my sense is that you might actually get more response to bispecifics and CAR-T in AL amyloidosis than even in myeloma, probably just because the overall clonal plasma cell burden tends to be much lower in AL amyloidosis. That’s a hypothesis, but I suspect it is probably true. So I think over the coming next few years, understanding what the place is for those sorts of new or more novel therapies is going to be a big part. And my guess is we’ll start moving a little earlier in the algorithm. Depleter agents. Those are more of a mixed bag. So there have been three major Phase III trials of depleters, and technically all three have failed. And the most recent one, you know, there may be some subtlety to it, and it seemed like the kappa light chain group seemed to derive benefits. But, you know, you have to be careful in looking at subgroups of overall negative trials. So I find that intriguing, but hardly definitive. And I think the main takeaway from depleters for AL amyloidosis is that despite a lot of hope, so far they’ve been a bit disappointing.
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