IMS 2025 | The impact of intensive chemotherapy-based bridging on outcomes of CAR-T therapy in multiple myeloma

This has been a hot topic in the field, actually, IMS, remains a hot topic. You know, what is the best bridging therapy option for our patients? We used to believe that bigger is better, and actually I led one of the first analyses of that at UCSF. I’m a senior author on it, where we looked at this question with regard to alkylators. We used to say that, look, this patient has aggressive disease biology, you know, high relapse, extramedullary disease, et cetera. Let’s fight fire with fire, right? The myeloma is aggressive. Let’s fire our heaviest multi-agent chemotherapy at them to bring everything down and get them to CAR-T therapy. And retrospective data didn’t work. Patients who got the high-dose aggressive chemotherapy actually had worse PFS after CAR-T cell therapy, and there are confounders in that. The U.S. Myeloma Consortium also looked at something similar and found the same result, basically. The patients who were getting intensive chemotherapy for their bridging regimens had worse outcomes thereafter, worse efficacy, and probably some level of confounding that the patients who have the aggressive disease biology are the ones that you feel obligated to give them all this aggressive chemotherapy, and those patients will do worse afterwards just because, again, they had the aggressive disease biology in the first place that made you want to give them the aggressive chemotherapy thereafter. So we’ve kind of been in a standstill with that where, you know, with both the studies that were published, you’re kind of like, well, probably it’s not good, but maybe it’s still helpful. And so Dr Franken and colleagues was a German analysis I wrote a commentary for, published earlier this year on Blood Advances, looked at the same question in their cohort and again found that patients, they did it by just the number of chemotherapy drugs in the regimen. And they found that the more alkylators there were, the more alkyl chemotherapy drugs there were in the regimen, the worse patients did in terms of progression-free survival after CAR-T. So they found the same conclusion. But what I really like about their paper is they took a deep dive into toxicities as well. And they found very clearly that those patients, the more chemotherapy that you got during bridging, the more ICAT, the more hematotoxicity, the more long-lasting your cytopenias were, and the higher your infection density is. Not just the number of infections, not just yes or no infections, but infection density. The number of infections per month was much higher in the patients who’d gotten one, two, or three chemotherapy drugs as opposed to zero chemotherapy drugs as part of bridging. When I’m talking about high-dose alkylators and efficacy, again, there are confounders there. The patients who have aggressive disease biology need aggressive bridging, and so maybe that’s why they’re having poor outcomes. So I can’t really blame the high-dose chemotherapy for poor efficacy, I don’t think, but I can blame the high-dose chemotherapy for the toxicities. There is no doubt in my mind that giving someone lots of cyclophosphamide and etoposide and doxorubicin and all these chemo drugs will cause their bone marrow to be suppressed, will cause them to have low blood counts, will cause them to have infections. That is very real. And I think this paper shows without a doubt here that, you know, bigger is not better. Bigger is actually worse. Using chemotherapy here is not the tool we think it is, actually harming a lot of our patients. Now, it’s easy for me to identify problems, right, without having a solution for them. And so in our commentary, what we talk about is a separate paper in Blood earlier this year that I was a part of, led by Dr Dhakal from MCW, Dr Sidana from Stanford, looked at the role of talquetamab as a bridging therapy. And basically, I think that is a far smarter and better option. We always talk about the IMWG using CAR-T therapy before bispecifics. This is one of the rare scenarios where we might recommend flipping that script, where someone has aggressive disease biology and you have access to talquetamab, which is a GPRC5D target bispecific, use that for bridging and then go to BCMA and CAR-T. Talquetamab does not cause cytopenia. Talquetamab actually does not cause much in the way of infections because it doesn’t actually hit normal plasma cells and B cells that much. So I think in all the ways for all the patients in the past where I may have been tempted to give them high-dose chemotherapy with bridging, now I would say let’s get them to four prior lines and give them talquetamab instead. I think it’s a far better option, both in terms of safety but also efficacy.

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