IMS 2025 | The impact of induction therapy on outcomes for patients with functional high-risk myeloma

Earlier this year, the high-risk criteria for multiple myeloma were updated, and I think a lot of welcome changes happened with it. You know, for example, you know, 1p is now featured, TP53 mutations, so by sequencing is now featured. This is the first time that something besides cytogenetics are being included in the definition, the IMS/IMWG consensus criteria for high risk, and interestingly, a high beta-2-microglobulin, which is a measure of tumor burden, without any kidney issues is also considered high risk. Excellent steps, but again, we’re putting all of our eggs into this diagnosis bucket. All the patient’s lab values from diagnosis, their destiny forevermore is cast as high risk versus standard risk. And we know that it’s not that simple. We know that probably, depending on the study, 20 to 30% of patients have what we call functional high-risk disease biology, where they have a relapse earlier than expected. And many times we don’t know why. They don’t have any of the high-risk features that we typically know about. There may be things, you know, Dr Martin Kaiser published a paper showing that maybe gene expression profiling at diagnosis can explain a lot of these unexplained early relapses. But I can tell you that, you know, until we have those tools available, it’s terrifying for patients, really terrifying for me too, when someone’s suspected to have four years of mileage and remission after transplant, and all of a sudden they’re having a relapse eight months after transplant. I’ve had it happen. It’s devastating. One thing that’s always kind of lingered in our mind, that hopefully tomorrow we can kind of put this to rest during my oral session. You know, we know that functional high-risk disease biology, a lot of it’s driven by tumor biology, for sure. The myeloma cells are probably a bit more aggressive for whatever reason. We know that it’s partially driven by T-cell biology. The T-cells, particularly after transplant, often maintain some level of immunosurveillance. If the T-cells go, you know, defunct, then patients have a relapse early. People have always wondered whether the induction therapy matters. But the idea that, well, someone had an early relapse of transplant, but they didn’t get what I would have given in hindsight, like Dara-VRd quadruplet therapy. They only got CyBorD or they only got, you know, Vd or something along those lines. didn’t get a modern induction regimen. Maybe that’s why they’re having an early relapse and I shouldn’t be worried. Long story short, we looked at published data from three CIBMTR trials, which CIBMTR is the largest registry, I think, in the world of post-transplant outcomes. We looked at all the patients from those trials who had relapse within one year of transplant. We actually also looked at 18 months after transplant, 24 months after transplant, and we looked at what of the different risk factors that predict it, and was induction therapy one of those risk factors? Long story short, it was not. ISS stage mattered. So, apropos to my point earlier about beta-2-microglobulin does seem to make a difference. A high beta-2-microglobulin, high ISS stage, those patients have earlier relapses. Cytogenetic high risk, so deletion 17p, 4;14, etc., also a higher risk of functional high risk. But whether they got RVd, KRd, CyBorD, Vd, whatever induction regimen they got did not affect basic outcomes for patients in terms of functional high risk, their prognosis thereafter. Some limitations there, obviously, none of the patients in these published studies have gotten quad regimens, as an example, and they were all transplanted. Functional high risk can happen even for non-transplanted patients. But the point here is that when functional high-risk disease biology is identified, historically, those patients have very poor post-functional high-risk outcomes in terms of progression-free survival and overall survival from that point onwards, regardless of what induction therapy they received. So we need to reach into our bag of tricks and find better treatments for these patients. Dr Costa presented a CARTITUDE-4 sub-analysis last year, or two years ago, showing, for example, that in CARTITUDE-4, CAR-T performed way better than standard treatments for these functional high-risk patients. And indeed, I think that’s one of the areas of consensus this particular meeting is that not everybody needs CAR-T at first relapse, but for functional high-risk disease biology, no matter what they got at induction, honestly, even if they didn’t get a daratumumab-based induction regimen at frontline, if they have an early relapse, earlier than expected, I think CAR-T really should be in the discussion for them and really should be preferred.

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