SOHO Italy 2025 | Managing early relapses in multiple myeloma: bispecifics, ADCs & CAR-T

One of the things that’s really evolved across the last 10 to 15 years in myeloma has been the utilization of the novel therapies. These are drugs like IMiDs, like Revlimid, proteasome inhibitors like bortezomib, and monoclonal antibodies like daratumumab. But one of the things we’ve also seen is the increased utilization of quadruplet-based induction therapy, meaning most patients now are going to be receiving either a triplet or a quad up front and many of our patients being exposed, if not refractory to, IMiDs, PIs, and monoclonals. Meaning we need to reframe how we approach early relapse in myeloma because although regimens like Dara-Pom-Dex have been highly utilized in the early relapse, some of these patients are going to be now Dara-refractory going into second line. So this is where some of the BCMA-targeted agents are really going to take a foothold. 

Now, of course, there’s been two big studies, KarMMa-3 and CARTITUDE-4, looking at ide-cel and cilta-cel in early relapse compared against CD38 and other comparator regimens, and both have come up superior. So for younger, fitter patients, especially those with functional high-risk, we really ought to consider the use of CAR-T either in first relapse with ciltacabtagene autoleucel or second relapse with idecabtagene vicleucel. 

Bispecific antibodies are not yet approved in early relapse. We’re hoping with the subsequent readout of a number of studies, including MajesTEC-5, that we will have them available perhaps later in the year or early next year, either as monotherapy or in combination. 

And at the moment, ADCs are not approved. Belantamab mafodotin was approved as a single agent, then taken off of approval in the US. However, based on the recent DREAMM-7 and DREAMM-8 studies reading out positive, we anticipate a likely re-approval for the combination of either Belantamab-Vel-Dex or Belantamab-Pom-Dex or both. And seeing as the fact that Belantamab-pomalidomide-dex has had durations of remission or both regimens around three years, you could imagine that if you gave a patient who’s older in the community who doesn’t have access to a bispecific or a CAR-T a CEPHEUS or IMROZ-like approach up front, Isa-VRd or Dara-VRd, and then follow them at first relapse with Belantamab-pom. Well, Isa-VRd had a median progression-free survival of around 90 months, and Belantamab-Pom is probably around 36 months. So we’re getting patients close to a decade of estimated PFS. And if diagnosed in your 80s, we are actually going to start having a larger number of people who never need to be admitted to the hospital, never need a transplant, but also don’t die of their myeloma. So it’s in a really an amazing new age. But embracing some of these novel targets like the BCMA drugs in the early relapse are very important.

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