ASH 2025 | Redefining high-risk myeloma in the context of upfront quadruplet therapy and ASCT

So in the era prior to anti-CD38 monoclonal antibodies, we embraced the notion of functional high risk as a definition for patients who have disease progression either within the first 18 months of treatment or first 12 months after transplant to indicate a group that doesn’t do very well in subsequent line of therapy irrespective of their cytogenetic risk. And that definition was carved around the notion that the overall survival for those patients with subsequent therapy was inferior to two years. Now, with quadruple induction and consolidation autologous transplant, the prognosis for patients with newly diagnosed myeloma has greatly improved in general. So fewer patients are having progressions. However, it’s not too far of a stretch to hypothesize that those who do progress despite this therapy have a more, you know, biologically aggressive disease. So we need to reconsider what’s the optimal timing is to call functional high risk in the era of quad and transplant. So we use a data set, again, of over 300 patients, treated with quadruple therapy and autologous transplant and post-transplant consolidation and maintenance to interrogate what was the best cutoff. And the bottom line is the 36th month defines a population that with progression before 36 months have a subsequent overall survival of two years, was actually 23.8 months. So we propose that in this modern era, we should consider functional high risk anybody progressing within the first 36 months. And that has implications for, you know, describing cohorts or patient population in clinical trials. Now, we took advantage of this data set to also interrogate how those people do with subsequent therapy. And overall, there was a lot of use of carfilzomib, pomalidomide, reuse of CD38 monoclonal antibody. So those patients received the best available therapy. But some of those patients receive a T-cell redirecting therapy, either a bispecific or CAR T-cell, at the next line of therapy, either through clinical trial participation or more recently through the availability of cilta-cel in second line. And what we found is that in multiple variable analysis, even factor in the functional high risk at 36 months and cytogenetic risk, the functional high risk at 36 months remains predictive of worse response, worse progression-free survival, and worse overall survival. But the T-cell redirecting therapy is strongly associated with better progression-free survival with a hazard ratio of 0.17. So I think that is, again, another piece of data that puts in perspective how high-risk those patients are, despite having only one prior line of therapy, and suggests that the use of novel agents, particularly T-cell redirecting therapy of some capacity, can perhaps modify the natural history of this otherwise very deadly condition.

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