IMS 2026 | Mechanistic differences between isatuximab and daratumumab in multiple myeloma

Isatuximab and daratumumab both target CD38, but they bind to different epitopes. Obviously, they’re broadly the same, but in detail, subtly different. Daratumumab depends upon complement-mediated killing. Isatuximab does to a much lesser extent and kills more directly. There’s also preclinical evidence of effects on the T-cell milieu and, in particular, T-regulating cells. Furthermore, mechanistically, if you have 1q amplification in your disease, there is preclinical evidence that’s quite compelling that there is relative resistance to complement-mediated killing by 1q amplified myeloma. So there may be subgroups of patients who benefit more from isatuximab and may be perhaps less sensitive to daratumumab. This is a very complex area. I think the preclinical evidence is compelling. The clinical evidence is much more mixed. There’s clearly isatuximab’s activity in 1q-amplified disease. And if you look at the hazard ratios in IMROZ compared to the hazard ratios in CEPHEUS, two large phase 3s of in CEPHEUS daratumumab-based therapy versus in IMROZ isatuximab-based therapy in newly diagnosed patients who are not transplant eligible. They both work in 1q-amplified disease, but the hazard ratio for isatuximab is that much more favorable. Having said that, at this meeting at IMS, there’s a European study looking broadly at Dara and Isa-exposed patients, and the conclusions there are that Isa is safer and that Dara, in fact, may be more efficacious. I think we have to be careful and look carefully at that data and make sure we’re not comparing apples to oranges. But I think the debate continues. And in my opinion, isatuximab, especially now with the on-body infusional device, is going to be much more convenient for patients than it has been in the past. I think at the same time, daratumumab has a wonderfully established record. It has the FASPRO technology. So it’s clearly right there. Between the two, how I think about it at the moment is really based on this 1q story. That I am more impressed by clinically at the bedside. Otherwise, it’s very dependent on the patient and the setting overall. I think both antibodies are remarkable. They’ve transformed the treatment landscape. The whole CD38 story in itself is probably one of the greatest innovations in myeloma to date. I think in that context, understanding these differences does require further study. But right at this point I think it is reasonable to think of isatuximab as the antibody of choice in higher risk disease and at the same time to recognize the real value of both antibodies and so it’s not an easy question but it’s an important one and we’ll continue to ask it.

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