Paul G. Richardson, MD: When you look at the impact of oral proteasome inhibition more broadly, it was a privilege to be a part of the TOURMALINE-MM1 study. In a recent report in the JCO [Journal of Clinical Oncology], we showed the final overall survival [OS] analysis. It crystallizes a lot of the points you made. The important message is that in this study, we randomized patients with [ixazomib plus] lenalidomide-dexamethasone vs lenalidomide-dexamethasone and placebo, and we were able to show that the overall survival and long-term follow-up of this study did not meaningfully change between the 2 arms. This is great news for patients because it means that those patients assigned to the control group had excellent salvage therapies because there was a significant PFS [progression-free survival] advantage to the triplet over the doublet. But it also points to another fact: interpreting overall survival in the relapsed/refractory space in myeloma is increasingly complicated because it depends on salvage therapies. As we think of interpreting data in this space, that becomes an additional consideration. Christina, what are your thoughts from this overall survival analysis from TOURMALINE-MM1?

Cristina Gasparetto, MD: You’re absolutely right. With the introduction of so many newer therapies, it’s impossible because the TOURMALINE-MM1 was targeting patients in early relapse. We were looking for a prolongation, a durability of response. Overall survival ultimately is the major end point. I ask, “Can we prolong the life of patients with myeloma?” This is good and bad. This is bad because we didn’t show that with this combination that we could impact the overall survival. But this is very good because we can rescue patients with additional therapies. That’s why I have a lot of questions about this combination in the newly diagnosed setting, as well as in the relapsed setting, or whether it’s still an effective combination. You can interpret the data either way.

Paul G. Richardson, MD: This is a very interesting point. In the relapsed/refractory space, there are a couple of other studies that we need to be aware of. In the BELLINI trial with venetoclax, we saw substantial PFS benefit across the board, but the survival switched. For those patients who aren’t 11;14 translocated, there was survival loss and decrement, pointing to a different phenomenon. That’s obviously not what we’re seeing here. To your point, Christina, we’re seeing that the triplet generates PFS advantage in early relapse. But in terms of the numerous options available, that doesn’t mean overall survival difference in terms of longer-term follow-up. Critically, it also tells us that the ixazomib platform, by virtue of its excellent tolerability, also doesn’t do harm later. This is very relevant in terms of tolerability issues, because they’re complex, not only the acute toxicities or chronic toxicities but also changes to the disease biology itself. This is 1 concern raised from BELLINI, that somehow venetoclax in the non–11;14 patients was generating something more adverse in their tumor biology because some of the data might have suggested that.

When we see trials in relapsed/refractory disease, where there’s PFS benefit but no OS benefit, especially if it’s an early relapse, this makes sense. I’m a little more cautious if we see substantial PFS benefit and we still don’t see an OS benefit, but it may be similar. That tells me something different, which may be that if you’ve got a big PFS benefit but no OS benefit, there may be subsets of patients in those 2 categories who are benefiting and not benefiting in the longer term, but that’s not what we’re seeing in TOURMALINE-MM1. We saw a very reasonable PFS benefit in favor of 3 drugs over 2, but not enormous. Nonetheless, that translates into survival equivalents with no evidence of a tolerability profile as being challenging or difficult for patients in real-world practice. That’s been shown.

Transcript edited for clarity.