ASCO 2024: Treating Myeloma Just Got More Complicated
Newly Diagnosed MM: The Era of Quads Solidifies
At ASCO 2024, two key trials with concurrent publications assessed the role of quadruplets (without the use of transplant): the IMROZ trial of a quadruplet of isatuximab/bortezomib/lenalidomide/dexamethasone versus bortezomib/lenalidomide/dexamethasone (VRd), and the BENEFIT trial (isatuximab/lenalidomide/bortezomib/dexamethasone versus isatuximab/lenalidomide/dexamethasone).
The IMROZ trial tested the addition of an anti-CD38 antibody to a triplet backbone, and the results are compelling. The PFS was not reached for the quad vs 54 months for VRd. Unlike in the belantamab trial (where the control arm underperformed), here the control arm really overperformed. In this case, we have never seen such a compelling PFS of 54 months for VRd before. (Based on other trials, VRd PFS has been more in the ballpark of 35-43 months.) This speaks to the fitness and biology of the patients enrolled in this trial, and perhaps to how we will not see such stellar results with this quad recreated in real life.
The addition of isatuximab did not seem to impair quality of life, and although there were more treatment-related deaths with isatuximab, those higher numbers seem to have been driven by longer treatment durations. For this study, the upper age limit was 80 years, and most patients enrolled had an excellent functional status--making it clear that frail patients were greatly underrepresented.
What can we conclude from this study? For fit, older patients (who would have been transplant-eligible in the United States), this study provides excellent proof of concept that very good outcomes can be obtained without the use of transplantation. In treating frail patients, we do not know if quads are safe (or even necessary, compared to gentler sequencing), so these data are not applicable.
High-risk cytogenetics were underrepresented, and although the subgroup analysis for such patients did not show a benefit, it is hard to draw conclusions either way. For me, this trial is further evidence that for many older patients with MM, even if you “can” do a transplant, you probably “shouldn’t, they will experience increasingly better outcomes.
The standard for newly diagnosed MM in older patients for whom transplant is not intended is currently dara/len/dex. Is isa/bort/len/dex better? I do not know. It may give a better PFS, but the addition of bortezomib will lead to more neuropathy: 60% of patients developed neuropathy here, with 7% developing Grade III/IV peripheral neuropathy.
To resolve this issue, highly individualized discussions with patients will be needed. The BENEFIT trial evaluated this question more directly, with a randomized comparison of Isa-VRd versus Isa-Rd (the role of bortezomib being the main variable assessed here) with a primary endpoint of MRD negativity at 10-5 at 18 months. Although MRD negativity allows for a quick read-out, having MRD as an endpoint is a foregone conclusion. Adding another drug will almost certainly lead to deeper responses. But is it worth it?
In the BENEFIT trial, the MRD negativity at 10-5 was 26% versus 53% with the quad. However, peripheral neuropathy rates were much higher with the quad (28% vs 52%). Without longer-term data such as PFS and OS, I do not know whether it is worth the extra risks of neuropathy for older patients. Their priority may not be eradication of cancer cells at all costs. Instead, it may be better quality of life and functioning while preserving survival.
To sum up: Post-ASCO 2024, the approach to newly diagnosed MM just got a lot more complicated. For fit, older patients willing to endure extra toxicities of neuropathy (and acknowledging that we do not know whether survival will be any better with this approach), a quad is a very reasonable option to offer while forgoing transplant, in resource-rich areas of the world, such as the United States. Omitting a transplant now seems very reasonable for most older adults. However, a nuanced and individualized approach remains paramount. And given the speed of new developments, even this suggested approach will be outdated soon!
Dr. Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.
