General Updates | The FDA approval of daratumumab for high-risk smoldering myeloma based on the AQUILA trial

I think what’s really important about this and truly unprecedented is that this is the first regulatory approval in the United States for therapy for high-risk smoldering multiple myeloma patients. We have previous randomized studies that have clearly hinted at the benefit of therapeutic intervention for patients who have smoldering myeloma that’s at higher risk of progression to active multiple myeloma, but we’ve never had a label-enabling registrational trial in this space with a positive result leading to a regulatory approval. So, you know, this is the very first time that this has happened. So it’s very exciting, and I think it’ll pave the way for additional randomized phase three studies in the space going forward.

AQUILA was a randomized Phase three study that took folks who have smoldering multiple myeloma at higher risk of progression to active multiple myeloma, and they were either randomly assigned to the active monitoring arm, which is the standard of care at the time, or to daratumumab monotherapy. They received the daratumumab at the standard dose subcutaneously in the standard schedule, and they received therapy for a total of three years. And the primary endpoint of the study was progression-free survival, and that’s progression to active multiple myeloma as defined by the SLiM-CRAB criteria – this is not just biochemical progression of smoldering multiple myeloma, so I think that that’s important to recognize. These patients were followed very closely, I would argue more closely than would happen in real-world practice. So patients had myeloma assessments done every 12 weeks through the study. They had yearly imaging, and that consisted of either a whole-body low-dose CT scan or a whole-body PET CT and annual MRI imaging of the spine and pelvis. And they had a bone marrow biopsy performed every two years at a minimum. So this was a very rigorously monitored group of patients. 

And importantly, you know, in this particular study, we saw, you know, that it met its primary endpoint. So there was a notable improvement in progression to active multiple myeloma, again, defined by IMWG SLiM-CRAB criteria. The hazard ratio for progression-free survival was 0.49. In the active monitoring arm, median progression-free survival was 41 and a half months. For those that received daratumumab, it had not been reached. And when we looked at how patients were progressing to active multiple myeloma, you can see that there is a reduction in risk of progression to CRAB criteria, active multiple myeloma, as well as SLiM criteria as well. 

The other thing that I think is important to recognize when we look at subset analyses, whether it’s by age, renal function, or by more modern definitions of high-risk smoldering multiple myeloma, you see a benefit with the daratumumab treatment. Nowadays, we’re using the IMWG 2020 criteria for high-risk smoldering multiple myeloma, which is based on the 20/2/20 criteria that were developed by the Mayo Clinic and published in 2018. So when we look at patients on this study that met criteria for high-risk smoldering myeloma on the new metrics, there, the progression-free survival advantage was even more clear. So the hazard ratio for PFS in that particular group of patients was 0.36, and the median progression-free survival in the active monitoring arm was 22.1 months, which is right around what you would expect to see in a high-risk group, and it had not been reached in the daratumumab arm. So even with more modern definitions of high-risk smoldering multiple myeloma, we’re clearly seeing that advantage. 

I think that the other thing, too, that’s attractive to patients is the fact that time to first treatment for active multiple myeloma was significantly delayed. So median time to start first-line treatment for multiple myeloma, active multiple myeloma, was 50 months for those in the active monitoring arm. And this is three or four drug therapy that these patients are going to go on and get. And in the daratumumab arm, you know, that median time to first-line treatment had not yet been reached. 

A lot of interest in what happens when someone is treated for smoldering multiple myeloma. What is the impact on subsequent therapy when they do go on to develop active multiple myeloma? So we looked at progression-free survival 2. So this is looking at what progression-free survival 2 looks like in the daratumumab arm and comparing that to patients who just get active monitoring and then go on to first-line therapy. And when you look five years out, 86% of the patients who got daratumumab, you know, were still alive and progression-free, you know, versus 78% in the active monitoring arm, and that was statistically significant with a hazard ratio of 0.58. And, you know, the formal analysis for overall survival has yet to be conducted because there haven’t been enough overall survival events to occur to trigger that particular analysis, but there’s a clear signal for overall survival advantage in the daratumumab arm of this study as well. So at the time of the initial primary analysis, at the five-year mark, 93% of the patients in the daratumumab arm are alive, in contrast to 86.9% for those on active monitoring. And the hazard ratio there was 0.52, with the 95% confidence intervals not crossing one. So very exciting information. 

I think other important aspects of this work, you know, whenever you’re intervening in a patient who has an asymptomatic condition, like smoldering multiple myeloma, you want to make sure that the treatment does not have a negative impact on quality of life. So we were looking at patient-reported outcomes, and when you look at the EORTC QLQ-C30, Global Health Status Scores, if anything, they were numerically better in the daratumumab arm as opposed to the active monitoring arm. So there clearly was no decrement in patient-reported outcomes. If anything, there may have been a slight improvement. 

And then when we look at the safety in general, I mean, not surprisingly, there were more adverse events that were reported in the daratumumab arm versus the active monitoring arm, you know, but aside from a somewhat higher rate of infection, most of which was low grade, really a very well-tolerated therapy. So I think that this is going to be a very interesting option and discussion for patients these days who have smoldering myeloma at high-risk for progression. 

So I think that anybody who has high-risk smoldering multiple myeloma, as defined by current criteria, and specifically I’m referring to IMWG 2020, the classic 20/2/20 model, you know, you have to have this discussion with patients and you have to review the data from this study. You know, I think some folks still do have some concern about what exposure to CD38 antibody therapy in the smoldering space will have on CD38-based induction therapy for someone receiving frontline therapy for active multiple myeloma, and that’s a reasonable concern. Our initial data when we look at next treatment in this particular study, it looks encouraging thus far. But it’s very small numbers of patients, so we have to take that with a grain of salt. But certainly that’s a discussion that you have to have with the patient, you know, but I think that they should have the option to receive this therapy. 

I think one of the things that’s going to be really important for industry and clinical research in general, as more and more patients with high-risk smoldering multiple myeloma do go on to receive daratumumab monotherapy, that they not be excluded from studies for newly diagnosed active myeloma. That is absolutely critical because if they continue to do that, that is going to be a strong detraction from patients wanting to do this in the real-world setting, recognizing that they could potentially limit their options on a clinical trial in the active space. So we really, as a myeloma community, really need to wrap our brains around that. But I think it’s a wonderful option. I think in particular, you know, for the patient who has a lot of comorbidities, who may not tolerate a triplet or a quadruplet therapy for active myeloma terribly well, daratumumab monotherapy, if they’ve got high risk for myeloma, daratumumab monotherapy is a very well-tolerated way to potentially kick the can down the road for that initial induction therapy. And potentially, if they’re old enough, you know, obviate the need to ever receive therapy for their active myeloma. So that’s the kind of discussion that I would have with a patient.

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