Experts Debate AQUILA Trial Findings in Smoldering Multiple Myeloma

Treating high-risk smoldering multiple myeloma with single-agent daratumumab (Darzalex) delayed progression to active myeloma, according to findings from the phase III AQUILA trial presented at the American Society of Hematology (ASH) annual meeting.

MedPage Today brought together three expert leaders in the field: Moderator Joseph Mikhael, MD, is joined by Amrita Krishnan, MD, and Tulio Rodriguez, MD, all of City of Hope, for a roundtable discussion. This first of four exclusive episodes focuses on the AQUILA trial and its implications for clinical practice.

Following is a transcript of their remarks:

Mikhael: Hello and welcome to this multiple myeloma roundtable at ASH 2024 in beautiful San Diego. It’s a pleasure to have you join us today as we think about some of the amazing data that have been presented here over the last several days at the American Society of Hematology annual meeting. This is sponsored by MedPage Today, and we’re very thankful for the opportunity to share this exciting work that’s going on, as it really is going to impact directly our clinical care even in the coming months.

I have the privilege of being with you today. My name is Joseph Mikhael, I’m a hematologist and myeloma physician based in Phoenix. I’m a professor at the City of Hope and the chief medical officer of the International Myeloma Foundation. I have two amazing friends and colleagues with me, Dr. Amrita Krishnan and Dr. Tulio Rodriguez. I’m going to let them introduce themselves more formally so we can know who they are. We’ll start with you, Amrita.

Krishnan: Pleasure to be here. My name is Amrita Krishnan, I am the director of the Multiple Myeloma Center at the City of Hope.

Mikhael: Dr. Rodriguez?

Rodriguez: Absolutely. Thank you for the opportunity. My name is Tulio Rodriguez, as you know, and I have the privilege of directing the division of hematology, bone marrow transplantation, and cellular therapy at City of Hope Chicago. Also a clinical professor of medicine within City of Hope.

Mikhael: So we’re just going to spend a few minutes thinking about these major areas of focus that we’ve seen over the last several days in multiple myeloma. And let’s start right with the most controversial one, with smoldering multiple myeloma. There may be no topic that divides myeloma doctors more than smoldering myeloma. I always say if I put 10 myeloma doctors in a room, I have 12 opinions.

And part of this was driven this week by arguably the most talked about abstract, the AQUILA study, which was a study of high-risk smoldering myeloma where patients were randomized in a phase III trial to either simply be monitored actively, which is pretty much the standard of care now, or single-agent daratumumab. And there were some very interesting findings of this. So what’s your take on this study?

Krishnan: So smoldering myeloma remains a very controversial area. As you know, we always want phase III trials and when they’re done, we still find issues with the phase III trial, so I think kudos for doing a phase III trial. Challenges are, in terms of the patient population, it was all-comers, not just higher-risk smoldering myeloma, there was a 16% incidence of grade 3 and higher infections in the daratumumab arm, which I think is sort of something we should take note of as well.

And in regards to overall survival, I need that a little bit more elucidated because trying to understand how many of those patients truly had access to CD38 antibody in the observation arm would be important.

Rodriguez: I absolutely agree. I think it’s a controversial topic. Nevertheless, it is bringing up some findings that are difficult to just ignore. And for example, it’s all based, I believe, in how we define high-risk smoldering myeloma. They came up with some identifications that I certainly agree that becomes a topic of discussion with our patients.

For example, they look into patients with bone marrow involvement of 50% to 60%. They also look into IgA [immunoglobulin A] isotype that we all know that … they behave a little bit more aggressively. So there were some characteristics that when you see those patients, even though they do have smoldering myeloma, they bring you some concern. And now we have some data to support intervention for some selected individuals.

And I think that that’s kind of the point. If you think that this is a one fit for all for everyone with smoldering myeloma, that’s absolutely not the case. Nevertheless, you have to admit that the way that they identified these high-risk individuals is something that we all knew, and I was very satisfied to see that was validated. And I think that this struck a conversation with your patient.

Mikhael: Yeah. Well, I think your last phrase was the perfect one. It’s a conversation. I don’t think it’s absolutely clear that every high-risk smoldering myeloma patient needs to be treated this way, but it now is a very legitimate option. There are a lot of us who thought, well, maybe if someone’s getting so close to active myeloma, we should just treat with full therapy. But this relatively benign therapy with fewer side effects, it may indeed delay and if not even prevent one day someone developing myeloma. So I’m looking forward to the longer-term follow-up because I think its impact, although we have a PFS [progression-free survival] benefit now, I think if we looked for a long-term impact on overall survival, that may even further the field. And I think it pushes us as the myeloma community to make sure that we work on these definitions that you’ve mentioned. Myeloma is such a heterogeneous disease.

It’s hard to put in simple buckets, and I think this study illustrates that. So I think the take-home message for clinicians today would be we need to have a conversation with our patients when they’re at that end of the spectrum of smoldering myeloma, that they’re very close to myeloma. In that situation, it’s possible to still monitor them very closely. We could give them single-agent daratumumab from historical studies, maybe even single-agent lenalidomide [Revlimid], or if you really believe they’re getting very close to active myeloma, treat them fully as myeloma. So there is choice there for our team.

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