Strategy for Treatment of High-Risk Smoldering Myeloma Prior to Disease Progression

At the 2025 Great Debates (GD) in Hematologic Malignancies meeting in New York, New York, Peter Voorhees, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina, discussed strategies and participated in a debate arguing in favor of patients with high-risk smoldering multiple myeloma (MM) receiving treatment in efforts to slow disease progression, citing findings from the phase 3 AQUILA study.

“I do think that there is a role for active surveillance in a good number of patients, and the discussion with the patients has to be very rigorous and nuanced so they can understand the strengths and weaknesses of the data that we've garnered thus far,” Dr Voorhees concluded.  

“It'll be important for us to do additional studies to determine whether more aggressive intervention in a more rigorously defined group of high-risk motor myeloma patients is even better than the control approach we're doing with monotherapy,” he added. 

Transcript:

Hello, I'm Peter Voorhees and I'm the myeloma lead at Levine Cancer Institute in Charlotte, North Carolina. I'm here in New York City for the Great Debates in Hematologic Malignancies. I had the pleasure of debating my good friend and colleague, Dr Faith Davies on the role of treatment in patients with high-risk smoldering multiple myeloma and I had the position, the stance of treating these patients with high-risk disease.

As folks know, patients with high-risk smoldering multiple myeloma typically have a 50% likelihood of developing active multiple myeloma within the first 2 years and that's a particular group of patients that we want to see if early intervention could potentially change long-term outcomes for those patients. I focused a lot on the phase 3 AQUILA study that was presented at the American Society of Hematology meeting back in December and was published in the New England Journal of Medicine at that time.

AQUILA was a phase 3 study that took patients with high risk smoldering multiple myeloma and assigned them to either 3 years of daratumumab therapy or active surveillance. The primary endpoint of this study was progression-free survival. Now, progression-free survival was defined not as biochemical progression of disease. It was defined as either death or progression to active multiple myeloma either defined by the traditional CRAB criteria or the SLiM criteria. 

These patients were monitored very closely over the course of the study. They had biomarkers for their myeloma drawn on a quarterly basis. They had extensive advanced imaging done on a yearly basis, and they had bone marrow examinations done every other year. The primary endpoint of the study, again, progression to active multiple myeloma, was met in favor of the daratumumab arm. The hazard ratio for progression-free survival is 0.49, that translates into a 51% reduction in the rate of deaths or progression to active multiple myeloma. That was highly statistically significant.

Now, one of the criticisms that's been leveled against this particular study is that the patient population was somewhat heterogeneous. There were patients that perhaps were not considered high risk in the modern era of myeloma definitions, if you will, so we did a post hoc analysis and we applied the currently used 2220 criteria for high risk smoldering multiple myeloma. We looked to see how that group of patients did in the daratumumab arm versus active surveillance and about 35 to 40% of the patients in the study in both arms met criteria for high-risk disease by that particular metric. 

To make a long story short, progression-free survival was clearly superior in the daratumumab arm versus the active surveillance arm. In fact, the hazard ratio for progression-free survival is even better for that group of patients. When we look at the number of high risk features that the patients had, whether they had 3 or more or less than 3 favored daratumumab, if you look at high risk cytogenetics versus standard risk cytogenetics favored daratumumab, one of the other concerns that folks have with regards to early intervention in high risk smoldering multiple myeloma, is the impact that that therapy can have on subsequent therapy when a patient does transition to active multiple myeloma.

We did look at progression-free survival-2 in this particular study, which is really looking at time from enrollment into AQUILA to not their first progression, but their next progression on active myeloma therapy. What we saw with that particular analysis is that the daratumumab arm performed better than the active surveillance arm with regards to PFS-2, demonstrating that there wasn't a significant degradation and benefit with therapy at the time of transition to active multiple myeloma. 

Then lastly, I would point out that while the number of survival events had not yet reached the number where a formal statistical analysis was going to be performed, we did look at overall survival as part of that primary analysis for progression-free survival. There was a clear superiority with regards to overall survival with the daratumumab intervention versus observation. 

Now, both groups of patients did very well. If you look 5 years out, 93% of those assigned to daratumumab are alive. If you look at the active surveillance arm, it was approximately 86%, so there is a difference. The 95% confidence intervals did not cross 1 for overall survival, so it suggests that there's this strong indication that daratumumab in these higher-risk smoldering multiple myeloma patients may have an overall survival advantage.

From a toxicity perspective, there was more grade 3 and higher infections for those receiving daratumumab versus active surveillance, but all of those infections were grade 3. There were no grade 4 or 5 infections. As far as cytopenia and other side effects, the daratumumab was very well tolerated. In fact, only about 5% of patients actually discontinued therapy because of adverse events. This data set is probably the most robust randomized data that we have in high risk smoldering multiple myeloma to date.

A lot of the issues with prior studies as far as sample size, rigor of evaluation by imaging, those sorts of things, all of that was done right in this particular study. For that reason, the FDA has picked this up and reviewed it for potential approval. In fact, there was an ODAC (Oncologic Drugs Advisory Committee) that was convened in May looking at the risk benefit of single agent daratumumab for this patient population. 

At the end of the day, the committee voted in favor 6 to 2 for treatment with daratumumab. It is now a category 1 NCCN designation for use in high risk smoldering multiple myeloma. Clinical trial is still part of the package as well, as well as active surveillance. Then lenalidomide gets its category 2B designation and we'll see if daratumumab gets FDA-approved. It would be the first regulatory approval of any agent in smoldering multiple myeloma to date.

It's a really exciting time, a good first step forward. I do think that there is a role for active surveillance in a good number of patients, and the discussion with the patients has to be very rigorous and nuanced so they can understand the strengths and weaknesses of the data that we've garnered thus far. 

It's really quite interesting, and it'll be important for us to do additional studies to determine whether more aggressive intervention in a more rigorously defined group of high-risk motor myeloma patients is even better than this control approach that we're doing with monotherapy. Anyhow, very exciting times.

Source:

Voorhees P. Debate- Should All Patients with High-Risk Smoldering Myeloma Be Treated? Yes vs No. Presented at the Great Debates in Hematologic Malignancies meeting. June 28-29, New York, New York.