Risk Stratification Guides Early Treatment in Smoldering Myeloma: Peter Voorhees, MD

Following the November 2025 approval of daratumumab and hyaluronidase-fihj (Darzalex Faspro; Janssen Biotech), The American Journal of Managed Care^® spoke with Peter Voorhees, MD, hematologist, Medical Oncology, Atrium Health Levine Cancer Institute. Rewatch part 1 of this interview to learn more about the potential of daratumumab and hyaluronidase-fihj to delay progression of smoldering multiple myeloma to active disease.

Here in part 2, Voorhees continues the discussion, emphasizing the importance of not only risk stratifying these patients but also carefully determining early regimens and involving patients in treatment decision-making conversations.

This transcript has been lightly edited for clarity; captions were auto-generated.

Transcript

How should clinicians balance the potential benefits of early intervention with concerns about overtreatment in an otherwise asymptomatic population?

At the time that this study [the phase 3 AQUILA trial (NCT03301220)] was initially conducted, we had yet to implement the Mayo 2018 criteria for defining high-risk smoldering multiple myeloma, which has since been validated by the IMWG [International Myeloma Working Group] and now goes by the IMWG 2020 criteria. We did a post hoc analysis applying modern definitions of high-risk smoldering multiple myeloma to the patients who were enrolled in this study. IMWG 2020 is commonly known as the 20-2-20 criteria. If you have more than 20% involvement of your bone marrow space with myeloma, that's a point. If you have an M-spike that's greater than 2 grams per deciliter, that gets you a point. If you have an affected-to-unaffected free light chain ratio of greater than 20, that gets you a point. You are considered at higher risk of progression to active multiple myeloma if you have 2 or more of those risk factors. Approximately 50% of those smoldering myeloma patients will go on to develop active disease over a 2-year time frame.

We went and we looked at that particular group of patients, and I think what's really important to recognize there is that the progression-free survival [PFS] was even more clear in that group of patients than it was in those who were considered at lower risk of progression to active multiple myeloma and those who were at intermediate risk. Here, the hazard ratio for PFS was 0.36, and importantly, in the active monitoring arm, the median progression-free survival was 22.1 months, which is awfully close to 2 years, which is exactly what we would expect based on the risk stratification of IMWG 2020.

I think it's important that you carefully dissect out those who truly have high-risk disease, and using more modern criteria for defining high-risk smoldering multiple myeloma is important. We certainly have to acknowledge that that will probably continue to evolve over the course of time.

I think the other question that folks have is, if someone is exposed to daratumumab in the smoldering multiple myeloma space, what impact is that going to have on efficacy of treatment for those who do go on to [be treated] for active multiple myeloma? We have limited data in that particular space currently. What little data that we have look promising thus far, but I think it's an open question. I think we need to see more events occur. We need to see how patients do on CD38-based triplets and quadruplets who have received daratumumab in the smoldering space, and it's certainly something that we have to discuss with our patients. But certainly, for a patient with significant comorbidities who might make a 3-drug or a 4-drug therapy for active multiple myeloma difficult, daratumumab monotherapy is a fairly gentle way of trying to reduce or delay time to progression to active multiple myeloma, and for older patients, potentially obviate the need for any active myeloma therapy at all.