Dr van Esser on the Toxicity Profile Associated With Carfilzomib/Lenalidomide/Dexamethasone in Myeloma

"[In smoldering multiple myeloma,] you should find a balance between acceptable toxicity and response depth. Since these are asymptomatic patients and it is a precursor condition to multiple myeloma, I think that we should only treat those that really have the risk to progress to multiple myeloma."

Dirk van Esser, MD, a PhD candidate in the Department of Hematology at Erasmus MC Cancer Institute, discussed safety findings from the phase 2 EMN15/HOVON147 trial (NCT03673826) evaluating carfilzomib (Kyprolis) plus lenalidomide (Revlimid) and dexamethasone (KRd) vs lenalidomide and dexamethasone (Rd) in patients with high-risk smoldering multiple myeloma (HR-SMM), as well as how to select patients for treatment in this asymptomatic population.

In the trial, which randomly assigned patients 2:1 to KRd (n = 35) or Rd (n = 22), grade 3/4 adverse effects (AEs) occurred in 82% vs 62% of patients, respectively, according to long-term follow-up data presented at the 2026 International Myeloma Society (IMS) Annual Meeting and Exposition. Grade 3 or higher nonhematologic AEs were more common with KRd (82% vs 57%), whereas grade 3 or higher hematologic AEs occurred at similar rates (15% vs 19%). Serious AEs were reported in 62% and 52% of patients, respectively, and no treatment-related deaths occurred.

The toxicity was manageable, and no new safety signals emerged for carfilzomib, van Esser said. One patient experienced a grade 3 cardiac event. As expected, infections were the most common AEs, with pneumonia the most frequent infection, he explained, adding that infection prophylaxis is required before administering the regimen in the clinic.

Determining which patients should receive treatment is one of the most frequently asked questions, and it is difficult to answer, van Esser noted. Clinicians should evaluate each patient individually, considering whether the patient has high-risk disease and meets the criteria for treatment, he said. For now, observation remains the standard of care for patients with low- or intermediate-risk disease, he added, and in the Netherlands, treatment for patients with high-risk disease is available only through clinical trials.

Looking ahead, van Esser said he is eager to see emerging data with T-cell–redirecting therapies and anti-CD38–based regimens in SMM, although long-term efficacy and toxicity data for these approaches are not yet available. He concluded that incorporating biomarkers, the SMM microenvironment, and circulating tumor cells will play an important role in better identifying which patients will progress to multiple myeloma.