Dr van Esser on Long-Term Follow-Up of the EMN15/HOVON147 Trial in Relapsed/Refractory Myeloma

"[Of] those patients treated with KRd, 57% became MRD negative after 9 cycles of induction, vs 5% of patients in the [lenalidomide and dexamethasone] group. That's a huge statistically significant difference."

Dirk van Esser, MD, a PhD candidate in the Department of Hematology at Erasmus MC Cancer Institute, discussed long-term follow-up data 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).

Smoldering multiple myeloma affects approximately 0.1% of the population, and patients with high-risk disease carry an approximately 50% risk of progression to multiple myeloma, van Esser explained. Rd had previously been shown to prevent progression with an acceptable toxicity profile, and a single-center study adding the proteasome inhibitor carfilzomib to that backbone yielded encouraging minimal residual disease (MRD)–negative complete response (CR) rates, prompting a head-to-head comparison, he noted.

Patients were randomly assigned 2:1 to receive 9 induction cycles of KRd (n = 35) or Rd (n = 22), followed by 24 cycles of lenalidomide maintenance. The primary end point was MRD negativity after induction, assessed centrally by next-generation flow cytometry at a sensitivity of 10⁻⁵. Data were presented at the 2026 International Myeloma Society (IMS) Annual Meeting and Exposition.

MRD negativity rates were 57% with KRd vs 5% with Rd (OR, 0.04; 95% CI, 0.00-0.28; P < .0001). Response rates also favored KRd, van Esser said.

At a median follow-up of 54 months, KRd significantly improved progression-free survival (PFS) vs Rd (HR, 0.25; 95% CI, 0.10-0.60); the median PFS was not reached vs 22.4 months (95% CI, 13.7-not reached). According to van Esser, the 3-year PFS rates were 85% and 45%, respectively. Progression to symptomatic multiple myeloma occurred in 6% of patients in the KRd arm vs 36% of those in the Rd arm (HR, 0.13; 95% CI, 0.03-0.62).

Two deaths occurred in the trial, both in the Rd arm—one from acute bleeding and one following progression to multiple myeloma with plasma cell leukemia—and neither was considered treatment related, van Esser added.

Grade 3/4 adverse effects occurred in 82% of patients who received KRd vs 62% of those who received Rd. The investigators concluded that this higher toxicity burden in an asymptomatic population warrants careful consideration before KRd is adopted in HR-SMM.