KRd Improves MRD Negativity and PFS but Raises Toxicity Concerns in High-Risk Smoldering Myeloma

Treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) significantly improved minimal residual disease (MRD) negativity and progression-free survival (PFS) compared with lenalidomide and dexamethasone (Rd) in patients with high-risk smoldering multiple myeloma (SMM), according to long-term results from the phase 2 HOVON147/EMN15 trial. The increased efficacy came with more grade 3 or 4 adverse events, raising questions about the appropriate intensity of treatment before symptomatic disease develops.¹

After induction, 57% of patients assigned to KRd achieved MRD negativity compared with 5% of those receiving Rd (P < .0001). At a median follow-up of 54 months, KRd reduced the risk of disease progression or death by 75% (HR, 0.25; 95% CI, 0.10-0.60). Median PFS was not reached with KRd and was 22.4 months with Rd.¹

Evaluating Early Treatment for High-Risk Disease

SMM is an asymptomatic plasma cell disorder positioned between monoclonal gammopathy of undetermined significance and active multiple myeloma. Patients do not have myeloma-defining end-organ damage, but those meeting high-risk criteria face a greater likelihood of progressing to symptomatic disease.

Earlier randomized studies established that lenalidomide-based treatment can delay progression in selected patients with high-risk SMM. In the QuiRedex trial, lenalidomide plus dexamethasone delayed progression to active multiple myeloma compared with observation. A separate randomized trial found that single-agent lenalidomide reduced the risk of progression or death by 72% compared with observation.^2,3

HOVON147/EMN15 examined whether adding the proteasome inhibitor carfilzomib to Rd could produce deeper disease control. Carfilzomib is approved for several regimens in relapsed or refractory multiple myeloma, but its use in SMM remains investigational.⁴

KRd Produces Deeper Responses

HOVON147/EMN15 was a prospective, multicenter, open-label trial conducted at 5 European centers. Investigators randomly assigned adults with high-risk SMM in a 2:1 ratio to KRd or Rd. High-risk disease was defined according to the Mayo 2008 and/or PETHEMA criteria.¹

Patients in the Rd group received lenalidomide 25 mg on days 1 through 21 and dexamethasone 40 mg weekly during each 28-day cycle. The KRd group received the same regimen with intravenous carfilzomib at 20/56 mg/m² on days 1, 8, and 15. Treatment included 9 induction cycles followed by 24 cycles of lenalidomide maintenance at 10 mg for patients without disease progression.¹

Of 58 enrolled patients, 57 were eligible for analysis. Thirty-five received KRd and 22 received Rd. The primary end point was MRD negativity following induction, assessed centrally by next-generation flow cytometry at a sensitivity of 10⁻⁵.¹

Beyond its effect on MRD, KRd reduced progression to symptomatic multiple myeloma. Progression occurred in 2 patients receiving KRd, or 6%, compared with 8 patients receiving Rd, or 36%. This corresponded to an 87% reduction in the hazard of progression to symptomatic disease (HR, 0.13; 95% CI, 0.03-0.62).¹

The results build on earlier phase 2 evidence showing that KRd can produce deep responses in high-risk SMM. In a separate study, intensive KRd induction followed by lenalidomide maintenance produced high MRD-negative response rates, although the single-arm design prevented a direct assessment against a less intensive regimen.⁵

Toxicity Complicates the Risk-Benefit Assessment

Grade 3 or 4 adverse events occurred in 82% of patients receiving KRd compared with 62% receiving Rd. The difference was driven by grade 3 or higher nonhematologic adverse events, reported in 82% and 57% of patients, respectively. Grade 3 or higher hematologic adverse events occurred at similar rates of 15% with KRd and 19% with Rd.¹

Serious adverse events were reported in 62% of the KRd group and 52% of the Rd group. No treatment-related deaths occurred.¹

These safety results are central to interpreting the trial. Preventing progression could spare patients from organ damage associated with active myeloma, but treatment toxicity is especially consequential for individuals who are asymptomatic when therapy begins. The small study population also limits the ability to characterize uncommon toxicities and determine whether improved MRD negativity will translate into an overall survival benefit.

For pharmacists, KRd would require monitoring for hematologic toxicity and complications associated with carfilzomib, including cardiac events, renal toxicity, hypertension, and infusion-related reactions. Medication counseling must also address the prolonged treatment schedule and the preventive intent of therapy.⁴

HOVON147/EMN15 demonstrates that KRd can produce deeper responses and delay progression compared with Rd. Its toxicity profile, however, supports the investigators’ conclusion that KRd should not be adopted broadly in high-risk SMM without further evaluation of patient selection and long-term benefit.¹

REFERENCES

1. Van Esser D, Schjesvold F, van der Holt B, et al. Long-term follow-up of the phase II EMN15/HOVON147 trial: carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with high-risk smoldering multiple myeloma. Presented at: 23rd International Myeloma Society Annual Meeting; September 2026. Abstract OA-37.

2. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438-447. doi:10.1056/NEJMoa1300439

3. Lonial S, Jacobus S, Fonseca R, et al. Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma. J Clin Oncol. 2020;38(11):1126-1137. doi:10.1200/JCO.19.01740

4. Kyprolis (carfilzomib) for injection. Prescribing information. Amgen Inc; revised 2025. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Kyprolis/kyprolis_pi.pdf

5. Kazandjian D, Hill E, Dew A, et al. Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Maintenance for Prevention of Symptomatic Multiple Myeloma in Patients With High-risk Smoldering Myeloma: A Phase 2 Nonrandomized Controlled Trial. JAMA Oncol. 2021;7(11):1678-1685. doi:10.1001/jamaoncol.2021.3971