Carfilzomib-Lenalidomide-Dexamethasone in Transplant-Ineligible Multiple Myeloma: High MRD Negativity and PFS Benefit in the EMN20 Trial

Highlights

• Carfilzomib-lenalidomide-dexamethasone (KRd) achieved a remarkable 60% MRD negativity rate at 2 years versus 0% for lenalidomide-dexamethasone (Rd) alone in newly diagnosed, transplant-ineligible multiple myeloma patients.
• The KRd regimen conferred a strong progression-free survival (PFS) benefit, with the median PFS not reached compared to 20.9 months for Rd (HR 0.24, p=0.00084).
• Toxicities with KRd were predictable and generally manageable, though included higher rates of hematologic and cardiac events.
• The trial was halted early due to evolving standards of care, emphasizing the dynamic landscape of first-line myeloma therapy.

Study Background and Disease Burden

Multiple myeloma is a plasma cell malignancy predominantly affecting older adults, many of whom are ineligible for autologous stem cell transplantation (ASCT) due to age, comorbidities, or frailty. Before the introduction of anti-CD38 monoclonal antibodies like daratumumab, the combination of lenalidomide and dexamethasone (Rd) represented the standard first-line therapy for these patients. However, disease control remains suboptimal, with high relapse rates and limited depth of response. Achieving measurable residual disease (MRD) negativity is increasingly recognized as a key surrogate for long-term outcomes. The EMN20 trial addresses the question of whether adding carfilzomib—a second-generation proteasome inhibitor—to Rd could further improve depth of response and progression-free survival (PFS) in this challenging population.

Study Design

EMN20 was a randomized, open-label, multicenter, phase 3 trial conducted across 27 centers in Italy. The study enrolled adults with newly diagnosed, transplant-ineligible multiple myeloma, classified as fit or intermediate-fit per International Myeloma Working Group (IMWG) frailty score, with measurable disease and ECOG performance status <3.

Patients were randomized to:

• Carfilzomib-lenalidomide-dexamethasone (KRd): Carfilzomib 20 mg/m² IV day 1 of cycle 1, then 56 mg/m² on days 8, 15 (cycle 1), subsequently 56 mg/m² days 1, 8, 15 (cycles 2-12), and days 1, 15 (cycle 13 onward, up to 5 years); lenalidomide 25 mg PO days 1-21; dexamethasone 40 mg PO days 1, 8, 15, 22—28-day cycles until progression or intolerance.
• Lenalidomide-dexamethasone (Rd): Same lenalidomide and dexamethasone schedule as above.

The primary endpoints were MRD negativity (by next-generation sequencing with sensitivity 10⁻⁵) at 2 years and PFS, analyzed in the intention-to-treat (ITT) population. The study planned to enroll 340 patients but was stopped after 101 were enrolled, as daratumumab-Rd became the new standard in Italy.

Key Findings

Of 101 enrolled, 82 patients (43% female, median follow-up 35.2 months) were randomized (KRd n=42, Rd n=40).

MRD Negativity:

• KRd: 25/42 (60%; 95% CI 43–74%) achieved MRD negativity at 2 years.
• Rd: 0/40 (0%; 0–9% CI) (p<0.0001).

Progression-Free Survival (PFS):

• KRd: Median not reached.
• Rd: Median 20.9 months (15.7–not reached).
• Hazard ratio (HR) for progression or death: 0.24 (95% CI 0.11–0.56), p=0.00084.

Safety:
KRd was associated with higher rates of grade 3 or worse adverse events, including:

• Neutropenia: 22% (KRd) vs. 15% (Rd)
• Thrombocytopenia, diarrhea, cardiac events, infections, and hypertension (all more frequent with KRd)
• Serious adverse events: SARS-CoV-2-related pneumonia was the most common in both groups.
• Treatment-emergent deaths: 2 (KRd, both COVID-19) vs. 4 (Rd: myocardial infarction, heart failure, septic shock, COVID-19).

Statistical and Clinical Significance:
The difference in MRD negativity (60% vs. 0%) is both statistically robust and clinically meaningful, suggesting a much deeper response with KRd. The PFS benefit (HR 0.24) is substantial, though median overall survival was not reported due to follow-up duration and study size.

Expert Commentary

The EMN20 trial provides compelling evidence that KRd markedly increases the rate of deep remission (MRD negativity) and prolongs PFS compared to Rd in newly diagnosed, transplant-ineligible myeloma patients. The study’s findings are particularly notable given that MRD negativity is increasingly seen as a surrogate for survival and a marker of therapeutic success. While the trial was underpowered due to early closure, the magnitude of benefit for both MRD and PFS is difficult to ignore.

Toxicity remains a consideration, especially with increased cardiac events and cytopenias in the KRd arm. However, the adverse event profile aligns with known risks of carfilzomib and was generally manageable in this relatively fit older population. The most frequent serious event—COVID-19 pneumonia—reflects the pandemic context rather than therapy-specific risks.

Current guidelines now recommend daratumumab-lenalidomide-dexamethasone as first-line therapy in this setting, limiting the direct applicability of KRd as a new standard. Nevertheless, the results suggest a potential role for KRd in select patients who are not candidates for anti-CD38 therapy, have contraindications, or require alternative proteasome inhibitor–based strategies. Additionally, the high MRD negativity rates highlight the biological potency of carfilzomib-based regimens and may inform future combination or sequencing strategies.

Conclusion

The EMN20 trial demonstrates that weekly carfilzomib added to lenalidomide-dexamethasone achieves unprecedented rates of MRD negativity and prolongs progression-free survival in transplant-ineligible, newly diagnosed multiple myeloma. While the evolving treatment landscape now prioritizes anti-CD38 regimens, KRd remains a potent option, especially for patients unable to receive daratumumab. The study reinforces the importance of depth of response and MRD as key endpoints in myeloma clinical trials and practice.

References

• Bringhen S, Cani L, Antonioli E, et al. Carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed myeloma ineligible for autologous stem-cell transplantation (EMN20): a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2025;12(8):e621-e634. doi:10.1016/S2352-3026(25)00162-0. PMID: 40769686.
• Facon T, Kumar S, Plesner T et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380:2104-2115.
• International Myeloma Working Group (IMWG) consensus criteria and guidelines.