CONFERENCE UPDATE: ASH 2023

KRd offers durable survival benefits among patients with transplant-ineligible multiple myeloma

HEMATOLOGY
12 Feb 2024

STUDY DESIGN

Lenalidomide-dexamethasone (Rd) had been the standard of care for transplant-ineligible (NTE) patients with newly diagnosed multiple myeloma (NDMM).1 In the FIRST trial, Rd showed a median progression-free survival (PFS) of 26 months, with a median PFS of 8.4 months in the high-risk subgroup.1 As the efficacy with Rd was still limited, there remains an unmet need for treatment options that offer longer clinical efficacy, particularly for fit to intermediate-fit patients, for whom the treatment goal is to achieve deep and prolonged response.1

The EMN20 trial was a multicenter, randomized, phase 3 trial that evaluated the clinical efficacy of the 3-drug regimen of carfilzomib plus lenalidomide-dexamethasone (KRd) compared to the Rd regimen in treating NTE NFMM fit to intermediate-fit patients.1 A total of 82 patients were enrolled and randomized to receive either KRd (n=42) or Rd (n=40) until disease progression.1 After 2 years of treatment, patients from the KRd arm who achieved minimal residual disease (MRD) negativity were switched to Rd alone while those that showed MRD positivity continued KRd for 5 years.1 The protocol was halted in Nov 2021, following the introduction of frontline daratumumab (Dara)-Rd.1

The primary endpoints were MRD status after 2 years of treatment, which was evaluated from MRD assessments performed in patients who achieved very good partial response (VGPR) during the first 2 years of the study period, and PFS.1 Key secondary endpoints included response rates (partial response [PR], very good partial response [VGPR], complete response [CR], overall survival (OS), and safety.1

 

Primary endpoint: 

  • The primary endpoints were MRD status after 2 years of treatment and PFS1
  • Overall, 50% and 60% of patients in the KRd group achieved MRD negativity at 1 year and 2 years, respectively, which were both significantly higher than in the Rd group (year 1: 50% vs. 0%; p<0.0001, year 2: 60% vs. 0%; p<0.0001)1
  • There were 9 and 21 PFS events in the KRd group and the Rd group, respectively1
  • Median PFS was not reached in the KRd group and was 20.9 months in the Rd group1
  • The 2-year PFS rate of the KRd group was also higher than that of the Rd group (81% vs. 48%), with patients from the KRd group experiencing a 72% reduction in the risk of disease progression or death (HR=0.28; 95% CI: 0.13-0.60; p=0.0013)1

Secondary endpoints:

  • Key secondary endpoints included PR, VGPR, CR and OS1
  • Compared to their Rd counterparts, patients from the KRd group exhibited significantly higher PR (95% vs. 78%; p=0.04), VGPR (93% vs. 45%; p<0.0001), and CR (52% vs. 5%; p=0.0002)1
  • The 2-year OS was 89% in the KRd group and 74% in the Rd group (HR: 0.36; 95% CI: 0.11-1.17; p=0.09)1

Safety:

  • Overall, treatment-related toxicities were predictable and manageable1
  • The most frequent grade 3-5 adverse events (AEs) were neutropenia (22%), infections (17%), cardiovascular AEs (12%), and thrombocytopenia (10%) in the KRd group, and neutropenia (12%), infections (12%), and skin AEs (10%) in the Rd group1
  • Regarding AEs of special interest (AESI), 12% of patients in the KRd group developed cardiac AEs, while 32% had experienced vascular AEs of any grade. Hypertension of any grade occurred in 29% of patients in the KRd group while none occurred in Rd group1
  • The KRd group had a slightly lower discontinuation rate than the Rd group (12% vs. 15%)1

 

“The upfront treatment of KRd-Rd regimen had led to unexpectedly high rates of MRD negativity that delayed the progression among patients with NTE NDMM, which manifested into optimal clinical responses and progression-free survival benefits, regardless of age or size of genetic risk.”
Dr. Benedetto Bruno
Division of Hematology,
Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino,
University of Torino,
Torino, Italy

 

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