KCd Regimen Does Not Show Non-Inferiority to Autologous HSCT in Multiple Myeloma

The combination of carfilzomib, cyclophosphamide, and dexamethasone (KCd) failed to meet the criteria for non-inferiority vs autologous hematopoietic stem-cell transplantation (HSCT) in patients with multiple myeloma, according to findings from the phase 2 CARDAMON study (NCT02315716).

In the open-label phase 2 study of approximately 300 patients, 57.7% achieved at least a very good partial response when given the induction regimen of KCd, meeting 1 of the co-primary end points of the study.

While the criteria for non-inferiority were not met, there was a marginal difference in progression-free survival (PFS) between the treatments. This suggests that further studies are needed to explore deferred autologous HSCT in various subgroups, including patients who are minimal residual disease (MRD) negative after induction.

“Our results show that KCd consolidation did not meet the criteria for non-inferiority when compared with upfront transplantation. However, the non-inferiority margin was only exceeded by a small amount [confidence limit –11·1%, prespecified margin –10%], although this study was a phase 2 trial with 15% significance level. Therefore, there are likely to be subgroups of patients for whom deferred transplantation might be an option, which should be explored in future prospective trials,” wrote the study authors led by Kwee Yong, PhD, Cancer Institute, Clinical Hematology Department at University College London Hospitals NHS Foundation Trust, London, UK, in findings published in the Lancet Hematology.

The randomized, open-label, phase 2 CARDAMON trial examined the combination of cyclophosphamide and dexamethasone, 2 standard chemotherapy drugs, plus carfilzomib in newly diagnosed, transplantation-eligible patients with multiple myeloma. Investigators evaluated patients across 19 hospitals in England and Wales, UK.

Patients eligible for enrollment were aged 18 years or older with an ECOG performance status of 0–2, a life expectancy of 3 months or more, and measurable disease. Once enrolled, patients received 4 28-day cycles of carfilzomib at 56 mg/m2 intravenously (IV) on days 1, 2, 8, 9, 15, and 16, oral cyclophosphamide at 500 mg on days 1, 8, and 15, and oral dexamethasone at 40 mg orally on days 1, 8, 15, and 22, followed by peripheral blood stem cell mobilization.

Those who had at least a partial response were randomly assigned in a 1:1 ratio to receive either high-dose melphalan (Alkeran) and autologous HSCT or 4 cycles of the KCd combination. Every patient that was randomized was given 18 cycles of carfilzomib maintenance at 56 mg/m2 via IV infusion on days 1, 8, and 15.

The primary end points of the trial were response rate and PFS with secondary end points of assessing toxicity and tolerability, disease response rate, PFS, overall survival, MRD conversion following treatment, and MRD conversion following maintenance.

A total of 281 patients were enrolled between June 16, 2015, and July 8, 2019, and 218 proceeded to randomization. The KCd consolidation group included 109 patients, 99 of whom completed consolidation. In the HSCT group, there were 109 patients and 104 of them underwent transplantation. Seven more patients (2 in the KCd group vs 5 in the HSCT group) withdrew from the trial prior to the initiation of carfilzomib maintenance.

Among those enrolled, the median age was 59 years (interquartile range [IQR], 52-64), 166 (59%) patients were male, and 115 (41%) were female. White patients made up 71% of those enrolled while another 17% were Black, 8% were Asian, 2% identified as Mixed, and 1% identified as other.

From the time patients were randomized, the median follow-up was 40.2 months (IQR 32.7-51.8). Of the 281 patients, 162 (57.7%; 95% CI, 51.6-63.5) achieved at least a very good partial response after induction. For the HSCT group, the 2-year PFS was 75% (95% CI, 65-82) compared with 68% (95% CI, 58-76) in the KCd group, exceeding the non-inferiority margin. Additionally, the overall response rate was 85.8% among 241 of 281 the patients (81.1–89.6). Among these patients, 22.8% were MRD negative.

Regarding safety, the most common grade 3 or 4 adverse events (AEs) in the KCd induction and consolidation groups were lymphocytopenia (26% of patients who started induction vs 14% of patients who started consolidation) and infection (18% vs 15%). During carfilzomib maintenance, the most common AEs included hypertension (21% in the KCd consolidation group vs 23% in the HSCT group) and infection (16% vs 25%).

At any time in the trial, treatment-related serious AEs were seen in 109 (39%) of the 278 patients who started induction. Infections were the most common at 29%. Five patients (2%) died from treatment-emergent AEs during induction, including 3 from infection, 1 from cardiac event, and 1 from renal failure, and 1 patient during maintenance after autologous HSCT of esophageal carcinoma.

“The CARDAMON trail provides preliminary evidence that MRD assessment after induction could be used to guide treatment choice. Future trials that stratify by a composite of genetic risk and depth of response will be able to accurately identify patients likely to benefit from autologous HSCT, leading to a personalized treatment approach,” concluded the study authors.

REFERENCE:

Yong K, Wilson W, de Tute RM, et al. Upfront autologous haematopoietic stem-cell transplantation versus carfilzomib-cyclophosphamide-dexamethasone consolidation with carfilzomib maintenance in patients with newly diagnosed multiple myeloma in England and Wales (CARDAMON): a randomized, phase 2, non-inferiority trial [published online ahead of print, 2022 Dec 15]. Lancet Haematol. 2022;S2352-3026(22)00350-7. doi:10.1016/S2352-3026(22)00350-7