Marginal PFS Difference With Autologous HSCT and KCd Consolidation in Multiple Myeloma

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Based on findings from the phase 2 CARDAMON studies, further research is needed to explore deferred autologous hematopoietic stem-cell transplantation in some subgroups of patients with multiple myeloma.

The phase 2 CARDAMON (NCT02315716) study failed to meet the criteria for non-inferiority vs autologous hematopoietic stem-cell transplantation (HSCT) in patients with newly diagnosed multiple myeloma.

In the study, patients in the experimental arm were administered carfilzomib at 56 mg/m2, cyclophosphamide at 500 mg, and dexamethasone at 40 mg, followed by peripheral blood stem cell mobilization (KCd). Other patients were given high-dose melphalan flufenamide (Pepaxto) and autologous HSCT followed by carfilzomib maintenance.

While the criteria for non-inferiority was not met, a marginal difference in progression-free survival (PFS) was seen, suggesting the need for further studies to explore deferred autologous HSCT in some subgroups of patients.1

“Rather than showing superiority, our study sought to assess if ongoing treatment with KCd was non-inferior to KCd induction followed by autologous HSCT in newly diagnosed, transplantation-eligible patients with multiple myeloma, with both groups receiving carfilzomib maintenance. 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 study authors in findings published in The Lancet Hematology.

CARDAMON is a randomized, open-label, phase 2 trial which enrolled patients across 19 hospitals in England and Wales, UK. Patients enrolled were those with newly diagnosed multiple myeloma who were transplantation-eligible, aged 18 years or older, and had an ECOG performance status of 0-2 received.

In the experimental arm of the trial, patients received 4 28-day cycles of intravenous (IV) carfilzomib at 56 mg/m2 on days 1, 2, 8, 9, 15, and 16, cyclophosphamide at 500 mg orally on days 1, 8, and 15, and oral dexamethasone at 40 mg on days 1, 8, 15, and 22. This was followed by peripheral blood stem cell mobilization.

Patients who had at least a partial response (PR) were randomly assigned in a 1:1 fashion to receive either high-dose melphalan and autologous HSCT or 4 cycles of KCd.

Primary end points of the trial included the proportion of patients with at least a very good partial response (PR) after induction and difference in progression-free survival (PFS) rate at 2 years. Investigators also assessed safety in all patients who started treatment.

A total of 281 patients were enrolled in the trial between June 16, 2015, and July 8, 2019, and 218 were then randomized. One hundred and nine patients were administered treatment with the KCd regimen (99 of whom completed consolidation) and 109 were assigned to the HSCT group (104 of whom underwent transplantation).

Seven patients ended up withdrawing prior to the initiation of carfilzomib maintenance, including 2 patients in the KCd consolidation group vs 5 in the HSCT group.

Among those enrolled, the median age was 59 years (interquartile range [IQR], 52-64). A majority of patients were male (59%), 71% of patients were White, 17% were Black, 8% were Asian, 2% identified as Mixed, and 1% identified as other.

The median time from starting induction therapy to randomization was 5.6 months (IQR 5.3-5.9), the median follow-up from registration was 45.5 months (37.1-56.9), and the median follow-up from the time of randomization was 40.2 months (IQR 32.7-51.8).

A total of 162 patients of the 281 (57.7%; 95% CI, 51.6-63.5) had at least a very good PR. The ORR in the entire intention-to-treat population was 85.8% and seen in 241 of 281 patients (81.1-89.6), and 22.8% of patients were minimal residual disease-negative. At 2 years, the PFS was 77% (95% CI, 65-82) for patients in the HSCT group compared with 68% (95% CI, 58-76) in the KCd group.

Looking at safety, the most common grade 3/4 adverse events (AEs) during KCd induction and consolidation consisted of lymphocytopenia in 26% of patients who started induction and 14% who started consolidation, and infection in 18% for induction and 14% for consolidation. During carfilzomib maintenance, the most frequent grade 3/4 AEs included hypertension (21% in the KCd consolidation group vs 23% in the HSCT group) and infection (16% vs 25%).

At any point during the study, treatment-related serious AEs were observed in 39% of patients who started induction. Infections were the most common treatment-related AEs at 29%. Moreover, 5 patients had treatment-emergent deaths during induction. Three were due to infection, 1 was from a cardiac event, and 1 was from renal failure. One patient during maintenance after autologous HSCT also died of a treatment-emergent AE.

Based on these findings, the KCd regimen did not meet the criteria for non-inferiority in comparison with autologous HSCT. However, the marginal difference in PFS warrants further research to evaluate deferred autologous HSCT in various subgroups.

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 randomised, phase 2, non-inferiority trial. Lancet Haematol. 2023;10(2):e93-e106. doi:10.1016/S2352-3026(22)00350-7
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