On Friday 13th September 2019, at the 17th International Myeloma Workshop (IMW), in Boston, US, Pieter Sonneveld and Hervé Avet-Loiseau presented their work from the CASSIOPEIA trial.
The phase III CASSIOPEIA trial is comparing the standard treatment of bortezomib, thalidomide, and dexamethasone (VTd) with daratumumab plus VTd (D-VTd) for pre-autologous stem cell transplant (ASCT) induction and post-ASCT consolidation in terms of stringent complete response (sCR) in patients with newly diagnosed multiple myeloma (NDMM). Patients were administered with four cycles of VTd or D-VTd prior to transplant, and then two cycles of VTd or D-VTd after transplant. We previously reported a presentation from the CASSIOPEIA trial at the American Society of Clinical Oncology (ASCO) annual meeting (which can be found here), where researchers reported a 53% reduction in the risk of progression or death with D-VTd compared with VTd.
Pieter Sonneveld from the Erasmus MC Cancer Institute, Rotterdam, NL, presented a subgroup analysis of CASSIOPEIA, focussing on patients with high-risk NDMM.1 In this high-risk subgroup, defined as those with ISS stage III (n= 165), and a cytogenetic risk status (either del17p ≥ 50% abnormal cells, or t(4;14) ≥ 30% abnormal cells; n= 168), response rates (≥ CR) were similar (Table 1). In terms of post-consolidation measurable residual disease (MRD), there were a higher proportion of patients displaying MRD-negativity with D-VTd than with VTd (64% vs 44% when looking at all patients, 34% vs 20% in patients who had CR or sCR), and this was also true for patients in the high-risk subgroups (Table 1). Pieter Sonneveld also presented progression-free survival (PFS) data which suggests a reduced risk of progression or death with D-VTd vs VTd in both the ISS stage III (HR 0.66; 95% CI 0.32 – 1.39) and cytogenetic high-risk (HR 0.67; 95% CI 0.35 – 1.30) groups.
Although the study did not demonstrate a benefit, in terms of sCR, of D-VTd over VTd in the high-risk subgroups, D-VTd was beneficial in terms of MRD-negativity rates and PFS. Longer-term follow-up and a second round of randomization, ongoing in CASSIOPEIA, should enhance results.
Table 1: Post-consolidation depth of response in high-risk subgroups
|ISS Disease Stage III||Cytogenetic High Risk|
|≥ CR (%)||44||33||-||27||33|
|≥ Partial Response (PR) (%)||42||56||-||48||53|
|Overall Response Rate (ORR) (%)||86||89||-||84||85|
|MRD negative rate (%)||64||46||0.0190||60||44|
|≥ CR MRD negative rate %||39||25||0.0516||29||23|
In the second presentation of data from the CASSIOPEIA trial, Hervé Avet-Loiseau from the Unite de Genomique du Myelome, IUCT Oncopole, Toulouse, FR, presented data on MRD for all patients in the intention to treat (ITT) population. 2 The group aimed to assess concordance between multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) in assessing MRD. Analysis of MRD was performed post-consolidation, at 100 days after ASCT. Missing results were assumed to be MRD-positive. Samples were assessed by MFC, and then by NGS subject to sample availability. There were a total of 733 patients from the total CASSIOPEIA cohort (n= 1085) who had bone marrow aspirates evaluated by both MFC and NGS (D-VTd n= 371, VTd n= 364). Numbers of patients who were negative for MRD (at a standard threshold of 10-5) as assessed by MFC and NGS are detailed in Table 2. Concordance between the two MRD evaluation methods was 83.5% regardless of response. In patients who demonstrated a ≥ CR, methods were in 94.4% agreement. Also, the agreement between the two methods was similar in each treatment group (82.7% in the D-VTd group, and 84.3% in the VTd group). Analysis of PFS by MRD status demonstrated that there was a PFS benefit in patients with MRD negativity and that there was additional PFS benefit in patients in the D-VTd group.
Results of this analysis show that both techniques perform similarly in evaluating MRD and that the use of daratumumab does not interfere with either MRD assessment method. As NGS does not require plasma, it may offer an alternative option if plasma is unavailable. In addition, daratumumab increases the number of patients who achieved MRD negativity.
Table 2: Post-consolidation MRD negativity rates at day 100 post-ASCT
|D-VTd, n (%)||VTd, n (%)||p value|
|MFC||346 (63.7)||236 (43.5)||< 0.0001|
|NGS||210 (56.6)||134 (36.8)||< 0.0001|