Data from CASSIOPET, a companion study of the phase 3 CASSIOPEIA trial, revealed that baseline findings from positron emission tomography combined with computed tomography (PET/CT) had prognostic value in transplant-eligible, newly diagnosed patients with multiple myeloma (MM), according to data presented by Philippe Moreau, MD, from University Hospital Hôtel-Dieu in Nantes, France, and colleagues. In the study, PET negativity was associated with better outcomes, paramedullary disease was associated with worse outcomes (observed in 17% of patients), and daratumumab improved progression-free survival (PFS) regardless of PET status at baseline.
In the CASSIOPEIA trial, daratumumab was added to the standard-of-care regimen of bortezomib/thalidomide/dexamethasone (D-VTd) in transplant-eligible, newly diagnosed MM patients. This significantly reduced the risk of disease progression or death, and improved rates of stringent complete response, complete response or better, and minimal residual disease (MRD)-negativity rates versus bortezomib/thalidomide/dexamethasone (VTd) alone. This translated to a 53% reduction in the risk of progression or death in the D-VTd arm after 18.8 months of follow-up. Overall survival data are still immature, but with a trend favoring the daratumumab arm.
Although MRD-negativity is associated with improved outcomes, relapse still occurs in MRD-negative patients, potentially due to the presence of focal bone disease. Final analysis of the IFM 2009 trial, previously reported in Blood (www.ncbi.nlm.nih.gov/pubmed/30249784), showed that double-negative patients—those with no residual disease assessed by both MRD (measured by multiparametric flow cytometry) and PET/CT—achieved better PFS than those who were not double-negative.
The CASSIOPET companion study evaluated the prognostic value of PET/CT at diagnosis, post-consolidation PET–complete response (PET-CR) rates of D-VTd versus VTd, and concordance between MRD and PET-CR negativity in the CASSIOPEIA trial. The primary objective was comparing PFS in double-negative patients versus those who were not double-negative, after a longer median follow-up of 29 months.
In Part 1 of CASSIOPEIA, more than 1000 newly diagnosed patients with MM were randomized to 4 cycles of pre–autologous stem-cell transplant (ASCT) induction and 2 cycles of post-ASCT consolidation with D-VTd or VTd; patients were also randomized to receive no maintenance, or single-agent daratumumab as maintenance. Evaluations of MRD on bone marrow aspirates were performed for all patients regardless of response (both after induction and after consolidation), and results were correlated with imaging data for the PET/MRD end point of CASSIOPET.
PET/CT scans were performed at baseline (prior to first dose) and post-consolidation (day 100 post-ASCT). An independent team of nuclear medicine physicians, blinded to patient treatment, interpreted the images. A total of 137 D-VTd patients and 131 VTd patients had assessable baseline PET prior to their first dose, and 101 D-VTd and 83 VTd patients were evaluable for PET measurements post-consolidation. At baseline, 20.1% of patients were PET-negative and 79.9% were PET-positive.
The investigators observed high post-consolidation response rates. Of the 184 patients with post-consolidation PET measurements, almost 90% of patients were PET-negative, with 118 patients (64.1%) achieving a CR and 47 patients (25.5%) achieving unconfirmed CRs. A total of 10.3% of patients were PET-positive after consolidation, with 17 (9.2%) achieving partial responses, and 2 patients with stable disease.
PET at baseline proved prognostic. Twelve-month and 18-month PFS rates in PET-negative versus -positive patients at baseline were 100% versus 92.5% and 100% versus 87.5%, respectively, but PFS was improved in both PET-negative and -positive patients with D-VTd.
An assessment of post-consolidation concordance of PET/CT and MRD revealed that 102 patients were MRD- and PET/CT-negative. Post-consolidation double-negativity rates of PET/CT and MRD were 47.5% for VTd and 66.7% for D-VTd (odds ratio, 2.2; P = .0105), demonstrating that more D-VTd than VTd patients reach double-negativity after consolidation. Double-negative patients also enjoyed longer PFS, confirming the findings from the previously reported IFM 2009 trial.
“Patients who were PET-negative at baseline enjoyed a longer PFS than PET-positive patients,” he said. “This was highly significant, with a hazard ratio of 0.4,” noting that PET-negativity is not of low prognostic value, as is often assumed, but rather, “PET-negativity at baseline is probably reflecting a different and less proliferative disease. This information is important.”
“With more mature data, PET-CR/MRD-negativity concordance may provide insight into utilizing both methods as a predictive surrogate for patient outcomes,” said Dr Moreau.
Moreau P, et al. ASH Abstract 692.