Although recent studies have illustrated complete response (CR) rates >50% for transplant-eligible patients with multiple myeloma (MM) treated with optimized induction followed by high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT), many patients relapse early. Patients who relapse are generally thought to have very low survival, but this has not been explored with the most recent therapies for treating patients with MM. Understanding which patients are most likely to relapse could improve survival, and as such, this analysis set out to define practical guidelines for predicting patients at risk of unsustained CR after bortezomib, lenalidomide, and dexamethasone (VRD) as induction therapy, HDT/ASCT, and VRD consolidation.
To accomplish this aim, the authors completed a subanalysis of the data from the phase 3 PETHEMA/GEM2012MENOS65 trial. This trial was designed to compare progression-free survival (PFS) in patients receiving 1 of 2 pretransplant conditioning regimens, BUMEL or MEL-200.
This subanalysis included 262 patients who were in CR after consolidation. During the trial, patients were treated with six 28-day VRD induction cycles. Patients received conditioning treatment (either BUMEL or MEL-200), and 3 months after transplantation, they received 2 cycles of consolidation treatment with VRD. After this, patients were enrolled in the PETHEMA/GEM2014MAIN clinical trial that was designed to compare maintenance treatment with lenalidomide and dexamethasone (RD) versus RD and ixazomib after autologous hematopoietic stem-cell transplantation for 2 years. After this, patients continued with RD for 3 years if they were minimal residual disease (MRD) positive or stopped therapy if they were MRD negative. Unsustained CR was defined as disease progression within 12 months of HDT/ASCT.
Both the presence of baseline anemia (<10 g/dL) and the International Staging System had a significant effect on PFS in CR after consolidation. In a multivariate analysis for PFS, ECOG (0 vs ≥1) and plasma cell counts (≤20% vs >20%) were independently useful for prognosis. The authors also analyzed other tests typically performed on negative immunofixation and found that plasma cell enumeration by morphology is not a valuable prognostic analysis, and the median percentage of plasma cells by morphology was 1.7% (range, 0-5). Only 4 (1.5%) of the patients with negative immunofixation had >5% bone marrow plasma cells and were not classified as in CR. Of the patients in CR, approximately one-fourth (56/248, 23%) displayed an abnormal serum free light chain (sFLC) ratio, but this did not seem to affect PFS compared with those with normal sFLC, indicating that this stringent CR criterion is not a good predictor of relapse. Interestingly, persistent MRD was identified in 29% of patients (76/257) and was highly correlated with inferior PFS (3-year rates of 49% vs 83%; P <.00001). Despite maintenance therapy, 14 (6%) patients had unsustained CR and low survival (only 3 patients remain alive). After consolidation, many patients with unsustained CR had persistent MRD (77%), whereas only 27% of patients with sustained CR were characterized by persistent MRD (P <.00001). Later CR achievement after HDT/ASCT also varied by whether CR was sustained (68%) or unsustained (36%; P = .0085). Notably, high-risk cytogenetics and other baseline characteristics did not predict relapse or unsustained CR.
This study determined that MRD assessment combined with response kinetics are useful for predicting patients who may relapse following optimized induction, HDT, and ASCT. Morphologic and sFLC measurements did not prove to be predictors of unsustained CR.
Reference
- Abstract and Poster EP936. EHA 2020. June 12, 2020. How to define and predict unsustained CR in transplant-eligible multiple myeloma: a sub analysis of the GEM2012MENOS65 trial.