by ecancer reporter Vanessa Lane

For many years, the goal of treatment for multiple myeloma (MM) was to achieve objective responses, mainly partial response (PR) and disease control.

However, the introduction of high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) and the availability of novel agents has enabled many patients to achieve a complete response (CR) associated with prolonged survival.

Established response criteria have had to be revisited in order to detect minimal residual disease (MRD).

This is because the majority of patients with MRD have persistent levels of residual disease below the sensitivity of bone marrow morphology, protein electrophoresis with immunofixation and light chain quantitation even after attaining CR, and will eventually relapse.

These have included the serum free light chain (sFLC) assay in conjunction with immunohistochemistry and/or immunofluorescence to define a more stringent degree of CR (sCR), and the utilisation of multiparameter flow cytometry (MFC) and polymerase chain reaction (PCR) to define immunophenotypic and molecular responses, respectively.

Data on the prognostic significance of sCR remain limited, and the role of the sFLC assay has recently been questioned.

Recent studies suggest that MFC and PCR responses may be more relevant prognostic factors, both of which have shown a strong correlation with the quality of response to HDT/ASCT and progression free (PFS) and overall survival (OS); MFC has been found to be more applicable for use in routine laboratories.

The correlation between these surrogate markers have also shown a strong correlation to response in the non-transplant setting in patients treated with novel agents. Currently, the results for the use of these markers are limited to small groups of patients, mostly eligible for transplantation, and carried out before the introduction of novel agents. It is therefore  important to evaluate the clinical relevance of these prognostic markers in the era of novel agents and within the context of clinical practice.

Latest results from the MRC Myeloma IX Study

The MRC Myeloma IX Study is the largest randomised study to date to examine the role of thalidomide maintenance in multiple myeloma (MM) patients. The mode of action of thalidomide includes direct apoptotic, antiangiogenic effects and modulation of the bone marrow microenvironment.

These activities against the myeloma clone suggest that, after induction therapy, with either a consolidation block or maintenance therapy, thalidomide may reduce or suppress residual disease, prolonging the disease-free interval and potentially improve survival.

The MRC Myeloma IX Study included 820 patients and had a prolonged median-duration follow-up of 46 months. The data show a significant improvement in progression-free survival (PFS) across the entire patient cohort (23 vs 15 months), and this benefit was particularly notable in intensively treated patients, with a median benefit of 7 months. The results were less impressive in older patients, treated on a nonintensive pathway, where the median improvement in PFS was only 2 months.

The assessment of minimal residual disease (MRD) in this trial was particularly important on assessing the depth of response to treatment. Results of thalidomide maintenance trials are conflicting. After autologous stem cell transplantation (ASCT), thalidomide maintenance therapy has been associated with improved PFS.  An overall survival (OS) benefit has not been demonstrated consistently, although a recent meta-analysis did show a trend toward improved OS.

In the MRX study, a significantly higher proportion of thalidomide treated patients achieved MRD negativity after induction. In intensively treated patients, MRD negativity at day 100 post ASCT was highly predictive of superior outcomes. There was no statistically significant effect of MRD status after induction in the non-intensively treated patients. In all intensively treated patients investigated by multiparameter flow cytometry (MFC) in maintenance, PFS was greatest in those who were MRD negative and who had thalidomide.