Day 2 of the 14th International Myeloma Workshop in Kyoto, Japan saw a review of the latest understanding in minimal residual disease (MRD), how to improve the initial management of transplant eligible patients and possible mechanisms that could be used to predict future progression of smouldering myeloma and monoclonal gammopathy of undetermined significance (MGUS) to full-blown multiple myeloma (MM).

Minimal residual disease

High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) and novel agents such as thalidomide, lenalidomide and bortezomib have considerably improved complete response (CR) rates in MM. The majority of patients with MM have persistent levels of residual disease that are below the sensitivity of bone marrow morphology, protein electrophoresis with immunofixation and light chain quantitation even after attaining CR, and will eventually relapse. As a result, measurement of MRD by more sensitive methods, that can be used as tools for predicting patient outcomes and guiding therapeutic decisions has become more relevant. A number of surrogate markers for long term survival in MM have been identified. However, identifying the optimal surrogate marker best able to quantify MRD after therapy in clinical practice needs to be confirmed. The use of these markers will also allow improved monitoring of the effects of novel treatments, as well identify patients who are at risk of disease progression and may require additional treatment. Newer methods available for monitoring MRD in MM include polymerase chain reaction (PCR) and multiparameter flow cytometry (MFC) for assessing the changes within the bone marrow. MFC has been found to be more applicable for use in routine laboratories. Both of these surrogate markers have shown a strong correlation with the quality of response to HDT/ASCT and progression free (PFS) and overall survival (OS). This correlation has also been noted in the non-transplant setting in patients treated with novel agents.

MRC Myeloma IX Study

In the MRC Myeloma IX Study the effect of thalidomide on PFS and OS in MM patients was analysed through the assessment of MRD with MFC. 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 MFC in maintenance, PFS was greatest in those who were MRD negative and who had thalidomide. Some consolidation was observed with thalidomide in patients who were MRD positive. It was concluded that the assessment of the depth of response by MFC of MRD would be useful in future evaluation of therapy in induction, consolidation and maintenance.

Initial therapy in transplant eligible patients

The standard of care in transplant eligible patients (under the age of 65 years of age) is HDT with melphalan followed by ASCT. The utilisation of thalidomide, bortezomib and lenalidomide have further improved OS in these patients. However, many patients still relapse and the assessment of risk of progression at diagnosis is needed to optimise therapeutic strategies.

At the chromosomal level, an abnormal karyotype (reflecting proliferation) and the presence of t(4;14) or del(17p) cytogenetic abnormalities by FISH, are the main factors associated with poor outcomes. Gene expression profiling (GEP), CGH/SNParray and sequencing have also been used, with variable degrees of accuracy and available data. Further factors during and after treatment, including the depth and duration of remission are also important tools in predicting outcomes.

The utilisation of risk assessment may help direct treatment, with initial results suggesting that induction therapy with novel agents may particularly benefit patients with a greater risk of progression. Additional efficacy data with novel therapeutics has led to the investigation of three drug induction treatment without ASCT. The initial results have been compelling and have led to the question of whether ASCT should be used early in all eligible patients, or as a salvage therapy at the time of progression for patients achieving a high quality response.

The golden chalice in MM remains the search for a cure. We may be getter a little closer to this in a subgroup of patients where lower risk has been identified, absence of MRD is confirmed and currently available HDT/ASCT and novel therapies are used. However, much more is still needed in order to begin to develop practical steps towards a cure in the wider population of MM patients.

Smouldering MM/MGUS

Studying smouldering myeloma and MGUS, precursors to MM, offers the potential to better diagnose and prevent full blown MM. MGUS resembles MM, but the level of antibodies in the blood are lower, as is the level of  protein. With smouldering myeloma, the protein builds up slowly over time. The risk of MGUS patients developing  full-blown MM increases by about 1% every year. The risk of smouldering myeloma transforming into MM is much higher. However, the risk of progression from smouldering MM to MM varies considerably among individual patients.

At the molecular level, transformation from precursor to full-blown MM is a gradual process, with several overlapping oncogenic events within plasma cells and the marrow microenvironment accumulating from normal plasma cells through precursor disease to full-blown MM.

These include hyperdiploidy and primary immunoglobulin translocations at the 14q32 locus and cyclin D dysregulation. In addition, abnormal plasma cells in MGUS, smouldering myeloma and MM produce a broad range of immunoreceptors that are stimulated and contribute to the clonal proliferation observed in bone marrow biopsies. Many secondary oncogenic events have been implicated in the transition from MGUS and/or smouldering myeloma to full-blown MM and from newly diagnosed MM to advanced and/or refractory disease. These secondary genetic events may, in part, be dependent on the primary lesion.

Furthermore, complex alterations to microenvironmental interactions occur in the transition from MGUS to MM. An apparent manifestation in myeloma genesis is the interaction between abnormal plasma cells, cells in the bone marrow microenvironment and the bone, which ultimately leads to characteristic lytic lesions in approximately 80% of MM patients. Although osteoclastic activation and osteoblastic inactivation leading to lytic lesions is a criterion for progression from MGUS and/or smouldering myeloma to MM, recent studies have revealed increased risk of bone fractures in patients with MGUS and smouldering MM.

A number of biomarkers that can be used to predict the progression from smouldering MM to full-blown MM include bone marrow plasma cell (BMPC) levels, IgG, M-component level, serum freelite chain (FLC) level and immune features of bone marrow. A 98% prediction of progression can be achieved with cut-offs of ≥60% BMPC and FLC ≥100%. Enhancement of the Spanish immunophenotyping methodology to assess immune cells in the peripheral blood and bone marrow and utilisation of PET/CT, whole body MRI and other sensitive imaging techniques have been investigated. These techniques, in association with more sensitive assessments of renal function and use of molecular testing will improve the identification of early stage disease progression.