As treatments lead to deeper and more sustained responses, new markers for measuring and predicting treatment response that are more sensitive than current endpoints are required.
This page will explore response measurement criteria for Multiple Myeloma (MM). In addition, it will cover minimal residual disease (MRD), which is currently being investigated as a potential surrogate endpoint for survival outcomes in clinical studies.
The International Myeloma Working Group (IMWG) response criteria were introduced to help standardise assessment of response in MM and have since been universally adopted in myeloma clinical trials.
Over time a number of important changes have been made to the IMWG uniform response criteria, including: a more stringent definition of complete response (CR) to treatment based on the availability of more sensitive analytical techniques; the introduction of a very good partial response (VGPR) category, to help distinguish patients who have had near disappearance in their monoclonal (M)-spike but are still immunofixation-positive from those who have merely had a 50% reduction in their serum M-spike; and, in 2016, the incorporation of MRD assessment.
A complete response defined as the negative immunofixation on the serum and urine, disappearance of any soft-tissue plasmacytomas and <5% plasma cells in the bone marrow
The current IMWG uniform response criteria also include the following categories for deeper responses than CR:
VGPR is defined as serum and urine M-component detectable by immunofixation but not on electrophoresis, or ≥90% reduction in serum M-component plus urine M-component <100 mg/24 hour.
PR is normally defined as ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and the serum FLC assay is also unmeasurable, ≥50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was ≥30%.
In addition to the above criteria, if present at baseline, a ≥50% reduction in the size of soft-tissue plasmacytomas is also required.
SD is defined as any state that does not meet the criteria for CR, VGPR, PR or progressive disease (PD).
PD is defined as an increase of >25% from lowest response value in any one or more of the following:
Despite achieving a CR following induction therapy, some patients with MM subsequently go on to relapse with poor outcomes – suggesting that some residual disease remains.
The MRD-negativity threshold defines undetectable disease. In the updated International Myeloma Working Group response criteria for MM, MRD negativity is defined as the absence of clonal plasma cells in bone marrow aspirates at a minimum sensitivity of 1 in 105 nucleated cells or higher, in patients who have achieved a CR.
The MRD-negativity threshold is considerably more sensitive than the criteria for CR, which require negative immunofixation in the urine and serum, disappearance of any soft-tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.
To detect MRD at levels of 1 in 10⁵–10⁶ cells, tests with high sensitivity and specificity are required.
Next-generation sequencing (NGS) or next-generation flow (NGF), in combination with PET-CT are recommended for the assessment of MRD in bone marrow aspirates at the minimum threshold of 1 in 105 cells. Flow cytometry is another commonly used technique for evaluating MRD in bone marrow samples.
Adapted from Kumar et al. 2016 and Paiva et al. 2015
CT, computed tomography scan; MRI, magnetic resonance imaging scan; NGF, next-generation flow; NGS, next-generation sequencing; PET, positron emission tomography scan
NGS or NGF are the latest MRD assessment techniques used to analyse cells collected from bone marrow biopsies or aspirates. The procedures to obtain bone marrow biopsies and aspirates are painful for the patient and, as they are taken from a single site, may not reflect the heterogeneous nature of MM and result in false-negative results. To minimise false-negative results, the IMWG recommended the use of PET-CT. Mass spectrometry analysis of M-protein as a new way to measure MRD is being considered using peripheral blood samples, and in some cases, bone marrow samples.
Imaging negative criteria provide a measure of disease outside of the bone marrow – requiring the disappearance of positive lesions seen at baseline or on previous positron-emission tomography/computed tomography PET-CT scans.
If MRD negativity can be shown both inside (using NGS or NGF) and outside (using imaging) of the bone marrow, and can be confirmed by assessments at least one year apart, it is considered to be sustained.
MRD testing over time may provide the best assessment of a sustained response; however, the optimal timing and frequency of MRD evaluation is still under investigation.
MRD negativity is correlated with prolonged PFS and OS.
Several meta-analyses have shown that overall, MRD-negative status is associated with significantly better PFS and OS compared with being MRD positive.
Deeper responses mean better outcomes. Patients with CR who are also MRD negative showed better PFS and OS compared with those who remained MRD positive. The superiority of MRD negativity over CR is even seen in patients with high-risk cytogenetic abnormalities.
An increasing number of clinical trials are using MRD-negativity assessment as a primary or secondary endpoint.
Further clinical trials are being conducted to understand whether MRD-negative status can be used to assess treatment response and to guide treatment decisions in clinical practice.
Currently, an MRD consortium, the International Independent Team for Endpoint Approval of Myeloma MRD (i2 TEAMM), is developing a meta-analysis based on primary source data to be provided by investigators examining MRD in randomised Phase III trials. This meta-analysis will be submitted to the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the designation of MRD as a surrogate endpoint for PFS and OS.
Early diagnosis is critical in MM. An array of diagnostic methods can be used to characterise a patient’s MM, allowing for individualised treatment and management.
Treatment aims to extend survival by stopping or slowing growth and spread of myeloma cells. In addition, therapy can alleviate patients’ symptoms and complications, and improve quality of life.