Educational theme: Measurable residual disease (MRD)

This month’s educational theme on the Multiple Myeloma (MM) Hub is centered around measurable residual disease (MRD; also referred to as minimal residual disease).

Despite enormous advances in the treatment, MM remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. MRD is a very useful marker for measuring those residual cells which eventually lead to relapse. Therefore, MRD has been used to guide the therapeutic strategies for MM patients and is now a key parameter for assessing treatment efficacy. As a consequence, there is an increasing clinical interest to achieve MRD negativity in the bone marrow of MM patients.

Methods to detect MRD differ in sensitivity. Flow cytometry or PCR-based assays can detect MRD close to 10-4 or 10-5, whereas next-generation sequencing (NGS)-based assays offer better sensitivity and can detect as low as one myeloma cell in 10-6 bone marrow cells. These technologies can be used for MRD evaluation in MM patients depending on local availability. However, some issues remain to be clarified such as standardization, sample source and samples processing.

The meta-analysis by Nikhil Munshi et al.1 was one of the first studies to clearly demonstrate the importance of MRD for patients with MM in complete remission (CR). Patients in CR still have a substantial disease and MRD enables the detection of the exact percentage of remaining cancer. Importantly, the study showed that patients in CR with MRD negative status had significantly improved outcomes, including progression-free survival (PFS) and overall survival (OS), as compared to MRD positive patients in CR. These results urged for the use of MRD as a standard endpoint for clinical trials in MM.

 Prof. Nikhil Munshi |Impact of MRD on survival in MM patients in CR

There are many unanswered questions regarding the use of MRD as a treatment guide for patients with MM. These were raised during a MM Hub interview with Maria Victoria-Mateos at the 2019 EBMT meeting. As MM is an incurable disease for most patients, it is crucial for MRD negativity to be maintained for as long as possible. To achieve this, it is unclear whether patients with MRD negative status should receive continuous maintenance therapy or not.

Maria Mateos | EBMT 2019 | The use of MRD in clinical decision making for maintenance therapy in MM

Multiple clinical trials have assessed different maintenance treatments in regard to efficacy and MRD status in patients with MM. Among these, is the Myeloma XI study, which showed that patients achieving MRD negativity benefit the most from ongoing lenalidomide maintenance therapy compared to observation, in newly-diagnosed MM (NDMM) patients after autologous stem cell transplantation (ASCT).

Moreover, the phase III trial CASSIOPEIA also used MRD negativity (<10-5) as a clinical endpoint. This study compared daratumumab plus bortezomib, thalidomide and dexamethasone (D-VTd) to VTd alone in patients with NDMM. The results of this trial were summarized in an article by the MM Hub and showed that adding daratumumab to the VTd regimen significantly improved the depth of response as measured by MRD negativity 64% vs 44% (p<0.0001).

MRD status evaluation is also being performed in the FORTE trial as summarized by the MM hub here and discussed in our interview with Francesca Gay at the 2019 EHA meeting, shown below. This study compared carfilzomib, lenalidomide, and dexamethasone (KRd) induction followed by high-dose melphalan plus ASCT consolidation and KRd maintenance to KRd alone in patients with NDMM. The second randomization for maintenance lenalidomide or lenalidomide plus carfilzomib was performed by MRD measurement at baseline, post-induction and prior maintenance. MRD measurements are planned annually for these patients. So far, the results of the FORTE trial show that KRd plus ASCT lead to high and sustained MRD negativity rates at one year, especially in high-risk patients.

EHA 2019 | Results from FORTE trial of KRd in NDMM

The advantages and limitations of surrogate parameters like MRD negativity as endpoints in MM clinical trials were further explored by the MM Hub in a summary article of Prof. Shaji Kumar’s review from the BELLINI trial. In this trial, MRD <10-4; <10-5 and 10<-6 were used as outcome indicators, with all three rates being statistically higher in patients with relapsed or refractory MM treated with venetoclax plus bortezomib and dexamethasone (VenBd) compared to placebo plus Bd. Nevertheless, on March 2019 the FDA enforced a partial hold on trials involving venetoclax for the treatment of MM due to the high death rate observed in the venetoclax arm of the BELLINI trial when compared to placebo (21% versus 11%). For more information on this read here a summary from the MM Hub.

Ongoing trials

Although MRD is currently being considered as a surrogate marker for PFS and OS, there are still unanswered questions regarding its optimal use. At the moment, a combined trial from a French group and the Dana Farber Cancer Institute is comparing MRD status progression after ASCT in patients with MM who will be receiving either maintenance treatment for one year or continuously until disease relapse.

Moreover, the Spanish Myeloma Group is currently evaluating lenalidomide in combination with dexamethasone and ixazomib as maintenance therapy for up to two years with an MRD status evaluation step (NCT02406144). If patients are MRD negative following this two-year maintenance they will stop any treatment, while if they are MRD positive they will continue maintenance with lenalidomide and dexamethasone for an additional three years. With the results of these and other ongoing studies, it is certain that MRD evaluation will have a place in patient follow-up and treatment guidance for MM.

The MM Hub will be covering all the latest updates on MRD assessment and its clinical significance as a prognostic marker for MM patient outcomes. Make sure you follow us for the next update!

  1. Munshi, N. et al., (2018). Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood, 132(23), 2456–2464. DOI:10.1182/blood-2018-06-858613
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