Minimal residual disease (MRD) testing is increasingly important for the assessment of treatment response in patients diagnosed with multiple myeloma. In fact, MRD negativity is consistently associated with a better PFS and overall survival.1, 2, 3, 4, 5, 6, 7, 8, 9
In this issue of the Journal, Sherrod et al.10 publish a timely review article focusing on MRD testing after stem cell transplantation for patients with multiple myeloma. They review and discuss novel biochemical assays (including serum-free light-chain assays and heavy-chain/light-chain assays) as well as novel methods to measure MRD, including multi-parametric flow cytometry, PCR, next-generation sequencing and functional imaging modalities. They outline the main literature on this topic and highlight on the strengths and weaknesses of each of these assays and approaches. Furthermore, they address practical questions related to MRD testing after stem cell transplantation for patients with multiple myeloma. As part of their conclusion, they point out the clear need for International Myeloma Working Group response criteria to be revised and updated to include MRD.
In the final part of their paper, Sherrod et al.10 conclude that the treatment paradigm for multiple myeloma continues to evolve, and as the depth and duration of responses continue to improve, more sensitive measures of disease evaluation should be integrated into the response algorithm. As MRD research continues to develop, in their opinion, two clinical areas will be of particular interest with regard to the use of high-dose melphalan (HDM) therapy followed by autologous stem cell transplant (ASCT) in multiple myeloma.
The first interest area involves the question of whether it is beneficial for multiple myeloma patients to move forward with upfront HDM-ASCT or if a delayed HDM-ASCT following a set number of therapeutic cycles is equally good or better. As pointed out by Sherrod et al.10 the role of upfront versus delayed HDM-ASCT is being evaluated in the ongoing Intergroupe Francophone du Myélome (IFM)-Dana-Farber Cancer Institute (DCMI) study (NCT01208662), in which patient receive three cycles of RVd (lenalidomide, bortezomib and dexamethasone) combination therapy followed by upfront HDM-ASCT, followed by two additional cycles of RVd and lenalidomide maintenance versus an additional five cycles of RVd and lenalidomide maintenance with the option of a delayed HDM-ASCT at relapse. The duration of lenalidomide maintenance is restricted to 1 year in the IFM part of the study, whereas the DFCI part of the study uses lenalidomide maintenance until disease progression. At the 2015 American Society of Hematology (ASH) meeting in Orlando, Attal11 presented the results from the IFM part of the study, showing that the average PFS was longer in the arm with three cycles of RVd combination therapy followed by upfront HDM-ASCT, followed by two additional cycles of RVd and 1 year of lenalidomide maintenance. In the upfront HDM-ASCT arm, 93% of patients underwent ASCT and five toxic deaths occurred during mobilization or in the actual transplant phase (1.4%). ASCT was found to improve PFS (hazard ratio=1.5, 95% confidence interval=1.2–1.9). The 3-year post-randomization PFS rate was 61% in the upfront HDM-ASCT arm versus 48% in the delayed HDM-ASCT arm. Overall survival was not statistically different between the two arms.
Interestingly, in a sub-analysis also presented by the French IFM Group at the ASH 2015 meeting, Avet-Loiseau et al.12 had assessed depth of response among patients in the two study arms of the IFM part of the study. This sub-analysis showed that there were more patients obtaining a complete response (CR) in the upfront HDM-ASCT arm. Similarly, the rate of MRD negativity varied between the two arms. Specifically, they found that MRD 1/1 000 000 (that is, 10−6) negativity was more common among CR patients in the upfront HDM-ASCT treatment arm. In accord with the literature,9 the higher rates of CR and MRD 10−6 negativity were associated with a longer PFS; thus, the observed longer PFS in the upfront HDM-ASCT treatment arm was driven by a higher proportion of patients achieving deeper responses. Importantly, when Avet-Loiseau et al.12 evaluated clinical outcomes among patients who reached MRD 10−6 in either of the two treatment arms, based on small numbers, they observed no statistical difference with regard to PFS. The observation that the actual therapy given to reach a deep response does not matter—whereas the fact that the multiple myeloma patient has obtained a deep response matters (MRD 10−6 negativity)9—is very similar to observations done by the UK myeloma study group.13, 14
The second interest area involves response-based multiple myeloma therapy. As opposed to a fixed number of RVd cycles, Sherrod et al.10 discuss that the actual MRD status could potentially be used to identify patients who benefit from upfront ASCT as a response-deepening strategy. As proposed by Sherrod et al.10 a modern study design would be to randomize patients who achieve MRD 10−6 negative status to upfront HDM-ASCT versus delayed HDM-ASCT; in parallel, patients who do not achieve MRD 10−6 negativity after a defined number of combination cycles (for example, six) could be randomized to various treatment strategies, such as immediate HDM-ASCT versus further cycles of induction until the achievement of MRD 10−6 followed by re-randomization to HDM-ASCT, or not. In our opinion, an MRD-driven study—built on modern combination therapy (such as carfilzomib, lenalidomide and dexamethasone)8—is a logical next step from where we are right now (Figure 1). Response-based treatment strategies will define the depth of response required for sustained benefit and avoid overtreatment of those who have achieved maximal benefit.
As stated by Sherrod et al.10 the answers to these future questions are of particular interest in the United States, since increasing numbers of patients will become MRD 10−6 negative after having received modern therapies that are readily available through Food and Drug Administration approval. Overall, MRD testing in multiple myeloma care has the potential to better assess response to treatment, to risk stratify patients on clinical trials and to be integrated in treatment decisions in the standard of care setting. Beyond the use of MRD testing to tailor therapy for newly diagnosed multiple myeloma patients, determination of MRD status during maintenance therapy may also have a role to define the optimal duration of therapy after HDM-ASCT.