Current rationale for the use of MRD-driven therapy in MM

How to use measurable residual disease (MRD) to define or guide treatment decisions is currently a key topic of discussion for optimizing outcomes for patients diagnosed with multiple myeloma (MM).¹ Areas of consideration include the prognostic value of MRD in the setting of transplant versus no transplant, guiding posttransplant therapy, the use/duration of maintenance therapy, the duration of therapy in patients who are not transplant eligible, and managing MRD resurgence.¹

During the 9th World Congress on Controversies in Multiple Myeloma (COMy), Costa¹ gave a presentation on the rationale behind the potential use of MRD guidance within these clinical settings. We summarize the key points in the article below. For more information on whether we are closer to using MRD-guided treatment decisions in MM, check out this interview from 64th American Society of Hematology (ASH) Annual Meeting and Exposition here.

Key points

Transplant or no transplant?

Deciding whether a patient should undergo or defer autologous stem cell transplantation (ASCT) remains an important consideration for clinicians. MRD status has the potential to guide this process; however, achieving MRD negativity with induction alone remains challenging. This has recently been made easier with the introduction of quadruplet induction regimens such as daratumumab, carfilzomib, lenalidomide, and dexamethasone, which showed negative MRD rates in patients of 38% compared with rates of 5.8% for lenalidomide, bortezomib, and dexamethasone only regimens.

Overall, ASCT has been shown to greatly increase negative MRD, with up to 50% of patients who were MRD positive prior to transplantation becoming MRD negative after treatment. However, in contrast, on average, patients experienced a 1.1 log₁₀ reduction in tumor burden during quadruple induction regimens and represents a significant rationale against deferring transplantation. Unfortunately, there are currently no comparisons of patients who are post-induction MRD negative treated with ASCT versus patients who haven’t received an ASCT. However, all trials indicate improvement in negative MRD rates with ASCT. The MIDAS (NCT04934475) trial of isatuximab-carfilzomib, lenalidomide, and dexamethasone will use MRD status to guide whether to defer transplant or not is currently underway.

Posttransplant therapy guidance

In the posttransplant setting, the impact of positive MRD has been shown to be greater than that of adverse cytogenetic risk. In the DETERMINATION trial (NCT01208662), the impact of MRD status was only partially alleviated by extended consolidation therapy.

While there is currently no randomized data available, the post-ASCT analysis of the MASTER (NCT03224507) trial highlighted that MRD-directed consolidation therapy mitigated the impact of positive MRD. Patients who are MRD positive posttransplant represent a key group who need to be targeted for treatment and as such represent a valuable starting point for future trials. A few of these trials have already begun including the AURIGA (NCT03901963) and COMMANDER (NCT04268498) trials.

Guidance on the use/duration of maintenance therapy

While there is currently no definitive answer on the use of MRD to guide maintenance therapy, the Myeloma XI trial (NCT01554852) recently highlighted that the impact of lenalidomide maintenance is reduced in patients who are MRD negative and over time.

The impact of novel treatments should also be noted with the use of posttransplant quadruplet regimens that incorporate anti-CD38 antibodies allowing for the attainment of deeper, more durable responses. In this case, as shown in the CASSIOPEIA trial (NCT02541383), the risk of progression is <10%; thus, the benefit of staying on maintenance therapy becomes questionable. The results of the MASTER trial also saw a similar conclusion, with most patients who achieved MRD negativity not progressing despite no maintenance therapy.

For patients who are diagnosed with non-transplant eligible newly diagnosed MM, the prognostic value of MRD remains. Interestingly, patients treated with monoclonal antibodies appear to experience deeper and longer-lasting MRD responses as seen in the MAIA (NCT02252172) and ALCYONE trials (NCT02195479). However, treatment duration is still currently guided by tolerance and standard approaches to efficacy. Due to the lack of data in this area, treatment de-escalation through MRD guidance remains a challenge.

MRD resurgence

It is inevitable that as up-front therapy options are continuously improved and patients experience deeper responses and sustained MRD negativity, many will want to become treatment free. As a result, MRD resurgence will become an increasing problem to contend with. Resurgence represents a concerning marker for imminent disease progression and highlights that clonal expansion post quadruple induction therapy is unlikely to be contained by singular induction treatment. In this scenario, MRD-driven guidance has the potential to aid in clone control and minimize the clinical impact of disease progression.

Conclusion

The use of MRD to guide treatment decisions remains complex and the decision should be tailored to the individual clinical circumstance. Few patients will be MRD negative prior to transplantation and the impact of deferral on progression-free survival is unknown. Use of guidance in this case should therefore be cautious. This also applies to non-transplant eligible patients where this is currently limited data to support the use of MRD guidance. In contrast, there is as strong rationale for use during MRD resurgence as it indicates imminent disease progression and may aid in clone control.