Minimal Residual Disease-Adapted Therapy in Multiple Myeloma: Current Evidence and Opinions

MRD Guided Treatment

Induction and Consolidation

While many clinical trials use MRD as a primary endpoint, only a few have integrated MRD into their study design to actively guide treatment duration and transition to maintenance.

In the MASTER trial (NCT03224507) therapy was stopped after two consecutive MRD-negative results in newly diagnosed myeloma (NDMM) patients, with continual MRD surveillance. 71% achieved sustained MRD-negativity, yielding 2-year progression free survival (PFS) of 87%. However, patients with two or more high risk cytogenetic abnormalities (HRCAs) had a high relapse risk (47% at 24 months), emphasizing that while MRD guided de-escalation is feasible for standard risk disease, high risk patients may require more aggressive or multimodal strategies.

The Elo-KRD trial (NCT02969837) similarly used MRD (10⁻⁶) to determine therapy duration without stem cell transplant. 44% of patients achieved sustained MRD-negativity and transitioned to maintenance. Those who became MRD-negative by cycle 8 achieved outstanding 3-year outcomes (PFS 92%, overall survival (OS) 100%). Standard risk patients benefited most, while high risk disease remained challenging, mirroring findings from the MASTER trial.

Data from IFM-2009 and DETERMINATION trials showed no additional survival benefit for immediate stem cell transplant in patients already MRD-negative. In other words, patients who achieved MRD-negativity can move directly to maintenance without compromising survival, supporting a more personalized, less intensive treatment approach. In the MANHATTAN trial, 82.7% of MRD-negative patients chose to skip upfront stem cell transplant, achieving 1-year PFS and OS of 98% and 100%, respectively.

Several ongoing trials are also exploring MRD status to personalize therapy in multiple myeloma. For example, MASTER-2 and MIDAS, are exploring personalized treatment plans based on MRD status, testing new drug combinations and maintenance options.

Maintenance

Traditional maintenance therapy in multiple myeloma, often continued until disease progression, was established during an era of less powerful therapeutics. With modern, more effective therapies, the universal need for indefinite maintenance is being re-evaluated.

Studies like Myeloma XI show that patients who achieve MRD-negativity after stem cell transplant experience significantly longer PFS and OS, while extended maintenance may provide limited additional benefit for those with durable MRD-negative responses.

Long term analyses, including NCT02538198 and studies by Mohan et al., demonstrate that MRD levels rising predicts relapse within a year, underscoring the value of ongoing MRD monitoring. Trials such as FORTE, GEM2014MAIN, and TOURMALINE-MM3/MM4 further confirm that MRD dynamics, not just single timepoint results, should guide decisions on de-escalation or continuation of maintenance.

Ongoing clinical trials (like PERSEUS, DRAMMATIC, ATLAS, and MRD2STOP) are testing whether it’s safe for MRD-negative patients to stop maintenance treatment under close monitoring. Preliminary results suggest many patients can safely discontinue therapy under close MRD surveillance. Interestingly, studies like RADAR are looking into maintenance escalation based on MRD status.

As a side note, the REMNANT trial is testing whether early treatment intervention based on MRD relapse improves outcomes versus waiting for symptomatic or clinical relapse.

The idea is that MRD guided maintenance will allow for more individualized treatment, continuing therapy for those with residual disease while enabling carefully monitored treatment breaks for patients with durable, deep responses.

Figure 1: Clinical Trials for MRD Adapted Therapy.

Key Takeaways

• MRD testing is evolving from a prognostic tool into a practical guide for individualizing treatment in multiple myeloma.
• Studies are showing that sustained MRD-negativity can safely inform treatment de-escalation or cessation, reducing toxicity and improving quality of life.
• MRD resurgence could identify patients who may benefit from timely therapeutic re-engagement.
• MRD guided care is poised to become a central pillar of personalized myeloma management.

Authors

Meseha M, Hoffman J, Kazandjian D, Landgren O, Diamond B. Minimal Residual Disease-Adapted Therapy in Multiple Myeloma: Current Evidence and Opinions. Curr Oncol Rep. 2024 Jun;26(6):679-690. doi: 10.1007/s11912-024-01537-2. Epub 2024 Apr 27. PMID: 38676789; PMCID: PMC11169024.