Is MRD testing ready for prime time in multiple myeloma?

Prof. Edward A. Stadtmauer (University of Pennsylvania, PA, USA) discussed the how, when, and who of minimal residual disease (MRD) testing for patients with multiple myeloma [1].

The definition of hematologic response has evolved over time for multiple myeloma. The latest International Myeloma Working Group (IMWG) criteria for complete response includes negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytoma, and <5% plasma cells in bone marrow aspirates, with MRD included based on the IMWG 2016 criteria to provide more accurate response assessments [2]. However, “the role of MRD assessment for individual treatment decisions remains to be determined,” said Prof. Stadtmauer.

Bone marrow assessment of MRD has proven to be successful, with techniques including next-generation flow cytometry (NGF) and next-generation sequencing (NGS) [3-5]. These techniques also have downsides: “Bone marrow MRD assessment requires repeated invasive procedures and is limited by the known patchy nature of multiple myeloma and possibility of extramedullary disease [5],” said Prof. Stadtmauer. According to Prof. Stadtmauer, NGF and NGS are among the best methods available today, with imaging such as PET-CT providing additional information [6,7].

When should MRD assessments be performed? Optimal timing is uncertain for frontline treatment or during maintenance, but MRD negativity data are strongest through the first year of therapy [8]. In patients with high-risk multiple myeloma, “both sustained MRD negativity and combined bone marrow and imaging MRD may be needed,” said Prof. Stadtmauer [9]. Finally, in relapsed/refractory multiple myeloma, while achievement of MRD negativity is associated with better outcomes, most patients do experience relapse [10,11].

Another question that Prof. Stadtmauer posed is whether therapeutic decisions can be taken based on MRD status. MRD negativity is a strong and established prognosis marker, however, the impact on therapeutic decision-making remains to be determined [12]. The single-arm MASTER trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) induction showed that stopping therapy following 2 consecutive negative MRD assessments leads to low 12-month progression rates [13]. Similarly, in another single-arm trial of lenalidomide and dexamethasone (RD) maintenance, stopping therapy at 2 years if MRD assessment showed negativity led to low 4-year progression rates [14]. “Although these data are compelling and suggest the logical conclusion that deeper remission is better,” said Prof. Stadtmauer, “they do not clearly show that holding therapy after MRD negative status is superior to continuing therapy”.

The DETERMINATION trial of lenalidomide, bortezomib, and dexamethasone (RVD) induction with/without autologous stem cell transplant (ASCT) showed that postponing ASCT due to MRD positivity leads to worsened progression-free survival, while MRD negativity does not lead to a significant difference in terms of PFS regardless of whether ASCT is used or not [15]. Updated data from the PRiMER substudy of the STAMINA trial are expected soon, showing the prognostic value of MRD positivity following ASCT [16]. Several ongoing trials are aiming at determining whether MRD can be used to guide treatment decisions: MIDAS (NCT04934475), PERSEUS (NCT03710603), AURIGA (NCT03901963) and OPTIMUM EAA171 (NCT03941860) [6].

Dr Stadtmauer summarised by saying that “MRD assessment methods allow identification of patients with deep hematologic response and should be incorporated into all multiple myeloma clinical trials [6].” However, there is currently insufficient evidence to support MRD assessments for individual patient treatment decisions, with ongoing clinical trials aiming to evaluate whether MRD can guide therapy and monitor treatment decisions [6].

1. Stadtmauer EA. MRD driven strategies: key ongoing and future trials. Session III: MRD in clinical trials and application challenges in clinical practice. EMN 2024, 18–20 April, Turin, Italy.
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12. Martinez-Lopez J, et al. J Hematol Oncol. 2021;14(1):126.
13. Costa LJ, et al. Lancet Haematol. 2023;10(11):e890-e901.
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15. Richardson PG, et al. N Engl J Med. 2022;387(2):132-147.
16. Hahn TE, et al. Biol Blood Marrow Transplant 2019;25:S1-S6.

Posted on 22 April 202410 December 2024