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With novel therapeutics increasing complete response (CR) rates for patients with multiple myeloma, measurable residual disease (MRD)–negativity is becoming increasingly recognized as a robust prognostic indicator.1 Indeed, patients in CR and with an MRD–negative (MRD-) status have been found to experience prolonged disease- and progression-free periods compared to those in MRD–positive (MRD+) CR.1 This benefit has even extended to those with high–risk cytogenetics.2

Advances in assessing MRD

 

The two validated methods for assessing MRD status are based on next-generation flow cytometry (NGF) or next-generation sequencing (NGS) of bone marrow (BM) aspirates.1 However, BM sampling is not only invasive but limits analysis to the marrow alone.1 The development of less invasive liquid biopsy methods, involving the analysis of blood samples for residual cells or protein markers, has the potential to overcome these concerns.1,3 

At ASH 2022, Bruno Paiva, PhD, University of Navarra, Pamplona, Spain, explained that assessing MRD in blood is an unmet need across hematology, but believes the required tools are now available.  

In this video, Dr Paiva discusses the importance of synergistically using available techniques with his team’s work to overcome the sensitivity issues that have been presented when applying NGF or NGS approaches developed for BM MRD assessment for peripheral blood (PB)1,4. “For sequencing or flow it was our impression that we needed at least an extra log of sensitivity for effective monitoring in blood, and that is what we have achieved and presented for the first time at ASH,”5 says Dr Paiva. 

 

The new flow cytometry method leverages NGF, and introduces an enrichment step,5 which is “a small iteration to the method allowing to detect MRD systematically to 10-7 logarithmic range, even in some patients MRD 10-8. That is unprecedented using flow in myeloma.”  

Dr Paiva also notes how, using this technique, MRD assessment in PB could outperform BM testing in the identification of patients at ultra-high risk of relapse. 

MRD as a prognostic tool

 

In this video, Yi Lin, MD, PhD, Mayo Clinic, Rochester, MN, discusses the findings of a study that evaluated the prognostic value of MRD status one month after CAR-T therapy infusion in patients with myeloma. The study used a combination of BM and positron emission tomography with computed tomography (PET/CT) assessment.6  

 

“An important thing that we’re seeing is serial sustained BM MRD- status has a very important prognostic value that is not unique to CAR-T,” explains Dr Lin. 

She discusses how, at month one, achieving MRD- status by both BM and PET/CT can be very reassuring for the patient, as they are likely to continue to be in response long term. At a median follow-up of 14.7 months, median progression-free survival (PFS) was significantly longer in those who were MRD- by both BM and PET/CT at month one (not available [NA; 95% CI: 280-NA] vs 360 days [95% CI: 163-NA] for MRD+ patients by one assessment method vs 70 days [95% CI: 38-NA] for MRD+ patients by both assessment methods [p<0.0001]).6

Dr Lin explains that since none of those who were MRD+ by either BM or PET at month one achieved a CR or stringent CR, and many did not convert to MRD- over time, the investigators believe this is a high-risk patient population that, at the minimum, requires closer monitoring. 

Similar results regarding the prognostic value of MRD status following CAR-T were also presented from the Phase II KarMMa trial (NCT03361748) of idecabtagene vicleucel (ide-cel)7 and Phase II portion of the CARTITUDE-1 (NCT03548207) study of ciltacabtagene autoleucel (cilta-cel)8. Here, Dr Paiva discusses the data from the KarMMa trial, which found that patients achieving early and sustained undetectable MRD after ide-cel have prolonged PFS.7

He also describes the study’s findings with regards to the prognostic value of the depth of serological and MRD responses: “At the very beginning, month one, only MRD status is informative… By contrast, [beyond] month one until month 12, both CR and MRD- are critical to identify patients that may enjoy long-term PFS after infusion with ide-cel.” 

Can MRD be used to guide treatment decisions?

 

 

“It has become quite routine to measure MRD– in patients who are undergoing therapy for multiple myeloma, but what’s lacking is what do you do with those results,” explains Morie Gertz, MD, MACP, Mayo Clinic, Rochester, MN, in this video. He notes that while trials such as MASTER (NCT03224507) have looked in a randomized fashion at the potential for MRD-directed treatment de-escalation in patients who are MRD-, this question is still under investigation. 

“This exploratory [MASTER] trial suggests that we may be able to use MRD- in decisions about intensive or continuous therapy for patients with multiple myeloma who are fortunate enough to achieve a stringent complete response with MRD-. Currently, that should only be done in the context of a clinical trial. I would discourage community physicians from using MRD- for anything other than a powerful prognostic factor,” states Prof. Gertz. 

One such study, exploring whether sustained MRD- status can support the discontinuation of lenalidomide maintenance post-transplant, had results presented at ASH 2022.9 Here, Alexander Lesokhin, MD, Memorial Sloan Kettering Cancer Center, New York, NY, discusses the rationale and results of the investigation. 

The majority of patients 13/15 (87%) enrolled in the first stage of the study did not have MRD recurrence 12 months after discontinuing lenalidomide maintenance, meeting the primary endpoint.9 Including the patients enrolled in stage 2, which is still accruing, sustained rates of MRD- at 6 months and 12 months were 17/18 (94%; 95% CI: 73%-99%) and 14/16 (88%; 95% CI: 62%-98%), respectively.9 PFS at 12 months was 94% (95% CI: 83%-100%).9 The patients who progressed could resume lenalidomide therapy. 

Insights into cancer biology from MRD

 

 

While MRD has traditionally been explored as a biomarker of treatment efficacy, at ASH 2022, Dr Paiva presented a different side to the story: “if we believe that persistence of MRD is one of the greatest barriers to prolonging patient survival, then we must study the biology of the MRD clone.” 

The study isolated persistent MRD clones and used multiomic profiling to compare the biology of these clones with that of tumor cells taken from the same patient at diagnosis and at relapse.10  

“By performing whole-exome and RNA-sequencing, we have shown that the MRD clone is a unique clone in the genomic evolution from diagnosis to MRD to relapse,” explains Dr Paiva, adding that this data could enhance understanding of treatment resistance and potentially inform new avenues to target it. 

Overall, MRD is emerging as one of the most important prognostic factors for patients undergoing treatment for multiple myeloma. With advancements in assessment techniques and studies underway to establish its potential utility in guiding treatment, the full benefit of MRD assessment for both healthcare professionals and their patients is yet to be seen. 

 

Listen to more expert insights on the role of MRD in myeloma in our podcast!

References

  1. Charalampous C, Kourelis T. Minimal residual disease assessment in multiple myeloma patients: Minimal disease with maximal implications. Frontiers in Oncology. 2022 Jan 26;11. 
  2. Avet-Loiseau H, Lauwers-Cances V, Corre J, et al. Minimal Residual Disease in Multiple Myeloma: Final Analysis of the IFM2009 Trial. Blood. 2017 Dec 7;130(Supplement 1):435. 
  3. Colmenares R, Álvarez N, Barrio S, et al. The minimal residual disease using liquid biopsies in hematological malignancies. Cancers. 2022 Mar 3;14(5):1310. 
  4. Sanoja-Flores L, Flores-Montero J, Puig N, et al. Blood monitoring of circulating tumor plasma cells by next generation flow in multiple myeloma after therapy. Blood. 2019 Dec 12;134(24):2218–22. 
  5. Notarfranchi L, Zherniakova A, Lasa M, et al. Ultra-sensitive assessment of measurable residual disease (MRD) in peripheral blood (pb) of multiple myeloma (mm) patients using bloodflow. Blood. 2022 Nov 15;140(Supplement 1):2095–7.  
  6. Bansal R, Ailawadhi S, Larsen JT, et al. Prognostic value of month 1 bone marrow and pet mrd status in car-T therapy for myeloma. Blood. 2022 Nov 15;140(Supplement 1):1862–4.  
  7. Paiva B, Manrique I, Rytlewski JA, et al. Early and sustained undetectable measurable residual disease (MRD) after Idecabtagene Vicleucel (IDE-CEL) defines a subset of multiple myeloma (MM) patients in KARMMA achieving prolonged survival. Blood. 2022 Nov 15;140(Supplement 1):2104–5.  
  8. Munshi NC, Paiva B, Martin T, et al. Efficacy outcomes and characteristics of patients with multiple myeloma (mm) who achieved sustained minimal residual disease negativity after treatment with Ciltacabtagene Autoleucel (CILTA-cel) in CARTITUDE-1. Blood. 2022 Nov 15;140(Supplement 1):4652–4.  
  9. Korde N, Diamond B, Burge M, et al. Maintenance therapy cessation for sustained MRD negative multiple myeloma patients. Blood. 2022 Nov 15;140(Supplement 1):2397–8.  
  10. Guerrero C, Puig N, Cedena Romero MT, et al. Multiomics profiling of measurable residual disease (MRD) for understanding the biology of ultra-drug resistance in multiple myeloma (MM). Blood. 2022 Nov 15;140(Supplement 1):246–8. 
Written by Hannah Balfour
Edited by Elitsa Kamberska & Thomas Southgate

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