Modified Delphi Method Identifies Consensus Areas for Routine Minimal Residual Disease Testing in Multiple Myeloma
Authors: Ramasamy Karthik , Avet-Loiseau Hervé , Blimark Cecilie Hveding , Delforge Michel , Gay Francesca , Manier Salomon , Martinez-Lopez Joaquin , Mateos Maria-Victoria , Mohty Mohamad , van de Donk Niels W.C.J. , Weisel Katja 
Published: November 2021

Abstract
Background: Despite evidence from clinical and real-world studies demonstrating a consistent association between minimal residual disease (MRD) negativity and improved survival in patients with newly diagnosed or relapsed/refractory multiple myeloma (MM), MRD testing has not been fully integrated into routine clinical practice. A paucity of data from clinical trials of MRD-directed therapy is a contributing factor. Until more data are available, consensus regarding the practical utility of MRD testing in MM established via a modified Delphi process can help guide clinical practice.
Objective: To establish areas of consensus and non-consensus regarding the current utility of MRD status to assess and confirm response to MM therapy, and to provide guidance regarding its utility in disease management.
Methods: The modified Delphi process, a systematic validated approach to gain consensus, is composed of two or more iterative rounds of surveys answered by a panel of experts. This expert Delphi panel comprised 61 practicing hematological oncologists from 14 European countries (Figure). A group of 11 advisors (within the panel) developed the survey questions and analyzed the results. Survey 1 assessed experts' opinions on and challenges associated with MRD testing in different clinical situations. Survey 2 further refined the use of MRD testing, methodologies, and frequency in different clinical settings using case studies. Consensus to an individual question was defined a priori as 75% agreement or disagreement by the panel. Of the 61 experts, most (87%) had treated ≥50 patients with MM in the 12 months prior to the study, and all had experience with MRD testing in MM in routine clinical practice and/or clinical trials. All members completed Survey 1, and 53 (87%) completed Survey 2.
Results: The advisors determined that two rounds of surveys were sufficient for data interpretation.
Only 64% of the Delphi panel felt suitably informed regarding the use of MRD testing in MM, and only half reported that MRD is covered in the treatment and/or prognostic guidelines that they use, suggesting that MRD-testing guidelines are limited. The panel reached consensus agreement that clinicians will benefit from more education/resources in the use of MRD testing to guide treatment decisions (92%) and guidelines on the use of MRD testing in routine MM care (75%).
Panel consensus agreement was reached on MRD testing in routine care for patients who are transplant-eligible (TE), in good fitness, and who have achieved complete response (CR; Table). Panel consensus was also reported for TE patients who are positive on positron emission tomography-computed tomography (PET-CT) scan, with PET-CT and MRD assessment of the bone marrow (BM) being deemed complementary tests post-transplant. If a patient is transplant-ineligible and in CR, panel consensus agreement for MRD testing was achieved for younger patients (≤70 years). However, for those ≥75 years old, there was consensus agreement that MRD testing is recommended if the patient is fit and in CR (Table). For patients with relapsed MM who achieve CR with reinduction therapy, consensus was reached for MRD testing. Panel consensus agreement was reached for repeated MRD testing in routine care for CR patients at a frequency of &gt;6 months to annually (Table). In addition to the TE patient cohort, the panel agreed that high-risk disease is a key driver for MRD testing.
On MRD testing use for treatment decisions, the panel did not reach consensus on any clinical scenarios that would lead to their support for treatment discontinuation, nor on the type of relapse (biochemical or MRD-positivity) that would prompt treatment re-initiation.
Conclusions: In this modified Delphi study, the panel reached consensus that clinicians require MRD routine care guidelines and education on MRD testing. A patient's CR status, transplant eligibility, fitness, and high-risk disease status were drivers for MRD testing. Consensus was also achieved for PET-CT being complementary to BM MRD in TE patients and regular MRD testing of &gt;6 months frequency. There was no consensus on treatment decisions based on MRD data. Results from on-going clinical studies will allow further refinement of this guidance.
Figure 1 Figure 1.

Disclosures
Ramasamy: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blimark: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding. Delforge: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Manier: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Regeneron: Consultancy, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinez-Lopez: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mateos: Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria. Mohty: Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Astellas: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria. van de Donk: Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Weisel: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria.