Minimal Residual Disease in Multiple Myeloma

Minimal residual disease (MRD) detection represents a sensitive tool to appropriately measure the response obtained with therapies for multiple myeloma (MM) patients. The achievement of MRD negativity has superseded the conventional complete response (CR) and has been proposed as a surrogate endpoint for progression-free survival and overall survival.

Several techniques are available for the detection of MRD inside (next-generation sequencing, flow cytometry) and outside (PET/CT, magnetic resonance) the bone marrow, and their complementary use allows a precise definition of the efficacy of anti-myeloma treatments. (1)

In EMN clinical trials, MRD has been assessed by conventional 2nd generation Flow Cytometry with a sensitivity of 10-4-10-5. (2)

Nowadays more sensitive techniques are being investigated in ongoing clinical trials:

  • Next generation Flow (NGF): a 10-color 2-tube technique is used with higher sensitivity (up to 10-6) vs. conventional 8-color flow-MRD with a high number of nucleated cells acquired (~10 millions) and the use of the automatic population separator, which eliminated the operator-dependent variability. Baseline sample is not mandatory, thus allowing MRD tracking in post-treatments time-points.
  • Next Generation sequencing (NGS): (Clonoseq®, Adaptive Biotechnologies, Seattle, US-WA) allowed the achievement of high sensitivity levels (up to 10-6) in several clinical trials when compared with ASO-PCR. In 2018, FDA approved this technique, which is well standardized, with a 90-92% of applicability due to marker identification (thus requiring baseline bone marrow) and without the need for patient-specific reagents. (3)
  • PET/TC: imaging PET can detect focal lesions or extramedullary myeloma disease, outside the bone marrow, allowing the complementary evaluation of BM techniques due to spatial heterogeneity of myeloma disease. Recently, PET complete metabolic response has been standardized thanks to the introduction of the Deauville score and its impact on outcome. (4)
  • In collateral sub-studies, liquid biopsy is being tested to detect circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in early phases of treatment to evaluate the concordance with BM techniques and possible discordances in patchy disease. An alternative serological method, the quantitative immunoprecipitation mass spectrometry (QIP-MS), is also going to be developed. This polyclonal antibody-based technology identifies intact immunoglobulins at a higher sensitivity when compared to standard SPEP and it can be studied as additional MRD analysis, thus offering a new way to detect MRD in peripheral blood for MM patients.



  1. Mina R, Bonello F, Oliva S. Minimal Residual Disease in Multiple Myeloma: Ready for Prime Time? Cancer J. 2021 May-Jun 01;27(3):247-255. doi: 10.1097/PPO.0000000000000519. PMID: 34549914.
  2. Oliva S, Bruinink DHO, Rihova L, D’Agostino M, Pantani L, Capra A, van der Holt B, Troia R, Petrucci MT, Villanova T, Vsianska P, Jugooa R, Brandt-Hagens C, Gilestro M, Offidani M, Ribolla R, Galli M, Hajek R, Gay F, Cavo M, Omedé P, van der Velden VHJ, Boccadoro M, Sonneveld P. Minimal residual disease assessment by multiparameter flow cytometry in transplant-eligible myeloma in the EMN02/HOVON 95 MM trial. Blood Cancer J. 2021 Jun 3;11(6):106. doi: 10.1038/s41408-021-00498-0. PMID: 34083504; PMCID: PMC8175611.
  3. Mina R, Oliva S, Boccadoro M. Minimal Residual Disease in Multiple Myeloma: State of the Art and Future Perspectives. J Clin Med. 2020 Jul 7;9(7):2142. doi: 10.3390/jcm9072142. Erratum in: J Clin Med. 2020 Aug 13;9(8): PMID: 32645952; PMCID: PMC7408660.
  4. Zamagni E, Nanni C, Dozza L, Carlier T, Bailly C, Tacchetti P, Versari A, Chauvie S, Gallamini A, Gamberi B, Caillot D, Patriarca F, Macro M, Boccadoro M, Garderet L, Barbato S, Fanti S, Perrot A, Gay F, Sonneveld P, Karlin L, Cavo M, Bodet-Milin C, Moreau P, Kraeber-Bodéré F. Standardization of 18F-FDG-PET/CT According to Deauville Criteria for Metabolic Complete Response Definition in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2021 Jan 10;39(2):116-125. doi: 10.1200/JCO.20.00386. Epub 2020 Nov 5. PMID: 33151787.