In patients with MM treated with high dose chemotherapy followed by autologous stem cell transplantation, the presence of minimal residual disease (MRD) at 100 days post-transplant has been shown to be an independent adverse prognostic factor for both progression-free survival (PFS) and overall survival (OS).1-10 The predictive power of MRD-positivity in this population holds when only those patients in conventional complete response (CR) are analyzed, and in both standard- and high-risk patients as determined by cytogenetic testing.2-11 Studies also suggest that the presence of MRD following allogeneic stem cell transplant is associated with adverse PFS and OS.6, 12
Most studies of MRD in multiple myeloma have set the threshold for MRD-positivity at 10-4, primarily due to the technical limitations of the most often used techniques, flow cytometry and allele-specific oligonucleotide PCR (ASO-PCR). The clonoSEQ MRD Test has been shown to be concordant with both of these techniques, with most discordances attributable to its increased sensitivity and ability to detect MRD at the level of 10-6.4, 14 Studies using the clonoSEQ MRD Test showing that patients with MRD levels between 10-4 and 10-6 have worse prognosis than those with MRD less than 10-6 support the clinical relevance of increased sensitivity.4, 15, 16
Clinical Validation Data
The clonoSEQ MRD Test has Prognostic Value in Multiple Myeloma
- A study of 133 patients on GEM clinical trials (GEM00, GEM05 and GEM2010) found that MRD assessment by sequencing was prognostic for time to tumor progression (TTP; Figure 1) and overall survival (OS; Figure 2).4
- Additionally, sequencing identified two subgroups of CR patients that had significantly different TTP (Figure 3).4
MRD negativity by sequencing was associated with significantly longer TTP (median 80 vs. 31 months, p <0.0001)
MRD negativity by sequencing was associated with significantly longer OS (median not reached vs. 81 months, p = 0.02)
MRD negativity by sequencing was associated with significantly longer TTP (median 131 vs. 35 months, p = 0.0009) in CR patients
- Ferrero S, Ladetto M, Drandi D, et al. Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival. Leukemia. 2015;29(3):689-695.
- Landgren O, Owen RG. Better therapy requires better response evaluation: Paving the way for minimal residual disease testing for every myeloma patient. Cytometry. Part B, Clinical cytometry. 2015.
- Mailankody S, Korde N, Lesokhin AM, et al. Minimal residual disease in multiple myeloma: bringing the bench to the bedside. Nature reviews. Clinical oncology. 2015;12(5):286-295.
- Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014;123(20):3073-3079.
- Paiva B, Puig N, Garcia-Sanz R, San Miguel JF. Is This the Time to Introduce Minimal Residual Disease in Multiple Myeloma Clinical Practice? Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(9):2001-2008.
- Paiva B, van Dongen JJ, Orfao A. New criteria for response assessment: role of minimal residual disease in multiple myeloma. Blood. 2015;125(20):3059-3068.
- Paiva B, Vidriales MB, Cervero J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112(10):4017-4023.
- Puig N, Sarasquete ME, Balanzategui A, et al. Critical evaluation of ASO RQ-PCR for minimal residual disease evaluation in multiple myeloma. A comparative analysis with flow cytometry. Leukemia. 2014;28(2):391-397.
- Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31(20):2540-2547.
- Rawstron AC, Davies FE, DasGupta R, et al. Flow cytometric disease monitoring in multiple myeloma: the relationship between normal and neoplastic plasma cells predicts outcome after transplantation. Blood. 2002;100(9):3095-3100.
- Paiva B, Gutierrez NC, Rosinol L, et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood. 2012;119(3):687-691.
- Putkonen M, Kairisto V, Juvonen V, et al. Depth of response assessed by quantitative ASO-PCR predicts the outcome after stem cell transplantation in multiple myeloma. European journal of haematology. 2010;85(5):416-423.
- Paiva B, Martinez-Lopez J, Vidriales MB, et al. Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(12):1627-1633.
- Ladetto M, Bruggemann M, Monitillo L, et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia. 2013.
- Takamatsu H, Murata R, Zheng J, et al. Prognostic Value of Sequencing-Based Minimal Residual Disease Detection in Patients with Multiple Myeloma Who Underwent Autologous Stem Cell Transplantation. Abstract presented at: American Society of Hematology Annual Meeting 2015.
- Avet-Loiseau H, Corre J, Lauwers-Cances V, et al. Evaluation of Minimal Residual Disease (MRD) By Next Generation Sequencing (NGS) Is Highly Predictive of Progression Free Survival in the IFM/DFCI 2009 Trial. Abstract presented at: American Society of Hematology Annual Meeting 2015.