scholarly journals Monitoring the M-protein of multiple myeloma patients treated with a combination of monoclonal antibodies: the laboratory solution to eliminate interference

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Somayya Noori ◽  
Christie P. M. Verkleij ◽  
Marina Zajec ◽  
Pieter Langerhorst ◽  
Patricia W. C. Bosman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Response Assessment ◽  
M Protein ◽  
Single Patient ◽  
Additional Advantage ◽  
Quantitative Monitoring ◽  
Immunofixation Electrophoresis ◽  
Protein Diagnostics ◽  
Minimal Residual

Abstract Objectives The therapeutic monoclonal antibody (t-mAb) daratumumab, used to treat multiple myeloma (MM) patients, interferes with routine, electrophoretic based M-protein diagnostics. Electrophoretic response assessment becomes increasingly difficult when multiple t-mAbs are combined for use in a single patient. This is the first study to address the analytical challenges of M-protein monitoring when multiple t-mAbs are combined. Methods In this proof-of-principle study we evaluate two different methods to monitor M-protein responses in three MM patients, who receive both daratumumab and nivolumab. The double hydrashift assay aims to resolve t-mAb interference on immunofixation. The MS-MRD (mass spectrometry minimal residual disease) assay measures clonotypic peptides to quantitate both M-protein and t-mAb concentrations. Results After exposure to daratumumab and nivolumab, both t-mAbs become visible on immunofixation electrophoresis (IFE) as two IgG-kappa bands that migrate close to each other at the cathodal end of the γ-region. In case the M-protein co-migrates with these t-mAbs, the observed interference was completely abolished with the double IFE hydrashift assay. In all three patients the MS-MRD assay was also able to distinguish the M-protein from the t-mAbs. Additional advantage of the MS-MRD assay is that this multiplex assay is more sensitive and allows quantitative M-protein-, daratumumab- and nivolumab-monitoring. Conclusions Daratumumab and nivolumab interfere with electrophoretic M-protein diagnostics. However, the M-protein can be distinguished from both t-mAbs by use of a double hydrashift assay. The MS-MRD assay provides an alternative method that allows sensitive and simultaneous quantitative monitoring of both the M-protein and t-mAbs.

scholarly journals New criteria for response assessment: role of minimal residual disease in multiple myeloma

Blood ◽  
2015 ◽  
Vol 125 (20) ◽  
pp. 3059-3068 ◽  
Author(s):  
Bruno Paiva ◽  
Jacques J. M. van Dongen ◽  
Alberto Orfao
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Response Assessment ◽  
Baseline Risk ◽  
Multiparameter Flow Cytometry ◽  
New Criteria ◽  
Minimal Residual

Abstract Assessment of minimal residual disease (MRD) is becoming standard diagnostic care for potentially curable neoplasms such as acute lymphoblastic leukemia. In multiple myeloma (MM), the majority of patients will inevitably relapse despite achievement of progressively higher complete remission (CR) rates. Novel treatment protocols with inclusion of antibodies and small molecules might well be able to further increase remission rates and potentially also cure rates. Therefore, MRD diagnostics becomes essential to assess treatment effectiveness. This review summarizes reports from the past 2 decades, which demonstrate that persistent MRD by multiparameter flow cytometry, polymerase chain reaction, next-generation sequencing, and positron emission tomography/computed tomography, predicts significantly inferior survival among CR patients. We describe the specific features of currently available techniques for MRD monitoring and outline the arguments favoring new criteria for response assessment that incorporate MRD levels. Extensive data indicate that MRD information can potentially be used as biomarker to evaluate the efficacy of different treatment strategies, help on treatment decisions, and act as surrogate for overall survival. The time has come to address within clinical trials the exact role of baseline risk factors and MRD monitoring for tailored therapy in MM, which implies systematic usage of highly sensitive, cost-effective, readily available, and standardized MRD techniques.

scholarly journals Pre-Transplant M Protein Level Predicts Minimal Residual Disease Status after Autologous Stem Cell Transplantation in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4903-4903
Author(s):  
Zachary S Meyer ◽  
Mohamed Manaa ◽  
Yan Han ◽  
Magdalena Czader ◽  
Attaya Suvannasankha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Research Funding ◽  
Residual Disease ◽  
M Protein ◽  
Post Transplant ◽  
Minimal Residual

Abstract Introduction: Autologous stem cell transplantation has been a staple treatment modality in patients with multiple myeloma for more than 30 years. Multiple studies have shown increased survival among patients who undergo transplant when compared to those who receive chemotherapy alone, even amongst elderly patients. Despite the efficacy associated with transplant among populations as a whole, individual response to therapy is variable and difficult to predict. Recent studies however have demonstrated that achieving minimal residual disease (MRD) negativity is associated with increased survival in patients with multiple myeloma. In this study, we performed a retrospective analysis on patients with multiple myeloma who underwent autologous stem cell transplantation and investigated potential markers to predict post-transplant MRD status. Patients and Methods: Patients with a diagnosis of multiple myeloma that underwent treatment with high-dose melphalan followed by autologous stem cell transplantation at the Indiana University Simon Cancer Center between 2019-2020 were included in the analysis. Patient demographics, disease characteristics, pre-transplant and post-transplant laboratory values, and approximately day +100 post-transplant bone marrow sample results were collected. MRD analysis on post-transplant bone marrow aspirations was performed using 8 color flow cytometry panel with a total of 10 markers. The limits of quantification and detection were calculated at 5X10 -6 and 2X10 -6, respectively. Post-transplant data was analyzed to determine MRD status. MRD negativity was defined as having no identifiable M protein via serum protein electrophoresis (SPEP) or immunofixation electrophoresis (IFE) and having negative MRD on post-transplant bone marrow biopsy testing. Patients with insufficient data to determine post-transplant MRD status were excluded from the analysis. Univariate logistic regression was performed to assess the association of pre-transplant variables with post-transplant MRD status. Multivariate logistic regression model was utilized to analyze markers with a p-value <0.25 in univariate analysis. Results: 133 Patients were included in the analysis with average age at transplant being 60.84 years (range 32.18 years-78.13 years). 83/133 (62.41%) patients were male and 118/133 (88.72%) patients were white. 84/133 (63.16%) patients had achieved a VGPR or less according to the International Myeloma Working Group (IMWG) response criteria prior to transplant. Among all patients, age at transplant, gender, race, body mass index, glomerular filtration rate on day -1, serum albumin on day -1, kappa/lambda ratio on day -1, melphalan dose received, and multiple myeloma immunoglobulin subtype were not associated with response to therapy. Pre-transplant M protein positivity was associated with a higher likelihood of post-transplant MRD positive status with an odds ratio of 24.318 (p<0.0001). VGPR status or less on day -1 was associated with an increased post-transplant MRD positive status with an odds ratio of 6.223 (p<0.0001) however was not found to be statistically significant following multivariate analysis (p=0.0664). When restricting analysis to include only patients at VGPR status or less prior to transplant, pre-transplant M protein positivity and increased age at transplant were associated with increased likelihood of MRD positive status with odd ratios of 9.000 (p=0.0121) and 1.066 (p=0.0366) respectively. Both variables were shown to be statistically significant following multivariate analysis. Conclusions: Detectable levels of pre-transplant M protein via serum protein electrophoresis is associated with an increased likelihood of having positive minimal residual disease following autologous stem cell transplantation in multiple myeloma. Age at transplant does not predict minimal residual disease status among all patients undergoing transplant, however increased age at transplant may be associated with inferior outcomes in patients achieving a VGPR or less prior to transplantation. Figure 1 Figure 1. Disclosures Suvannasankha: The Veteran's Affair: Patents & Royalties; Karyopharm: Consultancy, Research Funding; Regeneron: Research Funding; Sutro: Research Funding; Glaxo Smith Kline: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Abonour: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jensen: Honoraria, Research Funding; Takeda: Research Funding; GSK: Consultancy, Honoraria, Research Funding. Abu Zaid: Syndax: Consultancy, Research Funding; Pieris: Current equity holder in publicly-traded company; Incyte: Research Funding; Pharamcyclic: Research Funding.

scholarly journals Role of Imaging in the Evaluation of Minimal Residual Disease in Multiple Myeloma Patients

2020 ◽  
Vol 9 (11) ◽  
pp. 3519
Author(s):  
Elena Zamagni ◽  
Paola Tacchetti ◽  
Simona Barbato ◽  
Michele Cavo
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Plasma Cells ◽  
Residual Disease ◽  
Imaging Techniques ◽  
Response Assessment ◽  
Response To Therapy ◽  
Whole Body ◽  
Minimal Residual

The International Myeloma Working Group (IMWG) recently introduced the evaluation of minimal residual disease (MRD) within the multiple myeloma (MM) response criteria, and MRD negativity assessed inside and outside the bone marrow is currently considered the most powerful predictor of favorable long-term outcomes. However, MRD evaluation has thus far relied on flow-cytometry or molecular-based methods, despite the limitations associated with the patchy infiltration of bone marrow (BM) plasma cells and the presence of extra-medullary (EMD). On the contrary, imaging-based sensitive response assessment through the use of functional rather than morphological whole-body (WB) imaging techniques, such as positron emission tomography with computed tomography (PET/CT) and magnetic resonance imaging (MRI), likely is a promising strategy to overcome these limitations in evaluating response to therapy and in the assessment of the MRD status in MM patients. However, despite the significant advances in the development and availability of novel functional imaging techniques for MRD evaluation, a worldwide standardization of imaging criteria for acquisition, interpretation, and reporting is yet to be determined and will be object of future investigations.

scholarly journals Heavy and Light Chain Monitoring in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1852-1852
Author(s):  
Noemi Puig ◽  
Teresa Contreras ◽  
Bruno Paiva ◽  
María Teresa Cedena ◽  
José J Pérez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Response Assessment ◽  
Advisory Committees ◽  
Minimal Residual

Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of bone marrow minimal residual disease (MRD) negativity. However, other methods of disease evaluation in serum such as heavy+light chain (HLC) assessment, with a potential complementary value to the IMWG response criteria, have also been tested. Aim: To evaluate the performance of HLC assay in HRsMM pts at diagnosis and after consolidation, comparing the results with standard serological methods and Next Generation Flow (NGF) for the assessment of bone marrow MRD. Patients and Methods: Ninety HRsMM pts included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and 2 further cycles of consolidation with the same regimen. All pts received maintenance treatment with lenalidomide for up to 2 years. SPEP and IFE were performed using standard procedures. Serum IgGk, IgGl, IgAk and IgAl HLC concentrations were measured using Hevylite (The Binding Site Group Ltd, Birmingham, UK) on a SPA PLUS turbidimeter. HLC concentrations and ratios were considered abnormal if they were outside the 95% reference ranges provided by the manufacturer. MRD was analyzed by flow cytometry following EuroFlow recommendations (sensitivity, 2x10-6). Standard response assignment was carried out as per the IMWG guidelines. Hevylite responses were assigned and HLC-pair suppression was defined as in Michalet et al (Leukemia 2018). Results: Out of 90 HRsMM pts, 75 had monoclonal intact immunoglobulin and samples available at diagnosis (50 IgG and 25 IgA). HLC ratio was abnormal in 98% of IgG pts and in 100% of IgA pts. Response assessment by Hevylite and standard IMWG criteria were available in 62 pts post-consolidation (Table 1). A good agreement was found between the two methods (kappa quadratic weighting = 0,6327 (0,4016 - 0,8638)). Among 46 pts with assigned CR as per the IMWG response criteria, there were 3 and 8 pts in PR and VGPR according to the Hevylite method, respectively. In 62 cases, paired Hevylite and MRD assessment data were available. Concordant results were found in 72.5% of cases (45/62; HLC+/NGF+ in 15 and HLC-/NGF- in 30 cases) while in the remaining 27.4% of cases results were discordant (17/62; HLC-/NGF+ in 6 and HLC+/NGF- in 11 cases). Post-consolidation, 24, 25.8 and 42.3% of the 62 samples were positive by SPEP, NGF and Hevylite, respectively. HLC-pair suppression was identified in 13/62 pts; 10 had severe HLC-pair suppression at the end of consolidation. After a median follow-up of 32 months (8-128), 93% of pts remain alive and progression-free. Three patients that have already progressed had their responses assessed post-consolidation. The first pt was assigned VGPR by the standard IMWG criteria and PR by Hevylite and was MRD positive by NGF; the second pt was assigned CR by IMWG criteria and Hevylite but had severe HLC-pair immunosuppression and was MRD positive by NGF; the third pt was in CR by IMWG and HLC criteria and was MRD positive by MFC. Conclusions: Moderate agreement was found between response assessment by Hevylite and the standard IMWG methods as well as between Hevylite and MRD assessment by NGF. Most discordances were a result of Hevylite detecting disease in samples negative by the standard methods, but longer follow-up is needed to ascertain its clinical value. HLC assessment could have anticipated the progression noted in 2 (out of 3) patients. Disclosures Puig: Takeda, Amgen: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Sanofi and Takeda: Consultancy. Rodriguez Otero:Kite Pharma: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios:Janssen: 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. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Ocio:Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Novartis: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Janssen: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; EDO: 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: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Front-line Management of Multiple Myeloma – How Can We Best Assess the Depth of Response?

2015 ◽  
Vol 11 (2) ◽  
pp. 105
Author(s):  
Michel Delforge ◽  
Keyword(s):  
Multiple Myeloma ◽  
Complete Remission ◽  
Residual Disease ◽  
Clinical Importance ◽  
Response Assessment ◽  
Front Line ◽  
Significant Group ◽  
New Agents ◽  
Depth Of Response ◽  
Minimal Residual

The outcome for patients with multiple myeloma (MM) is gradually improving due to the introduction of several new agents with strong antimyeloma activity. Both younger (transplant-eligible) and elderly patients benefit from this therapeutic progress. Although complete remission can be achieved in a significant group of MM patients, the majority of these patients will relapse because of the persistence of minimal residual disease. In this editorial, we discuss the different assays for response assessment in myeloma together with their limitations and clinical importance.

scholarly journals Role of urine immunofixation in the complete response assessment of MM patients other than light-chain-only disease

Blood ◽  
2019 ◽  
Vol 133 (25) ◽  
pp. 2664-2668 ◽  
Author(s):  
Juan-José Lahuerta ◽  
Ana Jiménez-Ubieto ◽  
Bruno Paiva ◽  
Joaquín Martínez-López ◽  
José González-Medina ◽  
...  
Keyword(s):  
Light Chain ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Complete Response ◽  
M Protein ◽  
Positive Rate ◽  
Immunofixation Electrophoresis

Abstract Response criteria for multiple myeloma (MM) require monoclonal protein (M-protein)–negative status on both serum immunofixation electrophoresis (sIFE) and urine (uIFE) immunofixation electrophoresis for classification of complete response (CR). However, uIFE is not always performed for sIFE-negative patients. We analyzed M-protein evaluations from 384 MM patients (excluding those with light-chain-only disease) treated in the GEM2012MENOS65 (NCT01916252) trial to determine the uIFE-positive rate in patients who became sIFE-negative posttreatment and evaluate rates of minimal residual disease (MRD)–negative status and progression-free survival (PFS) among patients achieving CR, CR but without uIFE available (uncertain CR; uCR), or very good partial response (VGPR). Among 107 patients with M-protein exclusively in serum at diagnosis who became sIFE-negative posttreatment and who had uIFE available, the uIFE-positive rate was 0%. Among 161 patients with M-protein in both serum and urine at diagnosis who became sIFE-negative posttreatment, 3 (1.8%) were uIFE positive. Among patients achieving CR vs uCR, there were no significant differences in postconsolidation MRD-negative (<10−6; 76% vs 75%; P = .9) and 2-year PFS (85% vs 88%; P = .4) rates; rates were significantly lower among patients achieving VGPR. Our results suggest that uIFE is not necessary for defining CR in MM patients other than those with light-chain-only disease.

Sign in / Sign up

Export Citation Format

Share Document