scholarly journals What to do with minimal residual disease testing in myeloma

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 137-141
Author(s):  
Elisabet E. Manasanch
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Body Position ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Routine Care ◽  
Whole Body ◽  
Position Emission Tomography ◽  
Minimal Residual

Abstract The role and use of minimal residual disease (MRD) testing has changed significantly over the past few years as it has become part of the routine care for response assessment in multiple myeloma. The most widely used standardized methods to assess MRD in myeloma in the bone marrow are multicolor flow cytometry and next-generation sequencing. Importantly, the depth of MRD negativity in the bone marrow correlates with improved progression-free survival and overall survival in myeloma. Whole-body position emission tomography–computed tomography and magnetic resonance imaging are also used to evaluate patchy and extramedullary disease, which may not be readily visible through bone marrow assessment. This article reviews a clinical case in which MRD testing, both in bone marrow and in functional imaging, is part of the standard of care. It also reviews the different modalities of MRD testing and current practice guidelines. Finally, patients with myeloma may be tested for MRD after treatment because this is part of the routine response assessment according to International Myeloma Working Group criteria and correlates with clinical outcomes. Important questions such as when to stop therapy for sustained MRD-negative patients or whether to change treatments for patients who go from MRD negative to positive without other evidence of disease relapse are being evaluated in clinical trials and remain controversial.

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 Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma

2021 ◽  
Author(s):  
Meera Mohan ◽  
Samantha Kendrick ◽  
Aniko Szabo ◽  
Naveen K Yarlagadda ◽  
Dinesh Atwal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Clinical Relapse ◽  
Landmark Analyses ◽  
Minimal Residual

Multiple myeloma (MM) patients frequently attain a bone marrow (BM) minimal residual disease (MRD) negativity status in response to treatment. We identified 568 patients who achieved BM MRD negativity following autologous stem cell transplantation (ASCT) and maintenance combination therapy with an immunomodulatory agent and a proteasome inhibitor. BM MRD was evaluated by next generation flow cytometry (sensitivity of 10-5 cells) at 3 to 6 months intervals. With a median follow up of 9.9 years from diagnosis (range, 0.4 - 30.9), 61% of patients maintained MRD negativity, while 39% experienced MRD conversion at a median of 6.3 years (range, 1.4 - 25). The highest risk of MRD conversion occurred within the first 5 years after treatment and was observed more often in patients with abnormal metaphase cytogenetic abnormalities (95%vs. 84%; P = 0.001). MRD conversion was associated with a high risk of relapse and preceded it by a median of 1.0 year (range, 0 - 4.9). However, 27% of MRD conversion positive patients had not yet experienced a clinical relapse with a median follow-up of 9.3 years (range, 2.2 - 21.2). Landmark analyses using time from ASCT revealed patients with MRD conversion during the first 3 years had an inferior overall and progression-free survival compared to patients with sustained MRD negativity. MRD conversion correctly predicted relapse in 70%, demonstrating the utility of serial BM MRD assessment to complement standard laboratory and imaging to make informed salvage therapy decisions.

Safety and Efficacy Of Abbreviated Induction With Only 4 Cycles Of Fludarabine (F), Cyclophosphamide (C) and Rituximab (R) In Physically Fit Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Early Complete Remission (CR) With Undetectable Minimal Residual Disease (MDR)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2886-2886
Author(s):  
Carolina Pavlovsky ◽  
Astrid Pavlovsky ◽  
Isolda Fernandez ◽  
Adriana Galeano ◽  
Francisco Lastiri ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Clinical Stage ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Blue Laser ◽  
Minimal Residual

Abstract Background Chemoimmunotherapy with 6 cycles of FCR is considered standard therapy for physically fit patients (pts) with Chronic Lymphocytic Leukemia (CLL). Many pts are unable to complete planned treatment, due to treatment related complications. Levels of minimal residual disease (MRD) have been shown to correlate with PFS in previously untreated patients with CLL (CLL8, Boettcher S et al. Leukemia, 2009). Achieving a negative MRD is therefore a mayor endpoint in treatment. Patients and methods From 4/2003, 39 physically fit pts with CLL who had IWCLL-NCI criteria for initiating treatment started therapy with FCR in our institution. Eleven pts had previously received chlorambucil/prednisone and 28 were not previously treated. Median age at start of therapy was 63 years (34-80), Binet´s clinical stage were A/B: 22 pts (56%) and C: 17 (44%). The CD38 expression was positive (>7% of cells) in 23 (59%) and negative in16 (41%) of the pts. After 4 courses of FCR response was assessed in peripheral blood (PB) or bone marrow (BM) using three colour flow Cytometry. Negative MRD was defined as < 0,1% of light chain restricted CD5+CD19+ B cells in PB and BM as assesed collecting 100000 CD19 cells in a three colour cytometer (FacsScalibur- blue laser ). All these patients stopped therapy after evaluation due to early CR with eradication of MRD. Results All patients had negative MRD in peripheral blood, 35 were also evaluated in bone marrow, 29 showed CR and 6 nodular partial remission (NPR). Neutropenia and infectious events grade 3-4 were observed in 24% and 7% of all the courses respectively. No pts died of toxicity. After a median follow-up of 81 months (4.6-120), progression free survival (PFS) and overall survival (OS) at 72 months was 51% and 75% respectively. Five pts died of progressive disease and 3 of a secondary neoplasm. Conclusion Stopping therapy in patients who achieve negative MRD after 4 cycles of FCR is safe and induces durable remission with a PFS and OS of 51% and 75% at 72 months exposing them to less chemotherapy. Large randomized trials are necessary to confirm this data. Disclosures: Pavlovsky: Novartis: Speakers Bureau; BMS: Speakers Bureau.

scholarly journals Bone Marrow Minimal Residual Disease Was an Early Response Marker and a Consistent Independent Predictor of Survival After Anti-GD2 Immunotherapy

2015 ◽  
Vol 33 (7) ◽  
pp. 755-763 ◽  
Author(s):  
Nai-Kong V. Cheung ◽  
Irina Ostrovnaya ◽  
Deborah Kuk ◽  
Irene Y. Cheung
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Cox Regression ◽  
Predictive Accuracy ◽  
Residual Disease ◽  
Independent Predictor ◽  
Progression Free Survival ◽  
Early Response ◽  
Concordance Index ◽  
Minimal Residual

Purpose Immunotherapy is a standard of care for children with high-risk neuroblastoma, where bone marrow (BM) is the predominant metastatic site. Early response markers of minimal residual disease (MRD) in the BM that are also predictive of survival could help individualize patient therapies. Patients and Methods After achieving first remission (n = 163), primary refractory disease (n = 102), or second remission (n = 95), children with stage 4 neuroblastoma received anti-GD2 3F8 antibody immunotherapy. BM MRD before 3F8 treatment and after cycle 2 (postMRD) was measured using a four-marker panel (B4GALNT1, PHOX2B, CCND1, and ISL1) by quantitative reverse transcription polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Prognostic variables were tested in both univariable and multivariable analyses, and MRD markers were further assessed individually and in combination as binary composite (postMRD: 0 and 1) and as equal sum (postMRDSum: 0 to 4) using the Cox regression models, and their predictive accuracy was determined by the concordance index. Results When BM was evaluated after cycle 2, individual markers were highly predictive of PFS and OS. The prediction accuracy improved when they were combined in postMRDSum. A multivariable model taking into account all the variables significant in the univariable analyses identified postMRDSum to be independently predictive of PFS and OS. When the model for OS also included missing killer immunoglobulin-like receptor ligand, human antimouse antibody response, and the enrollment disease status, the concordance index was 0.704. Conclusion BM MRD after two cycles of immunotherapy was confirmed as an early response marker and a consistent independent predictor of survival.

scholarly journals Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stephanie L. Rellick ◽  
Gangqing Hu ◽  
Debra Piktel ◽  
Karen H. Martin ◽  
Werner J. Geldenhuys ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Tumor Cells ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Adherent Cells ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Minimal Residual

AbstractB-cell acute lymphoblastic leukemia (ALL) is characterized by accumulation of immature hematopoietic cells in the bone marrow, a well-established sanctuary site for leukemic cell survival during treatment. While standard of care treatment results in remission in most patients, a small population of patients will relapse, due to the presence of minimal residual disease (MRD) consisting of dormant, chemotherapy-resistant tumor cells. To interrogate this clinically relevant population of treatment refractory cells, we developed an in vitro cell model in which human ALL cells are grown in co-culture with human derived bone marrow stromal cells or osteoblasts. Within this co-culture, tumor cells are found in suspension, lightly attached to the top of the adherent cells, or buried under the adherent cells in a population that is phase dim (PD) by light microscopy. PD cells are dormant and chemotherapy-resistant, consistent with the population of cells that underlies MRD. In the current study, we characterized the transcriptional signature of PD cells by RNA-Seq, and these data were compared to a published expression data set derived from human MRD B-cell ALL patients. Our comparative analyses revealed that the PD cell population is markedly similar to the MRD expression patterns from the primary cells isolated from patients. We further identified genes and key signaling pathways that are common between the PD tumor cells from co-culture and patient derived MRD cells as potential therapeutic targets for future studies.

Early Molecular Response of Marrow Disease to Biologic Therapy Is Highly Prognostic in Neuroblastoma

2003 ◽  
Vol 21 (20) ◽  
pp. 3853-3858 ◽  
Author(s):  
Irene Y. Cheung ◽  
M. Serena Lo Piccolo ◽  
Brian H. Kushner ◽  
Nai-Kong V. Cheung
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Partial Remission ◽  
Progressive Disease ◽  
Residual Disease ◽  
Gm Csf ◽  
Stage 4 ◽  
Secondary Refractory ◽  
Minimal Residual

Purpose: A promising treatment strategy for stage 4 neuroblastoma patients is the repeated application of anti-GD2 immunotherapy after activating myeloid effectors with granulocyte-macrophage colony-stimulating factor (GM-CSF). To use early marrow response as a prognostic marker is particularly relevant for patients not likely to benefit from this therapy. Patients and Methods: Eighty-six stage 4 neuroblastoma patients older than 1 year at diagnosis were classified in four clinical groups on protocol entry: complete remission or very good partial remission (n = 33), primary refractory (n = 33), secondary refractory (n = 10), and progressive disease (n = 10). Bone marrow samples collected before and following treatment were assayed for GD2 synthase mRNA by real-time reverse transcriptase polymerase chain reaction. Response and survival analyses were performed on posttreatment samples before the third cycle at 1.8 months from protocol entry. Results: GD2 synthase mRNA was evident in pretreatment marrow samples of the four clinical groups (42%, 52%, 60%, and 80% of samples, respectively), with median transcript level of 10.0, 16.6, 26.5, and 87.2, respectively. This marker became negative following antibody plus GM-CSF in 77% of complete remission or very good partial remission, 45% of primary refractory, 25% of secondary refractory, and 0% of progressive disease group. Progression-free survival was statistically different between responder and nonresponder groups (P < .0001). Among patients with minimal residual disease, molecular responders had a significantly lower risk of disease progression at a median follow-up of 29.8 months (P = .0001). Conclusion: GD2 synthase mRNA is a sensitive response marker of neuroblastoma in the bone marrow. It is particularly useful for minimal residual disease evaluation and may potentially be useful as an early predictor of resistance to antibody plus GM-CSF immunotherapy.

scholarly journals Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 2984-2990 ◽  
Author(s):  
Stella M. Davies ◽  
Michael J. Borowitz ◽  
Gary L. Rosner ◽  
Kristin Ritz ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Response To Therapy ◽  
Oncology Group ◽  
Risk Status ◽  
Prognostic Features ◽  
Minimal Residual

Abstract Minimal residual disease (MRD) as a marker of antileukemic drug efficacy is being used to assess risk status and, in some cases, to adjust the intensity of therapy. Within known prognostic categories, the determinants of MRD are not known. We measured MRD by flow cytometry at day 8 (in blood) and at day 28 (in bone marrow) of induction therapy in more than 1000 children enrolled in Pediatric Oncology Group therapy protocols 9904, 9905, and 9906. We classified patients as “best risk” if they had cleared MRD by day 8 of therapy and as “worst risk” if they had MRD remaining in bone marrow at day 28, and tested whether MRD was related to polymorphisms in 16 loci in genes hypothesized to influence response to therapy in acute lymphoblastic leukemia (ALL). After adjusting for known prognostic features such as presence of the TEL-AML1 rearrangement, National Cancer Institute (NCI) risk status, ploidy, and race, the G allele of a common polymorphism in chemokine receptor 5 (CCR5) was associated with more favorable MRD status than the A allele (P = .009, logistic regression), when comparing “best” and “worst” risk groups. These data are consistent with growing evidence that both acquired and host genetics influence response to cancer therapy.

Analysis of minimal residual disease in bone marrow by NGF and in peripheral blood by mass spectrometry in newly diagnosed multiple myeloma patients enrolled in the GEM2012MENOS65 clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8010-8010
Author(s):  
Noemi Puig ◽  
Bruno Paiva ◽  
Teresa Contreras ◽  
M. Teresa Cedena ◽  
Laura Rosiñol ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Prognostic Value ◽  
Residual Disease ◽  
Newly Diagnosed ◽  
Time Points ◽  
Minimal Residual

8010 Background: Analysis of minimal residual disease (MRD) in the bone marrow (BM) of patients with multiple myeloma (MM) is accepted by the IMWG to evaluate treatment efficacy and is a well-established prognostic factor. However, there is an unmet need to explore the clinical value of MRD in peripheral blood (PB). Methods: Newly diagnosed MM patients enrolled in the GEM2012MENOS65 trial received six induction (Ind) cycles of bortezomib, lenalidomide, and dexamethasone (VRD) followed by autologous stem cell transplantation (ASCT) and 2 further cycles of consolidation (Cons) with VRD. MRD was analyzed in BM using Next Generation Flow (NGF) and in serum by Mass Spectrometry (MS) using IgG/A/M, κ, λ, free κ and free λ specific beads, both after Ind, at day 100 after ASCT, and after Cons. Sequential samples from the first 184 patients were analyzed. Results: Results of both methods were in agreement (NGF+/MS+ and NGF-/MS-) in 83% of cases post-Ind (152/184), 80% post-ASCT (139/174) and 76% post-Cons (128/169). Stratifying by the log range of MRD by NGF, discordances (NGF+/MS- and NGF-/MS+) seemed to increase at the lower MRD ranges, being 22%, 21% and 19% from ≥10−5 to <10−4 and 21%, 21%, 23% at ≥x10−6(post-Ind, ASCT and Cons, respectively). Analysis of discordances showed that they could be partly explained by the higher percentages of cases found to be positive by MS as compared by NGF at part of the time-points analyzed and at each log range of MRD. From ≥10−5 to <10−4, MRD was detected by NGF in 36%, 28%, 20% of cases post-Ind, ASCT and Cons, respectively vs MS in 37%, 29%, 21% of them; at ≥x10−6, NGF was positive in 11%, 14%, 19% of cases vs MS in 23%, 19% and 16% of them. Considering NGF as a reference, the negative predictive value (NPV) of MS per MRD range (≥10−5 to <10−4 and ≥x10−6, respectively) was: post-Ind: 83% (p<0,0001), 94% (p=0,034); post-ASCT 86% (p<0,0001), 90% (p=0,022); post-Cons 89% (p<0,0001), 85% (p=0,0469). Despite these discordances, the prognostic value of each technique in terms of undetectable MRD and progression-free survival (PFS) was consistent at all time-points (Table) and further, discordant cases (NGF+/MS- and NGF-/MS+) did not display a significantly different PFS as compared to NGF-/MS- cases. Conclusions: The results of MRD assessed by NGF in BM and by MS in PB show a significant concordance and are associated with a similar prognostic value analyzed in terms of PFS. Given its high NPV, MRD in peripheral blood by MS provides a gateway for BM aspiration/biopsy and MRD assessment by NGF.[Table: see text]

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