scholarly journals Prognostic value of minimal residual disease response assessment in multiple myeloma

2015 ◽  
Vol 26 ◽  
pp. vii25
Author(s):  
Hiroyuki Takamatsu
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Prognostic Value ◽  
Residual Disease ◽  
Response Assessment ◽  
Disease Response ◽  
Minimal Residual

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]

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 Prognostic Value of Sequencing-Based Minimal Residual Disease Detection in Patients with Multiple Myeloma Who Underwent Autologous Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1788-1788 ◽  
Author(s):  
Hiroyuki Takamatsu ◽  
Ryoichi Murata ◽  
Jianbiao Zheng ◽  
Martin Moorhead ◽  
Naoki Takezako ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Clinical Outcome ◽  
Stem Cell Transplantation ◽  
Minimal Residual Disease ◽  
Prognostic Value ◽  
Residual Disease ◽  
Employment Equity ◽  
Equity Ownership ◽  
Minimal Residual

Abstract Background: Autologous stem cell transplantation (ASCT) in conjunction with therapeutic drugs such as bortezomib, thalidomide, and lenalidomide can dramatically improve response rates and the prognosis of patients with multiple myeloma (MM). However, most patients with MM are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Here we utilized a next-generation sequencing (NGS) approach for MRD assessment, which offers at least 1 to 2 logs greater sensitivity (10-6) compared to allele-specific oligonucleotide PCR (ASO-PCR) and flow cytometry, respectively (Faham et al Blood 2012). Previous studies have shown that NGS-based MRD assessment 90 days post-ASCT has prognostic value (Martinez-Lopez et al Blood 2014). In this study, we compared the prognostic value of MRD assessment in autografts and bone marrow (BM) samples from MM patients in the ASCT setting. Methods: One hundred and twenty-three Japanese patients with newly diagnosed MM who received various induction regimens prior to ASCT were retrospectively analyzed. All patients received ASCT and were followed between June 15, 2004 and April 25, 2015. All patients had achieved a partial response (PR) or better after ASCT. Analyzed samples included: (1) BM slides from 96 MM patients at diagnosis, (2) fresh/frozen BM cells from 27 MM patients at diagnosis, (3) autografts and/or (4) post-ASCT BM cells obtained at the time of best response based on serum and urine tests. IGH-based ASO-PCR was performed as described previously (Methods Mol Biol 2009). NGS-based MRD assessment was performed using the immunosequencing platform (Adaptive Biotechnologies, South San Francisco, CA) (Martinez-Lopez et al Blood 2014). Results: We compared MRD results in 51 samples assessed by ASO-PCR and NGS. We observed a high correlation between NGS and ASO-PCR results at MRD levels of 10-5 or higher (r=0.86, P<0.0001). Twenty-seven samples were positive by NGS and negative by ASO-PCR, demonstrating the higher sensitivity of NGS (10-6 or higher) vs ASO-PCR (10-4-10-5). We evaluated the association of clinical outcome with post-ASCT BM MRD assessment. Patients who were MRD negative by NGS (defined as <10-6) in post-ASCT BM cases (N=21) showed a significantly better progression free survival (PFS) compared to MRD positive patients (N=31) (P =0.005) (Fig 1A). When restricting the analysis to the 39 patients in complete response (CR), patients who were MRD negative by NGS (N=20) showed a significantly better PFS than those that were MRD positive (N=19) (P =0.042). We also evaluated the association of clinical outcome with autograft MRD assessment. 53 patients received post-ASCT therapy using novel agents such as bortezomib/lenalidomide/thalidomide, and 45 patients did not. Among the 45 patients who did not receive post ASCT treatment, patients with NGS-based MRD negativity in the autograft (N=11) had a significantly better PFS (P=0.012) and tended to have a better OS (p=0.203) than those who were MRD positive (N=34), with prognosis clearly stratified by the quantitative level of MRD (Figs 1B, 1C). MRD assessment from the 53 patients who did receive post ASCT treatment tended to show a similar pattern. Finally, we studied whether clinical outcomes would have been altered by treatment in this cohort. Patients whose autografts were negative by NGS-based MRD assessment (N=19) had 100% PFS and OS at 5 years post ASCT irrespective of whether or not they received post ASCT treatment. Conversely, post ASCT treatment had a significant effect on the outcome of patients whose autografts were MRD positive by NGS. Specifically, the NGS-based MRD positive patients who received post ASCT treatment (N=45) had a significantly better PFS (P=0.003) and tended to have a better OS than those that were untreated (N=34) (Figs 1D, 1E). Conclusions: In this study, we show the prognostic value of NGS-based MRD assessment in autografts of patients with MM. The NGS platform has improved sensitivity compared with ASO-qPCR in detecting MRD in autografts. Importantly, this retrospective study suggests that therapeutic intervention based on NGS-based MRD positivity has a significant effect on patient outcome in the post-ASCT setting. Disclosures Zheng: Adaptive Biotechnologies Corp.: Employment, Equity Ownership. Moorhead:Adaptive Biotechnologies Corp.: Employment, Equity Ownership. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder.

Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma

2021 ◽  
Author(s):  
Luciano J. Costa ◽  
Saurabh Chhabra ◽  
Eva Medvedova ◽  
Bhagirathbhai R. Dholaria ◽  
Timothy M. Schmidt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Progression Free Survival ◽  
High Rate ◽  
Newly Diagnosed ◽  
Serious Adverse Events ◽  
Disease Response ◽  
Minimal Residual

PURPOSE The MASTER trial combined daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) in newly diagnosed multiple myeloma (NDMM), using minimal residual disease (MRD) by next-generation sequencing (NGS) to inform the use and duration of Dara-KRd post-autologous hematopoietic cell transplantation (AHCT) and treatment cessation in patients with two consecutive MRD-negative assessments. METHODS This multicenter, single-arm, phase II trial enrolled patients with NDMM with planed enrichment for high-risk cytogenetic abnormalities (HRCAs). Patients received Dara-KRd induction, AHCT, and Dara-KRd consolidation, according to MRD status. MRD was evaluated by NGS at the end of induction, post-AHCT, and every four cycles (maximum of eight cycles) of consolidation. Primary end point was achievement of MRD negativity (< 10–5). Patients with two consecutive MRD-negative assessments entered treatment-free MRD surveillance. RESULTS Among 123 participants, 43% had none, 37% had 1, and 20% had 2+ HRCA. Median age was 60 years (range, 36-79 years), and 96% had MRD trackable by NGS. Median follow-up was 25.1 months. Overall, 80% of patients reached MRD negativity (78%, 82%, and 79% for patients with 0, 1, and 2+ HRCA, respectively), 66% reached MRD < 10–6, and 71% reached two consecutive MRD-negative assessments during therapy, entering treatment-free surveillance. Two-year progression-free survival was 87% (91%, 97%, and 58% for patients with 0, 1, and 2+ HRCA, respectively). Cumulative incidence of MRD resurgence or progression 12 months after cessation of therapy was 4%, 0%, and 27% for patients with 0, 1, or 2+ HRCA, respectively. Most common serious adverse events were pneumonia (6%) and venous thromboembolism (3%). CONCLUSION Dara-KRd, AHCT, and MRD response-adapted consolidation leads to high rate of MRD negativity in NDMM. For patients with 0 or 1 HRCA, this strategy creates the opportunity of MRD surveillance as an alternative to indefinite maintenance.

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 Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma

Blood ◽  
2014 ◽  
Vol 123 (20) ◽  
pp. 3073-3079 ◽  
Author(s):  
Joaquin Martinez-Lopez ◽  
Juan J. Lahuerta ◽  
François Pepin ◽  
Marcos González ◽  
Santiago Barrio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Deep Sequencing ◽  
Prognostic Value ◽  
Residual Disease ◽  
Complete Response ◽  
Disease Detection ◽  
Sequencing Method ◽  
Key Points ◽  
Minimal Residual

Key Points MRD assessment by sequencing is prognostic of TTP and OS in multiple myeloma patients. Among patients in complete response, MRD assessment by sequencing enables identification of 2 distinct subgroups with different TTP.

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