Pre-Transplantation Level of Minimal Residual Disease Detected by Quantitative Real-Time IgH-PCR Is a Prognostic Parameter in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4871-4871
Author(s):  
Roland Fenk ◽  
Mark Korthals ◽  
Guido Kobbe ◽  
Ulrich Steidl ◽  
Thorsten Graef ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prognostic Factors ◽  
Tumor Cells ◽  
Residual Disease ◽  
Residual Tumor ◽  
Prognostic Group ◽  
Tumor Level ◽  
Minimal Residual

Abstract Background: High-dose chemotherapy with autologous stem cell transplantation has improved outcome and survival of patients with multiple myeloma. However, the majority of patients suffer from relapse. Using real-time quantitative (RQ) PCR we have shown before (Haematologica 89,2004) that the amount of residual tumor cells in the bone marrow of patients before transplantation is of prognostic relevance. In this study we evaluated in a larger group of patients with multiple myeloma whether a pre-transplantation level of clonotypic cells in the bone marrow is predictive for time-to-progression (TTP) and overall survival (OS). Further, we compared results with known prognostic factors. Patients and Methods: Bone marrow samples of 19 patients with stage II/III multiple myeloma were obtained after induction therapy but before transplantation. Immunoglobulin heavy chain (IgH) RQ-PCR using patient-specific Taqman probes was performed to quantify pre-transplantation tumor levels. The proportion of clonotypic cells was assessed as IgH/2 beta-actin ratio in percent. Medical records of patients were reviewed for prognostic factors and outcome. Results: The median level of residual tumor cells in bone marrow of all patients at the time before transplantation was 0.3 %. At 23 month median follow-up after transplantation the median TTP and OS in our study were 14 and 36 month, respectively. The threshold level of 0.03% clonotypic cells identified two prognostic groups (p<0.0001, log rank). Twelve patients in the bad prognostic group had an early relapse with a median TTP of 9 month (range: 3 – 17 month). All patients in the good prognostic group (n=7) had ongoing remissions after a median follow-up of 24 month (range: 13–44 month). Univariat analysis was performed including other prognostic factors at the time before transplantation such as cytogenetic abnormalities, beta2-microglobulin, hemoglobulin, platelet count, LDH, CRP, serum albumine and age. Besides the pre-transplant level of minimal residual disease, CRP level was predictive for TTP. In multivariat analysis using a step-wise cox regression model grouping by pre-transplantation tumor level was the only prognostic factor for TTP (p = 0.05). Moreover, low pre-transplantation tumor levels also showed a trend for a better OS, but in multivariat analysis only normal cytogenetics were predictive for a superior outcome (p = 0.03). Conclusion: Quantitative molecular assessment of pre-transplantation tumor level in the bone marrow is an independent prognostic parameter for the progression-free survival of patients with multiple myeloma and thus helps to guide therapeutic interventions

scholarly journals The Prognostic Significance of Minimal Residual Disease Detection after Induction and ASCT to the Patients with Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4956-4956
Author(s):  
Weiqin Yao ◽  
Zhu Mingqing ◽  
Yao Feirong ◽  
Lingzhi Yan ◽  
Song Jin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Plasma Cells ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Depth Of Response ◽  
Minimal Residual

Abstract Objective: In the last decade the outcome in multiple myeloma in CHINA has greatly improved due to the new, effective therapies including PIs and Imids. But responses to treatment and survival remains heterogeneous because of patient characteristic, disease biology and mechanisms of drug resistance. More and more studies have established the link between depth of response and improved PFS and OS. multiparameter-flow cytometry (MFC) is a main method to detect minimal residual disease(MRD) in myeloma. Sensitivity will be at least at 10-4 to 10-5 by 10-color MFC. Imaging techniques such as PET-CT are important for EMD and bone MRD detection. whole body DWI-MRI is a new imaging technique by mean of the apparent diffusion coefficient(ADC) which can qualify the depth of response to antineoplastic treatment. This study was designed to evaluate the prognostic significance of MRD by 10-color MFC and imaging to the MM patients after induction.Methods: 102 patients with newly diagnosed MM were enrolled at the First Affiliated Hospital of Soochow University from July 2015 to July 2017. All patients were diagnosed and the response were assessed by IMWG criteria. The median of age was 58 (31-75).There were 46 patients with IgG type , 24 IgA , 14 light chain, 18 others. 34 Patients in ISS stageⅠ,34 in stage Ⅱ, 30 in stage Ⅲ. All patients received 4-6 cycles of triplet bortezomib based or lenalidomide based induction therapy. Transplantation available patients received APBSCT with BUCY condition followed by 4-6 cycles of bortezomib based or lenalidomide based consolidation which were given to transplantation unavailable patients too. Lenalidomide and thalidomide were used for over 2y of maintenance therapy. Bone marrow aspirates for MRD imaging MRD assessment were obtained at the end of induction and 1year after ASCT.The median of follow-up was 13 (2-29) months.Results: According to MRD by MFC and imaging after induction therapy and 1 year after ASCT, the patients were divided into different groups. MFC negativity was 33%(29/88) after induction therapy compared with 63%(32/51) after ASCT (X2=11.636,P=0.001). After induction therapy, the median PFS was 22 months for MRD positive group compared with not reached with MRD negative group by MFC (P=0.042) in patients with very good partial remission(VGPR) and above. The 2 years PFS was 100% for those with MRD negative compared with 60% for MRD positive by imaging. The 2 years PFS was 80% for those have multiclonal normal plasma cells compared with 52.6% for those without. The median PFS was not reached for MFC MRD negative patients 1 year after ASCT compared with 20 months for positive patients. (P=0.002). Multivariate analysis including high risk cytogenetics(17p-, t(4;14), t(14;16)), sex, age, ISS, chemotherapy, ASCT, CR/VGPR, normal PCs showed that the MFC MRD and ASCT were independent prognostic factor.Conclusions: Patients with MFC MRD negative after induction therapy or ASCT is a better prognostic marker than CR or even the best marker. Imaging MRD negativity and the appearance of normal plasma cells in the bone marrow suggests a better prognosis.We will have a try to do more research on overall survival(OS),include longer follow-up and a larger number of patients enrolled. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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.

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.

Using MALDI-TOF mass spectrometry for tracking of minimal residual disease in peripheral blood from patients with multiple myeloma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19525-e19525
Author(s):  
Marion Eveillard ◽  
Even Rustad ◽  
Mikhail Roshal ◽  
Yanming Zhang ◽  
Amanda Ciardiello ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Maldi Tof ◽  
Minimal Residual ◽  
Active Disease

e19525 Background: Minimal residual disease (MRD) negativity after completed therapy is associated with longer progression-free survival (PFS) in patients with multiple myeloma (MM). Current standard of care for MRD testing use flow cytometry and/or next generation sequencing (NGS)-based assays applied on bone marrow (BM) aspirate samples. To develop a strategy for MRD tracking in peripheral blood (PB), we were motivated to evaluate MALDI-TOF head-to-head with established bone marrow-based MRD assays. Methods: We used MALDI-TOF mass spectrometry to detect M-proteins in PB. Our cohort included patients who had serum samples available at 2 timepoints including during active disease and within 60 days of MRD results as determined by flow cytometry of BM aspirates. The cohort enrolled 71 patients (26 females, 45 males) with a median age of 61 years (37-78 years). Twenty-seven patients had high-risk cytogenetics at baseline. Patients were classified at diagnosis as ISS1 (n = 38), ISS2 (n = 18) or ISS3 (n = 6). The flow cytometry based MRD assay was performed using MSKCCs 10-color, single-tube method. MALDI-TOF analysis was performed as described by Mills et al. Samples taken during active disease were used to identify the mass/charge ratio of the M-protein at baseline and in follow-up samples. MALDI-TOF results were compared to flow cytometry bone marrow-based MRD results. Results: The median time between diagnosis and the MRD timepoint was 13.4 months (3.4-91 months). MALDI-TOF in PB and flow cytometry BM-based MRD results were concordant for 44/71 (62%) patients (8+/+, 36 -/- respectively) while 27 were discordant (10 +/-, 17-/+). Fifty-four of 71 patients were in complete response (CR) (45/54 in sCR) at the time of MRD. MALDI-TOF was still positive in 13 of these 54 CR patients. In this cohort, the median PFS since MRD assessment was not reached in the 2 subgroups of double negative patients (n = 31) or in patients with a positive result in at least one technique (n = 23) with a median follow-up of 11.2 months (0-34.6 months). Conclusions: In 44/71 (62%) samples, MALDI-TOF of PB results and flow cytometry BM-based MRD results were concordant. MALDI-TOF of PB may be useful for detecting measurable residual disease and for the monitoring of MM patients during maintenance therapy with the future goal to rule out early recurrent disease.

Molecular Level of Minimal Residual Disease in Bone Marrow Before High-Dose Therapy and Autologous Stem Cell Transplantation Is a Prognostic Parameter in Patients with Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1496-1496 ◽  
Author(s):  
Roland Fenk ◽  
Mark Korthals ◽  
Nina Sehnke ◽  
Ingmar Bruns ◽  
Akos Czibere ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Induction Therapy ◽  
Residual Disease ◽  
High Dose ◽  
High Dose Therapy ◽  
Prognostic Group ◽  
Minimal Residual

Abstract Background: Using real-time quantitative (RQ) PCR we recently (Haematologica89,2004) identified a prognostic cut-off level of residual clonotypic cells in the bone marrow of patients with multiple myeloma before high-dose therapy (HDT) and autologous peripheral blood stem cell transplantation (PBSCT). In this study we validate this report with a larger number of patients. Patients and Methods: Bone marrow samples of 68 patients with stage II/III multiple myeloma and heavy chain disease were obtained at the time of diagnosis and after induction therapy and stem cell collection but before single HDT and autologous PBSCT. Sequencing of the patient specific immunoglobulin heavy chain (IgH) locus was successful in 51 patients (75%). For 49 patients (72%) RQ-PCR using allele-specific oligonucleotide (ASO) Taqman probes together with LightCycler technology could be established with a sensitivity of 10−4 to 10−6 and linear amplification conditions. The proportion of clonotypic cells was assessed as IgH / 2 beta-actin ratio in percent. Patients were divided in two prognostic groups by a threshold level of 0.03% clonotypic cells. Results: The median level of residual tumor cells in bone marrow of all patients at the time before transplantation was 0.05% (range: 0–21%). Time to progression (TTP) from the time of diagnosis of patients in the ¨good¨ prognostic group (n = 21) was 51 months and significantly (p = 0.002) longer in comparison to 20 months of patients with a pre-transplantation minimal residual disease level of more than 0.03% in BM (n = 28). Overall survival (OS) of patients within the ¨good¨ prognostic group was also significantly prolonged (median OS: not reached versus 46 months, p = 0.03). Univariate analysis also revealed kind of maintenance / consolidation therapy (thalidomide, interferon, reduced intensity conditioning (RIC) allogeneic transplant) and cytogenetic banding analysis as prognostic markers for TTP. For OS kind of maintenance therapy, cytogenetic abnormalities, ISS stage, CRP and LDH levels were of prognostic relevance. In multivariat analysis grouping by pre-transplantation MRD level was an independent prognostic factor for either TTP and OS. Conclusion: Quantitative molecular assessment of pre-transplantation tumor level in the bone marrow is an independent prognostic parameter for TTP and OS of patients with multiple myeloma. This finding has two controversial implications. One conclusion could be, that induction therapy should be continued and intensified e.g. with novel agents until a low MRD level is achieved. An alternative conclusion is, that a low tumor burden after induction therapy may be a surrogate parameter for chemosensitive disease, which makes patients more susceptible for high-dose chemotherapy. Therefore, further MRD studies are needed to answer this important question.

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.

Depth of response and minimal residual disease status in ultra high-risk multiple myeloma and plasma cell leukemia treated with daratumumab, bortezomib, lenalidomide, cyclophosphamide and dexamethasone (Dara-CVRd): Results of the UK optimum/MUKnine trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8001-8001
Author(s):  
Martin F. Kaiser ◽  
Andrew Hall ◽  
Katrina Walker ◽  
Ruth De Tute ◽  
Sadie Roberts ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Plasma Cell ◽  
Residual Disease ◽  
Cell Leukemia ◽  
Ultra High Risk ◽  
Grade 3 ◽  
Minimal Residual

8001 Background: Patients with ultra high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with plasma cell leukemia (PCL) continue to have dismal outcomes and are underrepresented in clinical trials. Recently, improved responses with anti-CD38 monoclonal antibody combination therapy have been reported for NDMM patients. We report here outcomes for NDMM UHiR and PCL patients treated in the OPTIMUM/MUKnine (NCT03188172) trial with daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction, augmented high-dose melphalan (HDMEL) and ASCT. With final analysis follow-up surpassed in Feb 2021, we report here early protocol defined endpoints from induction to day 100 post ASCT. Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with PCL (circulating plasmablasts > 20%) were included in OPTIMUM across 39 UK hospitals. Patients received up to 6 cycles of Dara-CVRd induction, HDMEL and ASCT augmented with bortezomib, followed by Dara-VR(d) consolidation for 18 cycles and Dara-R maintenance. Primary trial endpoints are minimal residual disease (MRD) status post ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. Data is complete but subject to further data cleaning prior to conference. Results: Median follow-up for the 107 patients in the safety population was 22.2 months (95% CI: 20.6 – 23.9). Two patients died during induction due to infection. Bone marrow aspirates suitable for MRD assessment by flow cytometry (10-5 sensitivity) were available for 81% of patients at end of induction and 78% at D100 post ASCT. Responses in the intention to treat population at end of induction were 94% ORR with 22% CR, 58% VGPR, 15% PR, 1% PD, 5% timepoint not reached (TNR; withdrew, became ineligible or died) and at D100 post ASCT 83% ORR with 47% CR, 32% VGPR, 5% PR, 7% PD, 10% TNR. MRD status was 41% MRDneg, 40% MRDpos and 19% not evaluable post induction and 64% MRDneg, 14% MRDpos and 22% not evaluable at D100 post ASCT. Responses at D100 post ASCT were lower in PCL with 22% CR, 22% VGPR, 22% PR, 22% PD, 12% TNR. Most frequent grade 3/4 AEs during induction were neutropenia (21%), thrombocytopenia (12%) and infection (12%). Grade 3 neuropathy rate was 3.7%. Conclusions: This is to our knowledge the first report on a trial for UHiR NDMM and PCL investigating Dara-CVRd induction and augmented ASCT. Response rates were high in this difficult-to-treat patient population, with toxicity comparable to other induction regimens. However, some early progressions highlight the need for innovative approaches to UHiR NDMM. Clinical trial information: NCT03188172.

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 Minimal residual disease may predict bone marrow relapse in patients with hairy cell leukemia treated with 2-chlorodeoxyadenosine

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1556-1560 ◽  
Author(s):  
S Wheaton ◽  
MS Tallman ◽  
D Hakimian ◽  
L Peterson
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Hematoxylin And Eosin ◽  
Anti Cd20 ◽  
Minimal Residual

Minimal residual disease (MRD) can be detected in bone marrow core biopsies of patients with hairy cell leukemia (HCL) after treatment with 2-chlorodeoxyadenosine (2-CdA) using immunohistochemical (IHC) techniques. The purpose of this study was to determine whether the presence of MRD predicts bone marrow relapse. We studied paraffin- embedded bone marrow core biopsies from 39 patients with HCL in complete remission (CR) 3 months after a single cycle of 2-CdA. Biopsies performed 3 months posttherapy and annually thereafter were examined by routine hematoxylin and eosin (H&E) staining and IHC using the monoclonal antibodies (MoAbs) anti-CD45RO, anti-CD20, and DBA.44. At 3 months after therapy, 5 of 39 (13%) patients had MRD detectable by IHC that was not evident by routine H&E staining. Two of the five patients (40%) with MRD at 3 months have relapsed, whereas only 2 of 27 (7%) patients with no MRD and at least 1 year of follow up relapsed (P = .11). Over the 3-year follow-up period, two additional patients developed MRD. Overall, three of six (50%) patients with MRD detected at any time after therapy have relapsed, whereas only 1 of 25 (4%) patients without MRD has relapsed (P = .016). These data suggest that the presence of MRD after treatment with 2-CdA may predict relapse.

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