scholarly journals Post-Induction Undetectable Minimal Residual Disease at 10 -5 Sensitivity Level within Marrow and/or Stem Cell Graft Overrides Cytogenetic High Risk

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2909-2909
Author(s):  
Guldane Cengiz Seval ◽  
Klara Dalva ◽  
Dilek Oz ◽  
Sule Mine Bakanay ◽  
Ender Soydan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Post Induction ◽  
Sensitivity Level ◽  
Stem Cell Graft ◽  
The Impact ◽  
Minimal Residual

Abstract Introduction: Post-induction minimal residual disease (MRD) within but not outside (peripheral blood/stem cell graft) of marrow among transplant eligible patients with multiple myeloma (MM) is currently recognized as poor-prognostic. Emerging number of studies are evaluating MRD within the context of cytogenetic risk. In this study we aimed to quantify circulating plasma cells (PCs) by flow in apheresis products (graft=gMRD) and compare with marrow MRD(mMRD) and outcome according to cytogenetics. Patients & Methods: Four hundred eleven subsequent newly diagnosed multiple myeloma (NDMM) patients transplanted (AHCT) between September 2006 - June 2021 were included prospectively. Standard-risk cytogenetics(SR) is defined as t(11;14), t(6;14), or a normal karyotype , whereas del(17p13), t(4;14), t(14;16), t(14;20), + 1q21 and complex findings are high-risk cytogenetics (HR). In the sample drawn for HPSC quantification of the graft and bone marrow, the number of clonal PCs were quantified by Flow. CD27 PC7 orCD27 A750, CD56 A700, CD19 ECD, CD38 FITC orCD38 A750, CD138 APC, CD45 KO, CD81 PE, CD117 PC7, polyclonal Rabbit Anti-Human Kappa or Lambda Chains /FITC antibodies and acquisition of at least 10 5 cells per tube Analysis was performed using the Navios Flow Cytometer (3L10C, Beckman Coulter) using the Kaluza software (Beckman Coulter, USA) according to the criteria defined by Montero et al and also abnormal distribution of kappa vs. Lambda expression. Undetectable MRD was defined as absence of clonal PCs at a sensitivity of 10 -4 prior to 2017(n=217) and 10 -5 after 2017(n=131). MRD assessment is similar in the graft and marrow. Impact of postinduction MRD analysis was performed in 131 patients with MRD data of 10 -5 sensitivity level. Results were reported in the intention-to-treat (ITT) population for mMRD. Results: Median follow-up after AHCT was 61.5 months (range:3.2-168) (prior to 2017) and 17.7 months (range: 3-47.4) (after 2017). Induction regimen consisted of bortezomib without or with immunomodulatory drug (IMID) 78.8%, 2.8% (prior to 2017) and 74.1%, 22.9% (after 2017). Consolidation 18% (n=39/217), 22.1% (n=29/131) (prior and after 2017) and maintenance 21.2% (n=46/217), 35.1% (n=46/131) (prior and after 2017) were administered based on the response to AHCT. Cytogenetically HR was observed 14.1% (n=47) (among total cohort) and 15.8% (n=19) (after 2017 cohort). Post-induction biochemical response distribution among patients with undetectable MRD are shown in Table-1. MRD assessments were performed at a sensitivity of 10 -4 and 10 -5 in graft (n=147 and 76), marrow (n=18 and 4) or both (n=52 and 51). A statistically significant correlation was detected between marrow and graft MRD only at sensitivity level 10 -5 (SE: 0.638, p<0.001). Additionally, correlations between CR and gMRD (Kappa coefficient (SE): -0.284, p=0.03); CR and mMRD (SE: -0.452, p:0.001) were found. Since marrow and graft MRD results are correlated, all graft and marrow results were merged for the multivariate analysis (MVA) (Table-2). Having undetectable vs detectable MRD in either graft or marrow estimates a 2 years-PFS of 83.6% vs 46.5% (p=0.007). Among 42 MRD(-) patients, only four (two with HR)have relapsed. There is a tendency for better two year probability of PFS with undetectable mMRD vs gMRD at 10-5 ( not reached vs 84.7% ; ns)(Figure 1). The patients (after 2017) are divided into four groups according to MRD status and cytogenetic risk stratification: MRD(-)SR (n=35; 29.2%), MRD(-)HR (n=7; 5.8%), MRD(+)SR (n=66; 55%), MRD(+)HR (n=12; 10%). Kaplan-Meier curves revealed significant differences in PFS among these groups (p=0.03) (Figure-2). Conclusion: Our real-world triplet drug induction-based experience shows for the first-time post-induction mMRD and MRD to be correlated with each other and with PFS. PFS with MRD(-) at 10 -5 results have displayed a better outcome compared to 10 -4. MVA showed MRD and age to determine PFS, independent from post-induction CR, ISS and cytogenetic risk. Although observed less frequently, achieving post-induction MRD(-) either in graft or marrow may ameliorate the poor prognosis of HR. With improvement in induction it may be possible to achieve more frequent MRD(-) and thus analyze the impact of each cytogenetics risk group ie 1q amplification separately. Furthermore, MRD in graft may be a non-invasive therapeutic efficacy tool which is subject to less sampling variation. Figure 1 Figure 1. Disclosures Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau.

scholarly journals Immunophenotypic Markers Associated with Minimal Residual Disease Status and Outcome in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

2021 ◽  
Vol 8 (8) ◽  
Author(s):  
Missassi G ◽  
◽  
Ikoma-Colturato MRV ◽  
Bortolucci CM ◽  
Conte-Spilari JE ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Prognostic Factor ◽  
Stem Cell Transplantation ◽  
Minimal Residual Disease ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Residual Disease ◽  
The Impact ◽  
Minimal Residual

Multiple Myeloma (MM) is one of the most common hematologic malignancies, with a heterogeneous prognosis. Therefore, the recognition of biomarkers can be useful to understand the differences in patient outcomes. Minimal Residual Disease (MRD) has been considered a very important prognostic factor in MM. In parallel, the prognostic value of immunophenotypic markers expressed in MM Plasma Cells (PCs) has also been described. The aim of this study was to assess the impact of CD27, CD28, CD45, CD56, CD117 and β2-microglobulin expressions on the outcome of 154 MM patients undergoing Autologous Stem Cell Transplantation (ASCT). The relation of each marker studied with the Overall Survival (OS) and Progression-Free Survival (PFS) was assessed, alone and in association with pre-ASCT MRD. Scores of good (GPM) and poor Prognostic Markers (PPM) were established, according to their respective survival curves. The expressions of CD27 and CD45 were associated to longer OS (p=0.013 and p=0.00, respectively) and PFS (p=0.00) as well as the absence of CD28 (OS p=0.026; PFS p=0.001) and CD56 (OS p=0.004; PFS p=0.009), in patients with undetectable MRD. The number of GPM showed an inverse correlation with the level of MRD (p=0.04), while a higher number of PPM was observed in patients with higher levels of MRD (p=0.04), which were also significantly associated with OS and PFS. In conclusion, although pre-ASCT MRD is a powerful prognostic factor in MM, these biomarkers can provide additional prognostic information and be used in the follow-up of MM patients.

scholarly journals 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 ◽  
Vol 119 (3) ◽  
pp. 687-691 ◽  
Author(s):  
Bruno Paiva ◽  
Norma C. Gutiérrez ◽  
Laura Rosiñol ◽  
María-Belén Vídriales ◽  
María-Ángeles Montalbán ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Complete Response ◽  
Multiparameter Flow Cytometry ◽  
Minimal Residual

Abstract The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day +100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n = 140) and GEM2005 < 65y (n = 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P = .002) and persistent minimal residual disease by multiparameter flow cytometry at day +100 after HDT/ASCT (hazard ratio 8.0; P = .005) were the only independent factors that predicted unsustained CR. Thus, these 2 parameters may help to identify patients in CR at risk of early progression after HDT/ASCT in whom novel treatments should be investigated.

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.

Minimal Residual Disease Studies in Multiple Myeloma Patients Achieving Complete Remission after Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) by RQ-PCR.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2418-2418 ◽  
Author(s):  
M. E. Sarasquete ◽  
R. García-Sanz ◽  
A. Balanzategui ◽  
P. Martínez-Sánchez ◽  
J. Martínez-López ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
High Rate ◽  
Taqman Probe ◽  
Patient Specific ◽  
Standard Curve ◽  
The Impact ◽  
Minimal Residual

Abstract Multiple myeloma (MM) remains as an incurable disease although new therapies can achieve a high rate of complete remissions (CR). Unfortunately, most patients ultimately relapse due to the persistence of minimal residual disease (MRD), and only a minority could be cured. Detection and quantification of these cells is an important tool for monitoring these patients and predicting a potential relapse. Here we analyze by RQ-PCR the MRD in MM patients achieving CR in order to classify them into different risk categories. MATERIAL AND METHODS: 38 MM patients uniformly treated according to the GEM-2000 (Spanish group for Myeloma) protocol, and that have achieved CR following PBSCT were included in the study. 22 were IgG, 9 IgA, 6 B-J and 1 non-secretory (κ/λ 21/16). 27 were male & 11 female with a median age of 58 (range 48–65). Bone marrow samples obtained at diagnosis and 3 months after transplant were analyzed. Complete (VDJH) and incomplete (DJH) Ig rearrangements were amplified with the Biomed-2 strategy (Leukemia2003;17:2257). PCR clonal products were sequenced on an ABI Prism 377 Sequence detector. VH, DH and JH segments were identified by comparing with germinal sequences on V-Base and BLAST databases. An ASO primer at the N-region was designed for each patient with the OLIGO 6.0 software. RQ-PCR was then performed on an ABI Prism 7700 using the ASO specific forward primer, a JH reverse intronic primer (JH1–6) and a TaqMan probe (JH1,2,4,5, JH3 or JH6) to amplify the patient specific rearrangement. Sample quality and quantity was controlled evaluating the standard curve of the albumin gene amplification. MRD was calculated according to ΔCT method. RESULTS: In 14 out of the cases included in the study, MRD investigation was not possible because the N-region was not longer enough to design the ASO primer (n=3), poor quality in the diagnostic sample to obtain the standard curve (n=8) or low plasma cell infiltration at diagnosis to obtain correct dilutions (n=3). The remaining 24 patients were classified into different risk groups according to the MRD level obtained 3 months after transplantation with a cut-off point of 0.01% tumor cells. Thus, progression free survival (PFS) was longer in those patients with MRD< 10−4 (p=0.03, figure 1A). By contrast, upon comparing the impact on PFS of immofixation (IFX) in these 24 patients that were in CR (defined by conventional electrophoresis criteria), it was observed that patients with IFX (−) didn’t showed a different outcome from those IFX (+) (figure 1B). CONCLUSION: In summary, although RQ-PCR is a labor and time-consuming technique, it is an useful tool for monitoring MRD in MM. The level of 10−4 can contribute to classify patients into 2 groups (high and low MRD) with different risk of relapse that can be used to design specific therapies.

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