Minimal Residual Disease in Multiple Myeloma Patients: Influence on Indicators of Progression Free Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5705-5705
Author(s):  
Andrei Garifullin ◽  
Sergei Voloshin ◽  
Irina Martynkevich ◽  
Alexey Kuvshinov ◽  
Elizaveta Kleina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factor ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Negative Group ◽  
Free Survival ◽  
Positive Group ◽  
Genetic Abnormalities ◽  
Minimal Residual

Abstract Background. Induction, consolidation of response and maintenance therapy are very effective approaches in the treatment of patients with multiple myeloma (MM). However, the majority of patients will inevitably relapse despite achieving progressively higher complete response (CR) rates. Activation of residual clonal plasmatic cells is a cause of relapse disease. Therefore, the assessment of minimal residual disease (MRD) is a strong prognostic factor for progression-free survival (PFS). Aim. To estimate influence of MRD on PFS indicators in MM patients. Methods. We analyzed 28 patients with MM (median age 56 years, male/female - 1.8:1). 5-color flow cytometry was used for immunophenotyping of bone morrow cells as well as definition of primary tumor cells phenotype and detection of MRD. Such markers as CD38, CD138, CD45, CD19, CD20, CD27, CD56 and CD117 were used to identify clonal plasma cells. In addition, MRD was assessed by FISH analysis in patients with genetic abnormalities; CT-PET carried out to patients with the MRD-negative CR. Results. Patients had bortezomib- or lenalidomide-based programs of therapy. Autologous stem cell transplantation (ASCT) was carried out in 18 patients. Performing ASCT statistically significantly increased frequency of MRD-negative CR (p<.01). Before ASCT MRD-negative CR was reached in 3/28 (10,7%) patients. After ASCT 9/18 (50,0%) patients were transferred to the MRD-negative group (6/9 patients before ASCT had MRD-positive CR, 1/9 - MRD status did not change, 2/9 - stringent CR was reached). One patient with MRD-negative CR had CT-PET positive specific lesions. 19/28 (67,8%) patients were transferred to the MRD-positive group (9/19 patients had CR, 5/19 - VGPR, 5/19 - PR). The median PFS didn't correlate with ASCT in general and the MRD-positive groups (р>.05). PFS in the MRD-negative group was better than in the MRD-positive group with CR (median was not reached vs median of 63.9 months, respectively; 2-year PFS was 100% vs 77%, respectively) (p=.0048). In addition, we analyzed the influence of CR in the MRD-positive group on PFS. Absence of CR is an inferior prognostic factor and is characterized by decrease of PFS in patients with MRD-positive status. The median PFS in the MRD-positive group with CR was 63.9 months and 26.0 months in the MRD-positive group without CR (VGPR and PR) (p=.049). Genetic abnormalities were detected in 7/26 (26.9%) patients before antimyeloma therapy: t(11;14) - in 5/26 (19.2%), del(13q) - in 3/26 (11.5%), t(4;14) - in 1/26 (3.8%), del(1p) - in 1/26 (3.8%). After treatment patients with CR (MRD-positive and MRD-negative) had normal genetic status by FISH. Only 1/7 patients with MRD-positive PR had residual clone with del(13q). Conclusion . Performing ASCT influences frequency of MRD-negative CR. The PFS indicators (median and 2-year PFS) were higher in the group of MM patients, who had MRD-negative status of the disease compared to than in the MRD-positive group. The FISH method had low sensitivity in detection of residual clone with genetic abnormalities, especially in patients with CR. Disclosures Shuvaev: BMS: Honoraria; Pfizer: Honoraria; Novartis pharma: Honoraria.

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

2021 ◽  
pp. JCO.21.01045
Author(s):  
Pieter Sonneveld ◽  
Meletios A. Dimopoulos ◽  
Meral Beksac ◽  
Bronno van der Holt ◽  
Sara Aquino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Primary Study ◽  
Controlled Clinical Trial ◽  
Newly Diagnosed ◽  
Consolidation Treatment ◽  
Minimal Residual

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

Detection and impact of minimal residual disease on outcome of chronic lymphocytic leukemia

2012 ◽  
Vol 153 (41) ◽  
pp. 1622-1628
Author(s):  
Márk Plander ◽  
Judit Skrapits ◽  
Tünde Bozsó ◽  
Tamás Szendrei ◽  
János László Iványi
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Minimal Residual

Introduction: Minimal residual disease is associated with longer overall survival in patients with chronic lymphocytic leukemia. Aim: The aim of the authors was to determine the clinical significance of remission and minimal residual disease on the survival of patients with chronic lymphocytic leukemia. Methods: Data from 42 first-line treated patients with chronic lymphocytic leukemia were analyzed. Minimal residual disease was determined by flow cytometry. Results: Overall response and complete remission was achieved in 91%, 86%, 100% and 87%, 0%, 60% of patients with fludarabine-based combinations, single-agent fludarabine and cyclophosphamide + vincristin + prednisolone regimen, respectively. Minimal residual disease eradication was feasible only with fludarabine-based combinations in 60% of these cases. The ratio of minimal residual disease was 0.5% on average. During a median follow-up period lasting 30 months, the overall survival of patients with fludarabine-resistant disease proved to be significantly shorter (p = 0.04), while complete remission without minimal residual disease was associated with significantly longer progression free survival (p = 0.02). Conclusion: Only fludarabine-based combinations were able to eradicate minimal residual disease in patients with chronic lymphocytic leukemia. Complete remission without minimal residual disease may predict longer progression free survival in these patients. Orv. Hetil., 2012, 153, 1622–1628.

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.

Value of Pretransplantation Minimal Residual Disease in Acute Myeloid Leukemia and Myeloablative Hematopoietic Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2510-2510
Author(s):  
Leyre Bento ◽  
Mi Kwon ◽  
Ismael Buno ◽  
Carolina Martinez-Laperche ◽  
Javier Anguita ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Negative Group ◽  
Rt Pcr ◽  
Positive Group ◽  
Multiparametric Flow Cytometry ◽  
Patients At Risk ◽  
First Remission ◽  
Minimal Residual

Abstract Abstract 2510 Relapse remains the main cause of treatment failure in patients with acute myeloid leukemia (AML) in first remission (CR1) after allogeneic hematopoietic stem cell transplantation (SCT). The detection of minimal residual disease (MRD) in AML has improved in the past years with multiparametric flow cytometry (MFC) and molecular analysis (RT-PCR). However the prognostic impact of pre-transplantation MRD and the outcome after SCT has not been well studied. The aim of this study was to evaluate pre-transplantation MRD in patients in first remission undergoing myeloablative allogeneic SCT. We retrospectively studied 35 consecutive patients receiving myeloablative SCT for AML in first cytologic remission after intensive chemotherapy with available MRD determination before transplant. MRD was studied by 4-color MFC on bone marrow aspirates, and quantitative RT-PCR (NPM1, WT1, MLL) on bone marrow and/or peripheral blood samples obtained within thirty days before transplant. Thirty-five patients consecutively transplanted in our institution between 1999 and 2012, and for which pre-transplant MRD data was available were analyzed (Table 1). Eighteen showed negative MRD pre-transplant whereas 17 showed positive values. Characteristics of patients were homogeneous between both groups, including number of chemotherapy cycles received before transplantation (Table 1). Within the MRD-negative group, 17 patients showed negative MRD by MFC (12 of them showed negative values also by PCR) and 1 patient showed negative MRD by PCR (MFC not available). Within the MRD-positive group, 9/17 (52%) patients showed MRD-positive values by MFC: in 5 cases MRD was also detected by PCR, only 1 showed negative PCR and in the remaining 3 cases, PCR was not available. On the other hand, in 8/17 (47%) patients MRD was not detected by MFC, however, PCR detected MRD in all of the cases in bone marrow (2), peripheral blood (4) or both samples (2). With a median follow-up of the whole series of 23 months, 2-years estimates of overall survival were 82% (95% CI, 97–55) and 30% (95% CI, 3–71) for MRD-negative and MRD-positive patients (p=0.045), respectively. Cumulative incidence of relapse were 21% (95% CI, 5–48) and 56% (95% CI 10–73) for MRD-negative and MRD-positive patients (p=0.11). In the MRD-negative group, cause of death was toxicity in 11% of the cases and relapse in 11%, while in the MRD-positive group, 17% of patients died due to toxicity and 23% due to relapse. Conclusions: Our data shows that the presence of MRD before allogeneic SCT in patients with AML in CR1 is associated with a significant worse OS rate compared to patients with negative MRD, as well as a tendency towards a higher risk of relapse. The detection of MRD by MFC correlates with the detection by PCR in most of the cases. However, in a significant group of patients, MRD was detected only by PCR. This could be related to differences in sensitivity between both methods. Further studies including larger series are needed to confirm these observations. Table 1 Patient and Disease Characteristics by MRD status Pre-transplant MRD MRD-negative MRD-positive N=35 18 17 Age at transplant (median, R) 36 (19-62) 42 (19-68) Gender (male/female) 8/10 12/5 Cytogenetics and molecular markers     Normal/Intermediate risk 77% 83%     FLT3+ 28% 27%     NPM1+/FLT3- 6% 7%     FLT3-/NPM1- 28% 40%     High-risk 22% 17% Secondary AML 16% 6% Cycles pre-transplantation (median, R) 3 (2-5) 3 (2-5) MRD detection     MFC only 27% 18%     RT-PCR only 5% 0%     Both 68% 82% Donor*     HLA-identical sibling 50% 35%     HLA-matched unrelated 22% 29%     SCU-dual 22% 24%     HLA-haploidentical related 6% 12% acute GVHD II-IV (n°/patients at risk) 44% (8/18) 24% (4/17) chronic GVHD lim/ext (n°/patients at risk) 53% (8/15) 57% (8/14) MRD: minimal residual disease, MFC: multiparametric flow cytometry, RT-PCR: real time PCR, GVHD: graft vs host disease, SCU-dual: single cord blood with co-infusion of selected CD34+ cells from a third party HLA-mismatched donor. *The MRD negative group includes 2 MAC SCU-dual cases with primary graft failure rescued immediatly by a second graft (1 Dual and 1 Haplo) using a RIC regimen. The MRD positive group includes 1 MAC SCU-dual case rescued immediatly by a second graft (1 Haplo). 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.

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.

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