MRD-negative Status Research Articles

Detection of Measurable Residual Disease May Better Predict the Outcome Rather Than Mutations Based on Next-Generation Sequencing in Acute Myeloid Leukemia with Biallelic Mutations of CEBPA

Objectives: Acute myeloid leukemia (AML) patients with biallelic mutations of CEBPA (bi CEBPA) have a 30-50% relapse rate after standard chemotherapy. This study established the value of multiparameter flow cytometric measurable residual disease (MFC-MRD) detection, mutations based on next-generation sequencing (NGS), and compares the outcomes of risk stratification treatment in adult bi CEBPA AML patients. Methods: From March 2014 to December 2018, 124 patients with newly diagnosed acute myeloid leukemia with bi CEBPA were treated with chemotherapy. Out of these, 93 patients were analyzed further by a sensitive NGS assay for mutations in 87 candidate genes. MRD was detected in all patients by MFC after each cycle of induction and consolidation chemotherapy and every 3 months later. Results: Among these patients, 73 patients were male (58.9%), and median age was 37.5 (16-69) years. The expression of CD34, CD117, CD7, HLA-DR, CD15, CD33 and CD13 in 124 patients were 120 (96.8%), 123 (99.2%), 112 (90.3%), 107 (86.3), 93 (75.0%), 115 (92.7%) and 107 (86.3%) respectively. The most common co-occurring mutations were found in the GATA2 (n=29/93, 31%), WT1 (n=20/93, 21.7%), NRAS (n = 13/93, 14.0%), CSF3R (n = 12/93, 12.9%), and TET2 (n = 9/93, 9.6%) genes. All patients (100%) achieved complete remission (CR) including 114 patients (91.9%) who achieved it with only 1 induction course. The median follow-up was 33.5 (4-69) months. The 3-year Cumulative incidence of relapse (CIR), disease-free survival (DFS) and overall survival (OS) were 32.8%, 64.7%, and 84.3%, respectively. Univariate analysis results shown that WT1 Wild-type was favorable factor of 3-year CIR (23.3% vs. 47.0%, P=0.022) and 3-year DFS (75.5% vs 53.0%; P=0.031), GATA2 Wild-type had good trend for lower CIR and longer DFS and CSF3R Wild-type had inferior trend for higher CIR and shorter DFS. Patients with sustained positive MRD status after 2 consolidation cycles and MRD negative status loses in any time defined as "MRD high risk" had higher CIR (3-year CIR, 100% vs 25.5%; P<0.001; 81.5% vs 6.4%; P<0.001, respectively) and worse DFS and OS (3-year DFS, 0% vs 71.5%; P<0.001; 16.8% vs 90.2%; P<0.001, respectively; 3-year OS, 39.0% vs 89.8%; P<0.001; 72.2% vs 96.5%; P=0.001, respectively ) than those with persistent negative MRD status that defined as "MRD low risk" (Figure). Multivariate analysis showed that MRD low risk was the only favorable factor of CIR, DFS and OS (CIR: HR=37.3, 95%CI: 8.6-161.3, P<0.001;. DFS: HR=24.6, 95%CI: 7.2-84.0, P<0.001; HR=28.2, 95%CI: 2.1-374.1, P=0.011; respectively). Thirty-two (91.4%) MRD high risk patients (P<0.001) relapsed at a median time of 8 months (range: 3-32 months) include 21 patients of MRD negative status loses in any time and 11 patients with positive MRD status after 2 consolidation cycles. In totally 35 relapsed patients, 3 patients give up, 19 (61.3%) patients achieved CR2 after induction again. 15 CR2 and 4 non-remission patients underwent allo-HSCT achieved superior 3-year OS (83.0% vs 5.1%; p= 0.034; 75.0% vs 0%; p=0.006; respectively) than chemotherapy. To assess the role of risk stratification treatment by transplant or non-transplant, the124 patients were divided into 2 groups by the unique risk factor: MRD high risk group (n=43, 34.7%) and MRD low risk group (n=81, 65.3%). In the MRD low risk group (median follow-up: 35 months; range: 4-65 months), there was no significant difference in probabilities of 3-year OS (92.3% vs. 96.9%, P=0.428) between the transplant and non-transplant cohorts. In the MRD high risk group (median follow-up: 30 months; range: 7-69 months), 3-year OS was significantly better in the transplant cohort than in the non-transplant cohort (84.0% vs. 44.3%, p=0.007).Conclusions: MRD high risk may better predict the outcome rather than mutations based on NGS in AML with bi CEBPA, and allo-HSCT may achieve superior survival in MRD high risk patients. Key words: Acute myeloid leukemia with biallelic CEBPA mutations; next-generation sequencing; multiparameter flow cytometric measurable residual disease; allogeneic stem cell transplantation; Chemotherapy Disclosures No relevant conflicts of interest to declare.

A Multicenter Phase I Study Combining Venetoclax with Mini-Hyper-CVD in Older Adults with Untreated and Relapsed/Refractory Acute Lymphoblastic Leukemia

A Multicenter Phase I Study Combining Venetoclax with Mini-Hyper-CVD in Older Adults with Untreated and Relapsed/Refractory Acute Lymphoblastic Leukemia

A Phase Ib/II Study of the BCL-2 Inhibitor Venetoclax in Combination with Standard Intensive AML Induction/Consolidation Therapy with FLAG-IDA in Patients with Newly Diagnosed or Relapsed/Refractory AML

A Phase Ib/II Study of the BCL-2 Inhibitor Venetoclax in Combination with Standard Intensive AML Induction/Consolidation Therapy with FLAG-IDA in Patients with Newly Diagnosed or Relapsed/Refractory AML

MRD Detection in Myeloma Cells: Comparison between Inexpensive 1-Tube 10 Color Multiparameter Flow Cytometry and Euroflow Multiparameter Flow Cytometry

Background: Achievement of MRD-negative status in MM patients has been demonstrated to be associated with better outcome. EuroFlow MM-MRD has been a global standard for MRD detection by MFC. In Japan, EuroFlow is limited to research use only, because the dynamics of the population have raised concerns about increasing health care expenditure in Japan. Therefore, it is desirable to develop an inexpensive FCM method with equivalent sensitivity to EuroFlow for detecting MRD. Aims: In this study, we analyzed the number and percentage of total plasma cells (PC), abnormal PC with EuroFlow MM-MRD and 10-color-MFC in 50 MM patients. Patients and Methods: Bone marrow samples collected from 50 MM patients were subjected to MRD detection by EuroFlow MM-MRD and 10-color-MFC simultaneously. EuroFlow MM-MRD was performed according to EuroFlow standard operating procedure. 10-color MFC was performed at BML corporation. Briefly, CD38 multiepitope FITC, CD138 V450, CD45 V500-C, CD56 PE, CD19 APC-H7, CD27 APC R700, CD81 BV605, CD117 PE-Cy7, cIgk APC and cIgl PerCP-Cy5.5 of monoclonal antibody were used according to the ICCS(International Clinical Cytometry Society) guidelines. Data were analyzed with FACSuite ver 1.2.1(Becton Dickinson) using a FACSLylic(Becton Dickinson). Wilcoxon signed-rank test was used for the comparison of paired variables. Results: The representative example of 10-color-MFC were shown in figure 1. We first compared the percentage of normal plasma cells in bone marrow. The percentage of normal plasma cells analyzed with 10-color-MFC and EuroFlow were 0.287% (range 0.001-1.0322%) and 0.257%(range0.0002-1.37%), respectively. The good correlation between them was observed (r=0.509). The percentage of myeloma cells determined with 10-color-MFC and EuroFlow were 0.0705%(range 0-0.9086%) and 0.0940% (range 0-1.3000%), respectively. Quantification of abnormal plasma cells were highly similar between 2 tests (r=0.977, figure 2). To compare the percentage of abnormal plasma cells analyzed with 10-color-MFC and EuroFlow, p-value determined with Wilcoxon signed-rank test was 0.0069 in 50 sample. However, when total bone marrow cells were 3 million cells, limit of detection (LOD) and limit of quantification (LOQ) in 10-color MFC were defined as 0.001% and 0.0017%, respectively. The correlation in samples with less than 3 million of bone marrow cells was not good (p=0.424). Only when 3 million or higher number of bone marrow cells were analyzed, better correlation is thought to be observed (p=0.0001). High concordant analytical results were observed with an overall qualitative concordance of 95%. Conclusion: Our 10-color-MFC demonstrated high sensitivity to detect MRD with good correlation and also inexpensive (about 100 dollars as of July 2019). However, 3 million or higher number of bone marrow cells is inevitable to demonstrate good correlation. In the country where high medical expenditure is not acceptable, our inexpensive MFC is considered as good alternative methods to detect MRD in MM patients. Disclosures Tsukada: Takeda Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene: Honoraria; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Kyowa Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd: Honoraria; Fujimoto Pharmaceutical: Honoraria; Ohtsuka Pharmaceutical: Honoraria; Asahi Kasei Pharma Corporation: Honoraria; MOCHIDA PHARMACEUTICAL CO., LTD.: Honoraria. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria.

Moxetumomab Pasudotox-Tdfk in Heavily Pretreated Patients with Relapsed/Refractory Hairy Cell Leukemia (HCL): Long-Term Follow-up from the Pivotal Phase 3 Trial

Moxetumomab Pasudotox-Tdfk in Heavily Pretreated Patients with Relapsed/Refractory Hairy Cell Leukemia (HCL): Long-Term Follow-up from the Pivotal Phase 3 Trial

An Allogeneic GM-CSF-Based Vaccine in Combination with Lenalidomide Induces Durable Remissions and Sustained Immunological Responses in Multiple Myeloma

Introduction: Novel therapies have significantly increased the complete response (CR) rates in multiple myeloma (MM) with corresponding improvement in progression free survival (PFS). However, the emergence of treatment resistant sub-clones leads to disease relapse in a significant number of patients. Despite continuous improvements, cancer vaccination strategies have not been effective in preventing disease progression. Possible reasons include suboptimal timing of administration, antigen selection, disease burden at the time of vaccination and lack of the appropriate adjuvant. Here, we present the results of a phase I/II trial evaluating an allogeneic MM cellular vaccine administered in the context of a minimal disease burden in combination with lenalidomide (Len) to prevent MM progression. Methods: The vaccine consists of two MM cell lines (U266 and H929) coupled to a GM-CSF producing leukemia cell line (K562, GVAX® platform). After irradiation, the vaccine was cryopreserved until further use. Patients achieving a near CR (nCR), defined as absent M-spike and positive urine/serum immunofixation, were observed for at least 4 months to monitor response stability before enrollment. Vaccination was administered at 1, 2, 3 and 6 months together with the PrevnarÒvaccine in patients continuing on Len maintenance. Bone marrow (BM) and peripheral blood (PB) samples were utilized for immune monitoring, T-cell receptor (TCR) sequencing, and B-cell receptor (BCR) sequencing for minimal residual disease (MRD) determination using the immunoSEQ®Assay (Adaptive Biotechnologies, Seattle, WA)at enrollment, 3 months, 1 year and long-term follow-up timepoints. Results: Of the 30 patients that were initially observed, 15 patients maintained a stable nCR for at least 4 months and were vaccinated at the established timepoints. Patients who either progressed or improved their clinical response transitioning to a CR were not considered eligible. TCR immunoSEQ analysis revealed both the appearance and expansion of new T-cell clones without overall changes in repertoire clonality, suggesting active response to vaccination in both BM and PB compartments. Persistence of expanded clones was detected by immunoSEQ up to 1 year after the first vaccine dose in all patients. Phenotypic analyses and antigen-stimulation assays on BM T cells demonstrated maintenance of MM-specific T-cell reactivity at all examined timepoints. Polyfunctional MM-specific T-cell responses were detected in follow-up samples up to 8 years after the first vaccine dose and surprisingly showed persistence of MM-specific T-cell immunity when compared to the 1-year time point. Although negative MRD status and depth of response directly correlated with disease remission, some patients developed a low, but persistent MRD and M-spike (<0.5 g/dL) without actually meeting criteria for disease recurrence. These findings suggest that while vaccination can further reduce the disease burden in some patients, the development of persistent immune equilibrium with vaccination is important for disease control. Strikingly, with a median follow-up time of 4.73 (range 2.9-7.25) years, the vaccine group (n=15) did not reach the median PFS (mPFS) with an overall PFS at 6 years of 75%, which is significantly higher than the mPFS of patients not enrolled due to achievement of CR (n=5, mPFS = 2.1 years, p<0.01). Conclusions: These data demonstrate that an allogeneic MM vaccine effectively stimulates antitumor immunity in the setting of low disease burden with Len. Moreover, polyfunctional antitumor immune responses were persistent up to 8 years post vaccination. It is likely that the diversity of antigens in the vaccine supported polyclonal MM-specific immune responses, thus establishing long-term MM control. Although depth of response to treatment is a critical factor in maintaining MM remission, the long-term persistence of functional MM-specific T-cell clones highlights the importance of an active immune response to prevent MM relapse. Overall, these findings suggest that allogeneic MM vaccination could be an integrative therapy to support persistent antitumor immunity and increase PFS, especially in patients who responded to treatment without achieving an MRD-negative status. Disclosures Huff: Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Karyopharm, Sanofi, MiDiagnostics: Consultancy. Rudraraju:WindMIL Therapeutics: Employment, Equity Ownership. Gittelman:Adaptive Biotechnologies: Employment, Other: Financial Interest. Johnson:Adaptive Biotechnologies: Employment, Other: Financial Interest. Ali:Celgene: Research Funding; Poseida: Research Funding. Noonan:WindMIL Therapeutics: Employment, Equity Ownership, Patents & Royalties; Aduro: Patents & Royalties: intellectual property on allogeneic MM GVAX. Borrello:BMS: Consultancy; Aduro: Patents & Royalties: intellectual property on allogeneic MM GVAX; WindMIL Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau.

Carfilzomib-Revlimid-Dexamethasone Vs. Carfilzomib-Thalidomide-Dexamethasone Weekly (After 2 Twice Weekly Cycles) Followed By Carfilzomib Maintenance Vs. Control in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) - Interim Efficacy Analysis of Combined Data (AGMT MM-02)

Carfilzomib-Revlimid-Dexamethasone Vs. Carfilzomib-Thalidomide-Dexamethasone Weekly (After 2 Twice Weekly Cycles) Followed By Carfilzomib Maintenance Vs. Control in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) - Interim Efficacy Analysis of Combined Data (AGMT MM-02)

The α-emitter astatine-211 targeted to CD38 can eradicate multiple myeloma in a disseminated disease model

AbstractMinimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10−5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine-211 (211At) deposits prodigious energy within 3 cell diameters, which is ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At-CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At-CD38 at 15 to 45 µCi at least doubled median survival of mice relative to untreated controls (P < .003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low-burden MRD, 3 studies demonstrated that single-dose 211At-CD38 at 24 to 45 µCi produced sustained remission and long-term survival (>150 days) for 50% to 80% of mice, where all untreated mice died in 20 to 55 days (P < .0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low-disease-burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients.

Standardization of High Sensitivity Minimal Residual Disease Monitoring in Multiple Myeloma: An Experience in Tertiary Cancer Centre

Minimal residual disease (MRD) status is the most relevant prognostic marker in multiple myeloma (MM). Recently, IMWG has incorporated MRD-negative status as a criterion to define stringent clinical response (sCR) using next-generation flow cytometry (NGF) i.e. high-sensitivity flow cytometry (HSFC). Herein, we present our experience in the standardization of HSFC and MRD monitoring in MM.

Standardization of High Sensitivity Minimal Residual Disease Monitoring in Multiple Myeloma: An Experience in Tertiary Cancer Centre

Minimal residual disease (MRD) status is the most relevant prognostic marker in multiple myeloma (MM). Recently, IMWG has incorporated MRD-negative status as a criterion to define stringent clinical response (sCR) using next-generation flow cytometry (NGF) i.e. high-sensitivity flow cytometry (HSFC). Herein, we present our experience in the standardization of HSFC and MRD monitoring in MM.

Comparison of minimal residual disease detection in multiple myeloma between SRL 8-color single-tube and EuroFlow 8-color 2-tube multiparameter flow cytometry methods

Most patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper responses are required. Next-generation sequencing (NGS) and multiparameter flow cytometry (MFC) methods have been used to assess MRD. However, NGS and MFC methods are generally expensive. Aims: We sought to determine the efficacy of a new, inexpensive, single-tube 8-color MFC method (SRL-Flow), which is based on the EuroFlow-next generation flow (NGF) (tube 2 only), to assess MRD-negative status.

MRD response in relapsed/refractory FL after obinutuzumab plus bendamustine or bendamustine alone in the GADOLIN trial

We report assessment of minimal residual disease (MRD) status and its association with outcome in rituximab-refractory follicular lymphoma (FL) in the randomized GADOLIN trial (NCT01059630). Patients received obinutuzumab (G) plus bendamustine (Benda) induction followed by G maintenance, or Benda induction alone. Patients with a clonal marker (t[14;18] translocation and/or immunoglobulin heavy or light chain rearrangement) detected at study screening were assessed for MRD at mid-induction (MI), end of induction (EOI), and every 6–24 months post-EOI/discontinuation by real-time quantitative PCR. At MI, 41/52 (79%) patients receiving G-Benda were MRD-negative vs. 17/36 (47%) patients receiving Benda alone (p = 0.0029). At EOI, 54/63 (86%) patients receiving G-Benda were MRD-negative vs. 30/55 (55%) receiving Benda alone (p = 0.0002). MRD-negative patients at EOI had improved progression-free survival (HR, 0.33, 95% CI, 0.19–0.56, p < 0.0001) and overall survival (HR, 0.39, 95% CI, 0.19–0.78, p = 0.008) vs. MRD-positive patients, and maintained their MRD-negative status for longer if they received G maintenance than if they did not. These results suggest that the addition of G to Benda-based treatment during induction can significantly contribute to the speed and depth of response, and G maintenance in MRD-negative patients potentially delays lymphoma regrowth.

Minimal residual disease monitoring in early stage follicular lymphoma can predict prognosis and drive treatment with rituximab after radiotherapy

Since 2000, we have investigated 67 consecutive patients with stage I/II follicular lymphoma (FL) for the presence of BCL2/IGH rearrangements by polymerase chain reaction (PCR), real time quantitative PCR (RQ-PCR) and digital droplet PCR (ddPCR). All patients were treated with involved-field radiotherapy (IF-RT) (24-30Gy). From 2005, patients with minimal residual disease (MRD) after IF-RT received rituximab (R) (375mg/m2 , 4 weekly administrations). The median follow-up is 82months (17-196). At diagnosis, 72% of patients were BCL2/IGH+. Progression-free survival (PFS) was significantly better in patients with undetectable/low levels (<10-5 ) of circulating BCL2/IGH+ cells at diagnosis and in those who were persistently MRD- during follow-up (P=0·0038). IF-RT induced an MRD- status in 50% of cases; 16/19 (84%) MRD+ patients after IF-RT became MRD- after R treatment. A significantly longer PFS was observed in MRD+ patients treated with R compared to untreated MRD+ patients (P=0·049). In early stage FL, both circulating levels of BCL2/IGH+ cells at diagnosis and MRD status during follow-up bear prognostic implications. Standard IF-RT fails to induce an MRD-negative status in half of patients. Most patients become MRD- following treatment with R and this is associated with a significantly better PFS.

PB1666 WHERE IS THE PLACE OF PET/CT IN DIAGNOSTIC IN PATIENTS WITH LYMPHOBLASTIC LYMPHOMA AND ACUTE LYMPHOBLASTIC LEUKEMIA WITH EXTRAMEDULLARY INVOLVEMENT?

Background:Positron emission tomography/computed tomography (PET/CT) is emerging as an essential diagnostic tool in characterizing suspicious neoplastic lesions and staging malignant diseases. Most studies regarding the possible role of FDG‐PET/CT in the management of acute lymphoblastic leukemia (ALL) patients are very limited. But one can suggest the high role of PET/CT in the assessment of residual lesions after chemotherapy in patients with lymphoblastic lymphoma (LBL) and ALL with extramedullary involvements.Aims:The aim of the study was to estimate the ability to accumulate 18F‐FDG radiopharmaceuticals by tumor cells in PET/CT in patients with ALL/LBL and assess the prognostic value of the PET/CT after the consolidation therapy (with or without autologous stem cell transplantation (autoSCT)) in patients with Ph‐negative ALL/LBL who received therapy according to the protocols of the Russian research group ALL‐2009/ALL‐2016.Methods:PET/CT was performed in 3 patients with different types of newly diagnosed ALL before the start of the therapy and after the end of induction. Characteristic of patients were: the first‐ male, 55 age, with BII type Ph‐negative ALL, with t(6;11) with generalized bone involvement and ossalgia; the second ‐ female, 33 age, with BII type Ph‐positive ALL, p190type of transcript without extramedullary involvement; and the third‐ female, 28 age, with TIII type ALL, with TCR A/D rearrangement, with massive mediastinal lesion, bilateral renal and ovarium involvement.PET/CT was applied in 10 patients with Ph‐negative ALL/LBL after the end of consolidation by ALL‐2009/ALL‐2016 protocols. The characterization of patients (Table): 6/4 (60%/40%) M/F, 9/1 (90%/10%) B/T type Ph‐negative ALL, 8/1/1 (80%/10%/10%) with mediastinum/lymph nodes/renal and ovarium involvements, 3/7 (30%/70%) with or without bone marrow involvement, nobody with CNS involvement, 5/5 (50%/50%) with or without autoSCT, 3/7 (30%/70%) with or without radiotherapy in consolidation.Results:The results of PET/CT in three patients with different variants of newly diagnosed ALL/LBL were analyzed and it was shown that all patients had metabolic activity of 18F‐FDG in all morphologically and immunohistochemically (immunophenotypically) confirmed lesions (SUV 3,9‐8,7).An analysis of the results of PET/CT after the consolidation therapy with/without autoSCT in patients with Ph‐negative ALL was performed, and it has shown that all patients had PET‐negative remission of the disease and MRD negative status in bone marrow by flow cytometry. With a median follow‐up of 20.5 months (from 15 to 44 months), only one patient out of 10 patients had isolated CNS relapse after 10 months of remission. In another 9 patients, with a median CR duration of 19 months (from 14 to 43 months), complete clinical and hematological remission is maintained.Summary/Conclusion:The results demonstrated that all specific lesions in ALL/LBL patients, medullary and extramedullary, were capable to accumule 18F‐FDG in PET. This fact provides opportunities for further studies of this method in assessing the completeness of remission in patients with extramedullary lesions. The value of PET/CT in ALL/LBL patients with central nervous system involvement remained unexplored. If the suggestions arising from this report are confirmed, FDG‐PET/CT may be included in future clinical practice for disease staging, evaluating the response to the chemotherapy in identified lesions and in the restaging for recurrence of extramedullary disease.image

Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab (DARA) in patients (pts) with transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): A multicenter, randomized, phase III study (PERSEUS).

TPS8055 Background: DARA, a human, CD38-targeting, IgGκ monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory MM (RRMM), and in combination with standard-of-care regimens in RRMM and transplant-ineligible NDMM. Given the initial safety and efficacy observed with DARA plus VRd (D-VRd) in the safety run-in cohort of the ongoing phase 2 GRIFFIN study in TE NDMM pts, the phase 3 PERSEUS study will evaluate the efficacy and safety of D-VRd versus VRd alone in TE NDMM. Methods: This is an ongoing multicenter, open-label, randomized phase 3 study of D-VRd versus VRd alone in TE NDMM pts. Approximately 690 pts across Europe will be stratified by ISS stage and cytogenetic risk (high risk defined as presence of del17p, t[4;14], or t[14;16]) and randomized in a 1:1 ratio. All pts will receive VRd (V: 1.3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-21; d: 40 mg PO Days 1-4, 9-12) for 4 pre-transplant induction and 2 post-transplant consolidation cycles (all 28-d cycles), followed by R (10 mg PO Days 1-28) maintenance until progressive disease (PD). Pts in the DARA group will also receive subcutaneous DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W in maintenance Cycles 7+ until PD. After induction, pts will undergo melphalan 200 mg/m2 conditioning and autologous stem cell transplantation (ASCT). Pts in the DARA group who achieve sustained minimal residual disease (MRD) negativity (10–5 threshold; assessed by NGS) for 12 months after ≥24 months of maintenance will stop DARA but continue R maintenance until PD; upon loss of CR or MRD-negative status, pts will restart DARA treatment. All pts will receive preinfusion medications. The primary endpoint is progression-free survival (PFS). Secondary endpoints include MRD-negative rate, overall response rate, PFS on next line of therapy, overall survival, time to and duration of response, health-related quality of life, pharmacokinetics, immunogenicity, stem cell yield after mobilization, time to engraftment post-ASCT, and safety. Clinical trial information: NCT03710603.

Correlation of minimal residual disease negativity (MRD-) with prognosis in high-risk myeloma (HRM).

8024 Background: MRD is a standard measurement for response assessment in MM. Despite new treatments, HRM patients continue to have poor prognosis. We evaluated the impact of MRD- in high vs standard (SRM) risk patients. Methods: We retrospectively evaluated all consecutive MM/plasma cell leukemia patients who had routine MRD testing by 1-tube 8-color advanced flow cytometry with 2,000,000 events and sensitivity level 10-5 at our center from 2015-2018 after initial therapy. Kaplan-Meier and log-rank test were used to assess survival estimates and differences between study groups. Results: 136 patients with MRD testing after initial therapy/autologous transplant (ASCT) were identified. Patient and disease characteristics are included in Table. At a median follow-up of 14 months (1-36), PFS and OS were significantly worse in HRM vs SRM. During the study period, 50% of HRM had progressed (relapse and/or death) vs 20% in SRM (p=0.0006). No patients with SRM died, but 4 (14%) in the HRM group did (p=0.0007). Regardless of MRD status, HRM patients had statistically significant worse PFS than SRM; at median f/u 10% SRM MRD-; 20% SRM MRD+; 40%HRM MRD-; 45% HRM MRD+ had either relapsed or died (p=0.0041). MRD status did not impact OS in either group (p=0.0914), however longer follow up is needed to assess survival. Conclusions: Genetic abnormalities (FISH/GEP) remain a powerful prognostic indicator for myeloma regardless of MRD status. For newly diagnosed myeloma patients treated with novel triple initial therapy and frontline ASCT, achieving MRD negative status didn’t mitigate the poor prognosis outcomes of HRM. [Table: see text]

Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma

BackgroundPreclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma.MethodsIn this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×106, 150×106, 450×106, or 800×106 CAR-positive (CAR+) T cells in the dose-escalation phase and 150×106 to 450×106 CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety.ResultsResults for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10−4 nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion.ConclusionsWe report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number, NCT02658929.)

Expectations and Experience: Optimising Efficacy and Maintaining Quality of Life in Follicular Lymphoma

Prof Salles provided an update on the ongoing first-line follicular lymphoma (FL) studies, demonstrating how analysis of the GALLIUM study data regarding the use of different chemotherapy backbones consistently showed the benefits of obinutuzumab (G) chemotherapy (G-chemo) versus rituximab (R) chemotherapy (R-chemo) in FL patients. An update from the PRIMA study showed that 10-year progression-free survival (PFS) was improved following the use of R maintenance compared with observation following induction. Prof Salles also provided an overview of the RELEVANCE study data, which showed that R plus lenalidomide was not superior to standard R-chemo for the treatment of first-line FL. Prof Seymour presented data showing that two-thirds of premature FL deaths occur in patients experiencing disease progression within 2 years of treatment, highlighting the need to identify patients at early risk of progression. Prof Seymour explored various prognostic and predictive tools that could be used to identify patients at high risk of death, but he noted that until these prognostic tools are available in the clinic, the high-risk population remains unidentifiable. Furthermore, the accuracy of these prognostic indices needs to be improved. Data analysis from the GALLIUM study showed that G-chemo decreased the risk of a disease progression event in the first 2 years by 46% compared to R-chemo. Prof Trotman explored the use of PET imaging and detection of minimal residual disease (MRD) to assess treatment outcomes. Prof Trotman showed that PET status at the end of induction is highly prognostic of the outcome. An exploratory analysis of the GALLIUM data showed that the application of the Lugano 2014 response criteria showed a rapid, deep separation of the PFS curves of patients achieving a complete metabolic response (CMR) versus those who did not. There was almost a 5-fold increase in risk of progression and in risk of death in patients failing to achieve CMR. An exploratory analysis of the MRD status of GALLIUM patients showed that a greater proportion of patients in the G-chemo arm achieved MRD-negative status at the end of induction (EOI). Interestingly, patients achieved similar MRD outcomes with G-chemo, regardless of chemotherapy backbone. Both PET and MRD status after induction were independently predictive of PFS. Dr Pettengell and Mr Bouguet discussed FL from both the clinician’s and the patient’s perspective, with a focus on health-related quality of life (HRQoL). They demonstrated how a marked decrease in HRQoL at progression highlights the importance of extending remission for FL patients. Dr Pettengell presented data from GALLIUM showing comparable quality of life for patients treated with either G-chemo or R-chemo. They also presented patient surveys showing that FL has a substantial physical and psychological impact on patients that both lasts beyond treatment and persists even during long-term remission.

The prognostic significance of minimal residual disease detection after first induction treatment in adult acute lymphoblastic leukemia patients treated with autologous stem cell transplantation

目的探讨成人急性淋巴细胞白血病（ALL）患者首疗程诱导治疗结束时微小残留病（MRD1）检测对自体造血干细胞移植（auto-HSCT）预后的意义。方法回顾性分析2006年2月1日至2017年4月30日行auto-HSCT的87例有流式细胞术MRD1检测结果的ALL患者临床资料，分析MRD1与ALL患者auto-HSCT后复发、生存的关系。结果26例（29.9%）ALL患者MRD1阳性。高危免疫表型比例在MRD1阳性组显著高于MRD1阴性组（34.6%对14.5%，P=0.038），初诊时年龄、性别、谱系（T/B）、免疫表型（标危/高危）、高白细胞计数（B-ALL>30×109/L或T-ALL>100×109/L）比例、伴高危染色体/基因比例、第1次完全缓解到移植的时间、预处理方案在MRD1阴性组和阳性组中差异均无统计学意义（P值均>0.05）。MRD1阴性患者、MRD1阳性患者的5年无白血病生存（LFS）率分别为75.7%、29.6%（P<0.001），总生存（OS）率分别为72.7%、47.3%（P=0.004）。多因素分析结果显示MRD1阳性是影响患者OS的独立危险因素（HR=3.007，95% CI 1.256~7.200，P=0.013），MRD1阳性和高危免疫表型是影响患者LFS的危险因素（HR=3.986，95% CI 1.813~8.764，P=0.001；HR=2.981，95% CI 1.373~6.473，P=0.006）。结论auto-HSCT不能逆转MRD1阳性患者的不良预后。MRD1阴性且在强化治疗中持续保持阴性患者可选择auto-HSCT治疗。

Efficacy of Maintenance Therapy Following Auto-HSCT Depending on MRD Status in Patients with Multiple Myeloma

Background: The results of international randomized clinical trials emphasize the expediency of maintenance therapy following auto-HSCT. However, these studies did not assess such important issues as the need for maintenance therapy in patients who have achieved complete remission (CR) or stringent CR following auto-HSCT. Probably, the results of studying MRD following auto-HSCT will allow receiving a substantiated answer to this question.Aims: To evaluate the efficacy of maintenance therapy following auto-HSCT depending on MRD in patients with multiple myeloma.Patients and methods: Over the period from January 2012 to April 2018, 70 MM patients (24 males and 46 females) aged 32 to 65 years (median=56) were enrolled into a prospective study. The disease stage according to the International Staging System (ISS) was I, II and III in 28, 19 and 23 patients, respectively. All patients received induction therapy with bortezomib; immunomodulatory drugs were used in 10 cases. After the induction therapy, a single and tandem auto-HSCT were performed in 57 and 13 patients, respectively. On Day 100 following auto-HSCT, bone marrow examination was carried out in order to determine MRD using six-color flow cytometry with a panel of antigens: CD38, CD138, CD45, CD56, CD117, CD19. MRD-negative status was diagnosed in case of detection of <20 clonal plasma cells among 2,000,000 white blood cells (<0.001%; detection limit 10-5). On Day 100 after the auto-HSCT, all patients achieved CR of the disease and were randomized to receive maintenance therapy with lenalidomide 15 mg/day from Day 1 to Day 21 of a 28-day course within a year or no such therapy. The follow-up period since the moment of MRD determination was 2-28 months (median 15). Survival curves were constructed using the Kaplan-Meier method. Statistical analysis was done using Statistica 10.Results: 37 patients were randomized to receive maintenance therapy with lenalidomide following auto-HSCT, including 23 patients in whom plasma cell immunophenotyping showed the lack of MRD and 14 patients in whom MRD-positive status was confirmed. Thirty-three patients were followed-up without further treatment after the auto-HSCT, including 24 cases with MRD-negative status and 9 cases with the presence of abnormal plasma cells in the bone marrow. The compared groups were comparable in respect of such parameters as age and the ISS stage.The differences between two-year PFS rates in MM patients with MRD-negative status following auto-HSCT who received (n=23) or didn't receive (n=24) the maintenance therapy, showed no statistical significance (p=0.3) and were 88% and 74%, respectively (Fig.1a). In patients with MRD-positive status following auto-HSCT who received lenalidomide, two-year PFS rate was significantly (p<0.05) higher and was 92% versus 45% in the group of patients who didn't receive the maintenance therapy (Fig.1b).Conclusion: Achievement of MRD-negative status following auto-HSCT was accompanied by high values of PFS regardless of the use or not use the maintenance therapy with lenalidomide (88% versus 74%, p=0.3). Prescription of the maintenance therapy to patients with MRD-positive status following auto-HSCT improves the PFS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.