Role Of Minimal Residual Disease Research Articles

Minimal Residual Disease-Adapted Therapy in Multiple Myeloma: Current Evidence and Opinions.

Multiple myeloma (MM) is a biologically heterogeneous malignancy with relatively uniform treatment paradigms. This review aims to assess the growing role of Minimal Residual Disease (MRD) assessment in facilitating response-adapted therapeutic decision making to individualize therapy in MM. MRD has been repeatedly demonstrated to provide strong prognostic information, superseding traditional IMWG response criteria. The use of MRD to modulate therapy remains controversial. Here, we review the existing landscape of MRD-adapted trial designs in both induction/consolidation and maintenance settings, including recent data from influential studies and retrospective analyses. We navigate existing data, leverage the increased resolution of longitudinal MRD assessments, and comment on trials in progress to explain our current utilization of MRD in the clinic. MRD transcends traditional response assessments by providing a window into disease-treatment interaction over time. As a strong patient-level surrogate, MRD has limited current use in individualizing treatment, but is poised to comprehensively shape treatment strategies at many key points in a patient's MM course.

Using Next Generation Sequencing to Identify Trackable Clonotypic Sequences for Minimal Residual Disease Testing in AL Amyloidosis

Introduction: Recent studies have shown that deeper free light chain responses are associated with improved outcomes in patients with systemic light chain (AL) amyloidosis, yet the optimal long-term goal remains unclear.(N Engl J Med 2018; 378:518-528) Unlike multiple myeloma, where the role of minimal residual disease (MRD) testing is well established, in AL amyloidosis the methods to best identify MRD, and whether achieving MRD would benefit disease outcomes, warrant further investigation. (Blood Cancer J. 2021 Jun 21;11(6):117; PLoS ONE 15(7): e0235713. https://doi.org/10.1371/journal.pone. 0235713) In AL amyloidosis, the toxic misfolded oligomers and amyloid deposits are both due to clonal immunoglobulin light chains and cause organ damage and death. Hence, the tracking of clonotypic light chain sequences could present a promising approach for detecting the maintenance of profound therapeutic responses. Our study aimed to assess the frequency with which next generation sequencing (NGS) detects light-chain clones consistent with the patient's clonal light-chain isotype and to determine whether the light-chain sequences identified were encoded by light-chain variable region genes considered AL-related.(Journal of Clinical Oncology 2019 37:15_suppl, 8010; Blood (2017) 129 (3): 299-306; PLoS One 2022 Feb 25;17(2):e0264407) Methods: Ninety patients diagnosed with AL amyloidosis between September 2016 and July 2023 at Tufts Medical Center and University of California San Francisco were included. Bone marrow samples from the 90 patients were sent to Adaptive Biotechnologies Inc. (Seattle, WA) for initial clone identification using the clonoSEQ Assay. IMGT/BlastSearch database (Version 1.2.1) was used to identify the clonotypic immunoglobulin light chain variable domains detected by the clonoSEQ assay. Samples were then divided in to two groups based on the consistency of paraprotein isotype with the trackable sequences, and Mann-Whitney U test was used to compare the difference of the numbers of clonotypic sequences. Results: Of the 90 patients with bone marrow samples sent for clone identification, 85 (94.4%) had at least one trackable clonotypic sequence, with a median number of 3 and a maximum of 11. Of the 85 patients with trackable sequences, 67 (78.8%) had an AL paraprotein isotype consistent with the detected clonotypic sequence isotype, 48 with light chain and 19 with heavy chain isotypes. Compared to the inconsistent ones, patients who had consistency in paraprotein and trackable sequences exhibited higher numbers of clonotypic sequences ( P = 0.001). With respect to marrow plasma cell infiltrations, both consistent and inconsistent groups had a median of 15% marrow plasma cells with no statistically significant difference between them by two-tailed Mann-Whitney. Of note, consistent with the restricted pattern of germline gene use in AL, the 48 patients also used AL-related variable region Ig light chain genes; the variable region light chain genes identified were AL-related and included IGKV1-33 (8 identified sequences), IGKV4-1 (4), IGKV1-16 (3), IGKV1-5 (1), GKV1-13 (1), IGLV6-57 (8), IGLV3-21 (6), IGLV1-44 (5), IGLV3-1 (4), IGLV1-40 (3), IGLV2-14 (3), IGLV1-51 (2). Conclusion: In patients with AL amyloidosis, the ClonoSEQ assay can identify a sequence consistent with the patient's light or heavy chain isotype almost 80% of the time. Of those cases in which a clonal light chain sequence was consistent with the patient's isotype, the genes identified were from the well described AL-related light chain variable region gene repertoire. These findings indicate that the size of the AL clone does not affect this outcome and suggest that other factors related to the adaptive immune dysregulation of AL or to the multiplex PCR process may be involved. ClonoSEQ can identify trackable clonotypic light chain sequences that are AL-related 56% of the time in patients with AL, a finding that may be relevant to patients with myeloma.

The role of minimal residual disease in therapy of pediatric acute lymphoblastic leukemia: a prospective cohort study

Background. During last 50 years there was a significant progress in understanding the nature of pediatric acute lymphoblastic leukemia (ALL). There were developed effective chemoradiotherapy regimens, new methods of diagnosis and emerged evaluation of treatment results. Determination of minimal residual disease (MRD) has become the most important factor in the patients stratification for risk-adapted treatment in the ALL IC-BFM 2009.
 Aim. To evaluate the survival rates of children with ALL according to the ALL IC-BFM 2009 protocol.
 Materials and methods. There were 136 people in the study of evaluating the effectiveness of therapy according to the ALL IC-BFM 2009 protocol: 69 boys and 67 girls (ratio 1.03:1). The median age is 4 years and 10 months. The observation period is from 26.01.2010 to 06.11.2022.
 Results. High survival rates of children with newly diagnosed ALL are achieved: overall survival (OS) is 91.2%, event-free (EFS) 82.4%, relapse-free (RFS) 88.6%. The best results are among patients of the standard risk group: OS, EFS and RFS reach 96.6%. In the intermediate group OS 96.2%, EFS 84.8% and RFS 88.3%. Worse results of survival are in the high risk group: OS 76.9%, EFS 65.4% and RFS 80.7%. Outcome analysis depending on the linear reveals a statistically insignificant difference in survival rates (for B-ALL OS 92.4%, EFS 83.1% and RFS 89.5%, for T-ALL OS 83.3%, EFS 77.8% and RFS 83.3%). It determines the tendency of improving the prognosis of pediatric T-ALL by optimizing the stratification of patients based on the indicators of MRD and the best direction of protocol.
 Conclusion. Results of survival rates of patients with ALL confirm high effectiveness of treatment according to the ALL IC-BFM 2009 protocol. MRD level on day 15 makes it possible to stratify patients and choose the optimal risk-adapted therapy.

Advances in the diagnosis and prognosis of minimal residual lesions of breast cancer.

To review the latest research of minimal residual disease (MRD) in breast cancer as well as some emerging or potential detection methods for MRD in breast cancer. Springer, Wiley, and PubMed databases were searched for the electronic literature with search terms of breast cancer, minimal residual disease, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, etc. RESULTS: Minimal residual disease refers to the occult micrometastasis or minimal residual lesions detected in patients with tumor after radical treatment. An early and dynamic monitoring of breast cancer MRD can contribute to clinical treatment decision-making, improving the diagnosis accuracy and prognosis of breast cancer patients. The updated knowledge regarding MRD in breast cancer diagnosis and prognosis were summarized, followed by the review of several emerging or potential detection technologies for MRD in breast cancer. With the developed new MRD detection technologies referring to CTCs, ctDNA and exosomes, the role of MRD in breast cancer has been growingly verified, which is expected to serve as a new risk stratification factor and prognostic indicator for breast cancer. This paper systematically reviews the research progress, opportunities and challenges in MRD in breast cancer in recent years.

The prognostic significance of hematogones in childhood B-cell acute lymphoblastic leukemia.

Recent studies have demonstrated hematogones (HGs) expansion to be associated with favorable outcomes in hematological diseases, especially in patients with acute myeloid leukemia and patients undergoing hematopoietic stem cell transplantation. Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children. As of now, minimal residual disease (MRD) remains the most compelling independent prognostic factor in childhood ALL. There is need for more prognostic tools for evaluating relapse risk. The goal of this study was to assess the prognostic value of HGs on relapse-free survival (RFS) and overall survival (OS) in childhood ALL. In this prospective cohort study, a total of 122 subjects with definitive diagnosis of precursor B lymphoblastic leukemia were evaluated. Flow cytometric HG detection was performed in bone marrow aspirates after induction and consolidation therapy. The median follow-up period of patients was 35.5±9.4 (SD) months. Patients who had at least 1.0% HGs had a significantly better RFS (p=.023). Moreover, univariate and multivariate analyses confirmed that positive HGs were independently associated with longer RFS (unadjusted model: hazard ratio=0.33, 95% CI=0.12-0.91, p=.031; adjusted model: hazard ratio=0.30, 95% CI=0.11-0.82, p=.020). Along with the role of MRD, our study shows the significance of HGs as an independent prognostic factor. The results indicate the independent prognostic value of HGs on RFS after adjustment for other prognostic factors, and can be beneficial for risk stratification and treatment modifications amongst pediatric B-cell ALL patients.

Adjuvant Immunotherapy in Patients with Early-Stage Non-small Cell Lung Cancer and Future Directions.

While cisplatin-based adjuvant chemotherapy has been the standard of care for the past two decades, the recent introduction of immunotherapy has heralded an important milestone in the adjuvant landscape of early-stage non-small cell lung cancer (NSCLC). The landmark approval of adjuvant atezolizumab based on disease-free survival (DFS) benefit in IMpower010 was swiftly followed by the recent data for use of adjuvant pembrolizumab in PEARLS/KEYNOTE-091, and similar trials involving other immune checkpoint inhibitors are eagerly anticipated. Although both atezolizumab and pembrolizumab demonstrated a significant DFS benefit in the intention-to-treat population, key subgroup analyses have raised questions about the role of predictive biomarkers such as PD-L1 expression and EGFR-mutation status. In this review, we examine the data from the two important trials (IMpower010 and PEARLS/KEYNOTE-091), discuss the controversies surrounding adjuvant immunotherapy including appropriate endpoints, biomarker selection and highlight key considerations in oncogene-driven NSCLC. Finally, we propose future directions including the impact of neoadjuvant therapy on developments in the adjuvant immunotherapy paradigm and role of minimal residual disease (MRD).

The Landscape of Maintenance Therapy Trials Following Autologous Transplant for Multiple Myeloma

BACKGROUND: The current standard for maintenance therapy following autologous stem cell transplant (ASCT) in patients with multiple myeloma (MM) is lenalidomide, an oral treatment with demonstrated overall survival benefit. Other options for MM may incur toxicities or require frequent visits to infusion centers and may thus not be best suited as maintenance. Patients with high-risk cytogenetic features have poorer outcomes than those considered to have standard risk disease, and national guidelines recommend doublet maintenance (with a proteasome inhibitor and lenalidomide in this setting). Currently, the role of minimal residual disease (MRD) in treatment decision making is unknown but MRD status in this setting may dictate treatment discontinuation in the future. We conducted a review of currently enrolling clinical trials to characterize therapeutic agents/strategies being used or evaluated in a maintenance setting, outcomes evaluated, the inclusion of high-risk patients, and the use of MRD response in guiding management decisions. METHODS: A comprehensive search was performed on the clinicaltrials.gov, clinicaltrialsregister.eu, and anzctr.org.au databases on March 2, 2022, using the keywords "newly diagnosed multiple myeloma", "transplant eligible multiple myeloma", and "maintenance in multiple myeloma". Only studies that were currently recruiting patients, or those listed as active but not yet recruiting were included. Studies that completed enrollment, were terminated, or had been presented or published were not included. Studies were included if patients were planned to undergo autologous stem cell transplant after induction therapy followed by maintenance strategy. If at least one arm received post-transplant maintenance therapy, and the maintenance therapy was specified in the trial description, it was included. Trials evaluating maintenance therapy after a salvage transplant or maintenance therapy in non-transplant settings were excluded. RESULTS: A total of 20 studies were analyzed. Table 1 highlights characteristics. Of the 20 studies, 11 (55.0%) were randomized and 9 (45.0%) were non-randomized. Six studies (30.0%) evaluated PFS as a primary outcome, and 2 studies (10.0%) included OS as a primary outcome. Four of the 20 (20.0%) studies included multiple primary endpoints in addition to time to event outcome, while 4 (20.0%) had a time to event outcome as the sole primary outcome being investigated. Of the 11 randomized studies, 2 studies evaluated OS (18.1%) and 5 evaluated PFS (45.5%) as primary endpoint. MRD negativity was included as a primary endpoint in 11 studies (55.0%) and a secondary endpoint in seven (35%). Of the 9 nonrandomized studies, 4 had a primary endpoint of MRD negativity rate (44.4%), 2 (22.2%) had response-based primary outcomes, and one (11.1%) had a time to event primary outcome. Of the total trials, two (10.0%) assessed or mandated discontinuation of maintenance therapy for those achieving MRD negativity. Table 2 describes maintenance regimens utilized. A total of 4 randomized studies assessed comparison of lenalidomide and another agent to lenalidomide alone with a primary endpoint powered for PFS/OS. Only one study limited enrollment to standard risk disease. No studies enrolled only "high-risk" disease. Amongst a total of 19 trials enrolling patients with high-risk disease, eight trials (42.1%) were offering or permitting patients with high-risk disease to receive single agent lenalidomide. CONCLUSION: Our study analyzing the landscape of current maintenance trials demonstrates that there are many promising clinical trial designs that adapt treatment based on the depth of responses and incorporate newer agents with enough statistical power to demonstrate OS advantage. However, there remains room for improvement, as evidenced by trials evaluating drugs with marked toxicity profiles in non-randomized single arm settings, patients with high-risk disease being permitted to receive treatment that may be inferior to what current guidelines recommend, and a lack of patient centered endpoints (such as OS or quality of life) being evaluated as primary endpoints. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MM-474 Minimal Residual Disease Perception and Utilization in Real-World Multiple Myeloma Treatment

Minimal residual disease (MRD) platforms carry prognostic and predictive value in hematologic malignancies. Yet, their role and adoption in the real world remains limited. Evaluate trends in self-reported perceptions and utilization of MRD in routine clinical care of multiple myeloma (MM) patients. U.S.-licensed oncologists and hematologists convened at a live meeting in January 2020 (cohort A) and April 2022 (cohort B) to review clinical updates presented at the 2019 and 2022 ASH annual meetings, respectively. Participant characteristics and demographics were collected via an online survey ahead of the meeting. During the meeting, participants responded to queries about their perceptions and use of MRD assessment in MM. In addition, both cohorts A and B were shown updated data on the role of MRD in routine MM care and were polled about MRD afterwards. Data were summarized using descriptive statistics. Cohort A and B were comprised of 58 and 51 participants, respectively; 60.3% and 60.8% identified their primary specialty as hematology/oncology; 60.4% and 84.3% practiced in a community-based setting. Myeloma was one of the top three hematologic malignancies treated by both cohorts. MRD status was not assessed in patients by 53.8% of cohort A (n=52) compared to 54.0% of participants in cohort B. Lack of evidence was a reported barrier in both cohorts (64.0% and 29.5% in cohorts A and B, respectively); additional lack of necessary guidelines for MRD utilization was a noted barrier in cohort B (30.8%). After reviewing new clinical data on MRD assessment in MM, 71.2% of cohort A participants requested more data and 78.0% of cohort requested guidelines to compel them to use or increase their use of MRD in MM. Over the past two years, community provider perception and utilization of MRD has not changed significantly, although providers demonstrated receptiveness to utilizing MRD if provided with adequate guidelines. It should be noted that current NCCN Guidelines and the International Myeloma Working Group guidelines provide guidance on the role of MRD during response assessment and surveillance periods. These findings suggest that further education on the role of MRD in routine care is needed.

Evaluation of MRD-status in post-induction period in pediatric patients with acute lymphoblastic leukemia.

The need to study the significance of minimal residual disease (MRD) at the induction therapy in patients with acute lymphoblastic leukemia (ALL) is beyond doubt. This has been confirmed by many years of work by many research groups. The role of MRD in the late stages of treatment and the impact of these values on patients survival requires research and discussion. To evaluate the influence of MRD-status in post-induction period on survival in patients with acute lymphoblastic leukemia. From 2010 to 2022, 135 patients with primary B-ALL enrolled in ALL-IC BFM 2009 protocol. Median age was 5.4 year (range 1-17). Male was 62 (49,5%) and female 73 (54,1%). The diagnosis was based on WHO 2016 criteria. Stratification on prognostic risk groups was carried out according to protocol criteria. Prednisone response evaluated at day 8 of treatment. The 15th, 33th, and 78th (as post-induction) day response was assessed by bone marrow cytology and level of MRD by flow cytometry. 5y-overall survival (OS) for patients with MRD-negative status on day 15 was 94,4±5,4% and 87,0±3,4% for MRD-positive (p=0,5). On day 33 patients with MRD-negative status achieved 5y-OS in 86,7±5,8% and 89,6±3,5% for MRD-positive (p=0,6).5y-OS for patients with MRD-negative status on day 78 was 90.8±4.0%, MRD-positive - 90,4+6.5%. DFS for MRD-negative status was 88.5±4.5%, for MRD-positive - 66.3±11.8% (p=0,1). EFS for MRD-negative patients was 87.2±4,6% and for MRD-positive 66.3±11.8% (p=0,09). We have found a tendency between MRD status on day 78 and the frequency of relapses in patients. At the moment, there are no reliable data on the effect of post-induction MRD status on survival. The assessment of MRD in the post-induction period has prognostic prospects and requires further study.

Abstract PD9-02: Peripheral immune subsets and circulating tumor DNA (ctDNA) in patients (pts) with residual triple negative breast cancer (TNBC) treated with adjuvant immunotherapy and/or chemotherapy (chemo): The OXEL study

Abstract Background: Poor clinical outcomes are noted in pts with TNBC who do not achieve a pathologic complete response (pCR). We characterized peripheral immune subsets and the role of minimal residual disease (MRD) detection via ctDNA in pts who participated in the OXEL study. Methods: OXEL (Opdivo® -XELoda ®) is a recently completed phase II open-label 3-arm randomized study of nivolumab (nivo), capecitabine (cape) or the combination as adjuvant therapy (tx) for pts with residual TNBC after appropriate neoadjuvant chemo. Residual disease was defined as ≥ 1.0 cm of primary tumor and/or nodal involvement. Eligible pts had completed definitive local tx. Pts were randomly assigned to nivo 360 mg iv q3wks x 6 (arm A); cape 1250mg/m2 po bid D1-D14 q3 wks x 6 (arm B); nivo 360mg iv q3wks + cape 1250mg/m2 po bid D1-D14 q3 wks x 6 (arm C). Peripheral blood mononuclear cells (PBMCs) and ctDNA were assessed at baseline (D1 of cycle 1), 6, and 12 wks and at time of recurrence, if applicable. PBMCs were stained with 30 markers and analyzed by flow cytometry to identify changes in 158 immune cell subsets at 6 wks, as a percent of total PBMCs. RaDaRTM, a deep sequencing based, tumor-informed personalized assay was utilized to detect the presence of ctDNA in plasma. Distant disease-free survival (DDFS) and overall survival (OS) were analyzed by the Kaplan-Meier method and Log-Rank test was used to compare DDFS and OS according to baseline MRD results. All pts will be followed for distant recurrence and survival for 3 yrs. Here we report the translational endpoints of the OXEL study. Clinical endpoints according to treatment received will be reported in a future analysis. Results: 45 pts were enrolled between 8/2018 and 6/2021. 29 (64%) were Caucasian and 14 (31%) were African American. Mean age at enrollment was 51 [+/- 12]. 93% of pts received a taxane-anthracycline containing neoadjuvant tx. 15 pts were randomized to each arm. DDFS probability at 1-yr and 2-yrs was 0.71 (+/- 0.07) and 0.66 (+/- 0.08) respectively. At 12 mos of median follow up, 13/45 pts (29%) experienced distant recurrence, none had local recurrence. 43 pts were evaluated for PBMC subsets. Changes in PBMC subsets at 6 wks were different amongst the arms; in arm A, reductions in NK subsets, including a 33% reduction in CD56dimCD16- cells, were observed, while in arm B, increases in naïve CD4+ T cells (+45%) and CD73+CD8+ T cells (+12%) and reductions in ki67+CD8+ T cells (-48%) were noted. In arm C, increases were observed in conventional dendritic cells (+36%), effector memory ki67+CD4+ T cells (+46%), and CD56dimCD16- NK cells (+29%). 33 pts underwent successful MRD analysis. 12/33 (36%) pts were MRD+ at baseline. 2/12 pts MRD+ at baseline subsequently cleared MRD, with undetectable ctDNA on future time points; neither patient has had recurrence to date. The remaining 10/12 MRD+ pts (83%) have experienced distance recurrence. 21/33 (64%) pts were ctDNA negative at baseline; 20/33 remained negative for all follow up timepoints. 10/11 pts experiencing distant recurrence were MRD+ at baseline, compared to 1/11 pt who became MRD+ at wk 6 post initiation of tx. At 12 mos of median follow-up, baseline MRD+ testing was significantly associated with an inferior DDFS ( p<0.0001 Log-rank test, median DDFS 4.0 mos vs. not reached) and OS (p=0.02 Log-rank test, median OS not reached for both groups). Results will be updated at the time of abstract presentation. Conclusions: Changes in PBMC subsets were associated with receipt of chemo and/or immunotherapy. Our results suggest that baseline MRD+ in pts without pCR is a poor prognostic factor. Future trials aiming to optimize adjuvant treatment with chemo and/or immunotherapy in residual TNBC should consider incorporating ctDNA as a selection marker of pts at higher risk of recurrence. Citation Format: Filipa Lynce, Candace Mainor, Xue Geng, Greg Jones, Ilana Schlam, Hongkun Wang, Ute Feger, Renee Donahue, Nicole Toney, Caroline Jochems, Jeffrey Schlom, Christopher Gallagher, Rita Nanda, Deena Graham, Erica M Stringer-Reasor, Neelima Denduluri, Julie Collins, Asma A Dilawari, Ami Chitalia, Shruti Tiwari, Raquel Nunes, Rebecca Kaltman, Katia Khoury, Margaret Gatti-Mays, Sandra M Swain, Heather A. Parsons, Paula Pohlmann, Claudine Isaacs. Peripheral immune subsets and circulating tumor DNA (ctDNA) in patients (pts) with residual triple negative breast cancer (TNBC) treated with adjuvant immunotherapy and/or chemotherapy (chemo): The OXEL study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-02.

Positron emission tomography/computed tomography (PET/CT) in multiple myeloma

Imaging plays apivotal role in the management of multiple myeloma (MM). Besides morphological imaging methods, such as whole-body X‑ray, computed tomography (CT) and magnetic resonance imaging (MRI), the hybrid modality positron emission tomography/CT (PET/CT) using the glucose analogue 18F‑fluorodeoxyglucose (18F‑FDG) as radiotracer is increasingly used. Aim of this review article is to outline the major applications of PET/CT in the diagnosis and management of MM, and to provide hints on the reading and interpretation. Background knowledge and guideline recommendations on imaging of MM are outlined and complemented by recent study results. Although 18F‑FDG PET/CT is not currently considered astandard method for the diagnosis of MM, it is avery powerful diagnostic tool for the detection of medullary and extramedullary disease, areliable predictor of survival and the most robust modality for treatment response evaluation. Moreover, it plays a significant role in minimal residual disease (MRD) assessment. On the other hand, practical considerations on local availability and costs limit the widespread use of PET/CT. In addition, false-negative and the seldom false-positive results and the heterogeneity of MM presentation inevitably make interpretation of PET/CT images challenging. PET/CT has ahigh value in the diagnosis, prognosis, and assessment of treatment response in patients with MM. Therefore, the role of the modality in the management of the disease is expected to increase in the near future.

Differences and Similarities in Treatment Paradigms and Goals between AL Amyloidosis and Multiple Myeloma

Although there are similarities in the treatment paradigms between AL amyloidosis and multiple myeloma, there are also fundamental differences. A similarity is of course the use of anti-plasma cell drugs in both diseases; however, the most serious mistake a hemato-oncologist can make is to use the same treatment schedule in dosing and frequency in AL amyloidosis patients as in multiple myeloma patients. AL amyloidosis patients with >10% bone marrow plasma cell infiltration in particular are at risk of receiving a more intensive treatment than they can tolerate. This difference in dosing and frequency is true for many anti-clonal drugs, but it is most apparent in the use of high-dose melphalan and autologous stem cell transplantation. While in multiple myeloma in the age group of ≤70 years, more than 80% of patients are fit enough to receive this intensive treatment, this is the case in less than 20% of AL amyloidosis patients. A similarity is the alignment in the goal of treatment. Although in AL amyloidosis has long been recognized that the goal should be complete hematological remission, this has become more apparent in multiple myeloma in recent years. A common goal in the coming years will be to evaluate the role of minimal residual disease to improve survival in both diseases.

Longitudinal MRD Assessment in Real-World Multiple Myeloma Patients Using Next-Generation Sequencing (clonoSEQ® Assay)

IntroductionAchieving minimal residual disease (MRD) negativity in multiple myeloma (MM) is positively correlated with prolonged PFS and OS (Landgren 2016, Munshi 2017), and longitudinal assessment of MRD can provide additional prognostication (Diamond 2021). This is substantiated by the inclusion of sustained MRD negativity (defined as two consecutive MRD negative results ≥12 months apart at 10 -5 threshold) within IMWG and NCCN guidelines as part of the response criteria for symptomatic MM. MRD has also recently been adopted as a potential primary endpoint in clinical trials, and there is increasing focus on the role of MRD in guiding treatment decisions, including discontinuation of therapy (Lahuerta 2021). Standardized, sensitive, and serial MRD assessment is useful to support both routine patient management consistent with guidelines, and clinical studies which incorporate MRD as a primary endpoint.NGS MRD (clonoSEQ Assay, Adaptive Biotechnologies, Seattle, WA) is currently the only FDA authorized test available for MRD assessment in patients with MM using bone marrow. The assay's standardization, sensitivity, and wide availability facilitates real-world evidence (RWE) analyses looking at MRD trends in MM patient cohorts over time. The aim of this abstract is to provide further insight into longitudinal MRD testing patterns and attainment of sustained MRD negativity in a real-world cohort of patients.MethodsThe study population includes a de-identified internal dataset of MM samples processed as part of Adaptive's clinical offering (excluding trials) to support routine patient management; patients were geographically dispersed and treated at a variety of institutions, and the analysis period was from January 2018 to July 2021. We examined sustained MRD negativity and other longitudinal patterns of MRD testing and negativity at deep MRD thresholds.ResultsIn the analysis period, we identified 1,561 MM patients with at least two MRD tests following a trackable sequence from a baseline clonality (ID) test. Of those patients, 616 had ≥3 tests. The median testing interval for patients with ≥2 MRD tests was 195 days. The median age was 66 and 59% were male, which is generally consistent with epidemiological data.When examining MRD monitoring longitudinally, of the 1,561 patients that had ≥2 MRD tests, 383 (24.5%) and 231 (14.7%) patients had sustained MRD-negativity for at least 12 months at 10 -5 and 10 -6 thresholds, respectively. Of the 616 patients with ≥3 MRD tests, 200 (32.5%) and 102 (16.6%) has remained negative throughout the testing period, 191 (31.0%) and 181 (29.4%) had converted from positive to negative, and 76 (12.3%) and 61 (9.9%) had converted from negative to a positive state at the respective thresholds. The trends within subgroups (only positive, only negative, negative -> positive, and positive -> negative) vary based on a deeper sensitivity threshold.ConclusionsSerial measurement of MRD can facilitate a dynamic assessment of risk for disease progression in patients with MM, and this real-world analysis of MRD clinical samples provides insight into serial testing patterns and sustained MRD-negativity using next-generation sequencing. [Display omitted] DisclosuresJiang: AstraZeneca LLC: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Adaptive Biotechnologies: Current Employment. Lee: Adaptive Biotechnologies: Current Employment. Eckert: Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Demaree: Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hewitt: Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months.

Sustained Residual Disease Negativity Assessed By Diffusion-Weighted Whole-Body MRI (DW-MRI) Has Strong Predictive Relevance for Survival in Newly Diagnosed Multiple Myeloma Patients on Maintenance Therapy after Autologous Stem Cell Transplantation (ASCT)

Sustained Residual Disease Negativity Assessed By Diffusion-Weighted Whole-Body MRI (DW-MRI) Has Strong Predictive Relevance for Survival in Newly Diagnosed Multiple Myeloma Patients on Maintenance Therapy after Autologous Stem Cell Transplantation (ASCT)

Undetectable minimal residual disease is an independent prognostic factor in splenic marginal zone lymphoma.

The role of minimal residual disease (MRD) in splenic marginal zone lymphoma (SMZL) has not been well studied. We prospectively designed a study to evaluate undetectable MRD (uMRD) by multiparameter flow cytometry as a prognostic factor. Residual disease level of <0·01% was defined as uMRD. A total of 71 newly diagnosed patients with bone marrow involvement were enrolled and all received rituximab-based therapy. The overall response rate (ORR) was 98·5% (70/71), with a complete remission (CR) rate of 54·9% (39/71). There were a total of 295 MRD detections in bone marrow and 77·4% patients (55/71) had uMRD. The 5-year progression-free survival (PFS) [(74·8±6·5)% vs. (31·4±12·6)%, P<0·001] and 5-year overall survival (OS) [(87·2±5·6)% vs. (68·9±13·4)%, P=0·035] were significantly higher in uMRD patients than in MRD-positive patients. The 5-year PFS in partial remission (PR) patients with positive MRD was significantly poorer than that of PR patients with uMRD [(21·1±12·9)% vs. (83·3±8·8)%, P=0·005]. Multivariate prognostic analysis revealed that uMRD was an independent good prognostic factor for PFS (hazard ratio 0·162, 95% confidence interval 0·041-0·635; P=0·009). All these results highlight uMRD as an independent prognostic factor in patients with SMZL, especially for patients who only achieve PR.

Persistence of the Minimal Residual Disease at the End of Induction Is Not a Factor of Poor Prognosis If Imatinib Was Changed to the Dasatinib By Ph+ RALL Protocol in Ph-Positive Acute Lymphoblastic Leukemia Patients

Introduction. The role of minimal residual disease (MRD) has been confirmed as a clear prognostic factor by some big studies in Ph-positive acute lymphoblastic leukemia (Ph+ ALL) patients. The persistent MRD positivity may be indicative of the emergence of resistant mutations and TKI therapy should therefore be changed in these patients according to the sensitivity. Ph+ RALL protocol suggests that if a patient does not achieve the major molecular complete remission (MolCR) at day +70, Imatinib should be changed to Dasatinib for subsequent therapy. Could the change of Imatinib to Dasatinib in cases with MRD persistence at the end of induction improve the prognosis of the Ph+ ALL patients? It hasn't been described yet.Aim. To evaluate the role MRD persistence at the end of induction (day +70) in Ph+ ALL patients treated by Ph+ RALL protocol.Patients and treatment. From 2010 January to 2017 July, 36 new Ph+ ALL cases were diagnosed in 3 centers of the RALL-group (median age 35 years (17-68), m/f 19(53%)/17(47%), CNS disease=1, WBC> 30*109/l= 16(44%), bcr/abl transcript p190/p210/p190+210 21(59%)/8(22%)/7(19%)). All patients were treated according to RALL protocol with parallel administration of Imatinib. This protocol is based mainly on 600 mg Imatinib with prednisolone, VNCR, L-asp, followed by 6-MP and MTX. Imatinib had to be substituted by Dasatinib (140 mg) after non-achievement of MolCR on day 70 of treatment. MolCR was stated if bcr/abl chimeric transcript was <0,01% by PCR with 10-4 sensitivity. All patients were considered as candidates for allogeneic HSCT if HLA-identical donor was available. 16 pts (44%) underwent HSCT in the first-line therapy: 2 (12,5%) autologous, 4 (25%) matched related and 10 (62,5%) matched unrelated.Results. Hematological complete remission (CR) was achieved in 32 (89%) of 36 pts (except two early deaths and 2 refractory cases). On day 70 MolCR was achieved in 18 (56%) of 32 pts. Death on therapy (within 3 months of induction/consolidation) was registered in 4 (11%) cases, in 2 patients of them after day 70th of the protocol in CR. The major issue is the non-relapsed mortality after unrelated allo-HSCT (n=3, aGVHD and severe infections, at a median +4 months after HSCT).The 5-y overall survival (OS) and disease-free survival (DFS) for all 36 pts was 56% and 47%, respectively.The 5-y OS was 65% vs 51% (p=0,35), and DFS was 49 vs 48% (p=0,9) in MRD-negative and MRD-positive patients on day 70th of the protocol (Picture). In a univariate analysis for Ph+ ALL patients the fulfilled of HSCT in the first-line therapy became statistically significant for DFS. The 5-y OS was 65% vs 48% (p=0,07), and DFS was 60% vs 32% (p=0,01) in transplanted vs non-transplanted patients by Kaplan-Meier analysis.Conclusions. We didn't revealany difference in efficiency of the therapy in Ph+ RALL protocol according to the MRD status at the day 70. We attribute the absence of the effect of MRD status after induction on the results of treatment, to the shift to Dasatinib (140 mg) after non-achievement of MolCR on day 70. The performance of HSCT in the first-line therapy reliably improved the efficacy in Ph-positive ALL patients on RALL protocol. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Application of Minimal Residual Disease in Hemato-Oncology: A Review of Its Current Utility in Trials, Regulatory Decisions and Clinical Practice

The concept of minimal residual disease (MRD) has become common across multiple hematological malignancies. However, there is considerable variation in the application of this concept to research activities and clinical practice across different diseases. We sought to investigate the current status of MRD testing in research, its standing with regulators, and its application in clinical practice, and interpreted the differences identified in light of the differentiating characteristics of each disease. Seven malignancies were considered: acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM).The technology used to detect MRD, or its near equivalents of major or deep molecular response (MMR) in CML, is under constant development; current techniques are based on polymerase chain reaction for all indications considered (including next-generation sequencing) or flow cytometry for four indications (ALL, AML, CML, and MM), with a role for imaging also proposed in MM.A review of the published literature (via PubMed) for each of the diseases identified multi-study meta-analyses describing the prognostic significance of MRD in ALL, CML, and MM; evidence of this relationship was based on analysis of individual studies for the other four diseases.In the context of the prognostic significance of MRD status, MMR is well established as an outcome in clinical trials in CML and is emerging as a trial outcome measure in other indications. A review of registered active Phase 2 and 3 clinical trials (via clinicaltrials.gov) found that MRD (or an equivalent such as molecular response) was listed as an outcome measure in 21% of trials in ALL, 17% in CLL, and 12% in MRD; this was more common in Phase 3 trials (15/40, 16/51, and 14/73 trials, respectively). MRD was listed as an outcome measure in 6% of trials in AML, 2% in DLBCL, and 6% in FL. Furthermore, the European Medicines Agency formally accepted MRD as an intermediate endpoint in CLL (effective from 2016), while MMR was recommended as a primary endpoint in CML in 2013; consultation is ongoing regarding acceptance of MRD in MM. The US Food and Drug Administration has led a number of workshops on the use of MRD in four indications (MM, CLL, AML, and ALL).Aside from academic interest and clinical development programs, the use of MRD testing to guide treatment is recommended in US and European clinical guidelines for ALL, CML, and the acute promyelocytic variant of AML, and in US guidelines for CLL; US guidelines for MM recommend assessment of MRD but do not suggest that the result should inform the course of treatment. For other malignancies, prognostic implications and utility in trial settings are acknowledged, but MRD testing is not recommended in practice.The role of MRD in a range of hematological malignancies appears to be evolving rapidly. MMR in CML has been important in trials and in clinical practice for a number of years, but has recently been followed by MRD in CLL, while MRD testing in MM is on the horizon. MRD evaluation is now an integral part of both adult and pediatric treatment protocols. The biological basis of each disease (targets for detection, location of disease), interacting with the available technology, treatments, and treatment intent, may have contributed to different speeds of uptake. Given the growing body of research on detection technologies and its role in other malignancies, we expect MRD testing to become increasingly widespread and its role to shift from prognosis to a key factor in determining treatment pathways. DisclosuresNo relevant conflicts of interest to declare.

Updates in the Management of CLL/SLL: Management of Relapsed/Refractory Disease and the Role of Minimal Residual Disease

In relapsed chronic lymphocytic leukemia (CLL), the choice of therapy depends on the risk profile, prior therapy, and patient comorbidities. The first novel agent for patients who had previously received chemoimmunotherapy is typically a BTK inhibitor or combination venetoclax + rituximab. For patients with problematic comorbidities, however, a PI3K inhibitor can be used, but generally this is reserved for later lines of therapy. For those who stop ibrutinib due to adverse events, there are broad options but data are still limited. For those whose disease progresses on a BTK inhibitor, the only prospective data are for use of venetoclax. For patients who have been treated with venetoclax + rituximab and experience relapse, retreatment is a possibility if they have had a durable remission. Finally, undetectable minimal residual disease is strongly predictive of durability of response for time-limited regimens but not for continuous BTK inhibition, and is generally not indicated for monitoring patients.

Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome.

Myeloid leukemia of Down syndrome (ML-DS) is associated with good response to chemotherapy, resulting in favorable outcomes. However, no universal prognostic factors have been identified to date. To clarify a subgroup with high risk of relapse, the role of minimal residual disease (MRD) was explored in the AML-D11 trial by the Japanese Pediatric Leukemia/Lymphoma Study Group. MRD was prospectively evaluated at after induction therapy and at the end of all chemotherapy, using flow cytometry (FCM-MRD) and GATA1-targeted deep sequencing (GATA1-MRD). A total of 78 patients were eligible and 76 patients were stratified to the standard risk (SR) group by morphology. In SR patients, FCM-MRD and GATA1-MRD after induction were positive in 5/65 and 7/59 patients, respectively. Three-year event-free survival (EFS) and overall survival (OS) rates were 95.0% and 96.7% in the FCM-MRD-negative population, and 60.0% and 80.0% in the positive population. Three-year EFS and OS rates were both 98.1% in the GATA1-MRD-negative population, and 57.1% and 71.4% in the positive population. Adjusted hazard ratios for associations of FCM-MRD with EFS were 14.67 (p = 0.01). Detection of MRD by either FCM or GATA1 after initial induction therapy represents a significant prognostic factor for predicting ML-DS relapse.

Re-Emergence of Minimal Residual Disease Detected by Flow Cytometry Predicts an Adverse Outcome in Pediatric Acute Lymphoblastic Leukemia

PurposeWhile the role of minimal residual disease (MRD) assessment and the significance of achieving an MRD-negative status during treatment have been evaluated in previous studies, there is limited evidence on the significance of MRD re-emergence without morphological relapse in acute lymphoblastic leukemia (ALL). We sought to determine the clinical significance of MRD re-emergence in pediatric ALL patients.MethodsBetween 2005 and 2017, this study recruited 1126 consecutive patients newly diagnosed with ALL. Flow cytometry was performed to monitor MRD occurrence during treatment.ResultsOf 1030 patients with MRD-negative results, 150 (14.6%) showed MRD re-emergence while still on morphological complete remission (CR). Patients with white blood cell counts of ≥50 × 109/L (p = 0.033) and MRD levels of ≥0.1% on day 33 (p = 0.012) tended to experience MRD re-emergence. The median re-emergent MRD level was 0.12% (range, 0.01–10.00%), and the median time to MRD re-emergence was 11 months (range, <1–52 months). Eighty-five (56.6%) patients subsequently developed relapse after a median of 4.1 months from detection of MRD re-emergence. The median re-emergent MRD level was significantly higher in the relapsed cohort than in the cohort with persistent CR (1.05% vs. 0.48%, p = 0.005). Of the 150 patients, 113 continued to receive chemotherapy and 37 underwent transplantation. The transplantation group demonstrated a significantly higher 2-year overall survival (88.7 ± 5.3% vs. 46.3 ± 4.8%, p < 0.001) and cumulative incidence of relapse (23.3 ± 7.4% vs. 64.0 ± 4.6%, p < 0.001) than the chemotherapy group.ConclusionsMRD re-emergence during treatment was associated with an adverse outcome in pediatric ALL patients. Transplantation could result in a significant survival advantage for these patients.