Measurable Residual Disease Negativity Research Articles

Asciminib plus dasatinib and prednisone for Philadelphia chromosome–positive acute leukemia

AbstractDasatinib is an effective treatment for Philadelphia chromosome–positive (Ph+) acute leukemia, but some patients develop resistance. Combination treatment with dasatinib and asciminib, an allosteric inhibitor of BCR::ABL1, may deepen responses and prevent the emergence of dasatinib-resistant clones. In this phase 1 study (NCT03595017), 24 adults with Ph+ acute lymphoblastic leukemia (ALL; ALL, n = 22; p190, n = 16; p210, n = 6) and chronic myeloid leukemia in lymphoid blast crisis (n = 2) were treated with escalating daily doses of asciminib in combination with dasatinib 140 mg daily plus prednisone 60 mg/m2 daily to determine the maximum tolerated dose. After a 28-day induction, dasatinib and asciminib were continued indefinitely or until hematopoietic stem cell transplant. The median age was 64.5 years (range, 33-85; 50% aged ≥65 years). The recommended phase 2 dose of asciminib was 80 mg daily in combination with dasatinib and prednisone. The dose limiting toxicity at 160 mg daily was asymptomatic grade 3 pancreatic enzyme elevation without symptomatic pancreatitis. There were no vaso-occlusive events. Among patients with de novo ALL, the complete hematologic remission rates at days 28 and 84 were 84% and 100%, respectively. At day 84, 100% of patients achieved complete cytogenetic remission, 89% achieved measurable residual disease negativity (<0.01%) by multicolor flow cytometry, and 74% and 26% achieved BCR::ABL1 reverse transcription polymerase chain reaction <0.1% and <0.01%, respectively. Dual BCR::ABL1 inhibition with dasatinib and asciminib is safe with encouraging activity in patients with de novo Ph+ ALL. This trial was registered at www.clinicaltrials.gov as #NCT02081378.

Discontinuation of maintenance therapy in multiple myeloma guided by multimodal measurable residual disease negativity (MRD2STOP)

MRD2STOP is a pragmatic trial evaluating maintenance therapy cessation guided by measurable residual disease (MRD) negativity in multiple myeloma (MM). Eligible patients had previous MRD < 10−5, received ≥1 year of maintenance, and were prospectively confirmed to have undetectable disease by positron emission tomography, bone marrow (BM) flow cytometry (limit of detection [LoD] 10−5), and BM clonoSEQ (LoD 10−6). BM aspirates enriched for CD138+ cells were analyzed by clonoSEQ to achieve MRD 10−7 sensitivity. We evaluated the incidence of disease resurgence and progression-free survival (PFS), stratified by 10−7 status. Forty-seven patients discontinued maintenance after a median of 36 months. Baseline MRD ≥ 10−7 was observed in 19% (9/47). The median follow-up post-discontinuation was 30 months. Disease resurgence (MRD 10 ≥ −6) occurred in 11 patients, including 5 disease progressions. One patient died from a second cancer. The estimated 3-year cumulative incidence of disease resurgence was 20% for patients with baseline MRD < 10−7 compared to 75% for MRD ≥ 10−7 (HR 7.8, 95% CI 2.2-27.6, p = 0.001). Baseline MRD ≥ 10−7 was associated with inferior PFS compared to MRD < 10−7 (HR 10.1, 95% CI 1.6–62.3; 3-year PFS 49% vs 92%). Maintenance discontinuation in patients with MM and MRD < 10−6 led to low rates of disease resurgence. MRD < 10−7 may be a superior cessation threshold, requiring further validation.

A Pilot Study of UM171-Expanded Cord Blood Grafts for Tandem Auto/Allogeneic Hematopoietic Cell Transplant in High and Ultra-High-Risk Myeloma Patients

Multiple myeloma (MM) remains associated with a poor outcome, particularly in patients with advanced disease and high-risk (HR) cytogenetics. To date, the only curative treatment is allogeneic (allo) hematopoietic cell transplantation (HCT), but high incidences of graft versus host disease (GVHD), non-relapse mortality (NRM) and disease progression remain important obstacles. Cord blood (CB) transplantation has been associated with low rates of relapse and chronic (c) GVHD, but its use has declined because of high incidences of infections, severe acute GVHD and high NRM. In other hematologic malignancies, UM171-expanded CB transplants have led to improved outcomes, allowing for the selection of smaller, better HLA-matched units. We aimed to investigate the safety and feasibility of single UM171-expanded single CB unit transplantation in frontline tandem auto/allo HCT for HR/ultra-HR MM patients. Newly diagnosed MM patients ≤ 65 years with an ISS stage II/III and del17p, t4,14, t14,16, t14,20, del1p or +1q, R-ISS 3, ≥ 2 cytogenetic abnormalities, or plasma cell leukemia without a sibling donor and availability of a 5-7/8 matched CB graft with ≥ 0.5 x 105 CD34+/kg and ≥ 1.5 x 107 TNCs/kg were eligible to this phase I/II prospective study (ClinicalTrials.gov NCT03441958). After induction and autologous HCT, patients received a reduced intensity conditioning regimen and were infused with 7-day UM171-expanded CD34+ cells, along with the lymphocytes contained in the CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety, kinetics of engraftment, incidences and maximum grades of acute and cGVHD at 1 and 2 years, assessment of measurable residual disease (MRD) and quality of life (QoL). Between 05/2018 and 11/2021, 20 patients were enrolled. One patient had an unsuccessful CB expansion with UM171, leaving 19 patients with a median age of 56 years. Median CD34+ cell dose infused after expansion was 4.62 x 106/kg (range: 0.79-5.76). Median times to achieve absolute neutrophil counts of 0.1 and 0.5 x 109/L were D+6 and D+10.5; median time to reach ≥ 20 x 109/L platelets was D+36. Full donor chimerism was achieved in all cell lineages by D+120 in recipients of reduced intensity conditioning. Cumulative incidences of grade II-IV, grade III-IV acute GVHD and moderate/severe cGVHD at 12 months were 68.4% (95% CI: 46-90), 5.3% (95% CI: 0-16%), and 10.5% (95% CI: 0-25%), respectively. With a median follow-up of 2.9 years (range: 0.46-5.3), cumulative incidences of relapse, PFS, OS and NRM at 3 years were 36.8% (95% CI: 14-59), 47.4% (95% CI: 29-76), 68.4% (95% CI: 50-93) and 15.8% (95%CI: 0-33), respectively. Median time to complete immunosuppression discontinuation was D+238. No unexpected adverse events were observed. Only one of 7 patients alive at 2 years with negative MRD at transplant has relapsed. Non-relapsing patients had a QoL after transplant similar to the general population. UM171-expanded CB transplant in HR/ultra-HR myeloma patients is feasible and allows the use of single CB units with a low risk of cGVHD. Patients with negative pre-transplant MRD might benefit most from a UM171-expanded CB transplant.

Measurable Residual Disease Testing in Multiple Myeloma Following T-Cell Redirecting Therapies.

Several novel T-cell-based therapies have recently become available for multiple myeloma (MM). These T-cell redirecting therapies (TRTs) include chimeric antigen receptor T-cells (CAR-T) and bispecific antibodies (BiAbs). In both clinical trial and real-world data, these therapies have demonstrated high rates of deep clinical response, and some are now approved for second-line treatment for relapsed MM. The deep and sustained clinical responses these therapies are capable of inducing will require sophisticated response monitoring to provide meaningful information for patient care. Obtaining measurable residual disease (MRD) negativity has been validated as an independent positive prognostic marker for progression-free survival (PFS) and overall survival (OS) in both newly diagnosed and relapsed refractory patients with multiple myeloma. Assessment for MRD negativity was performed in all of the trials for FDA-approved TRT. Here, we summarize pertinent data for MRD assessment following TRT in MM and provide a rationale and structured framework for conducting MRD testing post TRT.

Long-Term Survival and Immune Reconstitution of Donor-Derived Chimeric Antigen Receptor T-Cell Therapy for Childhood Molecular Relapse of B-Cell Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Measurable residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an independent risk factor for relapse in patients with acute lymphoblastic leukemia (ALL). This study aimed to assess the efficacy, safety, and immune reconstitution of chimeric antigen receptor T-cell (CAR-T) therapy in patients with molecular relapse after allo-HSCT. Eleven patients with molecular relapse of B-cell-ALL who underwent CAR-T therapy after allo-HSCT were enrolled. The rate of MRD negativity after a month of CAR-T infusion was 81.8%. Patients who bridged to second-HSCT after CAR-T therapy (n = 3) showed a trend of higher 3-year leukemia-free survival and 3-year overall survival than those who did not (n = 8; 100% vs. 75.0%; 95% CI, 45.0–104.9%; p = 0.370). No treatment-related mortalities were observed. Among patients who did not bridge to second-HSCT and remained in complete remission until the last follow-up (n = 6), five of them had not recovered normal immunoglobulin concentrations with a median follow-up of 43 months. CAR-T therapy may be a safe and effective treatment strategy to improve survival after allo-HSCT; however, the problem of prolonged hypogammaglobulinemia in patients who do not bridge to second-HSCT is worth noting.

Measurable residual disease by mass spectrometry and next-generation flow to assess treatment response in myeloma

AbstractQuantitative immunoprecipitation mass spectrometry (QIP-MS) allows the identification of the M-protein in patients with multiple myeloma (MM) otherwise in complete response, and could be considered suitable for measurable residual disease (MRD) evaluation in peripheral blood. In the context of the GEM2012MENOS65 and GEM2014MAIN trials, we compared the performance of QIP-MS in serum with next-generation flow (NGF) cytometry in bone marrow to assess MRD in paired samples obtained postinduction, transplant, consolidation and after 24 cycles of maintenance. At each time point, both NGF and QIP-MS were able to segregate 2 groups of patients with significantly different progression-free survival; when the evolution of the results obtained with either method was considered, maintaining or converting to MRD negativity was associated with longer survival, significantly better when compared with sustaining or converting to MRD positivity. Reemergence of MRD by QIP-MS was associated with high risk of imminent clinical progression. In conclusion, MRD evaluation by NGF and MS achieves similar prognostic value based in single time point assessments and kinetics. Thus, the minimally invasive nature of MRD monitoring by MS represents a breakthrough in highly sensitive response assessment in MM. The trials were registered at www.clinicaltrials.gov as #NCT01916252 (GEM2012MENOS65) and at EudraCT as #2012-005683-10; and as #NCT02406144 (GEM2014MAIN) and at EudraCT as 2014-00055410.

Are measurable residual disease results after consolidation therapy useful in children with acute lymphoblastic leukemia?

Measurable residual disease (MRD) is regularly tested at later timepoints after the end of first consolidation (EOC) in children with acute lymphoblastic leukemia (ALL). The question remains whether this is useful for detecting (molecular) relapse. We investigated the clinical relevance of MRD after EOC in intermediate risk patients treated on DCOG-ALL-10 (n = 271) and DCOG-ALL-9 (n = 122), with MRD <0.05% at EOC. EOC MRD-negative patients (n = 178) had excellent outcomes, irrespective of MRD results at later timepoints; 6-year cumulative incidence of relapse (6-y CIR) of 7.4% (95% CI, 3.9%–12.3%) for those with MRD negativity at all later timepoints compared to 3.8% (95% CI, 0.3%–16.8%) for those with one or more later timepoints being positive (p = 0.51). Patients with positive EOC MRD (n = 91) of whom the subsequent timepoints were MRD negative (n = 43), had comparable good outcomes, 6-y CIR of 7.0% (95% CI, 1.8%–17.2%). In contrast, patients being MRD positive at EOC and MRD positive at one or more subsequent timepoints (n = 48) had a higher risk of relapse, 6-y CIR 29.4% (95% CI, 17.2%–42.8%), p < 0.001. These findings were confirmed in the validation cohort of ALL-9 as well as using the updated EuroMRD guidelines. In EOC MRD-negative patients, subsequent MRD measurements can be abandoned. For EOC MRD-positive patients the subsequent MRD measurement might be informative for further risk stratification.

Induction prior to autologous haematopoietic cell transplantation in multiple myeloma.

Induction chemotherapy followed by autologous haematopoietic cell transplantation and post-transplant therapy (including maintenance therapy with or without prior consolidation) is still considered as the standard of care for newly diagnosed young and fit multiple myeloma patients. Over the last years, superiority of quadruplet regimens for induction was established, with the addition of an anti-CD38 monoclonal antibody to triplet regimen including a proteasome inhibitor, an IMiD (thalidomide or lenalidomide) or cyclophosphamide, and dexamethasone. Given quadruplet induction regimens are associated with deep response, including a high-rate of sustained measurable residual disease negativity in a significant proportion of patients, they are now recommended for induction chemotherapy when available.

Measurable residual disease (MRD) dynamics in multiple myeloma and the influence of clonal diversity analyzed by artificial intelligence

Minimal residual disease (MRD) assessment is a known surrogate marker for survival in multiple myeloma (MM). Here, we present a single institution’s experience assessing MRD by NGS of Ig genes and the long-term impact of depth of response as well as clonal diversity on the clinical outcome of a large population of MM patients; 482 MM patients at the University of California, San Francisco (UCSF) diagnosed from 2008 to 2020 were analyzed retrospectively. MRD assessment was performed by NGS. PFS curves were plotted by the Kaplan–Meier method. In the newly diagnosed group, 119 of 304, achieved MRD negativity at the level of 10−6 at least once. These patients had a prolonged PFS versus patients who were persistently MRD positive at different levels (p > 0.0001). In the relapsed disease group, 64 of 178 achieved MRD negativity at 10−6, and PFS was prolonged versus patients who remained MRD positive (p = 0.03). Three categories of MRD dynamics were defined by artificial intelligence: (A) patients with ≥3 consistently MRD negative samples, (B) patients with continuously declining but detectable clones, and (C) patients with either increasing or a stable number of clones. Groups A and B had a more prolonged PFS than group C (p < 10−7). Patients who were MRD positive and had not yet relapsed had a higher clonal diversity than those patients who were MRD positive and had relapsed. MRD dynamics can accurately predict disease evolution and drive clinical decision-making. Clonal Diversity could complement MRD assessment in the prediction of outcomes in MM.

Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial

Some challenges still exist with single-target B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies due to variable or negative BCMA expression, although they have yielded remarkable efficacy in relapsed or refractory multiple myeloma. We developed anti-BCMA/GPRC5D bispecific CARs to mitigate the limitations and potentiate the functions of CAR T cells. This single-arm, phase 1 trial was conducted at the Affiliated Hospital of Xuzhou Medical University (Xuzhou, China). The trial enrolled patients aged 18-75 years with relapsed or refractory multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-3. Anti-BCMA/GPRC5D bispecific CAR T cells were administered at 0·5 × 106, 1·0 × 106, 2·0 × 106, and 4·0 × 106 CAR T cells per kg in the dose-escalation phase, with additional patients included at the dose selected for the dose-expansion phase. The primary endpoint was safety, which included dose-limiting toxicity and maximum tolerated dose. Activity was also evaluated as a secondary endpoint. The maximum tolerated dose was chosen for the dose-expansion phase. Safety and activity analyses were done in all patients who received anti-BCMA/GPRC5D bispecific CAR T cells as defined in the protocol. This trial is registered with ClinicalTrials.gov (NCT05509530) and is complete. Between Sept 1, 2022, and Nov 3, 2023, 24 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (two patients discontinued due to rapid disease progression and one patient was withdrawn because of failed manufacture of CAR T cells), so 21 patients were infused with anti-BCMA/GPRC5D bispecific CAR T cells. Median follow-up was 5·8 months (IQR 5·2-6·7). Median age was 62 years (IQR 56-67). Eight (38%) patients were male, and 13 (62%) female. All patients were Chinese. At the 4·0 × 106 CAR T cells per kg dose, two patients had dose-limiting toxicities, of whom one died of subarachnoid haemorrhage (which was not considered to be related to the study treatment). The maximum tolerated dose was identified as 2·0 × 106 CAR T cells per kg. The most common grade 3 or worse adverse events were haematological toxicities in 19 (90%) patients (except lymphopenia). 15 (71%) patients had cytokine release syndrome, of which all cases were grade 1 or 2. One case of grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in a patient who received 4·0 × 106 CAR T cells per kg. No ICANS or grade 3 or worse organ toxicities were observed in patients who received 0·5-2·0 × 106 CAR T cells per kg. The overall response rate was 86% (18 of 21 patients), with 13 (62%) patients having a complete response or better, and 17 (81%) patients having measurable residual disease negativity. Of the 12 patients who received 2·0 × 106 CAR T cells per kg (three in the dose-escalation phase and an addition nine in the dose-expansion phase), the overall response rate was 92% (11 of 12 patients) with nine (75%) patients having a complete response or better. Anti-BCMA/GPRC5D bispecific CAR T cells show a good safety profile and encouraging activity in patients with relapsed or refractory multiple myeloma. National Natural Science Foundation of China. For the Chinese translation of the abstract see Supplementary Materials section.

Results of the Simultaneous Combination of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive ALL.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate by reverse transcriptase-polymerase chain reaction was 83% (67% at the end of course one), and the rate of measurable residual disease negativity by next-generation clono-sequencing was 98% (45% at the end of course one). Only two patients underwent hematopoietic stem cell transplantation (HSCT). Seven patients relapsed: two with systemic disease, four with isolated CNS relapse, and one with extramedullary Ph-negative, CRLF2-positive pre-B ALL. The estimated 3-year overall survival rate was 91% and event-free survival rate was 77%. Three patients discontinued blinatumomab because of adverse events (related, n = 1; unrelated, n = 2) and nine discontinued ponatinib because of cerebrovascular ischemia, coronary artery stenosis, persistent rash, elevated liver function tests with drug-induced fatty liver, atrial thrombus, severe arterial occlusive disease of lower extremities, pleuro-pericardial effusion, and debilitation. In conclusion, the simultaneous combination of ponatinib and blinatumomab is a highly effective and relatively safe nonchemotherapy regimen. This regimen also reduces the need for intensive chemotherapy and HSCT in first remission in the majority of patients.

MRD in Philadelphia Chromosome-Positive ALL: Methodologies and Clinical Implications.

Measurable residual disease (MRD) is integral in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This review discusses the current methods used to evaluate MRD as well as the interpretation, significance, and incorporation of MRD in current practice. New molecular technologies have allowed the detection of MRD to levels as low as 10- 6. The most used techniques to evaluate MRD are multiparametric flow cytometry (MFC), quantitative reverse transcription polymerase chain reaction (RT-qPCR), and high-throughput next-generation sequencing (NGS). Each method varies in terms of advantages, disadvantages, and MRD sensitivity. MRD negativity after induction treatment and after allogeneic hematopoietic cell transplantation (HCT) is an important prognostic marker that has consistently been shown to be associated with improved outcomes. Blinatumomab, a new targeted therapy for Ph + ALL, demonstrates high efficacy in eradicating MRD and improving patient outcomes. In the relapsed/refractory setting, the use of inotuzumab ozogamicin and tisagenlecleucel has shown promise in eradicating MRD. The presence of MRD has become an important predictive measure in Ph + ALL. Current studies evaluate the use of MRD in treatment decisions, especially in expanding therapeutic options for Ph + ALL, including tyrosine kinase inhibitors, targeted antibody therapies, chimeric antigen receptor cell therapy, and HCT.

Discontinuation of maintenance therapy in multiple myeloma guided by multimodal measurable residual disease negativity (MRD2STOP).

106 Background: Measurable residual disease (MRD) negativity is a potential marker for the absence of disease in multiple myeloma (MM), which could be used to guide treatment cessation. MRD2STOP (NCT04108624) is a prospective study investigating outcomes among patients with sustained multimodal MRD negativity who discontinue maintenance therapy. Methods: Discontinuation of maintenance was permitted if MRD negative by PET/CT, flow cytometry (limit of detection [LoD] 10-5), and NGS by clonoSEQ (threshold 10-6). Patients underwent serial blood testing along with clonoSEQ, flow, and PET/CT annually for 3 years. Concurrent BM aspirate samples also underwent CD138+ immunomagnetic enrichment analyzed using clonoSEQ to achieve MRD 10-7 sensitivity. Primary endpoints were MRD resurgence rate at the 10-6threshold, along with progression-free survival (PFS) and overall survival among those MRD negative by the standard non-enriched clonoSEQ. Results: 83 patients were screened, and 47 patients met eligibility to discontinue maintenance as of 1/21/24. Median age was 66 years (range 39-84). 17 (36%) had high-risk disease at diagnosis (8 with 1q copy abnormalities, 5 with ISS stage 3, 2 with t(4;14), 1 with t(14;16), and 3 with del17p). Most (45/47, 96%) had one line of therapy; 26 (55%) received a triplet and 19 (40%) a quadruplet. Prior autologous transplant was received by 30 (64%) and multi-drug consolidation in 36 (77%) prior to single-agent maintenance. 96% received lenalidomide as maintenance. Median duration of consolidation/maintenance therapy prior to discontinuation was 36 months (range 12-95), including 14 (30%) with &lt;27 months. Median follow-up was 30 months. Of 47 enrolled patients, 5 (11%) experienced disease progression and an additional 6 (13%) had MRD resurgence at 10-6. Of 11 MRD resurgent events, 4 (36%) were MRD 10-7 positive at baseline, and 3 (27%) were MRD 10-7 positive 1 year prior to MRD 10-6 resurgence. 2 second hematologic cancers occurred during follow-up: 1 Hodgkin lymphoma and 1 B-ALL, the latter which resulted in the only patient death on study. The estimated 3-year PFS was 85%, including 93% for patients MRD 10-7 negative (n=40) at baseline and 31% for those MRD 10-7 positive (n=7) at baseline (logrank p&lt;0.001). Among the MRD evaluable patients (n=45), the 3-year MRD-free survival (MRD-FS) was 68%; 78% for patients MRD 10-7 negative (n=38) and 33% for patients MRD 10-7 positive (n=7) (logrank p&lt;0.001). There were no differences in MRD-FS or PFS when stratified by high-risk disease, receipt of transplant, consolidation, or duration of maintenance. Conclusions: Discontinuation of maintenance therapy among patients with MM and multimodal MRD-negativity results in a high rate of sustained MRD-negativity and lack of disease progression. CD138+-enriched MRD samples using the clonoSEQ assay may help to even better identify patients who can discontinue therapy. Clinical trial information: NCT04108624 .

A post-hoc analysis of outcomes of patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) who received oral azacitidine (Oral-AZA) maintenance therapy in the QUAZAR AML-001 study.

6522 Background: AML-MRC represents 25%–34% of all AML cases, and patients with this AML subtype generally have poor outcomes. In this subanalysis of the QUAZAR AML-001study, we report outcomes of patients with AML-MRC who received Oral-AZA vs placebo (PBO). Methods: QUAZAR AML-001 was a phase 3 study of Oral-AZA maintenance therapy in patients with AML in first remission after intensive chemotherapy who were not eligible for hematopoietic stem cell transplantation (HSCT). Patients ≥ 55 years of age with AML and intermediate- or poor-risk cytogenetics received Oral-AZA 300 mg or PBO QD for 14 d per 28-d cycles. In this analysis, WHO 2008 criteria were used to identify patients with secondary AML and/or patients with AML-MRC (both groups are referred to as AML-MRC in this analysis). Data on mutational profiles at diagnosis were not available. Overall survival (OS) from time of randomization to time of death from any cause after censoring for HSCT, and relapse-free survival (RFS) from time of randomization, were calculated using the Kaplan–Meier method. Duration of measurable residual disease (MRD) negativity achieved on treatment was calculated from the first MRD-negative assessment. Results: Overall, 101/472 patients had AML-MRC; 56/238 (23.5%) patients in the Oral-AZA arm and 45/234 (19.2%) patients in the PBO arm. Karyotype/cytogenetics data at diagnosis were available for 87/101 (86.1%) patients with AML-MRC and 331/371 (89.2%) patients with non-AML-MRC. A greater proportion of AML-MRC than non-AML-MRC patients had poor-risk cytogenetics (20/101 [19.8%] vs 46/371 [12.4%]), del(5q) (10/87 [11.5%] vs 9/331 [2.7%]), and monosomy 7/del(7q) (9/87 [10.3%] vs 14/331 [4.2%]). Median OS did not significantly differ in patients with AML-MRC vs non-AML-MRC in either treatment arm (Oral-AZA: 19.9 mo vs 25.1 mo, P = 0.2694; PBO: 14.8 mo vs 14.9 mo, P = 0.2099). In both treatment arms, the median RFS was inferior for patients with AML-MRC vs non-AML-MRC (Oral-AZA 7.5 mo vs 10.5 mo, P = 0.0430; PBO: 3.7 mo vs 4.9 mo, P = 0.0109). Oral-AZA significantly prolonged median OS and RFS, and the duration of MRD negativity for patients with AML-MRC compared with PBO (Table). Conclusions: Oral-AZA significantly improved OS and RFS compared with PBO for patients with AML-MRC indicating that Oral-AZA maintenance is an effective treatment option for these patients with particularly poor prognosis. Clinical trial information: NCT01757535 . [Table: see text]

A phase 1b/2 study of pivekimab sunirine (PVEK, IMGN632) in combination with venetoclax/azacitidine for patients with newly diagnosed CD123-positive acute myeloid leukemia.

TPS6585 Background: Despite improved outcomes with azacitidine (AZA) and venetoclax (VEN) in newly diagnosed (ND) unfit acute myeloid leukemia (AML), only a subset of patients (pts) respond (CR 37%; CR/CRi 66%) and long-term survival remains inadequate (mOS &lt;15m, DiNardo NEJM 2020). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). CD123 is expressed on the majority of AML blasts and leukemic stem cells while minimally expressed on normal hematopoietic stem cells (Kovtun Blood Adv 2018). Pivekimab sunirine (PVEK, IMGN632) is an antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The IGN payload alkylates DNA and causes single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. Clinical data from the first 50 pts in the dose expansion cohorts 1 and 2 with ND AML demonstrated a 76% (22/29) MRD negativity rate (by flow cytometry, negativity threshold &lt;0.1%) (Daver ASH 2023), supporting the continued enrollment of the PVEK+AZA+VEN triplet and further evaluation of the regimen’s antileukemia activity and safety in consideration of potential registration-enabling trials. Methods: This is an open-label, multicenter, phase 1b/2 study of PVEK administered in a combination with AZA+VEN in pts with ND CD123-positive (CD123+ by flow cytometry or IHC) AML, with no prior treatment with hypomethylating agents (HMA). Pts will receive the recommended phase 2 dose of PVEK 0.045 mg/kg IV as a &lt; 30-minute outpatient infusion on day 7, AZA 75 mg/m2 SC or IV daily on days 1 to 7, and VEN 400 mg PO daily for up to 28 days in a 28-day cycle. During cycle 1, a bone marrow evaluation at or around day 21 is required to inform VEN dose duration. Current eligibility criteria for continued enrollment of AML patients unfit for intensive chemotherapy include age ≥ 75 years old, or age &lt; 75 years old with ECOG 2-3, or at least one defined comorbidity. The primary study objectives are to assess antileukemia clinical activity (composite CR [complete remission] rate, overall response rate, duration of remission) and MRD-negativity rates. Key secondary objectives are safety and tolerability, pharmacokinetics and immunogenicity. The PVEK+AZA+VEN triplet in pts with ND unfit AML is currently enrolling across sites in France, Germany, Italy, Spain, UK and USA. Clinical trial information: NCT04086264 .

Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies.

Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.

Final analysis of a phase II trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma without transplant

We evaluated the efficacy and safety of 24 cycles of Dara in combination with carfilzomib (K), lenalidomide (R), and dexamethasone (d) without autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma (NDMM) irrespective of ASCT eligibility in a single-arm, phase II study. The primary endpoint was the rate of stringent complete response (sCR) and/or measurable residual disease (MRD) < 10−5 by next-generation sequencing (NGS) at the end of cycle 8 (C8). MRD was also assessed on peripheral blood samples using both the EXENT® system and liquid chromatography–mass spectrometry (LC–MS). Forty-two patients entered the treatment phase; forty were evaluable for the primary endpoint. The rate of sCR and/or MRD < 10−5 following C8 was 30/40 (75%), meeting the statistical threshold for efficacy. The 10−6 MRD negative rate improved with treatment beyond C8. Agreement between EXENT® and NGS was high and increased over time; agreement between LC-MS and NGS was lower. The estimated 3-year progression-free survival progression-free survival was 85%, and 3-year overall survival was 95%. Upper respiratory infections occurred in 67% (7% grade 3–4). There were no treatment-related deaths. Extended frontline Dara-KRd induced a high rate of sCR and/or MRD negativity; the rate and depth of MRD negativity improved beyond C8.

Mass spectrometry–based assessment of M protein in peripheral blood during maintenance therapy in multiple myeloma

AbstractMass spectrometry (MS) can detect multiple myeloma–derived monoclonal proteins in the peripheral blood (PB) with high sensitivity, potentially serving as a PB assay for measurable residual disease (MRD). This study evaluated the significance of PB MS MRD negativity during posttransplant therapy in patients with newly diagnosed multiple myeloma. Serum samples from 138 patients treated in the phase 3 ATLAS trial of posttransplant maintenance with either carfilzomib, lenalidomide, and dexamethasone, or with lenalidomide alone were analyzed using EXENT MS methodology. We established feasibility of measuring MRD by MS in the PB in the posttransplant setting, despite unavailability of pretreatment calibration samples. There was high agreement between MRD by MS in the PB and paired bone marrow (BM) MRD results at the 10–5 threshold, assessed by either next-generation sequencing (NGS) or multiparameter flow cytometry (MFC) (70% and 67%, respectively). Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS negativity was associated with improved progression-free survival (PFS), which, in landmark analysis, reached statistical significance after 18 cycles after transplant. Combined PB/BM MRD negativity by MFC or NGS was associated with superior PFS compared with MRD negativity by only 1 modality. Sustained MS negativity carried similar prognostic performance to sustained BM MRD negativity at the 10–5 threshold. Overall, posttransplant MS assessment was feasible and provided additional prognostic information to BM MRD negativity. Further studies are needed to confirm the role and optimal timing of MS in disease evaluation algorithms. The ATLAS trial is registered at www.clinicaltrials.gov as #NCT02659293.

Molecular, clinical, and therapeutic determinants of outcome in NPM1-mutated AML

AbstractAlthough NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features associated with poor outcomes; however, only FLT3-internal tandem duplication (ITD) mutation and adverse karyotype are currently used for risk stratification because of inconsistent results and uncertainty about how other factors should influence treatment, particularly given the strong prognostic effect of postinduction measurable residual disease (MRD). Here, we analyzed a large group of patients with NPM1 mutations (NPM1mut) AML enrolled in prospective trials (National Cancer Research Institute [NCRI] AML17 and AML19, n = 1357) to delineate the impact of baseline molecular and clinical features, postinduction MRD status, and treatment intensity on the outcome. FLT3-ITD (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.01-1.63), DNMT3A (HR, 1.65; 95% CI, 1.32-2.05), WT1 (HR, 1.74; 95% CI, 1.27-2.38), and non-ABD NPM1mut (HR, 1.64; 95% CI, 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients who achieved MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse (CIR) and poorer OS. However, apart from the few patients with adverse cytogenetics, we could not identify any group of MRD-negative patients with a CIR >40% or with benefit from allograft in first remission. Intensified chemotherapy with the FLAG-Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin) regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the high-risk molecular subgroups.

Obinutuzumab vs rituximab for transplant-eligible patients with mantle cell lymphoma

AbstractObinutuzumab (O) and rituximab (R) are 2 CD antibodies that have never been compared in a prospective randomized trial of mantle cell lymphoma (MCL). Herein, we report the long-term outcome of the LyMa-101 trial, in which newly diagnosed patients with MCL were treated with chemotherapy plus O before transplantation, followed by O maintenance (O group). We then compared these patients with those treated with the same treatment design with R instead of O (R group). A propensity score matching (PSM) was used to compare the 2 populations (O vs R groups) in terms of measurable residual disease (MRD) at the end of induction (EOI), progression-free survival (PFS), and overall survival (OS). In LyMa-101, the estimated 5-year PFS and OS after inclusion (n = 85) were 83.4% (95% confidence interval [CI], 73.5-89.8) and 86.9% (95% CI, 77.6-92.5), respectively. At EOI, patients treated in the O group had more frequent bone marrow MRD negativity than those treated in the R group (83.1% vs 63.4%; χ2, P = .007). PSM resulted in 2 sets of 82 patients with comparable characteristics at inclusion. From treatment initiation, the O group had a longer estimated 5-year PFS (P = .029; 82.8% vs 66.6%; hazard ratio [HR], 1.99; 95% confidence interval (CI), 1.05-3.76) and OS (P = .039; 86.4% vs 71.4%; HR, 2.08; 95% CI, 1.01-4.16) compared with the R group. Causes of death were comparable in the 2 groups, the most common cause being lymphoma. O before transplantation and in maintenance provides better disease control and enhances PFS and OS compared with R in transplant-eligible patients with MCL. These trials were registered at www.clinicaltrials.gov as #NCT00921414 and NCT02896582.