bluuebunny/crossref_metadata_2025 huggingface dataset:
Stability of rare TP53 co-mutations in AML patients.
Authors: Bloom Kenneth Joel , Idica Adam , Smart Dave , Allen Wendy , Scanlon Enya , Clark Jordan
Published: May 2020

7528

Background: Acute Myeloid Leukemia (AML) is a devastating disease with poor overall survival. Access to precision medicines, is revolutionizing AML care and is driving an increase in Next Generation Sequencing (NGS) utilization to determine the genomic profile of patients with AML. Advanced analysis into the interplay between mutational status for multiple genes is granting access to new targeted and precision medicine treatment options with improved outcomes. Methods: Rate of NGS adoption and TP53 mutation status were determined for a cohort of 984 AML patients tested by NGS from the Diaceutics Diagnostic Index between 2017 and 2019. Mutation rate of other genes on the same NGS panel used to determine if TP53 status was determined and compared using the z-score test for two population proportions. The stability of TP53 and co-mutation status at time of diagnosis and relapse/refractory was also analyzed. Results: We have seen a 2-fold increase in the average routine clinical practice uptake of NGS in a representative real-world patient cohort (Q3 2017, n = 144; Q3 2019, n = 290). In a cohort of 984 AML patients tested by NGS 151 (15.3%) had a TP53 mutation (Exon 4-9). Of those that had a TP53 mutation, significant negative associations were observed with mutations in seven other genes (ASXL1 p = 0.00308, CEBPA p = 0.0027, FLT3 p < 0.00001, IDH1 p = 0.04338, NRAS p = 0.0012, RUNX1 p = 0.01878 and TET2 p = 0.0251). There were no statistically significant differences in TP53 mutation and other gene mutation rates between diagnosis and relapse/refractory timepoints. Conclusions: This data suggests that TP53 and other gene co-mutants may act in similar activation pathways resulting in rare detection. One possibility is that double mutants result in synthetic lethality leading to a low clonal population. Second, when co-mutated clones escape immune surveillance and regulation, it results in particularly aggressive leukemias with lower overall survival. The stability of TP53 and co-mutation is relatively stable, which has implications for testing algorithms and clinical utility as a marker of MRD. Although a clinical trial may be difficult due to low numbers of patients, a TP53 antagonist and targeted therapy may be a valuable treatment option in rare cases where co-mutation does exist. [Table: see text]
Molecular dissection of normal karyotype acute myeloid leukemia.
Authors: Shreve Jacob Tyler , Meggendorfer Manja , Mukherjee Sudipto , Walter Wencke , Hutter Stephan , Makhoul Ahed , Kerr Cassandra M. , Radakovich Nathan , Awada Hassan , Nagata Yasunobu , Guan Yihong , Kuzmanovic Teodora , Hasipek Metis , Jha Babal , Maciejewski Jaroslaw P. , Haferlach Claudia , Sekeres Mikkael A. , Haferlach Torsten , Nazha Aziz
Published: May 2020

7534

Background: Conventional cytogenetics remain one of the most important prognostic factors in acute myeloid leukemia (AML), though 50-60% of patients (pts) have normal karyotype (NK), conventionally classified as intermediate-risk, and have very heterogeneous outcomes. A fraction of mutations such as NPM1, FLT3-ITD, and CEBPa can improve risk stratification for some pts but underestimate the molecular complexity and interactions between these genes and others. Methods: Genomic and clinical data of 2,793 primary AML (pAML) pts were analyzed. A panel of 35 genes that are commonly mutated in AML and myeloid malignancies and have shown to impact OS was included. Correlation of each mutation with others and their impact on OS were evaluated. OS was calculated from the date of diagnosis to date of death or last follow-up. Results: Of 2,793 pts with pAML, 1,352 (48%) had NK and were included in the final analysis. The median age was 55 years (range, 18-93). The median number of mutations/sample was 3 (range, 0-7). The most commonly mutated genes were: NPM1 (49%), DNMT3A (37%), FLT3-ITD (24%), CEBPa (19%), TET2 (17%), IDH2 (17%), and RUNX1 (15%). In univariate Cox regression analysis, mutations in NPM1 (HR 0.81, p =0.008), and CEBPa (single mutant, HR 0.8, double mutant, HR 0.69, p< 0.001, respectively) were associated with longer OS, while mutations in DNMT3a (HR 1.26, p =0.003), FLT3-ITD (HR 1.49, p< 0.001), TET2 (HR 1.26, p =0.02), RUNX1 (HR 1.36, p =0.003), SRSF2 (HR 1.58, p <0.001), IDH1 (HR 1.29, p <0.001), and ASXL1 (HR 1.89, p <0.001) were associated with shorter OS. A total of 67% of pts had NPM1, DNMT3A, and FLT3-ITD mutated alone or in combination with each other. The median OS for pts with NMP1Mut/ DNMT3AWT/FLT3-ITDWT was 99.1 months(m), NMP1Mut/DNMT3AMut /FLT3-ITDWT 54.8m, NMP1Mu t/DNMT3AWT/FLT3-ITDMut 42.3m, NMP1Mut/DNMT3AMut/FLT3-ITDMut 13.4m, NMP1WT/DNMT3AMut/FLT3-ITDMut 13.1m, and NMP1WT/DNMT3AWT/FLT3-ITDWT (triple negative) 32.7m. The median OS for pts with 0-2 mutations/sample was 59.3m, compared to 34.1m for pts with 3-4 mutations, and 16.1m for pts with > 5 mutations ( p< 0.001). Conclusions: We propose a simplified and robust approach to risk stratify AML pts with NK based on the mutational status of NPM1, DNMT3A, FLT3-ITD (alone or in combination with each other), CEBPa, and the number of mutations/sample.
Characterization of clinical pharmacokinetics and exposure-response relationships of AMG 330, a bispecific CD33 T-cell engager antibody construct, in patients with relapsed/refractory AML.
Authors: Agarwal Suresh K , Bhagwat Sharvari , Mehta Khamir , Hindoyan Antreas , Stein Anthony Selwyn , Ravandi Farhad , Subklewe Marion , Walter Roland B. , Jongen-Lavrencic Mojca , Ossenkoppele Gert J. , Paschka Peter , Khaldoyanidi Sophia , Dutta Sandeep , Upreti Vijay V.
Published: May 2020

7536

Background: AMG 330 binds both CD33 and CD3 and redirects T cells toward CD33+ cells leading to T-cell‒mediated cytotoxicity against AML blasts. An ongoing open label phase I dose-escalation study (NCT02520427) has shown preliminary activity and acceptable safety in relapsed or refractory (R/R) acute myeloid leukemia (AML) patients (pts) (Ravandi et al. ASH 2018). Pharmacokinetics and exposure-response (E-R) relationships of AMG 330 were characterized in this trial. Methods: A continuous IV infusion of AMG 330 was evaluated at escalating target doses (range from 0.5 to 720 μg/day) using a 3+3 design with pts receiving step dose/s prior to reaching target doses of ≥ 30 μg/day. Population pharmacokinetics (popPK) using non-linear mixed effects modeling and E-R analyses were conducted to characterize relationships between AMG 330 exposure (steady-state concentration [Css]) at target dose, the baseline tumor burden, clinical response per revised IWG criteria and incidence of cytokine release syndrome (CRS). Results: As of Dec 10, 2019, 55 patients (males, 56.4%; median age, 58.0 [18.0–80.0] years) were enrolled in 16 cohorts. AMG 330 PK was best described by a one-compartment linear PK model. Dose dependent increases were observed in AMG 330 Css exposures. Responders typically showed higher AMG 330 Css than non-responders. Preliminary exploratory analysis indicated that higher AMG 330 exposures, lower baseline leukemic burden in bone marrow and CD33+ AML cells in peripheral blood, and higher baseline Effector:Target cell ratio may be associated with clinical response. Additionally, a positive relationship was observed for AMG 330 exposures and baseline leukemic burden (p < 0.05) with probability of CRS occurrence and severity. Based on the model, at a baseline leukemic burden of 20%, a 240 µg/day target dose is predicted to result in a 28% and 4% probability of developing CRS of grade ≥ 2 and ≥ 3, respectively. Conclusions: Clinical pharmacokinetic profile and E-R relationships of AMG 330 were characterized to identify optimal AMG 330 dosing regimens that minimize the risk for CRS in ongoing and planned clinical investigations. Clinical trial information: NCT02520427 .
Incidence of large granular lymphocytosis (LGL) in patients with late cytopenias after allogeneic blood or marrow transplantation (AlloBMT).
Authors: Messmer Marcus , Wake Laura , Tsai Hua-Ling , Jones Richard J. , Varadhan Ravi , Wagner-Johnston Nina D.
Published: May 2020

7544

Background: LGL - often called LGL leukemia - is a clonal disorder of T or NK cells often associated with cytopenias, autoimmunity, splenomegaly, and B symptoms. There are a limited number of studies of benign LGL expansion after alloBMT, some suggesting an association with improved transplant-related outcomes. In contrast, clinically significant LGL leukemia after alloBMT is only described in case reports. Methods: We cross referenced all patients receiving an alloBMT at Johns Hopkins since 2010 with patients who were evaluated for LGL expansion by peripheral blood (PB) flow cytometry (FC) since 2012. Results: There were 1930 alloBMTs from 1/1/10 to 7/1/19. PB FC for suspected LGL was sent on 153 unique patients after alloBMT, usually in the setting of cytopenias (97%). Median age was 59. 69 (45%) had LGL expansion (LGL+) at a median 194 days after alloBMT. Among LGL+, 53 (77%) had an absolute neutrophil count (ANC) < 1500. The majority of the alloBMTs were non-myeloablative (NMA) (97%), related (88%), and haploidentical (89%), consistent with our center’s characteristics. Graft vs host disease (GVHD) prophylaxis was post-transplant cyclophosphamide (PTCy), mycophenolate mofetil, and tacrolimus or sirolimus. 64 (93%) cases were T cell LGL (T-LGL) and 5 were NK cell. Of those with T-LGL, 43 were assessed for T cell receptor clonality. 21% were clonal, 53% oligoclonal, 5% polyclonal, and 21% indeterminate. There were no significant demographic or transplant-related differences between LGL+ and LGL- in our 153 patient cohort. LGL+ were more likely to have had CMV viremia (75% vs 26%, p < 0.0001), but not acute or chronic GVHD. LGL+ had higher lymphocyte counts (1520/cu mm vs 495, p < 0.0001) and a trend toward more neutropenia (77% vs 63%, p = 0.07). There were no differences in overall survival, relapse, or non-relapse mortality. 29 (42%) of LGL+ received immunosuppressive therapy (IST) for cytopenias. First line treatment was corticosteroids for 24 (83%). 65% had normalization of ANC with first line treatment, compared to improvements in anemia in 15% and thrombocytopenia in 36%. 34% of those treated required ≥2 lines of treatment. Conclusions: In contrast to prior studies, where LGL after alloBMT was asymptomatic and associated with improved transplant outcomes, we identified a high rate of LGL with cytopenias and no improvement in transplant outcomes. Neutropenia was common in LGL+ and usually improved with IST.
Bosutinib in patients with chronic phase chronic myeloid leukemia intolerant to prior tyrosine kinase inhibitors: Analyses from the BYOND study.
Authors: Saussele Susanne , Gambacorti-Passerini Carlo , García Gutierrez Valentin , Abboud Camille N. , Purcell Simon , Viqueira Andrea , Leip Eric , Ernst Thomas , Giles Frank , Hochhaus Andreas
Published: May 2020

7551

Background: Bosutinib (BOS) is approved for patients (pts) with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and in newly diagnosed pts in chronic phase (CP). Methods: The ongoing phase 4 BYOND study is further evaluating efficacy and safety of BOS (starting dose 500 mg/d) for CML resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). We report findings in pts intolerant to all prior TKIs. Data are reported ≥1 y after the last enrolled pt (~85% TKI-intolerant pts had ≥2 y follow-up). Results: Of 163 pts who received BOS, 156 had Ph+ CP CML. 73 pts entered the study due to intolerance; 29, 26 and 18 had 1 (CP2L), 2 (CP3L) and 3 (CP4L) prior TKIs, respectively. After a median follow-up of 30.4 mo, median treatment duration across all 3 cohorts (CP2L, CP3L, CP4L, respectively) was 25.3 mo (29.2, 24.6, 17.6) and median dose intensity was 292.0 mg/d (304.5, 284.8, 272.1). Across CP CML cohorts (CP2L, CP3L, CP4L, respectively), 84.9% of patients (82.8%, 88.5%, 83.3%) had ≥1 dose reduction and 83.6% (79.3%, 84.6%, 88.9%) had ≥1 dose interruption due to adverse events (AEs). At the data cutoff, 53.4% (CP2L 65.5%, CP3L 42.3%, CP4L 50.0%) were still receiving BOS. The most common reason for discontinuation was AEs (28.8%). The most common ( > 40%) treatment-emergent AEs (TEAEs) were diarrhea (87.7%) and nausea (43.8%). Grade 3/4 TEAEs in > 10% of pts were diarrhea (16.4%), increased alanine aminotransferase (19.2%) and increased lipase (12.3%). Most pts with a valid baseline assessment achieved major molecular responses (MMR) across therapy lines (Table). Deaths occurred in 4 pts (CP2L 1, CP3L 3, CP4L 0); none were related to BOS or CML. Overall survival rate (95% CI) at 2 y in TKI-intolerant pts was 97.2% (89.2–99.3); rates were 96.4% (77.2–99.5), 96.0% (74.8–99.4) and 100% (100–100) in CP2L, CP3L and CP4L pts, respectively. Conclusions: A long duration of treatment and high response rate were observed in TKI-intolerant pts treated with BOS. Despite being intolerant to all prior therapies, ≥50% of pts in the overall intolerant cohort remained on BOS treatment at the data cutoff and > 80% achieved/maintained MMR. These results further support BOS use in pts with Ph+ CP CML and intolerance to all prior TKIs. Clinical trial information: NCT02228382 . [Table: see text]
Clinical benefit of luspatercept in patients (pts) with lower-risk MDS (LR-MDS) and high transfusion burden in the phase III MEDALIST study.
Authors: Zeidan Amer Methqal , Garcia-Manero Guillermo , Dezern Amy Elizabeth , Fenaux Pierre , Greenberg Peter L. , Savona Michael R. , Jurcic Joseph G. , Verma Amit , Mufti Ghulam J. , Buckstein Rena , Santini Valeria , Laadem Abderrahmane , Zhang Jennie , Rampersad Anita , Sinsimer Daniel , Louis Chrystal Ursula , Linde Peter G. , List Alan F. , Sekeres Mikkael A.
Published: May 2020

7554

Background: Anemic pts with LR-MDS and high baseline RBC transfusion burden (HTB) have very few treatment options and constitute a pt population with significant clinical unmet need. In this secondary analysis of the MEDALIST trial (NCT02631070), we sought to evaluate the clinical benefit of luspatercept in this pt population. Methods: MEDALIST is a randomized, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of luspatercept in pts with anemia due to LR-MDS with ring sideroblasts (RS) (Fenaux & Platzbecker et al. NEJM. 2020;382:140-51). Pts were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to erythropoiesis-stimulating agents (serum erythropoietin > 200 U/L); and had anemia requiring regular RBC transfusions (≥ 2 units/8 weeks in the 16 weeks prior to randomization). 229 pts were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg; titration up to 1.75 mg/kg allowed) or PBO subcutaneously every 3 weeks. HTB was defined as ≥ 6 RBC units transfused/8 weeks. Results: 153 pts were randomized to luspatercept and 76 to PBO. As of July 1, 2019, 23/66 (34.8%) and 12/66 (18.2%) HTB pts receiving luspatercept achieved a ≥ 50% and ≥ 75% reduction from baseline in RBC transfusion burden over ≥ 24 weeks, respectively, vs 3/33 (9.1%; P = 0.0063) and 1/33 (3.0%; P = 0.0363) pts receiving PBO. 6/66 (9.1%) luspatercept-treated HTB pts and 1/33 (3.0%) PBO-treated HTB pt achieved RBC-transfusion independence (TI) ≥ 8 weeks in Weeks 1–24 ( P = 0.2699). The median (range) time to achieve RBC-TI with luspatercept was 50.0 days (1.0–100.0) and median (range) duration of RBC-TI in the luspatercept arm was 42.6 weeks (8.4–81.1). Mean number of transfusion events in Weeks 1–24 was 9.2 in the luspatercept arm vs 12.4 in the PBO arm (hazard ratio [95% confidence interval] 0.794 [0.660–0.956]). 65/66 (98.5%) luspatercept- and 29/33 (87.9%) PBO-treated HTB pts reported ≥ 1 treatment-emergent adverse event (TEAE); 11/66 (16.7%) and 3/33 (9.1%) pts, respectively, reported ≥ 1 TEAE leading to discontinuation. 28/66 (42.4%) luspatercept- and 15/33 (45.5%) PBO-treated pts reported ≥ 1 serious AE. Incidence of grade 3–4 TEAEs in HTB pts was similar between arms (53.0% luspatercept vs 54.5% PBO). Conclusions: Luspatercept treatment resulted in clinically significant reductions in transfusion burden and reduced number of transfusion events in HTB pts with LR-MDS with RS, with an acceptable safety profile consistent with the overall population. Clinical trial information: NCT02631070 .
Chronic myelomonocytic leukemia genomic signature correlates with the degree of bone marrow fibrosis: A single-institutional retrospective study.
Authors: Ally Feras , Jariwala Amar , Aoun Patricia A. , Telatar Milhan , Pillai Raju K. , Ali Haris , Snyder David , Louie Carrie , Afkhami Michelle
Published: May 2020

7559

Background: Chronic myelomonocytic leukemia (CMML) has features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. The median overall survival (OS) in most series is 20-40 months. CMML is a relatively rare entity, and there is limited understanding of prognostic molecular markers. CMML associated with bone marrow fibrosis grade 1, appear to have shorter progression free survival. In this study we investigated the correlation of mutations with bone marrow reticulin fibrosis in patients with CMML. Methods: We investigated a cohort of 41 consecutive patients diagnosed with CMML 0, 1, 2, and CMML-AML from 2014 to 2019 at our institute. The median age of 41 patients was 68 years (range, 34-82). 27% were females and 73% were males. This cohort consists of 8 (20%) patients with CMML0, 19 (46%) with CMML1, 8 (20%) with CMML2 and 6 (15%) with CMML-AML. Genomic DNA was extracted from the bone marrow aspirates and targeted mutation NGS libraries were prepared from 200 ng of genomic DNA using the SureSelect target enrichment system (Agilent Technologies Inc.). The gene panel consists of 73 genes focused on myeloid neoplasms. The data were curated on the basis of our molecular pathology and national databases. Additionally, clinical data and bone marrow (BM) reticulin fibrosis grades (n = 27 available) were retrieved from the patient’s medical record. Results: The mutational profile frequency in our cohort showed that the most common mutations were TET2 (31%), ASXL1 (31%), and SRSF2 (23%), with frequencies very similar to those reported in the literature. Of the 27 cases with an available reticulin stain, only low grade fibrosis (MF-0, n = 18. MF-1, n = 9) were identified in our cohort. The frequencies of mutations in ASXL1, U2AF1, TP53, JAK2 and RUNX1, positively correlated with low grade fibrosis (MF-1). Additionally, patients with higher frequencies of SRSF2, TET2, and SETBP1 mutations showed no fibrosis (MF-0). Conclusions: This study is the first to correlate the degree of fibrosis with the frequency of mutations in CMML. We found similar mutations spectrum reported in the literature in patients with CMML. The mutational profile associated with CMML cases appears to affect the degree of the bone marrow fibrosis at the time of diagnosis.
Is autologous transplantation (autoHCT) in relapsed diffuse large B-cell lymphoma (DLBCL) patients achieving only a PET/CT positive partial remission (PR) appropriate in the CAR-T cell era?
Authors: Shah Nirav Niranjan , Ahn Kwang Woo , Litovich Carlos , Fenske Timothy , Hamadani Mehdi
Published: May 2020

8000

Background: In relapsed, chemosensitive DLBCL patients (pts), autoHCT consolidation is a standard therapy option. With the approval of anti-CD19 CAR T-cells in 2017, relapsed DLBCL pts with residual PET/CT avid disease after salvage therapies are increasingly being offered CAR T-cells in lieu of autoHCT. According to Center for International Blood and Marrow Transplant Research (CIBMTR) data in 2018, the number of autoHCT for DLBCL in the U.S. decreased by ~45% from prior years, likely due to application of CAR T-cells for both chemorefractory DLBCL and chemosensitive DLBCL pts not achieving a complete remission. Using the CIBMTR database, we report outcomes of autoHCT in relapsed chemosensitive DLBCL pts achieving only a PET/CT+ PR prior to HCT. Methods: 249 relapsed DLBCL pts undergoing an autoHCT from 2003-13 with a PET/CT+ PR prior to transplant were identified. The study cohort was divided into two groups: (a) early chemo-immunotherapy failure (ECF) defined as pts with primary refractory disease (PRefD) or relapse within 12 months of diagnosis, (b) late chemoimmunotherapy failure (LCF) defined as pts relapsing ≥12 months. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and relapse. Results: 182 pts had ECF and 67 pts had LCF. The median age of ECF pts was 57 years versus (vs) 63 years for LCF (p < 0.01). ECF pts more frequently had stage III-IV at diagnosis (74% vs 54%, p = < 0.01). 79% of ECF pts had PRefD. The most common conditioning regimen was BEAM in both cohorts. The adjusted 5-year probabilities for PFS and OS (ECF vs LCF) was not different between the 2 cohorts: 41% vs 41% (p = 0.93) and 51% vs 63% (p = 0.09), respectively. Cumulative incidence of relapse at 5 years in similar order was 48% vs 57%, p = 0.27. On multivariate analysis compared to the LCF, pts with ECF had an increased risk of death (HR = 1.61, 95%CI 1.05-2.46, p = 0.03) but no increased risk in PFS or relapse. Conclusions: Using the CIBMTR registry, we report outcomes of relapsed DLBCL pts in a PR with residual PET/CT avid disease at time of autoHCT. While OS favored LCF pts, the adjusted 5-year PFS (41%) was comparable in both cohorts. This 5 year PFS is comparable to results reported in historical trials of auto-HCT for DLBCL. With no randomized data demonstrating superiority of CAR T-cell therapy in chemosensitive PR patients, these findings strongly support that autoHCT should remain the current standard of care for this patient population.
ASPEN: Results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM).
Authors: Tam Constantine Si Lun , Opat Stephen , D'Sa Shirley , Jurczak Wojciech , Lee Hui-Peng , Cull Gavin , Owen Roger G. , Marlton Paula , Wahlin Bjorn E. , Tedeschi Alessandra , Castillo Jorge J. , Siddiqi Tanya , Buske Christian , Leblond Veronique , Chan Wai Y. , Schneider Jingjing , Ro Sunhee K. , Cohen Aileen , Huang Jane , Dimopoulos Meletios A.
Published: May 2020

8007

Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. ASPEN is a randomized phase 3 study comparing zanubrutinib (ZANU), a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in WM patients. Methods: Patients with WM and MYD88 mutation were randomly assigned 1:1 to receive ZANU (160 mg twice daily) or IBR (420 mg once daily). Patients without MYD88 mutations were assigned to a separate cohort, received ZANU, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs >3). The primary end point was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% vs 15% in the subset of patients with relapsed or refractory (R/R) WM. Primary analysis was planned to occur at ~12 months after last patient enrolled. Results: In total, 201 patients were randomized from Jan 2017 to Jul 2018. The treatment groups were well balanced for important baseline factors, except in the ZANU arm there were more elderly patients (aged >75 years, 33.3% vs 22.2%) and more anemia (hemoglobin ≤110 g/L, 65.7% vs 53.5%). At a median follow-up of 19.4 months, the rate of CR+VGPR was 28.4% vs 19.2% with ZANU vs IBR, respectively (2-sided P=0.09). Rates of atrial fibrillation, contusion, diarrhea, edema peripheral, hemorrhage, muscle spasms, pneumonia, and adverse events (AEs) leading to discontinuation or death were lower with ZANU. The rate of neutropenia was higher with ZANU (Table); however, grade ≥ 3 infection rates were similar (17.8% vs 19.4%). Conclusions: ASPEN is the largest phase 3 trial of BTK inhibitors in WM and the first head-to-head comparison of BTK inhibitors in any disease. Although not statistically significant, ZANU was associated with a higher CR+VGPR response rate, and demonstrated clinically meaningful advantages in safety and tolerability compared to IBR. Clinical trial information: NCT03053440 . [Table: see text]
Autologous stem cell transplantation for untreated transformed indolent B-cell lymphoma in first remission: An international, multicenter propensity matched study.
Authors: Chin Collin K , Lim Kenneth JC , Lewis Katharine L , Jain Preetesh , Qing Yun , Feng Lei , Cheah Chan , Seymour John Francis , Ritchie David , Burbury Kate , Tam Constantine Si Lun , Fowler Nathan Hale , Fayad Luis , Westin Jason , Neelapu Sattva Swarup , Hagemeister Fredrick B. , Samaniego Felipe , Flowers Christopher , Nastoupil Loretta J. , Dickinson Michael
Published: May 2020

8021

Background: Transformation of untreated indolent B-cell lymphoma (Tr-iNHL) is associated with poor outcomes. Current practices are extrapolated from prospective studies of de novo large B-cell lymphoma (DLBCL) or small retrospective studies. High dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) is used as consolidation in first remission (CR1) in some centers but the evidence-base is weak. Methods: CLL/SLL, MCL as primary diseases and non-DLBCL transformations were excluded. Propensity score analysis (PSM) using the “greedy match” algorithm was used to match the baseline covariates to adjust for potential selection bias. Landmark analysis was performed with time zero at 3 months after completion of front line chemotherapy (FLC). Kaplan-Meier method and the Cox proportional hazards model were was used for time-to-event analysis including progression-free survival (PFS) and overall survival (OS). Results: 319 transplant eligible patients (age <75, LVEF >45%, no severe lung disease, CR by PET or CT >3 months after FLC) who received >/= standard RCHOP intensity FLC were identified across three centers in Australia & US. 283 (89%) patients had follicular lymphoma, 30 (9%) marginal zone lymphoma, 6 (2%) other subtypes. 49 patients underwent HDC and ASCT in CR1, a matched cohort of 98 pts based on age, stage, HGBL-DH and ECOG PS at diagnosis was generated with a 1:2 ratio using PSM. After a median follow-up of 3.6 (min: 0.1, max: 18.3) years, ASCT was associated with significantly superior PFS on multivariable analysis (MVA) (HR 0.51, 0.27-0.98; P=0.043). Univariate analysis demonstrated a trend towards inferior OS in the ASCT cohort (HR 2.36; 0.87-6.42; P=0.092) with more deaths in the ASCT arm due to PD (8% v 4%). Of the 40 patients (41%) with relapsed disease in the non-ASCT cohort–15 patients underwent salvage HDC & ASCT with 7/15 (47%) ongoing CR; 10 patients underwent CAR-T therapy (5 relapse post ASCT, 4 refractory disease, 1 relapse post FLC) with 6/10 (60%) ongoing CR; 3 patients underwent allogeneic SCT (2 relapse post ASCT, 1 relapse post FLC) with 2/3 (67%) ongoing CR. Conclusions: Although ASCT in CR1 may improve initial duration of disease control in de novo Tr-iNHL, the impact on OS is less clear with effective salvage therapies in the CAR-T era.
Clinical activity of cirmtuzumab, an anti-ROR1 antibody, in combination with ibrutinib: Interim results of a phase Ib/II study in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).
Authors: Lee Hun Ju , Choi Michael Y. , Siddiqi Tanya , Wierda William G. , Barrientos Jacqueline Claudia , Lamanna Nicole , Goldenberg Alec , Isufi Iris , Tuscano Joseph M. , Subbiah Suki , Weihe Elizabeth Kristine , Ianopulos Xen , Breitmeyer James Bradley , Hsu Frank J. , Wang Michael , Jamieson Catriona HM , Kipps Thomas J.
Published: May 2020

8036

Background: ROR1 is an onco-embryonic tyrosine kinase receptor that is re-expressed at high levels on many hematologic and solid cancers but not on normal adult tissues. ROR1 binds Wnt5a, resulting in increased tumor growth and survival, cancer cell stemness and epithelial mesenchymal transition. Cirmtuzumab (Cirm) is a humanized monoclonal antibody designed to inhibit the tumor promoting activity of ROR1. In this study, we examined the safety and efficacy of Cirm in combination with ibrutinib (Ibr) in MCL or CLL. Methods: As of Jan 29, 2020, 12 pts with relapsed refractory (RR) MCL were enrolled into Part 1 Dose Escalation (DE). All MCL pts had stage 3/ 4 at original diagnosis, 25% had bulky tumor at study entry, 58% had intermediate/high risk MIPI scores and the majority (83%) had ≥ 2 prior regimens. 34 pts with CLL [12 treatment naïve (TN) and 22 RR pts] enrolled into Part 1 DE (n = 18) or Part 2 Expansion (n = 16). At least 79% of CLL pts were high risk as determined by unmutated IGHV, 17p/p53 loss, and/or del 11q. DE pts received Cirm IV q2wks x 3-5 doses then q4wks plus Ibr (starting D28). Following DE, Cirm 600mg IV q2wks x3 then q4wks plus Ibr (420mg/day CLL or 560mg/day MCL) was chosen for Expansion. Results: Safety : only grade 1/ 2 AEs were reported as possibly related to Cirm alone, whereas the safety profile attributed to Ibr or Ibr / Cirm was similar to published data, with no new or unexpected events. Efficacy for MCL: 83% ORR, 33% (4) CR, 50% (6) PR, 17% (2) SD. CRs were achieved at a median of 3.6 mos in heavily pretreated pts, including 2 with bulky disease > 5cm. Prior therapy of the 4 CR pts: 2 pts failed R-Ibr (7-10 mos) and R-hyperCVAD, 1 pt, auto-SCT and allo-SCT, 1 pt, auto-SCT and CAR-T. Efficacy for CLL : 88% ORR (92% TN, 86% RR), 3% (1) CR, 85% (22) PR/ (7) PR-L, 12% (4) SD. In addition, 3 PR pts with CLL met criteria for “Clinical CR, bone marrow biopsy not performed”. The pt achieving a CR had RR disease with del 11q; this pt remains in remission > 6 mos after stopping all therapy. At a median follow-up of 9.9 mos, 100% of CLL pts are free of disease progression and > 82% remain on study. Conclusions: Cirm in combination with Ibr is a well-tolerated and active regimen for RR MCL and TN or RR CLL. In this evaluation of 46 pts, the ORR and PFS continue to improve with longer follow-up and additional pts, supporting continued investigation of this regimen in ROR1 expressing tumors. This study is ongoing and enrolling an Expansion arm for MCL pts and an open-label randomized Phase 2 in CLL pts comparing Ibr alone to Cirm /Ibr. Clinical trial information: NCT03088878 .
Haemophagocytic lymphohistiocytosis (HLH) in patients with large B-cell lymphoma treated with standard of care (SOC) axicabtagene ciloleucel (Axi-cel).
Authors: Ahmed Sairah , furqan fateeha , Strati Paolo , Westin Jason , Fayad Luis , Hagemeister Frederick B. , Lee Hun Ju , Iyer Swaminathan Padmanabhan , Nair Ranjit , Nastoupil Loretta J. , Parmar Simrit , Rodriguez Maria Alma , Samaniego Felipe , Steiner Raphael , Wang Michael , Pinnix Chelsea Camille , Flowers Christopher , Horowitz Sandra B. , Hawkins Misha , Neelapu Sattva Swarup
Published: May 2020

8057

Background: HLH is a rare but serious complication of chimeric antigen receptor (CAR) T cell therapy, characterized by severe immune activation, and immune mediated multi-organ failure. Diagnosis is difficult in the context of cytokine release syndrome (CRS) and optimal treatment and outcomes are unclear. Methods: Retrospective, descriptive analysis of patients with relapsed/refractory LBCL treated with SOC axi-cel at MD Anderson Cancer Center between 01/2018 - 10/2019 (data cut-off 12/21/2019). Progression-free survival (PFS) defined as time from axi-cel infusion to progression/death or last follow-up. Diagnosis of HLH per HLH-2004 and CART cell therapy toxicity guidelines (Neelapu, 2018) Results: One hundred and five patients with relapsed/refractory LBCL included, 6 diagnosed with HLH. No significant difference in baseline characteristics, disease stage, international prognostic index or inflammatory markers at baseline between groups, with exception of platelet count which was lower in HLH group 116 [37-129] versus 141 [9-391] (p = 0.07). Development of HLH was early after CART cell infusion at a median 11 days [7 – 78 days] with 3 patients having bone marrow hemophagocytosis; all 6 had abnormalities in liver function tests, fibrinogen, triglycerides, and at least 1 ferritin level > 10,000. CART toxicity in HLH cohort: 4 patients experienced grade 0-1 CRS, and 1 with grade 2 CRS while 3 HLH patients experienced grade 3-4 IEC-associated neurotoxicity syndrome ( ICANS), and 2 patients had grade 0-1 ICANS. Five HLH patients treated with high dose steroids, and tocilizumab; anakinra administered in 2 patients. Four of 6 patients had resolution of HLH with treatment and didn’t require escalation to HLH specific therapy however 1 patient was treated with steroids/etoposide. PFS and overall survival (OS) were significantly shorter in HLH group, PFS 1 months vs 8 months, respectively (p < 0.001) and median OS 2 months vs not reached, respectively (p = 0.001) follow up 10 months (95% CI 8-12 months). One patient died of acute respiratory failure, 2 patients died of HLH and multi-organ failure without progressive disease (PD). Of 3 remaining patients, all had radiographic PD at day 30, 2 of whom died of PD. Conclusions: HLH is likely an underreported complication of CART cell therapy, and patients with HLH have significantly worse outcomes. In this series the majority of patients died of PD, not the syndrome itself. More information is necessary to design treatment strategies that won’t compromise CART outcomes.
Alternative anti-CD20 antibody versus desensitization for lymphoma patients with drug hypersensitivity reactions requiring discontinuation of rituximab, obinutuzumab, or ofatumumab.
Authors: Ghione Paola , Joffe Erel , De Paola Nadia , Mainardi Timothy , Noor Sarah J. , Bobillo Sabela , Myskowski Patricia L. , Palomba M. Lia , Moskowitz Alison J. , Mato Anthony R. , Sha Fushen , Von Keudell Gottfried , Straus David J. , Noy Ariela , Younes Anas , Hamlin Paul A. , Brentjens Renier J. , Tejedor-Alonso Miguel Angel , Horwitz Steven M. , Zelenetz Andrew David
Published: May 2020

8062

Background: Immunotherapy with anti CD20 is often associated with mild easily manageable infusion reactions. In rare cases, patients experience severe drug hypersensitivity reactions (DHR) serum sickness or anaphylaxis. These in turn may lead to discontinuation of the drug. In our experience, switching to a different anti-CD20 agent is a feasible alternative to discontinuation or desensitization protocols. Methods: From our pharmacology database we identified all the patients that received rituximab and/or obinutuzumab, and/or ofatumumab, and/or all the patients who received a flat dose of less than 50 mL of the same drugs and were followed at our institution. From the medical record, we identified all the cases where the anti-CD20 antibody was changed due to allergy, serum sickness or other types of DHR, and all those who received minimal doses of anti-CD20 in the context of a desensitization protocol. DHRs were evaluated either by an allergist, or by retrospective review following the World Allergy Organization guidelines. Our primary comparison, was to assess the proportion of pts able to completed planned infusion of abs using either approach (Fisher’s exact Test). Results: Among 343 patients receiving at least two different anti-CD20 antibodies or a flat dose of < 50 mL, we identified 44 patients experiencing severe DHRs needing intervention. At the time of the reaction, 16 (36%) received the anti-CD20 as single agent, 24 (54%) in combination with chemotherapy, 4 (9%) in combination with ibrutinib or lenalidomide. In 9 (20%) patients the reaction was defined as anaphylactoid (8 rituximab; 1 obinutuzumab) and in 8 (18%) patients, all receiving rituximab, as serum sickness. Episodes of DHR were addressed with either desensitization (n = 29) or change of anti-CD20 agent (n = 25), 9 patients received both of these approaches, one patient switched anti-CD20 antibodies twice. Overall, 21 desensitizations were successful (72.4%), 8 failed; 23 changes of anti-CD20 were successful (92%) and 2 failed (p = 0.09). Conclusions: In patients with DHR use of an alternative anti-CD20 antibody is safe and is an alternative or complementary approach to anti-CD20 desensitization.
Weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in patients with multiple myeloma (MM) after one to three prior therapies: Initial results of the phase III BOSTON study.
Authors: Dimopoulos Meletios A. , Delimpasi Sosana , Simonova Maryana , Spicka Ivan , Pour Ludek , Kryachok Iryna , Gavriatopoulou Maria , Pylypenko Halyna , Auner Holger W , Leleu Xavier , Doronin Vadim , Kaplan Polina , Hajek Roman , Reuben Benjamin , Dolai Tuphan Kanti , Sinha Dinesh Kumar , Arazy Melina , Richardson Paul G. , Bahlis Nizar J. , Grosicki Sebastian
Published: May 2020

8501

Background: Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, leading to the reactivation of tumor suppressor proteins. In a phase 1b/2 study, the combination of once weekly (QW) selinexor with bortezomib and dexamethasone (SVd) was well tolerated with anti-MM activity in patients (pts) with PI-sensitive and PI-refractory disease. While twice weekly (BIW) bortezomib in combination therapy is efficacious, prolonged use is limited due to peripheral neuropathy (PN, 50-60%). The BOSTON study was designed to determine if SVd improves progression free survival (PFS), overall response rates (ORR) and reduces the rate of PN vs Vd. Methods: BOSTON is a global, phase 3, randomized study of QW SVd vs BIW Vd after 1-3 prior anti-MM regimens. The primary endpoint is PFS. Secondary endpoints include ORR, overall survival (OS) and PN (rates and EORTC QLQ-CIPN20 outcomes). Randomization is stratified by treatment with prior PI therapies, number of prior anti-MM regimens (1 vs > 1), and Revised International Staging System (R-ISS; Stage III vs I or II). Following confirmation of progressive disease, pts on Vd could cross over to either: 1) SVd for pts able to tolerate continued bortezomib or 2) selinexor and dexamethasone for pts with bortezomib intolerance. Results:402 pts were enrolled; 195 and 207 to SVd and Vd, respectively. Median age was 67 (range: 38-90). Most (59.6%) pts were > 65 years and 57.1% were male. R-ISS stage at the time of MM diagnosis was III for 18.5% of pts. Baseline characteristics were balanced across the 2 arms. SVd significantly prolonged PFS vs Vd (median 13.93 vs 9.46 months, HR = 0.70, P = 0.0066). SVd was associated with a significantly higher ORR (76.4% vs 62.3%, P = 0.0012). Median OS was not reached on SVd vs 25 months on Vd (P = 0.28). Most frequent treatment-related adverse events (grade ≥3) for SVd vs Vd were thrombocytopenia (35.9% vs 15.2%), fatigue (11.3% vs 0.5%) and nausea (7.7% vs 0%). Clinically important differences were reported on the motor, autonomic and sensory scales on CIPN20. PN rates (grade ≥2) were significantly lower with SVd vs Vd (21.0% vs 34.3%, P = 0.0013). Conclusions: BOSTON is the first phase 3 study to evaluate the clinical benefit of SVd for relapsed/refractory MM. The study met the primary endpoint: once weekly SVd significantly improved PFS and ORR compared to twice weekly Vd. Rates of PN were significantly reduced with numerically fewer deaths on SVd vs Vd. Full dataset will be presented at the meeting. Clinical trial information: NCT03110562 .
Updated analysis of a phase I/II study of venetoclax in combination with daratumumab and dexamethasone, +/- bortezomib, in patients with relapsed/refractory multiple myeloma.
Authors: Kaufman Jonathan L. , Baz Rachid C. , Harrison Simon J. , Quach Hang , Ho Shir-Jing , Vangsted Annette J. , Moreau Philippe , Gibbs Simon DJ , Salem Ahmed H. , Coppola Sheryl , Ross Jeremy A. , Masud Abdullah A. , Westrup Sally , Vue Jenny , Maciag Paulo Cesar , Bueno Orlando , Bahlis Nizar J.
Published: May 2020

8511

Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor that induces apoptosis in multiple myeloma (MM) cells in vitro. It has shown synergistic activity with bortezomib (V) and dexamethasone (d). Combination of the CD38 monoclonal antibody daratumumab (D) with Ven is hypothesized to further increase anti-myeloma activity based on dual mechanisms of pro-apoptotic effects on tumor cells and enhanced immune stimulation. Methods: This ongoing Phase 1/2, nonrandomized, multicenter study (NCT03314181) is evaluating safety, efficacy and pharmacokinetics (PK) of VenDd +/- V in patients (pts) with relapsed/refractory MM. In Part 1, pts with t(11;14) who received ≥1 prior line of therapy (PI and an immunomodulatory drug) were treated with VenDd [Ven QD + D 16 mg/kg IV + d 40 mg weekly]. In Part 2, pts irrespective of t(11;14) status, non-refractory to PIs and who received 1–3 prior lines of therapy were treated with VenDVd [Ven QD + D 16 mg/kg IV + V (1.3 mg/m2) + d (20 mg)]. A randomized, open-label expansion (Part 3) will further evaluate and compare safety and efficacy of VenDd (400 or 800 mg Ven dose levels) with control DVd in pts with t(11;14). Results: As of Dec 05, 2019, 48 pts were enrolled. Part 1 included 24 pts with t(11;14), median age 63 (range 51–76). Part 2 included 24 pts, median age 65 (range 41–80) of which 6 (25%) had t(11;14). Frequent adverse events (AEs; VenDd/VenDVd) were fatigue (71%/25%), diarrhea (58%/46%), nausea (46%/50%), insomnia (33%/50%), upper respiratory tract infection (33%/21%), cough (42%/9%), and dyspnea (25%/25%). Frequent Grade ≥ 3 AEs in pts on VenDd were neutropenia (17%), hypertension (12%), fatigue and hyperglycemia (8% each), and in pts on VenDVd were insomnia (21%), diarrhea and thrombocytopenia (8% each). Nine pts had infection-related Grade ≥ 3 AEs (5 VenDd, 4 VenDVd). Eighteen pts had a serious AE (11 VenDd, 7 VenDVd) with pyrexia (n = 3) being most common. One pt on VenDVd died of progressive disease. PK analyses showed that addition of D and V did not impact Ven exposure. Median follow-up time (VenDd/VenDVd) was 10 and 9 months. Overall response rate in VenDd/VenDVd was 96%/92% and 96%/79% had ≥ very good partial response rate. Median progression free survival and duration of response were not reached. Conclusions: Pts treated with VenDd +/- V continue to demonstrate a tolerable safety profile with encouraging efficacy, notably among pts with t(11;14) treated with VenDd. Safety, efficacy, PK, and cytogenetics analyses will be updated for presentation. Clinical trial information: NCT03314181 .
Measurable residual disease (MRD) assessed by mass spectrometry (MS) in peripheral blood versus next generation sequencing (NGS) in bone marrow in multiple myeloma treated on phase II trial of KRd+ASCT.
Authors: Derman Benjamin Avi , Stefka Andrew T , McIver Amanda , Jiang Ken , Kubicki Tadeusz , Jasielec Jagoda , Jakubowiak Andrzej J.
Published: May 2020

8513

Background: MRD-negativity in multiple myeloma (MM) assessed by NGS in bone marrow (BM) aspirate is associated with longer progression free survival (PFS) and overall survival. MS can detect monoclonal protein at a heightened sensitivity in peripheral blood (PB). We sought to assess the concordance of MS in PB and NGS in BM, comparing outcomes by MRD status. Methods: MRD was tested on paired PB and BM samples from transplant (ASCT)-eligible pts with newly diagnosed secretory MM who received treatment on a phase II clinical trial (NCT01816971) with KRd for 4 cycles, ASCT, KRd for 14 cycles, and lenalidomide maintenance (LM). Both NGS and MS were evaluable in 36 pts after a total of 18 cycles of KRd (C18) and in 24 pts after 1 year of LM. MS signatures were identified in pretreatment PB samples. C18 and after 1 year of LM PB samples were evaluated using both MALDI-TOF and liquid-chromatography-MS (LCMS) by the Binding Site Group. Paired MRD by NGS was performed by ClonoSEQ. 20/60 samples reached the limit of detection for 10−6 and 40/60 for 10−5. Results: There was substantial concordance between NGS and MALDI-TOF among the 60 samples ( κ= 0.667, 83% agreement) and fair concordance between NGS and LCMS ( κ= 0.348, 63% agreement). However, all 22 discordant samples (8 with NGS depth 10−6, 14 with NGS depth 10−5) were NGS−/LCMS+. 4/16 (25%) of these pts converted to NGS+, and 3/16 (19%) clinically progressed. There was stronger concordance between LCMS and NGS 10−6( κ= 0.615) than with NGS 10−5( κ= 0.375). At a median follow-up of 56 months, C18 LCMS−(n = 9) was associated with superior PFS vs all LCMS+(n = 27; p = 0.03) and independently vs NGS—/LCMS+ (n = 14; p = 0.04). There were 10 events (including 4 deaths) in the C18 LCMS+ group vs 0 in the LCMS− group. Conclusions: MRD assessment by LCMS in PB appears to reach and possibly exceed the sensitivity of MRD by NGS in BM at a depth of 10−5-10−6. LCMS positivity predicted conversion from NGS— to NGS+ in 25% of discordant cases, and LCMS negativity was a better predictor of superior PFS than MRD negativity by NGS. These observations need confirmation in larger prospective studies.
Clinical implications of loss of minimal residual disease (MRD) negativity in multiple myeloma.
Authors: Mohan Meera , yarlagadda naveen kumar , Atwal Dinesh , Pandey Yadav , Roy Arya , Parikh Richa , Lopez James , Thanendrarajan Sharmilan , Schinke Carolina D. , Alapat Daisy , Van Rhee Frits , Kendrick Samantha , Zangari Maurizio
Published: May 2020

8514

Background: Attainment of MRD negativity in multiple myeloma (MM) patients is increasingly considered an optimal therapeutic endpoint, but little is known about the MRD evolution in those who achieve this milestone. We investigated the clinical implication of loss of MRD negativity or MRD conversion in patients with ≥VGPR. Methods: We identified and followed 606 patients achieving a sustained ≥VGPR with bone marrow MRD negativity(≥ 2 consecutive reading) following treatment on a total therapy protocol and with a median follow-up of 10 y. All patient had negative PET and MRI DWIBS at enrollment. Serial BM aspirate MRD was determined by 8-color next generation flow (NGF, EuroFlow) with a minimal sensitivity of 10−5 cells. Results: Most MM patients were considered low risk with a UAMS GEP70 score of ≤ 0.66 (92%; 495/538) . While 60% (364/606) of patients had sustained MRD negativity, the remaining 40% (242/606) experienced MRD conversion with a 5.7 y median time from ASCT and 6.3 y from diagnosis. The risk of clinical relapse was significantly elevated in patients with MRD conversion compared to sustained MRD negativity (73%, 177/242 vs. 5%, 18/364; R.R. = 3.5; P< 0.0001). The median level of MRD positivity (> 0.2 ratio of MM cells to normal plasma cells) also highly correlated with relapse ( P< 0.0001). Loss of MRD negativity preceded clinical relapse by a median time of 1.1 years. Loss of MRD negativity without clinical relapse was seen in 27% (65/242). MRD conversion was associated with an inferior PFS and OS (PFS: 10.2 y vs. NR; P < 0.0001, H.R. 18.7; 95% CI 13.3 - 26.3 and OS: 26.1 y vs. NR; P= 0.01, H.R. 1.7; 95% CI 1.1 - 2.6). Furthermore, when MRD conversion was within 5 y of diagnosis compared > 5 y, patients had a worse OS ( P < 0.0001, H.R. 17.2; 95% CI 7.8 – 37.8). We also observed that MRD conversion later than 5 years from diagnosis did not affect the OS. In a subset of patients (n = 144) the timing of first MRD negativity following treatment was available. Attainment of MRD negativity within 6 months of diagnosis compared to any time after 6 months was predictive of future MRD conversion (65%, 17/26 vs.42%, 49/118; P = 0.03) and clinical relapse (54%, 14/26 vs.28%, 33/118; P = 0.02). Conclusions: MRD conversion occurs in a significant proportion of MM patients (40%) on long-term follow-up and predicts future clinical relapse. Significance of MRD conversion has a temporal relationship from diagnosis and portray inferior clinical outcome particularly within 5 years of diagnosis.