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Impact of minimal residual disease (MRD) in salvage autologous stem cell transplantation for relapsed myeloma: results from the NCRI Myeloma X (intensive) trial
de Tute, R. M., Cook, G., Cairns, D. A., Brown, J. M., Cavenagh, J., Ashcroft, A. J., Snowden, J. A., Yong, K., Tholouli, E., Jenner, M., et al
Bone marrow transplantation. 2024
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Prospective evaluation of minimal residual disease in the phase II FORTE trial: a head-to-head comparison between multiparameter flow cytometry and next-generation sequencing
Oliva, S., Genuardi, E., Paris, L., D'Agostino, M., Rogers, J., Rota-Scalabrini, D., Jacob, A. P., Patriarca, F., Luppi, M., Bertazzoni, P., et al
EClinicalMedicine. 2023;60:102016
Abstract
BACKGROUND Limited data are available on the concordance between multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for minimal residual disease (MRD) detection in a large trial for multiple myeloma (MM) patients. METHODS MRD was explored in the FORTE trial for transplant-eligible MM patients randomised to three carfilzomib-based induction-intensification-consolidation treatments and carfilzomib-lenalidomide (KR) vs R maintenance. MRD was assessed by 8-colour 2nd-generation flow cytometry in patients with ≥very good partial response before maintenance. NGS was performed in case of suspected complete response (CR) in a correlative subanalysis. Biological/prognostic concordance between MFC and NGS, conversion to MRD negativity during maintenance, and 1-year/2-year sustained MRD negativity were explored. FINDINGS Between September 28, 2015 and December 22, 2021, 2020 samples were available for MFC and 728 for the simultaneous MFC/NGS correlation in the "suspected CR population". Median follow-up was 62 months. Biological agreement was 87% at the 10(-5) and 83% at the 10(-6) cut-offs. A remarkable prognostic concordance was observed: hazard ratios in MFC-MRD and NGS-MRD-negative vs -positive patients were 0.29 and 0.27 for progression-free survival (PFS) and 0.35 and 0.31 for overall survival, respectively (p < 0.05). During maintenance, 4-year PFS was 91% and 97% in 1-year sustained MFC-MRD-negative and NGS-MRD-negative patients (10(-5)), respectively, and 99% and 97% in 2-year sustained MFC-MRD-negative and NGS-MRD-negative patients, regardless of treatment received. The conversion rate from pre-maintenance MRD positivity to negativity during maintenance was significantly higher with KR vs R both by MFC (46% vs 30%, p = 0.046) and NGS (56% vs 30%, p = 0.046). INTERPRETATION The significant biological/clinical concordance between MFC and NGS at the same sensitivity suggests their possible use in the evaluation of one of the currently strongest predictors of outcome. FUNDING Amgen, Celgene/Bristol Myers Squibb, Multiple Myeloma Research Foundation.
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Circulating Tumor Cells for the Staging of Patients With Newly Diagnosed Transplant-Eligible Multiple Myeloma
Garcés, J. J., Cedena, M. T., Puig, N., Burgos, L., Perez, J. J., Cordon, L., Flores-Montero, J., Sanoja-Flores, L., Calasanz, M. J., Ortiol, A., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;:Jco2101365
Abstract
PURPOSE Patients with multiple myeloma (MM) may show patchy bone marrow (BM) infiltration and extramedullary disease. Notwithstanding, quantification of plasma cells (PCs) continues to be performed in BM since the clinical translation of circulating tumor cells (CTCs) remains undefined. PATIENTS AND METHODS CTCs were measured in peripheral blood (PB) of 374 patients with newly diagnosed MM enrolled in the GEM2012MENOS65 and GEM2014MAIN trials. Treatment included bortezomib, lenalidomide, and dexamethasone induction followed by autologous transplant, consolidation, and maintenance. Next-generation flow cytometry was used to evaluate CTCs in PB at diagnosis and measurable residual disease (MRD) in BM throughout treatment. RESULTS CTCs were detected in 92% (344 of 374) of patients with newly diagnosed MM. The correlation between the percentages of CTCs and BM PCs was modest. Increasing logarithmic percentages of CTCs were associated with inferior progression-free survival (PFS). A cutoff of 0.01% CTCs showed an independent prognostic value (hazard ratio: 2.02; 95% CI, 1.3 to 3.1; P = .001) in multivariable PFS analysis including the International Staging System, lactate dehydrogenase levels, and cytogenetics. The combination of the four prognostic factors significantly improved risk stratification. Outcomes according to the percentage of CTCs and depth of response to treatment showed that patients with undetectable CTCs had exceptional PFS regardless of complete remission and MRD status. In all other cases with detectable CTCs, only achieving MRD negativity (and not complete remission) demonstrated a statistically significant increase in PFS. CONCLUSION Evaluation of CTCs in PB outperformed quantification of BM PCs. The detection of ≥ 0.01% CTCs could be a new risk factor in novel staging systems for patients with transplant-eligible MM.
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Rap1A, Rap1B, and β-Adrenergic Signaling in Autologous HCT: A Randomized Controlled Trial of Propranolol
Johnson, A. K., Lorimer, E. L., Szabo, A., Wu, R., Shah, N. N., D'Souza, A., Chhabra, S., Hamadani, M., Dhakal, B., Hari, P., et al
The Yale Journal of Biology and Medicine. 2022;95(1):45-56
Abstract
Successful hematopoietic cell transplantation (HCT) depends on rapid engraftment of the progenitor and stem cells that will reestablish hematopoiesis. Rap1A and Rap1B are two closely related small GTPases that may affect platelet and neutrophil engraftment during HCT through their roles in cell adhesion and migration. β-adrenergic signaling may regulate the participation of Rap1A and Rap1B in engraftment through their inhibition or activation. We conducted a correlative study of a randomized controlled trial evaluating the effects of the nonselective β-antagonist propranolol on expression and prenylation of Rap1A and Rap1B during neutrophil and platelet engraftment in 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for 1 week prior to and 4 weeks following HCT. Blood was collected 7 days (baseline) and 2 days (Day -2) before HCT, and 28 days after HCT (Day +28). Circulating polymorphonuclear cells (PMNC) were isolated and analyzed via immunoblotting to determine levels of prenylated and total Rap1A versus Rap1B. Twelve participants were randomized to the intervention and 13 to the control. Rap1A expression significantly correlated with Rap1B expression. Rap1B expression significantly correlated with slower platelet engraftment; however, this association was not observed in the propranolol-treated group. There were no significant associations between neutrophil engraftment and Rap1A or Rap1B expression. Post hoc exploratory analyses did not reveal an association between social health variables and Rap1A or Rap1B expression. This study identifies a greater regulatory role for Rap1B than Rap1A in platelet engraftment and suggests a possible role for β-adrenergic signaling in modulating Rap1B function during HCT.
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Optimizing the value of lenalidomide maintenance by genetic profiling - an analysis of 556 Myeloma XI trial patients
Panopoulou, A., Cairns, D. A., Holroyd, A. E., Nichols, I., Cray, N., Pawlyn, C., Cook, G., Drayson, M. T., Boyd, K. D., Davies, F. E., et al
Blood. 2022
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Editor's Choice
Abstract
Prediction of individual patient benefit from lenalidomide (Len) maintenance post autologous transplant (ASCT) remains challenging. We investigated here extended molecular profiling for outcome prediction in NCRI Myeloma XI (MyXI) trial patients. MyXI patients randomized to Len maintenance or observation post-ASCT were genetically profiled for t(4;14), t(14;16), t(14;20), del(1p), gain(1q) and del(17p) and co-occurrence of risk markers computed. PFS, PFS2 and OS were calculated from maintenance randomization, and groups compared using Cox proportional hazards regression. 556 MyXI patients, 17% with double hit MM (≥2 risk markers), 32% with single hit (1 risk marker) and 51% without risk marker, were analyzed. Single hit MM derived the highest PFS benefit from Len maintenance, specifically isolated del(1p), del(17p) and t(4;14), with approximately 40-fold (HR 0.02; 95% CI: 0.002-0.24; P=0.0012), 10-fold (HR 0.1; 95% CI: 0.02-0.58; P=0.0095) and 7-fold (HR 0.14; 95% CI: 0.04-0.45; P=0.0009) reduced risk of progression or death (PFS) compared to observation, respectively. This benefit translated into improved PFS2 HR 0.27 (95% CI: 0.13-0.54; P=0.0002) and OS HR 0.41 (95% CI: 0.18-0.93; P=0.03) for this group of patients over observation; median PFS was 10.9 vs. 57.3 months for observation vs. Len maintenance. Patients with isolated gain(1q) derived no benefit, and double hit MM limited benefit, regardless or risk lesions involved, from Len maintenance. Extended genetic profiling identifies patients deriving exceptional benefit from Len maintenance and should be considered for newly diagnosed patients to support management discussions along their treatment pathway.
PICO Summary
Population
Adults with newly diagnosed multiple myeloma participating in the Myeloma XI trial, who were genetically profiled for t(4;14), t(14;16), t(14;20), del(1p), gain(1q) and del(17p) and co-occurrence of risk markers (n=556)
Intervention
Lenalidomide (len) maintenance following autologous stem cell transplant (n=359)
Comparison
Observation after autologous transplant (n=197)
Outcome
Of the 556 participants analysed, 17% had double hit MM (≥2 risk markers), 32% had single hit (1 risk marker) and 51% had no risk marker Single hit MM derived the highest PFS benefit from Len maintenance, specifically isolated del(1p), del(17p) and t(4;14), with approximately 40-fold (HR 0.02; 95% CI: 0.002-0.24), 10-fold (HR 0.1; 95% CI: 0.02-0.58) and 7-fold (HR 0.14; 95% CI: 0.04-0.45) reduced risk of progression or death (PFS) compared to observation, respectively. This benefit translated into improved PFS2 HR 0.27 (95% CI: 0.13-0.54) and OS HR 0.41 (95% CI: 0.18-0.93) for this group of patients over observation; median PFS was 10.9 vs. 57.3 months for observation vs. Len maintenance. Patients with isolated gain(1q) derived no benefit, and double hit MM limited benefit, regardless or risk lesions involved, from Len maintenance.
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Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation
Vallet, N., Le Grand, S., Bondeelle, L., Hoareau, B., Corneau, A., Bouteiller, D., Tournier, S., Lew-Derivry, L., Bohineust, A., Tourret, M., et al
Blood. 2022
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Editor's Choice
Abstract
Administration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematological malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients' samples to decipher immune alterations associated with azithromycin intake and post-transplant relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T cells cytotoxicity against tumor cells and impaired T cells metabolism through glycolysis inhibition, mitochondrial genes downregulation, and immunomodulatory genes upregulation, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies.
PICO Summary
Population
Participants with haematological malignancies enrolled in the ALLOZITHRO trial (n=240)
Intervention
Azithromycin 250 mg x 3/week (n=123)
Comparison
Placebo (n=117)
Outcome
Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T cells cytotoxicity against tumor cells and impaired T cells metabolism through glycolysis inhibition, mitochondrial genes downregulation, and immunomodulatory genes upregulation, notably SOCS1.
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The day 100 score predicts moderate to severe cGVHD, transplant mortality, and survival after hematopoietic cell transplantation
Metafuni, E., Cavattoni, I. M., Lamparelli, T., Raiola, A. M., Ghiso, A., Galaverna, F., Gualandi, F., Di Grazia, C., Dominietto, A., Varaldo, R., et al
Blood Advances. 2022;6(7):2309-2318
Abstract
The aim of this study was to develop a predictive score for moderate-severe chronic graft-versus-host disease (cGVHD) on day +100 after allogeneic stem cell transplantation (HSCT). We studied 1292 patients allografted between 1990 and 2016, alive on day +100 after transplant, without cGVHD, and with full biochemistry laboratory values available. Patients were randomly assigned to a training and a validation cohort (ratio 1:1). In the training cohort, a multivariate analysis identified 4 independent predictors of moderate-severe cGVHD: gamma-glutamyl transferase ≥75 UI/l, creatinine ≥1 mg/dl, cholinesterase ≤4576 UI/l, and albumin ≤4 g/dl. A score of 1 was assigned to each variable, producing a low (0 to 1), intermediate (2 to 3), and high (4) score. The cumulative incidence of moderate-severe cGVHD was 12%, 20%, and 52% (P < .0001) in the training cohort, and 13%, 24%, and 33% (P = .002) in the validation cohort, respectively. The 5-year cumulative incidence of transplant-related mortality (TRM) was 5%, 14%, 27% (P < .0001) and 5%, 16%, 31% (P < .0001), respectively. The 5-year survival was 64%, 57%, 54% (P = .009) and 70%, 59%, 42% (P = .0008) in the 2 cohorts, respectively. In conclusion, Day100 score predicts cGVHD, TRM, and survival and, if validated in a separate group of patients, could be considered for trials of preemptive therapy.
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Impact of Center Experience with Donor Type on Outcomes: A Secondary Analysis BMT CTN 1101Open for Accrual June 2012Open for Accrual June 2012
Brunstein, C. G., O'Donnell, P. V., Logan, B., Dawson, P., Costa, L., Cutler, C., Craig, M., Hogan, W., M. Horowitz M, Horwitz, M. E., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND We reported on the results of Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) 1101, a randomized comparison between double umbilical cord blood (dUCB) and haploidentical (haplo) bone marrow (BM) with post-transplant cyclophosphamide (PTCy) in the nonmyeloablative setting that showed similar progression free survival (PFS) between the two treatment groups, but lower non-relapse mortality (NRM) and better of survival (OS) in the haplo arm. In this secondary analysis, we sought to investigate whether transplant center experience with haplo BM and/or dUCB hematopoietic cell transplant (HCT) had an impact on outcomes. PATIENTS AND METHODS All patients randomized in BMT CTN 1101 were included. Center experience was assigned based on the number transplants with each platform in the year prior to initiation of the study according to the Center for International Blood and Marrow Transplant Research (CIBMTR). Centers were then grouped as a dUCB-center (>10 dUCB, n=117, 10 centers), a haplo center (>10 haplo and ≤10 dUCB, n=110, 2 centers), or other-center (≤10 haplo and ≤10 dUCB HCTs, n=140, 21 centers). RESULTS After adjusting for age, Karnofsky performance score, and disease risk index, we found that haplo centers had lower overall mortality with this donor type, as compared to dUCB (HR 2.56, 95%CI, 1.44-4.56). In contrast, there were no differences in overall mortality between haplo and dUCB in centers that were experienced with dUCB (HR 1.02, 95%CI 0.59-1.79) or had limited-to-no experience with either dUCB or haplo (HR 1.36, 95%CI, 0.83-2.21). The higher risk of treatment failure and overall mortality in dUCB in haplo-experienced centers was driven by a significantly higher risk of relapse (HR 1.78, 95%CI, 1.07-2.97). CONCLUSION With the exception of worse outcomes among dUCB recipients in haplo-BM centers, the transplant center experience on the year prior to the initiation of BMT CTN 1101 had limited impact on the outcomes of this randomized clinical trial.
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Efficacy of expressive helping in adult hematologic cancer patients undergoing stem cell transplant: protocol for the Writing for Insight, Strength, and Ease (WISE) study's two-arm randomized controlled trial
Whitmore, L., Schulte, T., Bovbjerg, K., Hartstein, M., Austin, J., Luta, G., McFarland, L., Rowley, S. D., Nyirenda, T., Lewis-Thames, M., et al
Trials. 2021;22(1):722
Abstract
BACKGROUND During, shortly after, and sometimes for years after hematopoietic stem cell transplant, a large proportion of hematological cancer patients undergoing transplant report significant physical and psychological symptoms and reduced health-related quality of life. To address these survivorship problems, we developed a low-burden, brief psychological intervention called expressive helping that includes two theory- and evidence-based components designed to work together synergistically: emotionally expressive writing and peer support writing. Building on evidence from a prior randomized control trial showing reductions in physical symptoms and distress in long-term transplant survivors with persistent survivorship problems, the Writing for Insight, Strength, and Ease (WISE) trial will evaluate the efficacy of expressive helping when used during transplant and in the early post-transplant period, when symptoms peak, and when intervention could prevent development of persistent symptoms. METHODS WISE is a multi-site, two-arm randomized controlled efficacy trial. Adult hematological cancer patients scheduled for a hematopoietic stem cell transplant will complete baseline measures and then, after hospitalization but prior to transplant, they will be randomized to complete either expressive helping or a time and attention "neutral writing" task. Both expressive helping and neutral writing involve four brief writing sessions, beginning immediately after randomization and ending approximately 4 weeks after hospital discharge. Measures of symptom burden (primary outcome), distress, health-related quality of life, and fatigue (secondary outcomes) will be administered in seven assessments coinciding with medically relevant time points from baseline and to a year post-intervention. DISCUSSION The steady and continuing increase in use of stem cell transplantation has created growing need for efficacious, accessible interventions to reduce the short- and long-term negative physical and psychosocial effects of this challenging but potentially life-saving treatment. Expressive helping is a psychological intervention that was designed to fill this gap. It has been shown to be efficacious in long-term transplant survivors but could have even greater impact if it is capable of reducing symptoms during and soon after transplant. The WISE study will evaluate these benefits in a rigorous randomized controlled trial. TRIAL REGISTRATION Clinicaltrial.gov NCT03800758 . Registered January 11, 2019.
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Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial
Jackson, G. H., Pawlyn, C., Cairns, D. A., de Tute, R. M., Hockaday, A., Collett, C., Jones, J. R., Kishore, B., Garg, M., Williams, C. D., et al
PLoS medicine. 2021;18(1):e1003454
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Editor's Choice
Abstract
BACKGROUND Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy. METHODS AND FINDINGS The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51-0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19-5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world. CONCLUSIONS The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy. TRIAL REGISTRATION ClinicalTrials.gov ISRCTN49407852.
PICO Summary
Population
Patients with newly diagnosed multiple myeloma who underwent autologous stem cell transplantation (n=1056)
Intervention
Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc, n=526)
Comparison
Triplet control group (n=530): Lenalidomide, dexamethasone, and cyclophosphamide (Rdc, n=265) or thalidomide, dexamethasone, and cyclophosphamide (Tdc, n=265).
Outcome
After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group. Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis.