ALBERT

Description: Introduction. The impact of therapy in the management of disease relapse in patients with myeloma (MM) needs to be balanced with the impact on quality of life (QoL). The benefit of a salvage autologous stem cell transplant (ASCT2) has been demonstrated in terms of durability of response over non-transplant consolidation (NTC) (G Cook, et al., Lancet Oncology, 2013 Vol. 15, No. 8, p874-885). However, the impact of ASCT2 on patient reported outcomes (PRO) has not been reported to date. Therefore, patients' experience of pain and global measures of QoL, as part of a systematic assessment of PRO were measured at key points before, during and after randomisation in this multi-centre national phase III trial. Methods. 174 patients were randomised and data are presented on 171 who completed self-rated QoL assessments using EORTC QLQ-C30 and the EORTC myeloma module (MY-20). Pain assessments using BPI-SF were also incorporated. Genomic DNA was prepared from PBMNC using standardised GLP methods. Results. Completion rates for EORTC QoL and BPI-SF assessments were 83.3% and 77.1% at registration, and 59.6% and 53.8% at randomisation, respectively. Over half of patients reaching 1 year post-randomisation completed both assessments. EORTC QoL and BPI-SF forms had average 6% and 10% missing data, respectively. These completion rates are commensurate with previous longitudinal studies. EORTC QLQ-C30 Global health status/QoL subscale scores were significantly higher (better) in the NTC arm at 100 days and 6 month post-randomisation (P=0.0496), but not at later time points. BPI-SF pain scores showed significantly higher pain severity in the NTC (4.3/10) than the ASCT2 (2.9/10) patients only at 2 years post-randomisation. However, for pain interference with aspects of daily living, NTC patients reported significantly lower scores at 6 months (P=0.0155), 1 year post-randomisation (P=0.0466) and 2 years post-randomisation (P=0.0348). The MY-20 assessment showed that at 100 days and 6 months post-randomisation, the subscale scores for Side-effects of treatment were significantly higher in the ASCT2 arm than in the NTC arm, but not at later time points up to 2 years. Kaplan-Meier estimate of time-to-progression (TTP) by randomised allocation suggested that patients with an EORTC global QoL score greater than median (ie better QoL) at randomisation and who received ASCT2 had a significant TTP advantage over those receiving NTC (HR 0.3 (95% CI 0.15-0.61), p=0.006). However, with multivariate Cox regression analysis accounting for stratification factors this difference was not significant. Patients who reported a lower (ie better) than median level of concern on the Side-effects of treatment subscale and who received ASCT2 had a significant TTP advantage over those receiving NTC (Kaplan-Meier HR 0.24 (95% CI (0.10-0.55), p=0.003). This survival difference was still observed after multivariate Cox regression analysis (HR 5.02 (95% CI 1.00-25.20), p= 0.0499). We tested for genomic associations of SNPs from key genes reported to be involved in pain perception and analgesic responsiveness, and subjective outcomes. There were no significant associations for the opioid mu-receptor (OPRM1) and pain or QoL. However, the rs2236861 SNP in the opioid delta-receptor (OPRD1) showed nominally significant associations with worst pain (p=0.022), average pain (p=0.03) and pain interference (p=0.02) at baseline. The rs1045642 SNP in the ABCB1 drug transporter gene was nominally associated with worst pain (p=0.047) and average pain (p=0.019) after bortezomib-based induction therapy. A SNP rs13361160 in the chaperonin CCT5 gene was associated with worst pain (p=0.033), least pain (p=0.006) and pain interference (p=0.03). It was also associated with self-reported global QoL (P=0.014). Conclusions. We report the first PROs using self-reported QoL and pain assessments in myeloma patients having salvage ASCT or NTC. Global QoL was worse and side-effects of treatment higher after ASCT2 for up to 6 months post-randomisation but then equalised. Pain caused less interference with daily living after NTC but became more severe at 2 years, possibly associated with relapse. Patients who reported lower concerns about side-effects of treatment after ASCT2 had a significant TTP advantage. The genomic analyses suggest a potential inherited predisposition that influences both pain and quality of life and warrants further exploration. Disclosures Ahmedzai: Mundipharma: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Grunenthal: Consultancy, Research Funding, Speakers Bureau. Snowden:Sanofi: Consultancy; MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau. Williams:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Cavenagh:Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Parrish:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Yong:Amgen: Honoraria; Novartis: Consultancy; Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Autolous: Consultancy. Cavet:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Bird:Celgene: Speakers Bureau; Janssen: Other: Educational support; Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Ashcroft:Janssen: Consultancy, Other: Educational support. Brown:Bayer: Research Funding; Roche: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Morris:Celgene: Other: Meeting support; Janssen: Other: Meeting support. Cook:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Description: Introduction Multi-agent induction chemotherapy followed by autologous stem cell transplant (ASCT) is a standard of care for younger patients with multiple myeloma, aimed at maximising the depth and duration of first response (PFS1). However, the duration of PFS1 is variable between patients. Improved understanding of how to identify high risk patients who relapse early and the ability to design strategies applicable to their biology represents the central aim of personalized medicine approaches for MM. This landmarked analysis of the Myeloma XI trial was designed to identify the characteristics of patients with PFS1 of less than a year after ASCT. Patients and methods In MXI patients were randomised to induction therapy with CTD (cyclophosphamide, thalidomide and dexamethasone) or RCD (lenalidomide, cyclophosphamide and dexamethasone) and +/- CVD (bortezomib, cyclophosphamide, dexamethasone) intensification in patients with

Description: Background Darwinian evolution drives multiple myeloma (MM) and leads to diversity both within and between patients. This suggests the need for combinations of agents with different mechanisms of action targeting sub-clonal populations to maximize the depth of response and improve outcomes. Approaches to maximize response pre-transplant include the use of sequential pre-transplant consolidation with a different agent in sub-optimal responders or intensifying upfront combinations whilst aiming to minimize additional toxicities. Carfilzomib is a novel irreversible inhibitor of the proteasome that has been suggested to have greater activity than bortezomib, with deeper responses and improved outcomes. The Myeloma XI phase III randomized trial for newly diagnosed MM patients compared intensified induction with the quadruplet KCRD vs a response adapted approach of sequential triplet therapies for transplant-eligible MM patients. Methods KCRD was given in 28 day cycles (carfilzomib (K) 36mg/m2 IV d1-2, 8-9,15-16 (20mg/m2 #1d1-2), cyclophosphamide (C) 500mg PO d1,8, lenalidomide (R) 25mg PO d1-21, dexamethasone (D) 40mg PO d1-4,8-9,15-16), CRD in 28 day cycles (C 500mg PO d1,8, R 25mg PO d1-21, D 40mg PO d1-4, 12-15) or CTD in 21 day cycles (C 500mg PO d1,8,15 thalidomide (T) 100-200mg PO daily, D 40mg PO d1-4,12-15). All induction regimens were continued for a minimum of 4 cycles and to maximum response. Suboptimal responders (MR/PR) to CTD/CRD were randomized between pre-transplant intensification with a proteasome inhibitor (bortezomib, CVD) containing triplet or no further therapy prior to ASCT, patients with refractory disease (SD/PD) all received CVD. For all patients a maintenance randomization 3 months post ASCT compared lenalidomide given to disease progression to observation. Cytogenetic data, centrally analyzed, was available for a representative subset of patients. High-risk was classified as presence of t(4;14), t(14;16), t(14;20), del(17p) or gain(1q) and ultra-high risk the presence of more than one lesion. 1056 patients underwent induction randomization between December 2013 and April 2016 and were allocated to CTD n=265, CRD n=265, KCRD n=526. The groups were well matched across baseline variables with median age 61 (range 33-75). The median follow up for this analysis is 34.5 months. The independent data monitoring and ethics committee recommended immediate release of the data following an interim analysis. Results Intention to treat analysis of the initial induction regimens found that KCRD was associated with a significantly longer PFS than triplet therapy (HR 0.63, 95%CI 0.51, 0.76, median PFS KCRD NR vs CTD/CRD 36.2 months, p

Description: INTRODUCTION Features of high risk myeloma (MM) have been studied in detail but patients with longer term responses to first-line therapy are less well characterised. Identification of common features of this group may support optimised management. Here we analysed clinical and genetic characteristics of long-term responders of 4,249 trial patients from the UK MRC Myeloma IX (M-IX) and NCRI Myeloma XI (M-XI) trials. PATIENTS AND METHODS In M-IX patients were randomised between alkylating therapy (CVAD or MP) and thalidomide-based induction therapy (CTD). M-XI patients were randomised between thalidomide and lenalidomide based induction (CTD vs CRD) and a response-based bortezomib (CVD) intensification. Fitter patients received HD-Mel+ASCT consolidation. Patients were then randomised to thalidomide (M-IX) or lenalidomide (M-XI) maintenance or observation. Trials included symptomatic, newly diagnosed patients based on CRAB criteria. This analysis included 1,921 My-IX and 2,328 My-XI patients with median follow-up of 73 and 61 months (m), respectively. Genetic profiling was available for 1,866 patients. Patients with a long-term response post induction (PFS≥48m) were identified and their baseline characteristics, responses and treatment compared to those with PFS

Description: Introduction: Autologous transplantation (ASCT) in myeloma (MM) is standard consolidative therapy in first line therapy in eligible patients. We have shown definitely that a salvage ASCT in relapse setting can induce superior durability of responses (time-to-progression; TTP) over non-transplant consolidation with oral cyclophosphamide after a proteasome inhibitor-based re-induction schedule (ISRCTN601231201). The secondary end point of this multi-centre phase III randomised controlled trial was to evaluate the impact of salvage ASCT on the overall survival (OS_ of patients relapsing after a prior ASCT and delineate patient subgroups that may benefit the most. Patients and Methods: Eligible patients with MM relapsing after a prior ASCT were enrolled. All patients were re-induced with Bortezomib, Doxorubicin and Dexamethasone (PAD) therapy delivered in 2-4 21-day cycles before 1:1 randomization to either a second ASCT (melphalan 200mg/m2 iv; ASCT2 supported by either stored or remobilized stem cells) or low dose consolidation with weekly cyclophosphamide 400mg/m2 PO for 12 weeks (Non-Transplant Consolidation; NTC). Response was assessed (by IMWG criteria) after re-induction and 100 days post-randomization with TTP being determined as the primary end-point. Patients were stratified by β2microglobulin (β2M) at trial entry, ASCT1 TTP and response to re-induction, analyzed according to cytogenetic abnormalities by iFISH (unfavorable: t(4;14), t(14;16) and del17p) with OS was a key secondary endpoint. Results: 297 patients were entered into the study and 174 randomized from April 2008 to November 2012: ASCT2 n=89, NTC n=85. Median age was 61 (range 38-75) with 73.6% of patients relapsing more than 24 months from first ASCT. ORR to re-induction therapy was 79.4% with a 16.0% sCR/CR rate. Post-randomization, sCR/CR was significantly higher after ASCT2 (39.3% [95% CI 29.1,50.3] vs 22.4% [95% CI 14.0,32.7]; p=0á012). The median follow-up is 52 months (IQR range 41, 62) and the up-dated TTP demonstrates continued advantage in ASCT2 cohort compared to NTC (19 months [95% CI 16,26] vs 11 months [95% CI 9,12]; Log Rank p 24m (HR0.60, p=0.089), β2M level

Description: Background: The depth of response both pre- and post- autologous stem cell transplant (ASCT) has been shown to correlate with clinical outcome for myeloma patients. Maximizing response can be achieved by modifying therapy either at induction, transplant, consolidation or during maintenance. In this work we explore the role of pre-transplant induction therapy in the UK NCRI Myeloma XI clinical trial and whether the number of cycles of induction impacts on clinical outcome. Methods: Myeloma XI recruited 2568 newly diagnosed transplant eligible patients. Patients were initially randomized between immunomodulatory agent containing triplets comprising cyclophosphamide, dexamethasone and either lenalidomide or thalidomide (CRD vs CTD). Patients were treated to maximum response and for a minimum of four cycles of therapy. At maximum response, patients with a VGPR or CR proceeded straight to ASCT, whilst those with a suboptimal response (PR/MR) entered a second randomization between a bortezomib containing triplet (CVD) or no further therapy, and those with refractory disease (SD/PD) all received CVD. The protocol was amended subsequently to compare the upfront quadruplet KCRD to the response adapted approach. After ASCT patients were randomized between maintenance therapy with lenalidomide +/- vorinostat or no further therapy. In this exploratory analysis we compared baseline characteristics and outcomes for patients who received 4 cycles of initial induction (the protocol defined minimum), 5-6 cycles or 〉6 cycles. Patients who received 6 cycles. A comparison of baseline characteristics showed that the group receiving more induction therapy was associated with a higher ISS stage and greater disease burden at baseline. The percentage of patients with ISS stage II/III was greater in those receiving more cycles of therapy, 4 cycles 57.6%, 5-6 cycles 62.2%, 〉6 cycles 67.3%. The percentage bone marrow infiltration increased (BM plasma cells 〉20% was 32.3%, 42.3% and 43.4% respectively). Patients with an IgG paraprotein made up a larger proportion of those receiving more cycles 50.2%, 65.1% and 67.3% respectively, whereas those with IgA or light chain disease showed the opposite pattern. Age, sex and performance status showed no association. Cytogenetic risk was equally distributed across groups with a subset of standard risk patients requiring additional cycles of therapy, indicating some slow responders even in this good prognosis group. KCRD had a superior time to and depth of response; patients receiving KCRD required a median of only 4 cycles and had a much higher proportion of patients receiving only 4 cycles (KCRD 49.8%, CRD 29.7%, CTD 21.7%). Response at the end of 4 cycles of therapy and at the end of initial induction, Figure 1, shows that additional cycles deepened response. This was consistent across all induction regimens. Patients receiving 〉4 cycles of therapy, however, never attained as deep responses as those whose maximum response was achieved by 4 cycles and were therefore also more likely to receive subsequent therapy with CVD intensification in the response adapted arm of the study. Overall, the depth of response at the end of initial induction was associated with a significant effect on PFS (Median PFS: CR 63.3 months, VGPR 43.8 months, PR 30.6 months, p6 cycles of initial induction. Conclusions: The results suggest that continuing induction to maximum response is not detrimental to patient outcome and may have overcome an adverse impact of a less deep response. Continuing induction therapy until maximum response may improve outcomes for patients with an otherwise suboptimal response at the end of 4 cycles. Disclosures Pawlyn: Amgen: Consultancy, Honoraria, Other: Travel Support; Janssen: Honoraria, Other: Travel support; Celgene Corporation: Consultancy, Honoraria, Other: Travel support; Takeda Oncology: Consultancy, Other: Travel support. Jackson:Merck Sharp and Dohme: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau. Cairns:Merck Sharp and Dohme: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Striha:Celgene: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; MSD: Research Funding. Hockaday:MSD: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Millenium: Research Funding; Celgene: Research Funding; Abbvie: Research Funding. Jones:Celgene: Honoraria, Other: Travel support, Research Funding. Boyd:Celgene: Consultancy, Honoraria, Other: Advisory role; Janssen: Honoraria, Other: Travel and Accommodation expenses; Novartis: Consultancy, Honoraria. Kishore:Celgene: Honoraria; Takeda: Honoraria, Other: travel support. Garg:Takeda: Other: Travel Grant; Amgen: Honoraria, Other: Travel Support; Novartis: Other: travel support, Research Funding; Janssen: Honoraria. Williams:Celgene: Honoraria, Other: travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Other: travel support, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria, Other: travel support, Speakers Bureau. Karunanithi:Celgene: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding. Lindsay:Janssen: Consultancy; Novartis: Other: Travel support; Celgene: Honoraria, Other: Travel support; BMS: Consultancy, Other: Travel support; Takeda: Other: Travel support. Jenner:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Russell:Jazz Pharma: Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy. Kaiser:Bristol-Myers Squibb: Consultancy, Other: travel support; Chugai: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Other: travel support; Celgene: Consultancy, Honoraria, Research Funding. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen:Janssen: Consultancy, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel Support. Gregory:Celgene: Consultancy, Honoraria, Research Funding; Merck Sharp and Dohme: Research Funding; Janssen: Honoraria; Amgen: Research Funding. Morgan:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Davies:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Description: Introduction: Salvage autologous transplantation (sASCT) in multiple myeloma has been shown to induce superior durability of responses over low-dose alkylating consolidation therapy in the relapsed setting1. The optimum re-induction regimen leading to sASCT is yet to be defined though a combination of a proteasome inhibitor (PI) and immunomodulatory agent (IMiD) is likely to offer the best depth of response. UK-MRA Myeloma XII (ACCoRD study) aims to address the role of conditioning augmentation and post-transplant maintenance. As part of this study, a novel re-induction regimen was used, the results of an interim analysis (IA) of efficacy and safety are presented here. Patients and Methods: The ACCoRd study enrolled patients who relapsed requiring treatment more than 12 months after a previous ASCT (ASCT1), delivering novel re-induction therapy with ixazomib, thalidomide and dexamethasone (ITD) prior to being randomized between a conventional high-dose melphalan (HDM) sASCT versus an ixazomib-augmented (iMel) sASCT. A second randomization between observation and post-transplant ITD consolidation with ixazomib maintenance, was conducted at D+100 post sASCT. All patients underwent genetic risk categorization by a central laboratory. High-risk genetic lesions were defined as t(4;14), t(14;16), t(14;20), del(17p) or gain(1q). On an intent-to-treat (ITT) basis, responses were assessed in accordance with the IMWG criteria with MRD defined by the limit of the multi-parameter flow assay (70 years. The median observed TTP from ASCT1 was 31.5 months (range 9.8, 118.3). 15.8% of patients were deemed to have clinical relapse at trial entry based on CRAB criteria (anaemia 13.9%, renal disease 3.0% and hypercalcaemia 0.0%) and no significant difference in ASCT1 TTP was evident between clinical and biochemical relapse groups (21.8m vs 31.9m; Wilcoxon p=0.2201). 68.2% had standard risk disease, 24.2% had HR disease and 6.1% had UHiR disease at trial entry, with gain(1q) (25.8%) being the commonest abnormality at relapse. 62.5% had standard risk disease, 27.5% had HR disease and 10% had UHiR disease at diagnosis with gain(1q) (20.8%) being the commonest abnormality. The ORR was 66.3%, with ³VGPR in 26.7%. The ORR and ³VGPR did not differ between biochemical vs. clinical relapse (ORR 56.3% vs 68.3%; ³VGPR 12.5% vs 29.3%; P=0.5585), genetic risk status (SR/HiR: ORR 57.8% vs 50.0%; ³VGPR 20% vs 31.3%; P=0.5585) but prior PI exposure was important (exposed vs naive: ORR 53.5% vs 75.9%; ³VGPR 16.3% vs 34.5%; P=0.0290). Progressive disease (PD) was recorded in 11.9%, with PD more commonly seen in PI-exposed (18.6%) and HiR (18.8%). 59/101 patients proceeded to transplant randomization so far, the main reasons for failing to proceed was PD (11.9%). 475 cycles of ITD were administered to 99 patients, with a median of 5 cycles per patient (range 1, 7). 41 SAEs were reported in 30 patients with 17 SAEs suspected related to trial medication, summarized in Table 1. 45.5% of patients had treatment modifications (14.9% with ixazomib, 37.6% with thalidomide, 24.8% dexamethasone) with treatment discontinuations for toxicity reported in 3.9% of patients. The commonest reasons for treatment discontinuation were maximum response (67.3%), PD (11.9%) and withdrawal (7.9%). Conclusion: We demonstrate the efficacy and safety profile of the novel triplet combination of ixazomib, thalidomide and dexamethasone as a re-induction regimen suitable for patients progressing to a ASCT. Further data will be forthcoming as the trial continues to recruit towards target, with the true impact on depth of response pending interim analysis of the transplant randomization. G Cook, et al. The Lancet Oncology, Vol. 15, No. 8, p874-885. Table 1. Table 1. Disclosures Cook: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Parrish:Jazz: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau. Yong:TAkeda: Honoraria, Research Funding; janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Research Funding. Cavenagh:Takeda: Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Snowden:Jannssen/J&J: Other: Speaker fees; Jazz & Sanofi: Other: Speaker fees at ASH. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Garg:Amgen: Honoraria, Other: Travel Support; Novartis: Other: travel support, Research Funding; Janssen: Honoraria; Takeda: Other: Travel Grant. Cairns:Merck Sharp and Dohme: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Ashcroft:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau; Amaris Medical: Consultancy, Honoraria. Striha:MSD: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Hockaday:Janssen: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Millenium: Research Funding; MSD: Research Funding. Owen:Janssen: Consultancy, Other: Travel support; Takeda: Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding. Williams:Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel Support, Speakers Bureau; Janssen: Honoraria, Other: Travel support, Speakers Bureau. Cook:YAkeda: Honoraria; Jazz: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria; Amgem: Honoraria.

Description: Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed.

Description: Background - Although there has been a revolution in the treatment of chronic lymphocytic leukemia (CLL), the challenge remains to identify the right drugs for the right patients. It is widely accepted that CIT, including the 'gold standard' fludarabine, cyclophosphamide and rituximab (FCR), is contraindicated for patients with TP53 disruption and, more recently, unmutated IGHV genes. Also patients with short, dysfunctional telomeres were shown to have inferior outcomes when treated with FCR-based regimens. To date, a role for CD49d in this setting has not been established. Aims - Here we evaluated the ability of telomere lenght (TL) and CD49d to cooperate with IGHV gene status to predict progression-free survival (PFS) in patients treated with FCR-based regimens in the frontline setting in three UK trials, ARCTIC, ADMIRE and CLL4. Methods - The study included a discovery cohort of 245 CLL treated with FCR/FCR-like regimens according to the two UK trials ARCTIC and ADMIRE. As there was no significant difference in PFS between the three arms of the study (P = 0.97), analysis was performed on the combined cohort. The median follow-up was 77.5 months with 157 progressions and 76 deaths. Twenty-nine patients were TP53 deleted and/or mutated, with shorter PFS compared to cases without TP53 disruption (final cohort, 216 TP53 wild-type CLL). The validation cohort was composed of 119 CLL samples derived from patients randomised to receive fludarabine, cyclophosphamide (FC) from the UK CLL4 trial. The median follow-up was 67.2 months with 99 progressions and 77 deaths. Fifteen CLL were TP53 mutated/deleted, with shorter PFS compared to cases without TP53 disruption (final cohort, 104 TP53 wild-type CLL). TL was measured using the high-throughput STELA assay and patients were bifurcated into two groups with either short telomeres inside the fusogenic range (TL-IFR) or long telomeres outside the fusogenic range (TL-OFR). CD49d was measured by flow cytometry and dichotomized as CD49dpos and CD49dneg based on the established 30% cut-off. For IGHV gene status, the 2% cutoff was used to split patients in mutated (IGHV-M) and ummutated (IGHV-UM). Results - In the 216 CLL with wild-type TP53 status from the ARCTIC/ADMIRE trials, CD49d expression was a predictor of PFS (P=0.02; HR=1.46 [1.03-2.06]). In keeping with previous reports, patients with IGHV-UM genes (P

Description: Introduction. Minimal residual disease (MRD) is a powerful predictor of outcome in multiple myeloma (MM). A recent meta-analysis has confirmed this and demonstrated a hazard ratio for PFS of 0.41; 95% CI, 0.36-0.48; P 〈 .001 (Munshi et al, JAMA Oncol, Jan 2017). We have previously demonstrated the prognostic impact of MRD both following ASCT in transplant-eligible (TE) patients and following induction in transplant non-eligible (TNE) patients. There is more limited data on the applicability and significance of MRD assessment in the maintenance setting, largely as a consequence of high rates of drop-off historically within myeloma trials but improved outcomes have seen larger numbers of participants with samples at later timepoints. Patients and Methods. This analysis aims to assess the impact of MRD on PFS amongst patients receiving maintenance or no further therapy in the NCRI Myeloma XI trial. In this study patients were randomised between thalidomide (CTD) and lenalidomide (RCD) based induction therapies. For patients with a sub-optimal response to initial therapy, induction was supplemented with sequenced bortezomib-based induction (CVD). Intensively treated patients then proceeded to an autologous transplant and then responding patients from both intensive and non-intensive arms were subsequently randomised to maintenance with lenalidomide monotherapy, lenalidomide and vorinostat or no further therapy. Bone marrow aspirates were obtained prior to maintenance randomisation (100 days post ASCT for TE and at the end of (sequenced-) induction treatment for TNE) and 6 months post maintenance randomisation. This analysis represents a subset of 389 patients (median age 63.5 years) with an informative post maintenance randomisation bone marrow aspirate. MRD was assessed using flow cytometry (sensitivity 0.004%) with a minimum of 500,000 cells evaluated with six- or eight-colour antibody combinations including CD138/CD38/CD45/CD19/CD56/CD27 in all cases and CD81/CD117 added latterly. Results. Taking the group as a whole, MRD-negativity was demonstrated in 206/389 (55.8%) and this was associated with a significant outcome advantage as the median PFS was 〉50 months versus 20 months for MRD-positive patients (Fig.1(a), p