ALBERT

Description: Background: Maximising response in myeloma (MM) patients with effective induction regimens prior to autologous stem cell transplant (ASCT) improves progression-free and overall survival. Triplet regimens combining an immunomodulatory agent (IMiD) and/or proteasome inhibitor (PI) are standard of care, however a more personalised approach is achieved by sequential triplet combinations based on an individual's response. Alternatively, quadruplet regimens may be more effective and new generation PIs such as carfilzomib, with less off-target activity, provide the opportunity to investigate this whilst minimising the risk of increased toxicity. The UK NCRI Myeloma XI trial is a large, phase III study aiming to answer these questions in transplant eligible (TE) patients comparing the quadruplet carfilzomib, cyclophosphamide, lenalidomide and dexamethasone to the sequential strategy of triplet IMiD combinations (with thalidomide or lenalidomide) followed by additional PI triplet therapy for those with a suboptimal response (

Description: Introduction Up-front autologous stem cell transplantation (ASCT-1) post front line therapy with novel agents is standard of care in newly diagnosed multiple myeloma. The role for salvage transplantation (ASCT-2) in relapsed patients after retreatment remains unclear in the era of the novel agents. Majority of published studies include patients treated in pre-thalidomide era. Our retrospective study investigates the safety and efficacy of ASCT-2 in patients exclusively treated with novel drugs both at upfront and at relapse. Primary end point was non relapse mortality (NRM) at day 100. Secondary end points were progression free survival from ASCT-2 (PFS-2) and overall survival (OS) Patients and Methods Thirty-nine patients (21 female and 18 male) underwent ASCT-2 at 4 centres between 2008 and 2013. At initial presentation all received thalidomide based treatments pre ASCT-1. Therapy at progression was bortezomib based in 92% and thalidomide in 8%. Melphalan 200 mg/m2 was used as conditioning for 90% of patients, 140 mg/m2 in 10%. OS and PFS-2 were calculated from ASCT-2. Statistical analysis was carried out using IBM SPSS 19 for Windows. Results Median progression free survival (PFS-1) post ASCT-1 was 35 (10-90) months with 4 patients receiving thalidomide maintenance. Median age at ASCT-2 was 60 (37-68) years with a median stem cell dose of 2.7×106 (2-7) CD34 cells /kg body weight. All patients engrafted with median times to neutrophil (〉0.5) and platelet (〉20) engraftment of 12 days each with a day+100 and 1 year NRM of 0%. With a median follow up from ASCT-2 of 18 (3-52) months, the median PFS-2 was 18 (12-24) months and OS was 42 (33-50) months. PFS-1 of greater than 18 months was associated with prolonged PFS-2 (19 vs. 6 months, p=0.001, log rank), however there was no statistical difference observed for PFS-1 beyond 24 months. Similarly PFS-1 〉18 months predicted for improved OS (39 vs. 14 months, p=0.007, log rank). Age at ASCT-2(〉or 60 and with PFS-1 of 〉24 months had a median PFS-2 of 25months as compared to 14 months in patient age 24 months. Conclusion In the era of novel agents ASCT-2 can be safely delivered with 0% 1 year NRM. PFS-1 greater than 18 months gives better PFS-2 and OS suggesting a definite role of this therapy in a selected population Age greater than 60 years does not have adverse impact on either PFS or OS. Thus ASCT-2 should be considered in treatment strategies at disease progression and warrants further prospective studies Disclosures: No relevant conflicts of interest to declare.

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: Immunomodulatory (IMiD) compounds are effective therapies for multiple myeloma (MM) acting via modulation of the CUL4 E3-ubiquitin ligase cereblon. Based on their structure individual IMiD compounds have different substrate specificities altering both their efficacy and side effect profile. These mechanistic differences impact the optimum sequencing of these agents as induction and maintenance. Within the UK NCRI Myeloma XI trial we compared triplet induction regimens containing Lenalidomide (Len) or Thalidomide (Thal) and maintenance treatment with Len or observation. With extensive long term follow up data we have explored the interaction of the induction and maintenance use of Thal and Len before and after ASCT. Methods: Myeloma XI is a multicenter, randomized controlled trial for newly diagnosed MM, with pathways for transplant eligible (TE) and non-eligible patients. TE patients were randomized between Len or Thal plus cyclophosphamide and dexamethasone (CRD vs CTD) continued for a minimum of 4 cycles and to max. response. For patients with a suboptimal response there was a subsequent randomization to intensification with a proteasome inhibitor containing triplet or no further therapy prior to ASCT. A maintenance randomization at 3 months post ASCT compared Len till disease progression vs observation (Obs). Analyses by molecular risk strata were pre-specified in the protocol. Adverse cytogenetic abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), or del(17p): standard risk (SR, no adverse cytogenetic abnormalities), high risk (HiR, one adverse cytogenetic abnormality), or ultra-high risk (UHiR, two or more adverse cytogenetic abnormalities). Results: 2042 TE patients were randomized to CRD n=1021 and CTD n=1021. After a median follow up of 68 months (interquartile range 49-83) for the induction randomization, 1378 PFS and 728 OS primary endpoint events had occurred. Patients received a median (range) of 5 (1-18) cycles of CRD and 5 (1-13) cycles of CTD induction therapy. There were higher rates of haematological toxicity with CRD and peripheral neuropathy with CTD. CRD induction was associated with a significantly improved median PFS (hazard ratio (HR) 0.86, 95%CI 0.77, 0.96, CRD 36 months vs CTD 33 months, P=0.005, Figure 1A) and median OS (HR 0.81, 95%CI 0.70, 0.93, CRD 96 months vs CTD 85 months, P=0.004, Figure 1B). Responses were deeper with CRD (〉=VGPR 65.3%, PR 24.5%) than CTD (〉=VGPR 52.8%, PR 33.2%) and depth of response was associated with outcome. Significant heterogeneity in PFS outcome was identified between molecular risk groups with HiR and UHiR benefiting most from induction with CRD rather than CTD (SR HR 0.99 [95%CI 0.79, 1.24], HiR HR 0.58 [0.44, 0.78], UHiR HR 0.60 [0.38, 0.94], P.het 0.01). 897 TE patients were randomized to Len (n=496) and Obs (n=401). After a median follow up of 68 months (interquartile range 51-84) for the maintenance randomization, 527 PFS primary endpoint events had occurred. Lenalidomide was associated with a significant improvement in PFS compared to observation (median PFS Len 64 [54,76] vs Obs 32 [28,36], HR 0.52 [0.45,0.61], P

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: Background Lenalidomide is an effective treatment for myeloma and has been studied in a range of combination regimens worldwide. The results of these studies have suggested that prolonged exposure to lenalidomide is important to improve outcomes both as a maintenance agent post-transplant (Attal M et al NEJM 2012, McCarthy et al NEJM 2012) and in the transplant ineligible population (Palumbo A et al NEJM 2012, Benboubker L et al NEJM 2014). In the Myeloma XI study, the largest of its kind, we explored the use of oral lenalidomide continued to disease progression compared to no therapy in both newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) populations. Here we present the results of this maintenance randomization, which demonstrate the efficacy and safety of maintenance lenalidomide. Methods The Myeloma XI study is a Phase III, UK-based, multicenter, open-label, parallel group, randomized controlled trial for newly diagnosed symptomatic myeloma patients of all ages and includes a maintenance comparison of lenalidomide versus no maintenance. Newly diagnosed symptomatic myeloma patients both TE and TNE were enrolled to the study. Induction treatment in both pathways was with thalidomide or lenalidomide plus cyclophosphamide and dexamethasone, with appropriate dose reductions for TNE patients. TE patients proceded to a standard melphalan 200mg/m2 transplant. Patients were randomized to either maintenance lenalidomide or observation after achieving maximum response (TNE) or at 100 days after transplant (TE). Lenalidomide was administered at a dose of 10mg daily in 21/28 day cycles until disease progression. Dose adjustments for renal impairment and following AEs were permitted. The primary endpoints for the maintenance randomization were progression-free (PFS) and overall survival. Secondary endpoints included response, toxicity and PFS2. Time-to-event endpoints were measured from maintenance randomization. This abstract summarizes a preliminary analysis, final data will be presented at the meeting. The median follow up in this analysis is 26 months [IQR 12-41]. Results A total of 1550 patients, 828 TE and 722 TNE, median age 61 and 74 years, respectively, were randomized between lenalidomide (n=857) and no maintenance (n=693). The arms were well-balanced for clinical features and response to induction therapy (e.g. ISS stage III: 27% vs 23%, VGPR/CR: 73% vs 73%). The maintenance randomization has met its primary endpoint demonstrating a 55% reduction in risk of progression or death for lenalidomide compared to no maintenance (HR 0.45 [95%CI 0.39-0.52], median PFS 37 vs 19 months, p

Description: Background The Myeloma XI study is the first randomized study to investigate a response-adapted approach to induction therapy for newly diagnosed myeloma (NDMM). The study addresses whether, for patients achieving less than optimum response to an initial immunomodulatory (IMiD) triplet combination, defined as at least VGPR, the use of a sequential proteasome inhibitor (PI) based triplet can improve outcomes. In total 581 patients were randomized into the study which confirms the clinically significant benefit of deepening responses by utilizing treatment with a different mode of action, and that this leads to better outcomes. Methods This phase III, UK-based, multicenter, open-label, parallel group, randomized controlled trial for NDMM patients of all ages, randomized patients initially between a thalidomide or lenalidomide triplet combination with cyclophosphamide and dexamethasone. This IMiD triplet was continued for a minimum of 4 cycles (transplant eligible, TE) or 6 cycles (transplant non-eligible, TNE) and to maximum response. At the end of this IMiD regimen response was assessed. Patients with a suboptimal response (MR/PR) were randomized between further induction therapy with bortezomib, cyclophosphamide and dexamethasone (CVD) or no further induction therapy. Patients with a good response (VGPR/CR) proceeded straight to ASCT (if TE), whilst refractory (SD/PD) patients all received the CVD regimen. For patients receiving CVD, treatment was planned to continue to maximum response, and eligible patients would proceed to ASCT. The primary endpoints of the adapted approach randomization were progression-free survival (PFS) and overall survival. Secondary endpoints included upgrading of response compared to baseline and the impact of the PI combination in a high-risk subgroup. This abstract contains a preliminary analysis, final data will be presented at the meeting. The median follow up in this analysis is 29 months [IQR 17-44]. Results 581 patients (366 TE, 215 TNE) with initial response to IMiD of MR/PR were entered into the CVD randomization. In total 292/581 patients were randomized to receive sequential treatment with CVD. The arms were well-balanced with respect to clinical features and response (e.g. ISS stage: III 21% vs 19%, PR: 88% vs 88%). This randomization has met its primary endpoint. Overall the sequential use of CVD significantly improved PFS from a median of 24 to 30 months (HR 0.67 [95%CI 0.53-0.85], p=0.0005). This was largely due to a significant improvement seen in the TE pathway, HR 0.56 [95%CI 0.40-0.77], median PFS no therapy 31 months vs CVD 55 months, p=0.0003. In the TNE pathway there was an early benefit with improved median PFS 14 months vs 20 months, but similar hazard after 2 years (HR 0.83 [95%CI 0.60-1.17], p=0.297). Importantly upgrading of response was seen with 118/289 (41% [95%CI 35-47]) of evaluable patients who received CVD moving from MR/PR to VGPR/CR. 115/289 remained in the same response category MR/PR, but these patients still had a mean reduction in paraprotein during CVD of 24% [95%CI 11-17]. The upgrade in response was seen in both pathways and was not affected by the IMiD received in the initial induction randomization. The impact of CVD in cases with molecularly defined high-risk disease compared to standard and multiparameter flow cytometry assessment of minimal residual disease status will be presented at the meeting. In the transplant eligible pathway an improved depth of response persisted in the 253 patients completing ASCT with VGPR/CR responses post ASCT of 65% for those who were randomized to CVD (VGPR n=133, CR n=86) compared to 38% for those who went straight to transplant (VGPR n=120, CR n=46). Sequential CVD was well tolerated with patients receiving a median of 4 cycles of therapy (range 1-8). Relevant grade 3/4 toxicities were: neutropenia 7.1%, thrombocytopenia 7.5%, anaemia 3.1%, peripheral neuropathy 5.1%. Conclusion For the first time we have shown that the use of a response-adapted therapy based on the use of chemotherapeutic agents with a different mode of action in myeloma can improve response rates, both pre- and post-transplant and that these translate into improved PFS. On behalf of the NCRI Haem-Onc CSG Disclosures Jackson: Roche: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau. Davies:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Pawlyn:Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy. Jones:Celgene: Honoraria, Research Funding. Kishore:celgene: Other: travel grant. Garg:Janssen: Other: Travel support, Research Funding, Speakers Bureau; Takeda: Other: Travel support; Novartis: Other: Travel support, Research Funding. Williams:Takeda: Honoraria, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Karunanithi:Celgene: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding. Lindsay:Novartis: Other: Travel support; Janssen: Consultancy; Takeda: Other: Travel support; BMS: Consultancy, Other: Travel support; Celgene: Honoraria, Other: Travel support. Jenner:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel support. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kaiser:BMS: Consultancy, Other: Travel Support; Takeda: Consultancy, Other: Travel Support; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen:Takeda: Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Other: Travel support. Morgan:Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding.

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: Background Primary refractory myeloma is an important therapeutic challenge; understanding its clinical course and biology is essential if we are to recognize it early and target it therapeutically. Immunomodulatory (IMiD) drugs are widely used as induction therapy with good response rates but a small proportion of patients are refractory. The mechanism underlying IMiD resistance is poorly defined. Mutations in the cereblon pathway are a clear candidate but have not been widely looked for or reported. An important question is whether the primary refractory clone carries class-specific intrinsic resistance biology, leaving it sensitive to other non-cross reactive drugs, or if it is a universal resistance mechanism. We have examined the clinical course of patients with primary IMiD resistance, and whether they respond adequately to subsequent proteasome inhibition (PI), using the results of the largest clinical study in myeloma to date. Methods Myeloma XI is a UK based, open-label, parallel group, randomized controlled trial for newly diagnosed symptomatic myeloma patients of all ages. Treatment was with a combination of cyclophosphamide and dexamethasone plus either lenalidomide or thalidomide (CRD or CTD) for a minimum of 4 cycles (transplant eligible, TE) or 6 cycles (transplant non-eligible, TNE) or to maximum response. Those patients who had not achieved at least a minimal response or who had progressed during induction (PD) subsequently received a PI triplet (cyclophosphamide, bortezomib and dexamethasone, CVD). This abstract summarizes a preliminary analysis of these primary refractory cases, final data will be presented at the meeting. Results The study randomized 3894 patients of all ages giving adequate numbers to identify clinical/biological features in subgroups. Overall 207/3894 (5.3%) of patients had stable disease (SD) or PD at the end of the IMiD triplet. There was no significant difference between those who received thalidomide compared to lenalidomide (CTD: 110/1945, 5.7% CRD: 97/1949, 5.0%). A higher proportion of patients were refractory in the TNE pathway than TE (TE: 79/2042, 3.9%, TNE: 128/1852, 6.9%) 139 patients in the ITT population went on to receive treatment with bortezomib as part of the CVD regimen. The remainder n=69 were treated off protocol or died prior to treatment. CVD was well-tolerated in these patients with a median of 4 (1-8) cycles delivered. Of these patients 22/139 (16%) were also refractory to PI therapy whilst 57% upgraded their response compared to baseline: 32% [95%CI 24-40] to PR/MR and 25% [95%CI 18-33] to CR/VGPR. Patients with IMiD refractory disease had a significantly shorter PFS than those who responded to initial treatment median 8 vs 27 months, HR 2.10 [95% CI 1.77-2.49], p20% plasma cells in their bone marrow biopsy. There was a higher proportion of patients with light chain only disease and the percentage of patients with ISS stage III was double-refractory 41%, IMiD refractory 45% and responsive 29%. The proportions of patients with adverse translocations and high-risk copy number abnormalities will be presented at the meeting. Conclusions We present the first detailed analysis of IMiD refractory myeloma patients at diagnosis. There was no difference in the percentage of patients refractory to the different IMiDs thalidomide and lenalidomide. Very few patients were primarily refractory to both IMiDs and proteasome inhibitors, suggesting the mechanisms of primary resistance to IMiDs and PIs do not significantly overlap. However, where this did occur outcomes were poor. The biological mechanisms behind resistance will be further informed by molecular studies of these patients' tumour samples. On behalf of the NCRI Haem Onc CSG Disclosures Pawlyn: Takeda Oncology: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support. Davies:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:Takeda: Consultancy, Other: Travel Support; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy. Jones:Celgene: Honoraria, Research Funding. Kishore:celgene: Other: travel grant. Garg:Janssen: Other: Travel support, Research Funding, Speakers Bureau; Takeda: Other: Travel support; Novartis: Other: Travel support, Research Funding. Williams:Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau; Takeda: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Karunanithi:Celgene: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding. Lindsay:BMS: Consultancy, Other: Travel support; Novartis: Other: Travel support; Takeda: Other: Travel support; Janssen: Consultancy; Celgene: Honoraria, Other: Travel support. Jenner:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel support; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel support. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen:Takeda: Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Other: Travel support. Jackson:Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Morgan:Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Univ of AR for Medical Sciences: Employment; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Description: We recently demonstrated that the NF-kB subunit Rel A is associated with in vitro survival and clinical disease progression in CLL. We therefore hypothesized that Rel A would have prognostic significance in this disease. Rel A DNA binding was quantified in nuclear extracts derived from 131 unselected CLL patient samples using a quantitative DNA binding ELISA-based method. We tested the ability of Rel A to predict for the requirement for treatment and survival and compared our findings with other established prognostic markers. Rel A DNA binding was strongly associated with advanced Binet stage (P