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Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis–relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.

The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include maximizing response and the use of maintenance therapy. We used whole exome sequencing to study the genetics of paired samples taken at presentation and at relapse from 56 newly diagnosed patients, following induction therapy, randomized to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomization. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterized by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumor suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response, the evolutionary features were predominantly stable with a similar mutational and structural profile seen at both time points. There were no significant differences between patients relapsing after lenalidomide maintenance versus observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse. This trial is registered at clinicaltrials.gov identifier: 01554852.

Background Treatment of relapsed/refractory multiple myeloma (RRMM) remains challenging as durable remissions are achieved in patient sub-groups only. Identifying patients that are likely to benefit prior to or early after starting relapse treatments remains an unmet need. MUKseven is a trial specifically designed to investigate and validate biomarkers for treatment optimization in a 'real-world' RRMM population. Design In the randomized multi-center phase 2 MUKseven trial, RRMM patients (≥2 prior lines of therapy, exposed to proteasome inhibitor and lenalidomide) were randomized 1:1 to cyclophosphamide (500 mg po d1, 8, 15), pomalidomide (4 mg days 1-21) and dexamethasone (40 mg; if ≥75 years 20 mg; d1, 8, 15, 21) (CPomD) or PomD and treated until progression. All patients were asked to undergo bone marrow (BM) and peripheral blood (PB) bio-sampling at baseline, cycle 1 day 14 (C1D14, on-treatment) and relapse. For biomarker discovery and validation, IGH translocations were profiled by qRT-PCR, copy number aberrations by digital MLPA (probemix D006; MRC Holland), GEP by U133plus2.0 array (Affymetrix), PD protein markers by IHC and PB T-cell subsets by flow cytometry for all patients with sufficient material. Primary endpoint was PFS, secondary endpoints included response, OS, safety/toxicity and biomarker validation. Original planned sample size was 250 patients but due to a change in UK standard of care during recruitment with pomalidomide becoming available, a decision was made to stop recruitment early. Results In total, 102 RRMM patients were randomized 1:1 between March 2016 and February 2018. Trial entry criteria were designed to include a real-world RRMM population, permitting transfusions and growth factor support. Median age at randomization was 69 years (range 42-88), 28% of patients had received ≥5 prior lines of therapy (median: 3). Median follow-up for this analysis was 13.4 months (95% CI: 12.0-17.5). 16 patients remained on trial at time of analysis (median number of cycles: 19.5; range 8-28). More patients achieved ≥PR with CPomD compared to PomD: 70.6% (95% CI: 56.2-82.5%) vs. 47.1% (CI: 32.9-61.5%) (P=0.006). Median PFS was 6.9 months (CI: 5.7-10.4) for CPomD vs. 4.6 months (CI: 3.5-7.4) for PomD, which was not significantly different as per pre-defined criteria. Follow-up for OS is ongoing and will be presented at the conference. High-risk genetic aberrations were found at following frequencies: t(4;14): 6%, t(14;16)/t(14;20): 2%, gain(1q): 45%, del(17p): 13%. Non-high risk lesions were present as follows: t(11;14): 22%, hyperdiploidy: 44%. Complete information on all high-risk genetic markers was available for 71/102 patients, of whom 12.7% had double-hit high-risk (≥2 adverse lesions), 46.5% single-hit high-risk (1 adverse lesion) and 40.8% no risk markers, as per our recent meta-analysis in NDMM (Shah V, et al., Leukemia 2018). Median PFS was significantly shorter for double-hit: 3.4 months (CI: 1.0-4.9) vs. single-hit: 5.8 months (CI: 3.7-9.0) or no hit: 14.1 months (CI: 6.9-17.3) (P=0.005) (Figure 1A). GEP was available for 48 patients and the EMC92 high-risk signature, present in 19% of tumors, was associated with significantly shorter PFS: 3.4 months (CI: 2.0-5.7) vs. 7.4 (CI: 3.9-15.1) for EMC92 standard risk (P=0.037). Pharmacodynamic (PD) profiling of cereblon and CRL4CRBN ubiquitination targets (including Aiolos, ZFP91) in BM clots collected at baseline and C1D14 is currently ongoing. Preliminary results for the first 10 patients demonstrate differential change of nuclear Aiolos (Figure 1C), with a major decrease in Aiolos H-scores in 7/10 patients from baseline to C1D14 and reconstitution at relapse. T-cell PB sub-sets were profiled at baseline and C1D14 by flow cytometry. Specific sub-sets increased with therapy from baseline to C1D14, e.g. activated (HLA-DR+) CD4+ T-cells, as reported at last ASH. CD4+ T-cell % at baseline was associated with shorter PFS in these analyses in a multi-variable Cox regression model (P=0.005). PD and T-cell biomarker results will be updated and integrated with molecular tumor characteristics and outcome. Discussion Our results demonstrate that molecular markers validated for NDMM predict treatment outcomes in RRMM, opening the potential for stratified delivery of novel treatment approaches for patients with a particularly high unmet need. Additional immunologic and PD biomarkers are currently being explored. Disclosures Croft: Celgene: Other: Travel expenses. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Walker:Janssen, Celgene: Other: Research funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Novartis, Janssen: Research Funding; Janssen: Honoraria. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Wang:Celgene Corporation: Employment, Equity Ownership. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Pierceall:Celgene: Employment. Thakurta:Celgene: Employment, Equity Ownership. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy.

Background High-risk myeloma patients have unsatisfactory outcomes with current treatments and are in urgent need of improved diagnostic and therapeutic strategies. We have recently validated specific markers predicting high-risk disease in newly diagnosed MM (NDMM), in particular double-hit with presence of ≥2 consensus high-risk markers t(4;14), t(14;16), t(14;20), del(1p), gain(1q), del(17p) (Shah V, et al., Leukemia 2018) and diagnostic GEP SKY92 high risk signature (Sherborne A, et al., IMW 2017). Diagnostic tests for these markers were implemented in the UK multi-center OPTIMUM: MUK9 trial to prospectively stratify therapy for high-risk NDMM. Trial design OPTIMUM: MUK9 is a phase 2 trial for transplant eligible NDMM, consisting of two inter-related protocols: a molecular screening protocol (MUK9A) and an interventional trial (MUK9B) for high-risk MM identified in MUK9A. Patients with suspected or confirmed MM fit for intensive therapy enrolled in MUK9A have central molecular profiling at ICR, London, of CD138-selected BM MM cells for translocations, copy number aberrations (qRT-PCR; MLPA P425, MRC Holland) and SKY92 signature status (MMprofiler; SkylineDx). If clinically indicated SOC therapy (VTD, max. 2 cycles) can be given whilst central results are generated. Patients found to have high-risk MM by double-hit and/or SKY92 are offered enrolment into MUK9B. All other patients receive SOC (VTD, HD-MEL+ASCT) for which clinical data is collected. Patients diagnosed with plasma cell leukemia (PCL) can be enrolled directly in MUK9B. MUK9B treatment consists of quintuplet daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction (up to 6 cycles), bortezomib-augmented single HD-MEL+ASCT, Dara-VRd consolidation 1 (6 cycles), Dara-VR consolidation 2 (12 cycles) and Dara-R maintenance (until PD). Dose adjustments are permitted in order to maximize tolerability of long-term therapy. Patient reported outcomes (PRO) are recorded at baseline and throughout treatment. Response and MRD are centrally assessed (Birmingham, Leeds). Primary endpoint for MUK9A is feasibility of central molecular testing within 56 days turnaround time, which we report on here. Primary endpoint of MUK9B is treatment efficacy, comparing MUK9B PFS to near-concurrent molecularly matched high-risk patient outcomes from UK NCRI Myeloma XI using a Bayesian design. Secondary endpoints include safety, PFS2, MRD and OS and study of molecular evolution in high-risk disease. Results The protocol recruited 29/Sep/17 - 31/Jul/19 at 39 UK sites, achieving the recruitment target of 105 high-risk patients treated on MUK9B ahead of projections. At the time of analysis (12/Jul/19), 430 patients with suspected or confirmed NDMM have been recruited to MUK9A across 39 UK NHS hospitals. Of these, 376 (87%) patients were confirmed to have symptomatic MM (60.9% male; median age 61y (range 29-79)) as per updated IMWG diagnostic criteria (2014), including 9 (2%) PCL patients, with the remainder diagnosed as SMM/MGUS (31; 7%) or other (14; 3%). For 371 of the 376 symptomatic MM patients BM was received by the central laboratory and was of sufficient quality for profiling in 331 (89%) patients. Repeat samples were requested for all others and a sufficient sample received for 20/45 (44%). Central results were successfully reported within the pre-specified 56 day interval for all patients (median 17 days; IQR 13-22). Of 346 patients with a reported result, 128 (37.0%) have high-risk MM, with molecular characteristics mirroring Myeloma XI patients (Figure 1). PCL patients show expected characteristics as listed in Table 1. Basic demographics were not different between high-risk vs. non-high-risk. 101 high-risk patients have or are planning to enter MUK9B, 10 pending decision; 17 high-risk patients did not enter MUK9B, the majority due to ineligibility. 92 patients have started Dara-CVRD therapy. There are currently no safety concerns, the majority of patients are completing induction successfully; 1 patient stopped induction therapy due to adverse events. Updated results will be presented. Discussion Our data demonstrate feasibility of multi-center molecular stratified trial delivery for high-risk NDMM patients. These early trial results strongly support accelerated trial strategies for MM patient groups with high unmet need and rational drug development specifically for high-risk MM. Disclosures Jenner: Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Walker:Janssen, Celgene: Other: Research funding to Institution. Croft:Celgene: Other: Travel expenses. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses; Celgene, Janssen: Honoraria. Pratt:Binding Site, Amgen, Takeda, Janssen, Gilead: Consultancy, Honoraria, Other: Travel support. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Kaiser:Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses.

Background Mutations of RAF/RAS genes are one of the most common oncogenic events in multiple myeloma. Therapeutic targeting of RAF/RAS/MAPK signalling using small molecule inhibitors has led to significant responses in solid cancers. Recently, combined inhibition of key pathway kinases has demonstrated increased efficacy and decrease toxicity, leading to development of second-generation small molecules with dual inhibitory function. RO5126766 is a potent dual RAF-MEK inhibitor that has demonstrated significant clinical activity with minor toxicities in various solid cancers carrying RAS mutations in a currently ongoing phase I basket study (Trial number NCT204007509; Chenard-Poirier et al. ASCO 2017). Based on the drug's promising efficacy, the trial has been expanded to include myeloma patients with RAF/RAS tumour mutations to provide information on safety and preliminary efficacy in this patient population. We report updated results for RAF/RAS-mutant relapsed and refractory MM patients treated with RO5126766. Methods MM patients with relapsed or relapsed and refractory myeloma whose disease had progressed after at least 3 prior therapies were recruited to the study. All patients had been treated with an IMiD and a proteasome inhibitor and their tumours were confirmed to carry a RAS mutation by sequencing. Patients were treated with RO5126766 4mg twice weekly for 3 out of 4 weeks, in 28 day cycles, with the addition of optional weekly dexamethasone as per investigator's discretion. Response assessment was completed using IMWG criteria and toxicities were reported according to CTCAE version 4.0. Whole body diffusion-weighted MRI every 3 cycles was used for functional imaging disease assessment. Results At the time of analysis, a total of five patients were recruited; one was still receiving cycle 1 of therapy, with the four remaining patients being evaluable at the point of abstract submission. The median age of evaluable patients at initiation of treatment was 74 years (range 70-76). Patients had received median 4 (range 3-5) lines of prior therapy, including autologous stem cell transplant (75%). Three tumours had a KRAS mutation whilst in one tumour, synchronous KRAS and NRAS mutations were found. Three patients received RO5126766 alone, while 1 patient also received weekly concomitant dexamethasone. One patient (KRAS and NRAS mutations) achieved a partial response after 1 cycle of therapy but progressed after 7 months. A second patient achieved stable disease (confirmed biochemically and by functional MRI imaging) with single agent RO5126766 treatment and currently continues on trial having completed 8 cycles of therapy. The two remaining patients progressed after 2 and 1.5 cycles, with the latter patient receiving dexamethasone in combination with RO5126766. The two patients who received 7 and 8 cycles of RO5126766 experienced no clinically significant adverse events (AE), with commonly reported toxicities including grade 1 rash (2/2), grade 1 diarrhoea and grade 1 thrombocytopenia. This is in line with tolerability profile observed in the solid tumour cohorts (n=28 solid tumour patients recruited to date) of this basket trial. One patient developed worsening kidney impairment attributable to disease progression with rising serum free light chains and came off study. Interestingly, ocular toxicities, commonly associated with RAF-MEK inhibitors, were not observed in this patient cohort, which may be related to their dosing schedule. Conclusion In this basket study across RAS mutated tumours, the novel, dual RAF-MEK inhibitor RO5126766 as monotherapy in myeloma patients has shown promising single agent activity. In line with observations in the in parallel recruiting solid tumour cohorts, the dual RAF-MEK inhibitor RO5126766 is generally well tolerated and can be administered as an ongoing therapy. This has been observed in a solid tumour patient who has been receiving RO5126766 for 3.5 years with little and manageable toxicities. Longitudinal patient bone marrow trephine material has been collected and analysis of phospho-protein markers of RAS/MAPK pathway activation for PD biomarker evaluation will be performed. Recruitment to this study continues and data will be updated prior to the conference. Potential single-agent activity of RO5126766 with manageable toxicity grants further evaluation of its use as a molecularly targeted therapy in myeloma. Disclosures Sriskandarajah: Celgene: Other: Travel, Accommodation expenses, Speakers Bureau. Boyd:Celgene: Consultancy, Honoraria, Other: Advisory role; Janssen: Honoraria, Other: Travel and Accommodation expenses; Novartis: Consultancy, Honoraria. Shah:Sanofi: Other: Travel and Accommodation expenses; Celgene: Other: Travel, Accommodation expenses. Hall:Sanofi (Inst): Research Funding; Cambridge Major Laboratories (Inst): Research Funding; Accuray (Inst): Research Funding; Kyowa Hakko Karin (Inst): Research Funding; Astrazeneca (Inst): Research Funding; Bayer (Inst): Research Funding. Tunariu:Janssen: Speakers Bureau; Sanofi: Speakers Bureau. de Bono:Sanofi (Inst): Research Funding; AstraZeneca (Inst): Research Funding; GlaxoSmithKline: Other: Travel, Accomodation expenses; AstraZeneca: Consultancy, Honoraria, Other; Astellas Pharma: Consultancy, Honoraria, Other: Travel, Accommodation expenses; Sanofi: Consultancy, Honoraria, Other: Travel, Accommodation expenses; Genentech/Roche: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Orion Pharma GmBH: Other: Travel, Accommodation expenses; Qiagen: Other: Travel, Accommodation expenses; Taiho Pharmaceutical: Other: Travel, Accommodation expenses; Vertex: Other: Travel, Accommodation expenses; Genentech (Inst): Research Funding; Abiraterone Rewards to Investors (Inst): Patents & Royalties: Abiraterone; PARP inhibitors and DNA repair defects (Inst): Patents & Royalties: PARP inhibitors; Genmab: Other: Travel, Accommodation expenses. Banerji:Institute of Cancer research: Employment; Novartis: Consultancy; Onyx (Inst): Research Funding; Chugai Pharma (Inst): Research Funding; AstraZenca (Inst): Research Funding; Astex Pharmaceuticals: Consultancy. Kaiser:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Other: Travel Support; Bristol-Myers Squibb: Consultancy, Other: Travel support; Chugai: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

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 RESULTS In M-IX, 283 (25.8%) of transplant-eligible (TE) patients had PFS ≥48m whereas 58 (7%) of transplant non-eligible (TNE) patients reached PFS≥48m. In M-XI 410 (34.2%) patients had PFS≥48m for TE and 116 (10.2%) for TNE. Extended progression free survival translated to overall survival (OS) benefit with a median post progression OS of 36.9m for PFS≥48m vs 16.7m for PFS Clinical factors including ISS I (P The proportion of patients with a high risk lesion (Adverse translocation, Gain(1q) or Del(17p)) were lower in the PFS≥48m group than The majority of patients with PFS ≥48m showed ≥VGPR after induction +/- consolidation: 211 (76.4%) and 340 (84%) of PFS ≥48m patients in the TE arms and 26 (49.1%) and 87 (76.3%) in the TNE arms of M-IX and M-XI, respectively. 86.7% of patients who achieved a ≥VGPR had a PFS ≥48m in the absence of high risk lesions compared to 72.8% with any high risk lesion present (P=0.004). Some patients with PFS≥48m had only reached PR after induction; 56 (20.3%) and 57 (14.1%) of PFS ≥48m patients in the TE arm and 15 (28.3%) and 24 (21.1%) in the TNE arms of M-IX and M-XI, respectively. Baseline factors that were associated with still being able to achieve PFS≥48m from induction after only achieving a PR included the lack of high risk genetic lesions (P CONCLUSIONS Response assessment after induction+/-HD-Mel consolidation with baseline factors can define a patient group with superior outcomes in both TE and TNE patients and may influence future treatment strategies of MM patients undergoing first line therapy. Further analyses including modelling of predictors of response duration are ongoing and will be presented at the conference. Disclosures Shah: Celgene: Other: Travel, Accommodation expenses; Sanofi: Other: Travel and Accommodation expenses. Striha:Janssen: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; MSD: Research Funding; Amgen: Research Funding. Hockaday:Celgene: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; MSD: Research Funding; Millenium: Research Funding. Pawlyn:Celgene Corporation: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel Support; Janssen: Honoraria, Other: Travel support; Takeda Oncology: Consultancy, Other: Travel support. Jenner: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; 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. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel Support; Janssen: Consultancy, Other: Travel Support. Gregory:Celgene: Consultancy, Honoraria, Research Funding; Merck Sharp and Dohme: Research Funding; Janssen: Honoraria; Amgen: Research Funding. Morgan:Janssen: Research Funding; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Davies:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cairns:Celgene: Research Funding; Amgen: Research Funding; Merck Sharp and Dohme: Research Funding. Jackson:Roche: Consultancy, Honoraria, Speakers Bureau; Merck Sharp and Dohme: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau. Kaiser:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Other: travel support; Janssen: Consultancy, Honoraria; Chugai: Consultancy; Bristol-Myers Squibb: Consultancy, Other: travel support; Celgene: Consultancy, Honoraria, Research Funding.

Background and aims Treatment of relapsed/refractory myeloma (RRMM) remains a challenge as most approved and commonly accessible doublet treatments induce responses (≥PR) in less than half of patients. The combination of the classical alkylator cyclophosphamide with thalidomide (CTD) or lenalidomide (CRD) is standard of care in early lines of therapy in the UK and elsewhere. Data on the clinical value of cyclophosphamide and pomalidomide combination therapy in RRMM is currently sparse and lacking for patients that have previously been treated with cyclophosphamide in earlier lines of therapy. Material and Methods MUKseven is a randomised phase II study for RRMM patients comparing cyclophosphamide (500 mg po d1, 8, 15), pomalidomide (4 mg days 1-21) and dexamethasone (40 mg; if ≥75 years 20 mg; d1, 8, 15, 21) (CPd) versus standard pomalidomide and dex (Pd). Patients with ≥2 prior lines of therapy were randomised 1:1 to receive either CPd or Pd and treated until progression. The primary endpoint of the study is PFS, secondary endpoints include response, OS and safety and toxicity. Patients underwent bone marrow sampling and peripheral blood collection at baseline, on treatment and at relapse to correlate outcomes with disease biology. The original sample size was 250 patients but due to approval of pomalidomide by the UK funding agency NICE mid-recruitment, and resulting low enrolment rates, a decision was made to close the trial early. Results In total 102 evaluable RRMM patients were randomised between March 2016 and February 2018, 51 each to CPd and Pd treatment arms that were comparable regarding age, gender, ISS and ECOG performance status. Patients had received a median of 3 prior lines of therapy (range 2-8); all had been treated with proteasome inhibitors and lenalidomide and 94% of patients had received cyclophosphamide as part of earlier lines of therapy. Trial entry criteria were permissive and allowed ongoing red cell, platelet and growth factor support to reflect real-world practice in RRMM - 11% of patients required platelet and 16% G-CSF support before starting trial therapy. Treatment with CPd was associated with a significantly higher response rate (≥PR) of 68.6% (95% CI: 54.1 - 80.9%) compared to 47.1% (CI: 32.9 - 61.5%) for Pd (P=0.018). Five patients (9.8%) on CPd treatment reached CR vs. none with Pd therapy (Table 1). PFS data is currently maturing and will be presented at the conference. At the time of abstract submission 20 patients were still on trial treatment and 22.5% of evaluable patients had received trial therapy for 12 months or longer. Anaemia, fatigue and infection of any grade were common side effects and similar in frequency between treatment arms, whereas higher grade cytopenias were more frequent with CPd than Pd. More patients experienced at least one SAE with CPd treatment (44 patients) than with Pd (36 patients). Over 80% of SAEs suspected to be related to study drug for CPd and Pd arms were infections or cytopenias requiring admission for iv therapy. Five patients on the CPd arm and 4 patients on Pd discontinued therapy due to toxicity. Site and patient adherence to central bone marrow and peripheral blood collection was high with 92% of baseline samples, 87% at C1D14, 87% at C4D14 and 43% of samples at relapse received by central laboratories. High risk genetic lesions gain(1q), del(17p) and adverse translocations t(4;14), t(14;16) and t(14;20) were profiled, amongst other changes, using molecular assays (digital MLPA, TaqMan). Of the 66 patients for whom complete results were available at the point of abstract submission, 48.5% were found to have 1 high risk lesion and 13.6% ≥2 high risk lesions ("double-hit"). The best response achieved in patients with double hit tumours was PR in 1 out of 9 evaluable patients. Further genetic profiling and related exploratory analyses are ongoing. Discussion The combination of cyclophosphamide, pomalidomide and dexamethasone significantly increases response rates and depth of response compared to pomalidomide and dexamethasone in RRMM patients, even those that have already been exposed to cyclophosphamide combination therapy in previous lines of therapy. Primary endpoint PFS data for CPd vs. Pd will be presented at the conference. Analyses of outcomes in the context of molecular profiles are ongoing and will be presented at the conference. Disclosures Pawlyn: Celgene Corporation: Consultancy, Honoraria, Other: Travel support; Takeda Oncology: Consultancy, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel Support; Janssen: Honoraria, Other: Travel support. Garg:Amgen: Honoraria, Other: Travel Support; Novartis: Other: travel support, Research Funding; Janssen: Honoraria; Takeda: Other: Travel Grant. Boyd:Novartis: Consultancy, Honoraria; Janssen: Honoraria, Other: Travel and Accommodation expenses; Celgene: Consultancy, Honoraria, Other: Advisory role. Cook:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau. Kaiser:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Other: travel support; Bristol-Myers Squibb: Consultancy, Other: travel support; Janssen: Consultancy, Honoraria; Chugai: Consultancy; Celgene: Consultancy, Honoraria, Research Funding.

Introduction With a multifactorial mechanism of action and excellent PFS associated with prolonged exposure, lenalidomide (len) is an attractive candidate for maintenance therapy. Len exerts its action by interaction with cereblon (CRBN) which forms a ubiquitin ligase complex with cullin-4A (CUL4), damaged DNA binding protein 1 (DDB1) and regulator of cullins 1 (ROC1). Downstream effects are mediated via Ikaros, Aiolos, MYC, IRF4, basigin (BSG) and solute carrier family 16 member 1 (SLC16A1). The impact of selective pressure on MM clonal architecture and mutational load has not been assessed. Although not a DNA damaging agent there is an apparent effect of maintenance len increasing the risk of second cancers and a suggestion that it could select for aggressive clones in high risk disease. We addressed the hypothesis that len may increase the rate of mutation at relapse by performing whole exome sequencing (WES) on 70 paired presentation/relapse samples from patients enrolled to the Myeloma XI trial (MXI), 35 of whom received maintenance Len and 35 not. Methods WES was performed to a median depth of 125x on 70 presentation/relapse pairs from patients enrolled to the MXI trial. MXI is a phase III study comparing thalidomide, len and bortezomib induction combinations and len vs observation maintenance treatment in both transplant eligible (TE) and transplant non-eligible (TNE) NDMM patients. We selected patients who had completed induction +/- ASCT and been randomised to receive maintenance therapy with len or observation. All patients had disease progression determined by IMWG criteria at the time of the relapse sample. Of the 70 patients, 30 were enrolled in the TE pathway and 40 in the TNE pathway. The median time to relapse following maintenance randomisation was 323 days (296 len vs 325 observation). 35 patients (50%) achieved a CR as their best response, 26 (37%) a VGPR and 9 (13%) a PR. The median age was 66 and 69 for those receiving len and those being observed respectively. High risk disease status was confirmed in 33 (47%) patients at presentation (≥ 1of t(4;14), t(14;16), t(14;20), +1q, -17p, -1p). Results The median number of non-silent mutations (NSM) found at presentation and relapse was 37 and 41 respectively (p=0.25). In patients receiving len maintenance the median number of NSM at presentation was 37 vs 34 at relapse (p=0.69). In those being observed the median number of NSM at presentation was 42 vs 52 at relapse (p=0.21). Mutations in genes important in myeloma pathogenesis seen in more than one patient at presentation included KRAS (16), NRAS (14), DIS3 (6), HIST1H1E (2), RB1 (2), EGR1 (2), TP53 (2) and FAM46C (2). These were seen in a total of 37 (53%) patients. One patient had both an NRAS and KRAS mutation. At relapse 7 patients lost mutations (NRAS (3), KRAS (3), DIS3 (1)) and 6 patients gained mutations (KRAS (2), NRAS (2), TP53 (1), FAM46C(1)). Paired presentation/relapse copy number (CN) data (MLPA) was available for 38 patients (54%). At relapse there was evidence of a change in CN status with 5 (13%) patients gaining CN changes associated with high risk (gain 1q (4), del 17p (1). Six patients (9%) were found to have mutations in genes associated with len action; CRBN (1), IRF4 (1), DDB1 (2), SLC16A1 (2). No mutations were found in Ikaros, Aiolos, ROC1, CUL4 or BSG. The CRBN mutation was found at relapse only, in a patient who had achieved a CR and undergone 232 days of len maintenance. The IRF4 mutation was seen at presentation and relapse in a patient who achieved CR and received 754 days of len prior to relapse. Both patients with DDB1 mutations received len induction, ASCT, achieved CR and were randomised to observation. In one patient the mutation was seen at presentation and relapse whilst in the other only at relapse. Both patients with mutations in SLC16A1 were treated with len induction and ASCT to CR. In one patient, randomised to observation the mutation was seen at both time points and they relapsed after 156 days. The other, with the mutation present at presentation only was randomised to len maintenance and relapsed after 256 days. Conclusions This is the largest study comparing the genetics of presentation/relapse myeloma in a len treated population. Overall, the number of mutations at presentation vs relapse remained stable. We show that len does not affect the mutational load at relapse but may select for mutations conferring len resistance although at present further analysis is required to confirm this. Disclosures Jones: Celgene: Honoraria, Research Funding. Pawlyn:Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy. Cook:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jenner:Amgen: Consultancy, Honoraria, Other: Travel support; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel support. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:BMS: Consultancy, Other: Travel Support; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Chugai: Consultancy. Jackson:Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment.

Introduction A significant proportion of myeloma patients relapse early and show short survival with current therapies. Molecular diagnostic tools are needed to identify these high risk patients at diagnosis to stratify treatment and offer the prospect of improving outcomes. Two validated molecular approaches for risk prediction are widely used: 1) molecular genetic risk profiling [e.g. del(17p), t(4;14)] 2) gene expression (GEP) risk profiling, [e.g. EMC92 (Kuiper et al., Leukemia 2012)]. We profiled patients from a large multicentric UK National trial using both approaches for integrated risk stratification. Methods A representative group of 221 newly diagnosed, transplant eligible patients (median age 64 years) treated on the UK NCRI Myeloma XI trial were molecularly profiled. DNA and RNA were extracted from immunomagnetically CD138-sorted bone marrow plasma cells. Molecular genetic profiles, including t(4;14), t(14;16), Del(17p), Gain(1q) were generated using MLPA (MRC Holland) and a TC-classification based qRT-PCR assay (Boyle EM, et al., Gen Chrom Canc 2015, Kaiser MF, et al., Leukemia 2013). GEP risk status as per EMC92 was profiled on a diagnostic Affymetrix platform using the U133plus2.0-based, CE-marked MMprofiler (SkylineDx) which generates a standardised EMC92 risk score, called 'SKY92'. Progression-free (PFS) and overall survival (OS) were measured from initial randomization and median follow-up for the analysed group was 36 months. Statistical analyses were performed using R 3.3.0 and the 'survival' package. Results were confirmed in an independent dataset, MRC Myeloma IX, for which median follow-up was 82.7 months. Results Of the 221 analysed patients, 116 were found to carry an established genetic high risk lesion [t(4;14), t(14;16), del(17p) or gain(1q)]. We and others have recently demonstrated that adverse lesions have an additive effect and that co-occurrence of ≥2 high risk lesions is specifically associated with adverse outcome (Boyd KD et al, Leukemia 2011). 39/221 patients (17.6%) were identified as genetic high risk with ≥2 risk lesions (termed HR2). By GEP, 53/221 patients (24.0%) were identified as SKY92 high risk. Genetic and GEP high risk co-occurred in 22 patients (10.0%), 31 patients (14.0%) were high risk only by GEP and 17 patients (7.7%) by genetics only. SKY92 high risk status was associated with significantly shorter PFS (median 17.1 vs. 34.3 months; P Importantly, by multivariate analysis GEP and genetic high risk status were independently associated with shorter PFS (P We next investigated interactions between genetic and gene expression high risk status. Three groups were defined: 1) Patients with both SKY92 and genetic (HR2) high risk status (n=22), 2) either GEP or genetic high risk (n=48) or 3) absence of GEP or genetic (HR2) high risk status (n=151). Co-occurring GEP and genetic high risk status was associated with very short PFS (median 12.5 vs. 20.0 vs. 38.3 months; P We confirmed this finding in 116 transplant-eligible patients from the MRC Myeloma IX trial. Patients carrying both EMC92 and genetic high risk status had a median PFS of 7.8 vs. 25.5 months and median OS of 9.5 vs. 62.1 months (both P Conclusion We demonstrate, for the first time, that combined genetic and gene expression risk profiling identifies a group of patients with ultra-high risk disease behaviour with high fidelity, using molecular features of the disease. Our results indicate that GEP and genetic high risk profiling identify independently relevant, but inter-related features of high risk disease biology. Integrated genetic and gene expression risk profiling could serve as a valuable tool for risk stratified, innovative treatment approaches in myeloma. Figure Figure. Disclosures Jones: Celgene: Honoraria, Research Funding. Pawlyn:Takeda Oncology: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support. Jenner:Amgen: Consultancy, Honoraria, Other: Travel support; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding. Cook:Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Davies:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Morgan:Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Univ of AR for Medical Sciences: Employment; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Jackson:Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Kaiser:Takeda: Consultancy, Other: Travel Support; Amgen: Consultancy, Honoraria; BMS: Consultancy, Other: Travel Support; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy.