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Background The most common cause of severe renal impairment in myeloma (MM) is the direct effect of a high concentration of nephrotoxic monoclonal free light chains (LC) leading to MM cast nephropathy. Decreasing LC and therefore improving renal function is important for long term outcome. In the UK NCRI Myeloma XI trial the addition of the second generation PI carfilzomib (K) to the immunomodulatory agent (IMiD) lenalidomide, cyclophosphamide and dexamethasone (Rdc) improved progression-free survival (PFS) in newly diagnosed MM patients (NDMM) eligible for autologous stem cell transplant (ASCT) (median PFS KRdc not reached (NR) v Rdc 36 months HR 0.66 (95% CI 0.52, 0.83, P=0.0004). This exploratory subgroup analysis compares PFS and renal recovery between patients receiving KRdc and Rdc within renal function subgroups. Methods Myeloma XI is a phase III, randomized controlled trial with an adaptive design for symptomatic NDMM patients of all ages. This renal analysis is of the transplant eligible (TE) pathway and compares induction treatment with the quadruplet KRdc to triplet Rdc. Patients were randomized contemporaneously 2:1. All patients were randomized to post-ASCT R maintenance or observation. For further exploratory analysis patients randomized earlier in the study to Rdc were also included. Relevant exclusion criteria were acute renal failure non-responsive to 72 hours rehydration (creatinine >500umol/L, urine output =60 ml/min/1.73m2, moderately impaired 30-59 or severely impaired =500mg/L between the involved and uninvolved (dFLC). Renal recovery was defined as an improvement in eGFR of ≥25% at the end of induction therapy. Results 1547 patients were randomized to KRdc n=526 or Rdc n=1021 (265 contemporaneous, 756 not). In the contemporaneous group baseline renal function was normal in 609/791 (77.0%), moderately impaired in 141/791 (17.8%) and severely impaired in 40/791 (5.1%) (data n/a in 1 patient). Patients with moderately or severely impaired renal function had shorter PFS compared to those with normal renal function. Subgroup analysis showed consistent outcomes for KRdc compared to Rdc across all renal subgroups with no evidence of significant heterogeneity (Figure 1, Phet=0.9354). Further exploratory analysis combined patients with moderate or severe renal impairment into one group. Difference in PFS and renal recovery between patients with normal or impaired renal function and high (>=500) or low ( Within the group of patients with normal renal function at baseline those with high dFLC had shorter PFS than those with low dFLC. KRdc was associated with improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 39, NR) v Rdc 34 months (30, 39) and low dFLC KRdc NR (44, NR) v Rdc 41 (37, 47). In the group of patients with renal impairment at baseline KRdc was also associated with an improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 29, NR) v Rdc 32 months (28, 42) and low dFLC KRdc 37 (25, NR) v Rdc 27 (24, 33). In contrast to those with normal renal function, however, patients with renal impairment and high dFLC had a longer PFS than those with low dFLC. This observation was apparent whether patients received KRdc or Rdc and suggests that patients with high dFLC may have had reversible renal impairment, improving their ultimate outcomes. Supporting this hypothesis, measurable renal recovery in the renal impaired group at the end of induction was more common in patients with high dFLC (dFLC>=500 68.6% v dFLC Conclusions KRdc was associated with improved PFS compared to Rdc in NDMM patients across all renal subgroups. Irrespective of treatment, renal function is more likely to improve if attributable to nephrotoxic LC. Disclosures Pawlyn: Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Other: Travel expenses; Takeda: Consultancy, Other: Travel expenses. Menzies:Celgene, Amgen, Merck: Research Funding. Davies:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cook:Celgene, Janssen, Takeda: Research Funding; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, Sanofi: Honoraria; Karyopharm: Honoraria. Gregory:Celgene, Amgen, Merck: Research Funding; Janssen: Honoraria; Celgene: Consultancy. Jenner:Amgen, Janssen, Celgene, Takeda, Novartis, Sanofi, GSK: Consultancy; Janssen, Takeda, Amgen, Celgene, Novartis: Honoraria; Janssen, Celgene: Research Funding; Janssen, Takeda, Amgen: Other: Travel expenses. Jones:Celgene: Honoraria, Research Funding. Kaiser:Bristol-Myers Squibb/Celgene, Janssen, Karyopharm: Research Funding; Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, Celgene, AbbVie, Karyopharm, GlaxoSmithKline: Consultancy; Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda: Honoraria; Bristol-Myers Squibb, Takeda: Other: Travel expenses. Owen:Takeda: Honoraria, Other: Travel expenses; Janssen: Consultancy, Other: Travel expenses; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Karyopharm: Consultancy, Honoraria; Janssen: Research Funding; GSK: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Jackson:Takeda: Honoraria, Research Funding, Speakers Bureau; Gsk: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Cairns:Celgene, Amgen, Merck: Research Funding; Celgene: Other: Travel Support. OffLabel Disclosure: Carfilzomib, lenalidomide, dexamethasone and cyclophosphamide combination induction therapy for newly diagnosed myeloma

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.

Background: Successful vaccination against SARS-CoV2 is highly effective in preventing serious COVID-19 illness and is particularly recommended for at risk populations including patients with multiple myeloma (MM). However, there is uncertainty to which extent modern intensified therapies targeting plasma cell features might attenuate vaccination responses; some early vaccination recommendations for MM have proposed extended treatment breaks of several weeks to maximise vaccination success. Such an approach can be challenging in UHiR MM and pPCL, where maintaining treatment intensity is hallmark for preventing rapid relapse of the aggressive tumor. To address this uncertainty, we measured post-vaccination serological responses in patients treated uniformly with intensified Dara-VR consolidation and Dara-R maintenance post-ASCT for UHiR NDMM or pPCL in the UK OPTIMUM/MUKnine trial (NCT03188172). Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM or pPCL were recruited to OPTIMUM and received intensified post-ASCT consolidation with Dara-VR(d) for 18 cycles followed by maintenance with Dara-R until progression. In an exploratory analysis, centrally stored serum samples available for patients with a completed and documented vaccination history of two doses of an anti-SARS-CoV2 vaccine were analyzed for serological vaccine responses Total IgG/IgA/IgM Anti-SARS-CoV-2 spike glycoprotein was measured by ELISA (MK654; The Binding Site). As per UK national guidance and local availability, patients received two vaccine doses 12 weeks apart of either tozinameran (Pfizer/Biontech) or vaxzevria (AstraZeneca); serum taken at least 3 weeks after patients received their second dose was analyzed. Results were correlated with baseline characteristics and annotated with treatment and response data. Patient with available matched serological and vaccination status data at time of data cut-off (09 JUL 2021) were included. Collection of vaccination status data is ongoing and updated results comprising additional patients enrolled in OPTIMUM, as well as antigen levels, will be presented. Data will also comprise longitudinal antibody level measurements for patient with available sequential material. Results: Serological vaccine response data was available for 40 OPTIMUM patients with documented completed double vaccination status. Median patient age was 58.5 years (range 39-70) and clinical and molecular tumor features were similar to the overall trial safety population. All patients had received their second dose before June 2021. Of the 40 patients, 42.5% had received tozinameran and 57.5% vaxzevria. Baseline characteristics of the two groups were comparable. At time of second vaccine dose, 55% of patients were receiving Dara-VR consolidation treatment and 45% Dara-R maintenance. There was no recommendation to pause trial treatment for purposes of vaccination and no extended times off treatment for this reason were reported. Overall, 72.5% of patients had a positive vaccine antibody level as per manufacturer cut-point for high specificity evidence of antigen exposure (infection or vaccine). The response rate was nominally higher for vaxzevria (91.3%) than for tozinameran (47.1%), a dysbalance that will be further investigated with ongoing extension of the cohort. Of note, 90% of patients analyzed had reached a complete response (CR) of their MM prior to being vaccinated, and the majority of patients not in CR had a positive vaccine response. Response rates were nominally slightly higher in patients in receipt of Dara-R maintenance at time of second dose with 77.8% compared to Dara-VR consolidation with 68.2%. Conclusions: These results show a high serological response rate to COVID-19 vaccination in UHiR MM patients receiving intensified post-ASCT consolidation and maintenance therapy in remission. Findings suggest that continuation of intensified post-ASCT therapy for patients with aggressive tumors and a high risk of relapse are compatible with serological responses to commonly used COVID-19 vaccines. Disclosures Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Pfizer: Consultancy. Hall: BMS/Celgene: Research Funding; Janssen: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Pratt: Binding Site: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Cook: Karyopharm: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Amgen: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy.

Background: Outcomes for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with primary plasma cell leukemia (pPCL) remain unsatisfactory with current standard therapies. Traditional comparative trials randomising against a standard of care control arm are thus challenging for patients with UHiR NDMM or pPCL, and novel approaches to address their high unmet need are required. OPTIMUM/MUKnine (NCT03188172) is a 'digital comparator arm' trial for UHiR NDMM and pPCL patients with protocol defined outcome comparison against fully molecularly matched UHiR patients from the near-concurrent NCRI Myeloma XI/XI+ trial, the 'MyXI prior'. We report final analysis of the primary endpoint progression free survival (PFS) at 18 months for patients treated in OPTIMUM with Dara-CVRd induction, V-augmented ASCT and Dara-VRd consolidation, compared to the MyXI prior. Methods: Between Sep 2017 and Jul 2019, 472 patients from 39 UK hospitals with suspected NDMM or pPCL were screened. 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with pPCL (circulating plasmablasts >20%) were identified and recruited to OPTIMUM. Patients received up to 6 cycles of Dara-CVRd induction, V-ASCT, followed by Dara-VRd consolidation 1 for 6 cycles (Cons1), Dara-VR consolidation 2 for 12 cycles and monthly Dara-R maintenance until progression. This is the final analysis of the primary trial endpoint progression-free survival (PFS) at 18 months comparing OPTIMUM with the MyXI prior of patients treated with CRd or carfilzomib-CRd (KCRd) induction, ASCT and R maintenance or observation, using a Bayesian framework. Secondary endpoints include PFS, OS, safety and quality of life. Results: At median follow-up of 27.1 months (95% CI 25.1-29.3), median PFS was not reached for OPTIMUM patients. PFS was superior at the pre-specified time point of 18 months for OPTIMUM patients with an estimate of 81.7% (95% CI: 74.2-89.1) versus 65.9% (95% CI: 57.3-74.4) for the MyXI prior (Figure 1). PFS at 18 months was consistently shorter for both CRd (64.5%; 95% CI: 53.8-75.3) and KCRd (68.3%; 95% CI: 54.0-82.5) treated patients compared with OPTIMUM. There was a 99.5% chance of superior PFS outcome with OPTIMUM therapy compared to the MyXI prior within the Bayesian framework; easily surpassing the 85% pre-specified threshold of sufficient evidence of activity. The difference between trial treatments increased over time: 6 month estimates were similar across all treatment arms with OPTIMUM 95.3% (95% CI: 91.3-99.3), MyXI KCRd 95.1% (95% CI: 88.5-100.0), MyXI CRd 93.5% (95% CI: 88.0-99.0), while 12 month estimates were similar for OPTIMUM with 87.5% (95% CI: 81.2-93.9) and MyXI KCRd 87.8% (77.8-97.8), but lower in CRd 81.7% (95% CI: 73.0-90.3). The majority (94%) of patients who started OPTIMUM Cons1 completed all 6 cycles of therapy. Most frequent grade 3/4 adverse events (AEs) during Cons1 included thrombocytopenia (27.9%), neutropenia (21%) and infection (19.8%), however, grade 4 events were rare ( Conclusions: OPTIMUM demonstrated a clear PFS benefit at 18 months for intensified Dara combination therapy pre- and post-ASCT for UHiR NDMM and pPCL over the MyXI prior. Improvement of comparative benefit over time suggests particular efficacy of Dara-VRd in maintaining responses post ASCT, a key challenge in UHiR MM. This is, to our knowledge, the first prospective digital comparator trial for MM; central screening of an all-comer population combined with robust, detailed molecular matching maintained reliability and limited biases. These results demonstrate a novel framework for accelerated comparative evidence generation for patients with high unmet clinical need. Figure 1 Figure 1. Disclosures Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy. Hall: Janssen: Research Funding; BMS/Celgene: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Cook: BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. Pratt: Binding Site: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy.

Background Although the median age of patients with newly diagnosed multiple myeloma (MM) is 70-74 years, recruitment of frail older patients to clinical trials is poor. The International Myeloma Working Group (IMWG) frailty score predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living, the Lawton Instrumental Activity of Daily Living, and the Charlson Comorbidity Index, rather than age alone. Despite IMWG score prognostic biomarker capability, to date no evidence exists of its predictive biomarker potential. The UK-MRA Myeloma Risk Profile (MRP) has also been shown in both clinical trial and real-world populations to be a prognostic biomarker in transplant ineligible patients but prospective comparisons of the two scores have not been previously conducted. Study Design/Methods The FiTNEss trial (Myeloma XIV, NCT03720041, Figure 1A) is a UK-MRA phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not suitable for stem cell transplant. The primary objectives are 1) to compare early treatment cessation ( 2) to compare progression free survival for maintenance lenalidomide plus placebo (R) and lenalidomide plus ixazomib (IR). The FiTNEss trial is designed as an all-comers study with few exclusion criteria other than necessary for safety including some haematological and biochemical parameters, but there is no exclusion based on renal function. Patients with grade 2 or greater baseline peripheral neuropathy, current systemic infection or recent surgery or other cancer are excluded. Here we report the demographics for the first patients recruited, including IMWG frailty assessments and MRP to demonstrate the feasibility of recruiting frail patients to randomised phase III clinical trials. Results The FiTNEss trial opened on 04/08/2020 during the second wave of the COVID-19 pandemic in the UK. At the time of data cut off (14/07/2021) recruitment is active at 84 sites, with 180 patients randomised. Baseline characteristics for the randomised patients are shown in Figure 1B. The median age of patients is 77 years (range 64, 93) with 36.1% aged 76-80 and 26.1% over 80. In keeping with the older patient population 26.6% have an ECOG performance status of 2 or 3 and 31.7% ISS stage III. The IMWG frailty classification at baseline is FIT 43/180 (23.9%), UNFIT 53/180 (29.4%) and FRAIL 84/180 (46.7%). The effect of using age groups on the definition of patient frailty was explored. The IMWG frailty score defines all patients over 80 as FRAIL whilst an age of 76-80 contributes one point to the score. An analysis of patients' frailty was repeated with the contribution of age removed. For those aged over 80 years (n=47, 100% FRAIL) we found that 20 (42.6%) would have been re-classified as FIT and 18 (38.3%) as UNFIT, with only 9 (19.2%) retaining the FRAIL category. For those aged 76-80 (n=65, 53.8% UNFIT, 46.2% FRAIL) all 35 patients previously classified as UNFIT became FIT (53.8%) whilst 19 (29.2%) classed as FRAIL became UNFIT with 11 (16.9%) remaining FRAIL. The MRP classification, using age as a continuous variable, was Low-risk 45/180 (25.0%), Medium-risk 46/180 (25.6%), High-risk 75/180 (41.7%) and not available for 14/180 (7.8%) patients. Concordance between the IMWG frailty score and the MRP occurred in 48.9% of patients (88/180). 37.2% of FIT patients were classified as MRP Low-risk, 32.1% of UNFIT patients as MRP Medium-risk and 65.5% of FRAIL patients as MRP High-risk. Discussion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. Recruitment of patients classified as FRAIL was very high despite the COVID pandemic, likely due to the all-oral nature of the regimen under investigation enabling patients to avoid attendance at hospital day units for treatment and associated exposure risk. In the population recruited to date we found age to be a key contributor to the FRAIL category of the IMWG frailty score. Concordance between IMWG frailty score and MRP was highest in FRAIL/High-risk patients. The first interim analysis of the primary objectives is planned when 50% of required participants for R1 have reached 60 days post R1, which is anticipated in Q2 of 2022. Figure 1 Figure 1. Disclosures Cook: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Pawlyn: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Royle: BMS: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Coulson: BMS / Celgene: Honoraria; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy. Kishore: Sanofi: Other: Attending fees; Celgene: Other: Attending fees; Takeda: Other: Attending fees; Jannsen: Other: Attending fees. Rabin: BMS / Celgene: Consultancy, Honoraria, Other: Travel support for meetings; Takeda: Consultancy, Honoraria, Other: Travel support for meetings; Janssen: Consultancy, Honoraria, Other: Travel support for meetings. Best: BMS/Celgene: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Gillson: BMS / Celgene: Research Funding; Meck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Henderson: Takeda: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; BMS / Celgene: Research Funding. Olivier: Merck Sharpe and Dohme: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Celgene / BMS: Research Funding. Kaiser: AbbVie: Consultancy; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; Janssen: Consultancy, Other: Educational support, Research Funding; BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. OffLabel Disclosure: Frailty-score adapted dosing strategies

Introduction Despite efficacious modern induction combination therapies a subset of myeloma patients have high-risk disease which manifests as either primary refractory disease or early relapse following initial response. The presence of known molecular high-risk lesions explain the majority of these cases but understanding the factors influencing the poor phenotypic outcome for the remainder will help us improve outcomes further. This exploratory analysis of the Myeloma XI+ trial aimed to understand the population of patients with phenotypic high-disease in the context of carfilzomib and lenalidomide induction therapy. Methods The UK NCRI Myeloma XI trial is a phase III randomised controlled trial that recruited 2568 newly diagnosed transplant eligible patients, of which 526 were randomised to receive the induction combination KRdc comprising carfilzomib (K, 36mg/m2 IV d1-2, 8-9,15-16 (20mg/m2 #1d1-2)), lenalidomide (R, 25mg PO d1-21), dexamethasone (d, 40mg PO d1-4,8-9,15-16) and cyclophosphamide (c, 500mg PO d1,8) as part of an adaptive trial design. Induction therapy was planned for a minimum of 4 cycles or to maximum response prior to autologous stem cell transplant (ASCT). There was a subsequent randomisation to lenalidomide maintenance or observation at 3 months post ASCT. Primary refractory disease was defined as not achieving at least a minimal response (MR) at maximum response after at least 4 cycles of induction therapy or progression at any time during induction regardless of initial response. Early relapse (ER) after ASCT was defined as progression within 12 months of ASCT. Molecular risk was defined as the presence of one (high risk) or more than one (ultra-high risk) of the following lesions: del(17p), gain(1q), t(4,14), t(14;16) or t(14;20). Results The incidence of primary refractory disease with the KRdc combination was very low. Only 8/526 (1.5%) patients were primary refractory, all having progression during induction therapy with a median progression free survival of only 126 days. The number of patients is too small to draw any firm conclusions regarding the characteristics associated with primary refractory disease. 401/526 (76%) of patients underwent high dose melphalan and ASCT on trial after KRdc induction. Those that did not proceed to ASCT on trial were either ineligible, mostly due to not completing the minimum required induction therapy, or were deemed not fit to undergo the procedure based on patient/clinician decision. Of those patients who underwent ASCT, 36/401 (9.0%) relapsed within 12 months (ER). These ER patients had both a shorter PFS2 and second PFS suggesting a continued association with adverse outcome beyond first line therapy. Patients in the ER group were compared with those patients not relapsing until beyond 12 months after ASCT (nER). There was no difference in the sex, age or paraprotein or light chain sub-type of patients. There was evidence of a greater impact of bone marrow disease burden in the ER group with a lower haemoglobin (median 99 g/L vs 115, p = 0.0216), lymphocyte count (1.3 x10^9/L vs 1.8, p = 0.0012) and platelet count (187 x10^9/L vs 252, p = 0.0049) at baseline. Median bone marrow aspirate plasma cell infiltration was ER 33% vs nER 23%. There were no significant differences in ISS stage (ER ISS I 19%, II 50%, III 22%, nER ISS I 35%, II 36%, III 22%, p = 0.1434), lactate dehydrogenase, albumin or beta-2 microglobulin. Patients in the ER group were less likely to have received lenalidomide maintenance (ER 12/36 [33%] vs nER 222/365 [61%]). For some (4/36) not receiving lenalidomide was due to relapse occurring prior to reaching the maintenance randomisation point (100 days post-ASCT). For those with available data 75% of patients in the ER group had molecular high (50%) or ultra-high (25%) risk disease, whilst 25% had standard risk using the trial definition. The individual lesions accounting for high-risk status were: gain(1q) in ER 42% vs nER 35%; t(4;14) ER 50% vs nER 10%; del(17p) ER 8% vs nER 7%. Discussion The combination of a second-generation immunomodulatory agent and proteasome inhibitor in the KRdc induction regimen is associated with deep responses and only a very small proportion of patients have primary refractory disease. Early relapse after KRdc and ASCT occurred in 9% of patients and was associated with high bone marrow disease burden and molecular high-risk features. Disclosures Pawlyn: Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davies: Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Menzies: Celgene / BMS: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding. Henderson: BMS / Celgene: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Cook: Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Kaiser: AbbVie: Consultancy; Takeda: Consultancy, Other: Educational support; Seattle Genetics: Consultancy; Amgen: Honoraria; Pfizer: Consultancy; Karyopharm: Consultancy, Research Funding; GSK: Consultancy; Janssen: Consultancy, Other: Educational support, Research Funding; BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. OffLabel Disclosure: The KRdc combination is off label

Introduction: Molecular diagnostic testing for lymphoproliferative disorders (LPDs) includes detection of clonal immunoglobulin (IG) and/or T cell receptor (TCR) rearrangements, translocations, copy number alterations (CNA) and somatic mutations. To date, laboratories still rely on subjective and labour-intensive technologies, e.g. karyotyping/FISH to detect complex genomic alterations. Whole Genome Sequencing (WGS) can detect all genomic alterations, but factors such as cost, computation/storage, DNA requirements and poor detection of clinically relevant subclonal mutations limits the routine implementation of WGS in clinical diagnostics. We have developed "KaryoSequencing" (KS), a novel approach that combines targeted deep-sequencing, using a targeted hybridisation capture NGS panel, for rare mutation and translocation detection with shallow WGS (sWGS) for genome wide copy number analysis, in a single test. Methods: KS was validated using 138 clinical samples from patients with acute lymphoblastic leukaemia (ALL) (n=46), chronic lymphocytic leukaemia (CLL) (n=46) and plasma cell myeloma (PCM) (n=46) samples from 3 UK laboratories. Samples underwent library preparation and hybridisation using the EuroClonality-NDC assay. A KS library for each sample was prepared by combining the pre-capture and post-capture libraries at an optimised ratio to enable high coverage (>500 x) at regions covered by the targeted panel while providing 0.5-1x coverage genome-wide. Forty-six KS libraries were pooled and sequenced per NovaSeq 6000 run, using a 200-cycle SP flow cell and a 100bp paired-end strategy. For analysis of targeted regions, somatic mutation calling was performed using VarDict and structural variants (rearrangements and translocations) were detected using ARResT/Interrogate. For analysis of large chromosomal copy number variation using sWGS, a modified version of QDNASeq/ACE with a window size of 50kb was performed. For sWGS analysis, bioinformatic exclusion of all target capture regions and panel-specific off-target regions was performed using a panel of 48 DNA samples from healthy individuals ran on the same KS protocol. Results: Analysis of genome-wide copy number by sWGS was concordant in 477 of 503 (95%) evaluable FISH tests, including precise detection of hyper and hypo-diploidy and other complex karyotypes. The performance of the targeted deep-sequencing component of the KS approach was assessed to ensure comparable performance to previously validated results for the EuroClonality-NDC. The EuroClonality-NDC detected a clonal IG rearrangement in 46/46 (100%) CLL cases and in 42/46 (91.3%) PCM cases. Clonality was detected in 43/46 (93.5%) and 44/46 (95.7%) cases at an IG and TCR locus respectively in ALL, a disease entity known to exhibit cross-lineage rearrangements. Overall, 44 translocations were detected in the 138 samples by the EuroClonality-NDC. FISH results were available for 32 of the 44 translocations detected by NGS and were concordant in 29/32 (91%). In two PCM samples NGS and FISH reported a different translocation; in the ALL sample, the FISH pattern showed an additional copy but not a split signal. Across the entire cohort of 138 samples, KaryoSequencing detected 190 mutations with a variant allele frequency ranging from 4.0 - 97.6%. Of the detected mutations, 69/190 (36.3%) had a VAF Conclusions: KaryoSequencing demonstrated >95% sensitivity and specificity for detection of gross genome-wide copy number alterations while retaining the analytical performance for detection of rearrangements, translocations, and mutations for the lymphoid-specific targeted regions of the EuroClonality-NDC assay. KS is a cost-effective and high-throughput integrated alternative to current diagnostic strategies in haematological malignancies and can be implemented in routine clinical practice. Disclosures Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau. Gonzalez: Univ8 Genomics Ltd: Current holder of individual stocks in a privately-held company.

Introduction In traditional analysis of cancer clinical trials, key endpoints such as progression-free survival (PFS) and overall survival (OS) are often analysed separately. Using multistate models (MSMs) we can model these events simultaneously to holistically analyse the disease-treatment pathway. This provides meaningful estimates for the probability of disease progression and death at any point in the disease course, incorporating treatment and prognostic factors of interest. MSMs are also a useful tool to assess the relationship between how the time spent in one state affects the risk of transitioning to future states. In the context of myeloma (MM), this can be used to determine patient prognosis based on the time for which they remain in 1 st remission after initial treatment. Methods In the largest randomised trial of MM patients undertaken to date (NCRI Myeloma XI), newly diagnosed MM patients eligible for ASCT (NDMM TE) were randomised to induction, intensification and maintenance treatments. Maintenance randomisation, at ASCT+3 months, was to lenalidomide (R), lenalidomide plus vorinostat (RZ) or observation. Co-primary endpoints were PFS and OS analysed by Cox regression. An MSM was used for exploratory analysis of 1074 TE patients randomised to maintenance. Patients transitioned irreversibly between 4 states: 1 st remission, alive and in remission after 1 st progressive disease (PD1), alive and in remission after 2 nd PD (PD2) and dead (Figure 1). Time in 1 st remission was included as a covariate to assess the effect of early disease progression on subsequent state transitions ( Results The median follow-up from randomisation was 57m (interquartile range: 43-72m). MSM analysis found that a 1 st remission of At a snapshot at 5 years post-randomisation, those with a 1 st remission ≥18m had a 24.9% chance of being in the PD1 state, compared to just 6.4% and 1.1% in those with 1 st remissions of 12-18m and MSM analysis also found R and RZ were associated with a reduced risk of transition from 1 st remission to PD1 vs. observation (R HR 0.51, 95%CI 0.42-0.60; RZ HR 0.68, 95%CI 0.55-0.88), reflecting the results of the primary trial analysis of PFS. Primary trial analysis of OS found that R was associated with significantly longer OS than observation. However, MSM analysis found R was associated with an increased risk of death following both PD1 (HR 1.60, 95%CI 1.06-2.41) and PD2 (HR 1.46, 95%CI 1.03-2.07) vs. observation. This suggests that the OS benefit of R is gained by extending the time in 1 st remission. RZ was associated with increased risk of death without PD (HR 3.07, 95%CI 1.05-9.03) and death following PD2 (HR 1.49, 95%CI 0.99-2.26) vs. observation. The MSM also found that the expected duration in 1 st remission was longest for R and shortest for observation (R 56.7m, RZ 47.7m and obs. 38.6m). However, in the PD1 state (R 12.8m, RZ 15.7m and obs. 21.9m) and PD2 state (R 5.4m, RZ 7.3m and obs. 11.0m) this order was reversed, although the difference between the groups was reduced for later states. Discussion MSMs are a powerful tool for exploring the myeloma disease pathway, identifying associations between states and providing transition probabilities which can be easily interpreted to gain further insights to those obtained via traditional methods. MSMs are an effective method to visualise data, clearly demonstrating the association between early relapse post-ASCT and poor prognosis in NDMM. This work has expanded on the primary analysis of the maintenance randomised treatments in Myeloma XI, corroborating results previously observed and highlighting the potential effects of maintenance treatment on each stage of the disease pathway. Figure 1 Figure 1. Disclosures Craig: Celgene: Research Funding; Merck Sharpe & Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Pawlyn: Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kaiser: AbbVie: Consultancy; BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Other: Educational support; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy. Olivier: Celgene / BMS: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Merck Sharpe and Dohme: Research Funding. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jenner: Takeda: Consultancy; Pfizer: Consultancy; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau. Cook: Amgen: Consultancy; BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy. Davies: BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Cairns: Celgene / BMS: Other: travel support, Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding.

Background Early trials of long-term lenalidomide (len) use reported an increased incidence of second primary malignancy (SPM), particularly AML and MDS. Later, meta-analysis suggested the link to be secondary to len in combination with melphalan. Myeloma XI is a large phase III randomised trial in-which len is used as an induction and maintenance therapy. We have previously reported on early SPM incidence in the context of this trial and shown that haematological SPM (hSPM) incidence was not increased in association with len (Cumulative incidence 0.7% at 3 years). We have also published data showing that maintenance len is associated with improved survival in post-transplant patients. Here we present for the first time, a long-term analysis of SPM incidence in 4358 patients who have received maintenance therapy versus observation in the context of the Myeloma XI trial. Methods Myeloma XI is a phase III, randomised, multi-centre, parallel group design, open-label trial comparing thalidomide, len, carfilzomib and bortezomib combinations and len as maintenance treatment in NDMM patients. The trial includes transplant eligible (TE) and transplant non-eligible (TNE) pathways. TE patients received high dose melphalan supported by autologous stem cell transplantation if they achieve a very good partial response or better. Patients in both pathways were randomised to maintenance with len (+/- vorinostat) or active observation. Since May 2010, 4358 patients have been treated and assigned to induction. Median follow up is now 68 months (IQ range 49-83), with over 1100 patients enrolled for more than 5 years. A total of 1971 patients have entered maintenance with 1137 randomised to len and 834 observation (median 24 cycles (range 1-97)). Results The median time to SPM development from induction is 41.6 months (range 1.4 - 97.1). Cumulative incidence of all SPMs is 4.1% (95% CI 3.5, 4.7), 7.4% (6.6, 8.3) and 10.8% (9.5, 12.1) at three, five and seven years respectively (figure 1). 378 SPMs have been reported in 318 patients, 180 (57%) treated in the TNE pathway (IR 9.9%) and 138 (43%) in the TE pathway (IR 5.5%). The average age at the time of SPM is 78 and 68 for the TNE and TE pathways, respectively. Of the patients who developed an SPM 195 (61%) did so following maintenance randomisation. The incidence was highest in those receiving len based maintenance (n=145, IR 10.8%). In the observation arm 50 patients developed an SPM (IR 5.6%). The median time to SPM development from maintenance randomisation was 43 months in those receiving len and 40 months in the observation only group. One hundred and ten of the patients who developed an SPM following maintenance randomisation were in the TNE pathway with 77 patients receiving len. The overall incidence of SPM development in TNE patients receiving len maintenance is 15.4% and 9.9% for observation. Within the TE arm 85 SPM cases developed following maintenance randomisation with 68 patients receiving len. The overall incidence of SPM development in the TE patients treated with len maintenance is 7.7% and 3.1% for observation. Of the remaining patients 98, (31%) developed an SPM during induction and twenty five (8%) following induction but prior to maintenance. Forty eight patients developed a hSPM (IR 1.1%), MDS (n=20), AML (n=13), BLCBL (n=6), B-ALL (n=4), CML (n=1), mixed phenotype leukaemia (n=1), T-ALL (n=1), Burkitt lymphoma (n=1) and Hodgkin's Lymphoma (n=1). Of these cases, 35 patients were TE pathway treated, with 25 receiving lenlidomide maintenance (IR 2.8%). The median time to hSPM development in the TE patients was 51.8 months. The remaining 13 cases occurred in the TNE treated patients with 7 receiving lenalidomide maintenance (IR 1.4%). The median time to hSPM development in the TNE patients was 42.3 months. Of the remaining cases, 107 patients developed non-melanoma skin cancers (NMSC) (TE n34, IR 1.3% / TNE n73, IR 4.0%) and 181 patients developed solid tumours (TE n78, IR 3.1% / TNE n103, IR 5.6%). Forty one patients developed >1 SPM. Outcome analysis is underway and will be presented at the meeting. Conclusions The overall incidence of SPM is highest in TNE patients receiving lenalidomide maintenance but hSPM rates remain low. This suggests that advanced age is a considerable risk factor for the development of second cancers, particularly NMSC. Second haematological cancers were low in all groups, irrespective of maintenance allocation. Disclosures Jones: Celgene: Honoraria, Research Funding. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Drayson:Abingdon Health: Consultancy, Equity Ownership. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau. Gregory:Amgen, Merck: Research Funding; Abbvie, Janssen: Honoraria; Celgene: Consultancy, Research Funding. Owen:Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses. Boyd:Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Morgan:Celgene Corporation, Janssen: Research Funding; Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses.

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 Optimum outcomes were seen in those receiving Len as both induction and maintenance therapy (Figure 1C). Patients receiving CRD induction followed by Len maintenance (CRD-R) had a median PFS of 77 months [56, 86] compared to CTD-R 64 [49, 74], CRD-Obs 37 [33, 42] and CTD-Obs 44 [38, 51]. Conclusions: In this study the use of Len as both induction and maintenance was associated with the best outcomes irrespective of cytogenetic risk group. With long term follow up CRD induction for newly diagnosed transplant eligible myeloma patients was associated with both a PFS and OS benefit compared to CTD and was better tolerated. The PFS impact of CRD was particularly notable in patients with high and ultra-high risk disease. Lenalidomide maintenance was associated with significantly longer PFS than observation across all risk groups. on behalf of the NCRI Haematological Oncology Clinical Studies Group Disclosures Jackson: Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Pawlyn:Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Jones:Celgene: Honoraria, Research Funding. Kishore:Celgene, Takeda, Janssen: Honoraria, Speakers Bureau; Celgene, Jazz, Takeda: Other: Travel expenses. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Janssen: Honoraria; Novartis, Janssen: Research Funding. Lindsay:Celgene: Other: personal fees and non-financial support ; Takeda: Other: personal fees and non-financial support ; Amgen: Other: non-financial support. Russell:Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding. Gregory:Abbvie, Janssen: Honoraria; Celgene: Consultancy, Research Funding; Amgen, Merck: Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses; Celgene Corporation, Janssen: Research Funding. OffLabel Disclosure: CTD/CRD induction therapy and Lenalidomide maintenance 10mg 21/28 days

Introduction: Systemic AL amyloidosis is a rare multisystem disease caused by an underlying plasma cell dyscrasia with amyloid fibril deposition causing progressive organ failure. Treatment of the underlying plasma cell disorder underpins the management of AL amyloidosis with bortezomib-based regimes as standard first line treatment. Thalidomide has activity in AL amyloidosis used in low doses in combination with cyclophosphamide and dexamethasone. Carfilzomib (Kyprolis), a second generation irreversible inhibitor of the proteasome, is licenced for treatment of relapsed refractory myeloma. This prospective phase 1 multicentre study was designed to define the maximum tolerated dose (MTD) and recommended dose (RD) of one weekly dose of carfilzomib in combination with a fixed dose of thalidomide and dexamethasone (KTD) in patients with relapsed refractory amyloidosis. Methods and Patients Patients were recruited for treatment with carfilzomib in escalating dose cohorts using a 3+3 dose escalation design at three planned dose levels (Table 1) - all participants received carfilzomib 20mg/m2 on cycle 1 day 1. The primary endpoint was to define the MTD, RD and assess the safety and tolerability of KTD. The key secondary endpoint was a preliminary assessment of the activity of KTD. Results A total of 10 patients were recruited (6 male, 4 female) with a median age of 64 years (30% >70 years). The mean time from AL amyloidosis diagnosis for Dose levels 0 and 1 was 7.8 years (SD ±3.87 yrs.) and 3.2 years (SD ± 1.80) respectively. All non-refractory patients had received at least two previous lines of therapy, with a maximum of four previous lines of therapy. The median creatinine was 77.0µmol/L, the median NT-proBNP was 53.3pmol/L and dFLC at the time of treatment was 77.0mg/L. Three evaluable patients were recruited to Dose Level 0 with no dose limiting toxicities (DLTs) observed. A further 3 evaluable patients were recruited to Dose Level 1 - one patient experienced a DLT (acute kidney injury). Hence, 3 further patients were recruited at this dose level. One participant had a serious adverse event (SAE) following day 1 dosing at 20mg/m2 - deemed not evaluable for DLT assessment as received no further treatment. Three further patients were recruited at Dose level 1 with no further DLT's. The data monitoring committee decided that it was not in the patients' best interest to proceed to Dose level 2, as significant evidence of activity at dose level 1 and concern about potential toxicity. As of June 2019, 7 participants have completed 3 cycles and 4 participants (40%) have completed 6 cycles. Responses were determined centrally according to amyloidosis consensus criteria 2005. The overall hematologic response rate at end of 3 cycles was 70%. This included: complete response - 1 (10%); very good partial response - 3 (30%) and partial response 3 (30%). Of the 3 participants at Dose level 1, 1 participant had a VGPR, 1 had PR and 1 had no response (discontinued at the end of cycle 2). One patient had no response by the end of cycle 2 (discontinued due to toxicity) and 2 patients with DLT's were not assessable for response. A total of 3 participants had SAE's: 1. At dose level 1, grade 3 acute kidney injury which was deemed to be DLT, which recovered with supportive care. 2. At dose level 1, pyrexia, hypotension and hypoxia requiring intensive care admission after day 1 dose of 20mg/m2. There was no clear evidence of infection and this was deemed to be a SAE due to carfilzomib (but not DLT). 3. At dose level 1, grade 3 abdominal pain deemed unrelated to study medication. There were 66 other grade 1 or 2 adverse events reported from 9 participants from the first 3 cycles. There were no SUSARs or deaths in the study reported to date. None of the patients had worsening cardiac function. Results here are preliminary with further endpoints and detail to be presented when all participants have completed therapy. Conclusion This study defined, in combination with thalidomide and dexamethasone, the recommended dose of carfilzomib was 45mg/m2 on days 1, 8 and 15. The MTD of carfilzomib was not reached. Three participants experienced a SAE and a number of participants had grade 1-2 AE's. At the end of 3 cycles, 70% of participants achieved a hematologic response with 40% VGPR or better which appears comparable to other studies in relapsed AL amyloidosis. KTD is a potentially effective regime that can be considered for further study in relapsed refractory systemic AL amyloidosis. Disclosures Garg: Novartis: Consultancy, Honoraria. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kishore:Celgene, Jazz, Takeda: Other: Travel expenses; Celgene, Takeda, Janssen: Honoraria, Speakers Bureau. Pitchford:Amgen: Other: Research funding to institution. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Oughton:Amgen: Other: Research funding to institution. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Wechalekar:Amgen: Research Funding; GSK: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria.

Background Transplant non-eligible (TNE) myeloma patients are a very heterogeneous group that is not well-defined on the basis of age alone, but rather by the interplay of age, physical function, cognitive function and comorbidity better defined as 'frailty'. The International Myeloma Working Group (IMWG) has published a scoring system for myeloma patient frailty that predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL), and the Charlson Comorbidity Index (CCI). It has been proposed to be useful in determining the feasibility of treatment regimens and appropriate dose reductions but has not been validated prospectively. We hypothesize that by defining subgroups of patients based on the IMWG frailty score, and guiding up-front dose adjustments we can personalize therapy to improve treatment tolerability and therefore short-term outcomes, along with quality of life. In addition we plan to compare the use of single agent immunomodulatory (IMiD) based maintenance therapy with an IMiD and proteasome inhibitor maintenance doublet to try and improve long-term outcomes for patients. Study Design and Methods Myeloma XIV (NCT03720041) is a phase III, multi-center, randomized controlled trial to compare standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with the novel triplet ixazomib, lenalidomide and dexamethasone (IRd), and to compare maintenance lenalidomide (R) to lenalidomide plus ixazomib (IR) in patients with newly diagnosed multiple myeloma not suitable for a stem cell transplant. The trial outline is shown in Figure 1. All participants receive induction treatment with ixazomib, lenalidomide and dexamethasone and are randomized (R1) on a 1:1 basis at trial entry to the use of frailty score-adjusted up-front dose reductions vs. standard up-front dosing followed by toxicity dependent reactive dose modifications during therapy. Following 12 cycles of induction treatment participants alive and progression-free undergo a second randomization (R2) on a 1:1 basis to maintenance treatment with lenalidomide plus placebo versus lenalidomide plus ixazomib. Participants and their treating physicians are blinded to maintenance allocation. The primary objectives of the study are to determine: Early treatment cessation (within 60 days of randomization) for standard versus frailty-adjusted up-front dosingProgression-free survival (PFS, from maintenance randomization) for lenalidomide + placebo (R) versus lenalidomide + ixazomib (IR) The secondary objectives of the study include determining: progression-free survival (PFS) for standard versus frailty-adjusted up-front dosing reductions, overall survival (OS), overall response rate (ORR), treatment compliance and total amount of therapy delivered, toxicity & safety including the incidence of Second Primary Malignancies (SPMs), Quality of Life (QoL), cost-effectiveness of standard versus frailty-adjusted up-front dosing of IRd and cost-effectiveness of IR versus R. Exploratory analyses include the association of molecular subgroups with response, PFS and OS. Seven hundred and forty participants will be enrolled into the trial at R1 to give 80% power to demonstrate a difference in early cessation and ensure that at least 478 participants remain and are randomized at R2 (based on attrition rates in our previous study Myeloma XI). At R2 478 patients will give us 80% power to detect an eight month difference in PFS between R and IR. Disclosures Cairns: Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Takeda: Consultancy; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. Royle:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Best:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Bowcock:Takeda: Honoraria, Research Funding. Boyd:Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Drayson:Abingdon Health: Consultancy, Equity Ownership. Henderson:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Kishore:Celgene, Takeda, Janssen: Honoraria, Speakers Bureau; Celgene, Jazz, Takeda: Other: Travel expenses. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Consultancy; Celgene, Janssen: Honoraria; Celgene: Research Funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau. OffLabel Disclosure: Frailty adjusted dosing. Ixazomib and lenalidomide combination as maintenance.

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 Outcome varies considerably in newly diagnosed myeloma (NDMM), in particular in transplant eligible (TE) patients, ranging from a few years to decades. Autologous stem cell transplant (ASCT) remains the overall aim following induction therapy even with the advent of novel agents. Greater availability of novel treatments allows for complex combination induction and potentially maintenance therapies. Possible long-term unintended effects and affordability will likely make rational treatment stratification for populations in most need desirable, in particular for public health care systems. We report here an extended outcome analysis of 1,064 genetically and clinically characterised patients from the transplant treatment pathway of the NCRI Myeloma XI trial. Patients In Myeloma XI patients were randomised to induction therapy with CTD (cyclophosphamide, thalidomide and dexamethasone) or CRD (cyclophosphamide, lenalidomide and dexamethasone) and +/- CVD (cyclophosphamide, bortezomib, dexamethasone) intensification in patients with Genetic results for the high-risk markers t(4;14), t(14;16), t(14;20), gain(1q) and del(17p) were determined for all patients with sufficient material centrally by qRT-PCR and MLPA (MRC Holland). For a sub-set of patients with insufficient central material, local cytogenetic (FISH) reports were centrally reviewed and only those with a valid result for all risk markers included in this analysis. Differences in PFS, PFS2 and OS were assessed and compared using the log-rank test. Results Patient outcome was analysed by combining information on genetic risk defined as standard risk (SR) (no adverse lesions), high-risk (HR) (single adverse lesion: t(4;14), t(14;16), t(14;20), gain(1q) or del(17p)) or ultra-high risk (UHR) (≥2 adverse lesions) and International Staging System (ISS) 1 vs. ≥2. Genetic information was available for all 1064 patients. Baseline clinical characteristics (age, sex, race) were similar between groups, but 47.7% of UHR+ISS≥2 had an IgA paraprotein compared to 27.4% average across all groups. After a median follow up of 68 months (interquartile range 49-83) we found that the two most contrasting risk categories, UHR+ISS2/3 (10.1% patients) and SR+ISS1 (17.3%) were associated with the expected extreme clinical outcomes, with median PFS of 20 months vs. 50 months (P Across all genetic risk groups, fewer patients with ISS≥2 vs. those with ISS1 completed intention-to-treat HD-MEL and ASCT. For example, 65.4% of UHR+ISS≥2 completed ASCT vs. 76.1% of SR+ISS1 patients. The main reasons for patients not proceeding to ASCT were 'clinician decision/patient unfit' (43.5%), 'disease progression/death' (26.1%) or 'patient decision' (13%) for UHR+ISS≥2 patients, with fewer 'progression/death' (15%) and a more 'patient decision' in SR+ISS1. Across all groups, more patients were able to undergo ASCT following KCRD induction as opposed to CTD or CRD. This improvement was most notable in the UHR+ISS≥2 group: 82.4% KCRD vs. 58.9% CTD and 67.6% CRD. Differences in outcomes by risk group were comparable between PFS1 and PFS2. However, for UHR+ISS≥2, median PFS2 was 35 months and OS 43 months (delta=8 months), indicating limited efficacy of current treatments beyond 2nd line for this group. The difference between PFS2 and OS was markedly higher for HR+ISS≥2, with PFS2 52 months and OS 68 months. Conclusion Our results indicate the urgent need for improved treatment approaches for ultra-high risk patients, in particular those with UHR+ISS≥2. Our analysis demonstrates that fewer of these patients reach important therapeutic milestones such as ASCT if not effectively treated during induction. These patients are likely to derive the biggest benefit from early stratification and novel treatment approaches, as our data indicate that these patients obtain modest benefit from therapies beyond 2nd line. Disclosures Kaiser: Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. Paterson:Celgene, Amgen, Merck, Takeda: Other: Research funding to institution. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Consultancy; Celgene, Janssen: Honoraria; Celgene: Research Funding. Morgan:Celgene Corporation, Janssen: Research Funding; Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses. 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. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria.

Background: Isatuximab (ISA) targets CD38-expressing tumor cells through a combination of activities, including antibody-dependent cellular cytotoxicity, direct pro-apoptotic activity, and complement-dependent cytotoxicity. A phase I study evaluating ISA monotherapy demonstrated promising clinical activity in 35 patients with relapsed/refractory multiple myeloma (RRMM) (Martin T et al, J Clin Oncol 2014; 32:8532). This is an ongoing phase II study (NCT01084252) with 2 stages: stage 1 to select the dose for stage 2 of the study, and stage 2 to assess efficacy and safety of ISA monotherapy or in combination with dexamethasone in RRMM. In stage 1, patients were randomized to 1 of 3 dose groups: ISA 3 mg/kg Q2W, 10 mg/kg Q2W × 2 cycles then Q4W, or 10 mg/kg Q2W. Based on pharmacokinetic data, a fourth dose of 20 mg/kg QW × 4 doses then Q2W was added. The overall response rates (ORRs) for the 4 dosing schemes were 4% (1/23), 20% (5/25), 29% (7/24), and 24% (6/25), respectively. Based on these results, a dose of 20 mg/kg QW for cycle 1 followed by 20 mg/kg Q2W in subsequent cycles was chosen for stage 2 of the study (Richter J et al, J Clin Oncol 2016;34:8005). Here, we report the baseline characteristics and demographic data from stage 2 at the selected dosing scheme from stage 1. Full safety and efficacy data will be presented at the meeting. Methods: This study enrolled patients with MM who had previously received an immunomodulatory drug and a proteasome inhibitor. Patients received ISA monotherapy (20 mg/kg on Day 1, 8, 15, and 22 [QW] of cycle 1 followed by 20 mg/kg on Day 1 and 15 [Q2W] of subsequent cycles) or ISA in combination with dexamethasone (40 mg/day [20 mg/day in patients ≥75 years old]). The primary objective was to evaluate the activity of ISA as monotherapy and in combination with dexamethasone in patients with RRMM in terms of ORR. Results: A total of 165 patients received at least 1 cycle of treatment. Median age was 67 (37-85) years. Median time from diagnosis to first dose was 5.35 (0.7-23.0) years. Median number of prior lines was 4 (2-11) and median number of prior regimens was 6 (2-17). Patients received a median of 5 (1-17) cycles of treatment, with a median duration of exposure of 22 (1-69) weeks. Discontinuation occurred in 106 (64.2%) patients due to adverse events (15 patients, 9.1%), disease progression (85 patients, 51.5%), or patient decision (6 patients, 3.6%). Conclusion: The full efficacy and safety data for this heavily pre-treated RRMM population will be available for presentation at the meeting. Funding: Sanofi Disclosures Dimopoulos: Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria. Anttila:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Capra:Janssen: Research Funding, Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Research Funding; Sanofi: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cole:University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria. Hungria:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Jenner:Celgene: 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; 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. Vorobyev:Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Biocad: Consultancy; Takeda: Speakers Bureau; BMS: Speakers Bureau; Astellas: Speakers Bureau. Yanez Ruiz:Universidad de la Frontera: Employment. Yin:Sanofi: Employment. Hamlett:BDM Consulting Inc.: Employment; Sanofi: Consultancy. Vij:Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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 Patients who completed ASCT were identified with very early relapse (PFS1 Results Of 1274 patients receiving ASCT: 178 (14%) relapsed within 12m and 1096 (86%) thereafter. There were higher rates of ≥VGPR in the PFS1≥12m group (70% vs 59%) and in both groups most patients responded at ≥PR (PFS1 Inferior outcomes continued for the PFS1 As PFS1 Discussion Nearly three quarters of those with PFS1 Disclosures Bygrave: Amgen: Honoraria; Takeda: Honoraria, Other: Travel Support; Janssen: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support, Research Funding. Pawlyn:Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene Corporation: Consultancy, Honoraria, Other: Travel support; Takeda Oncology: Consultancy, Other: Travel support; Janssen: Honoraria, Other: Travel support. Davies:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; ASH: Honoraria; TRM Oncology: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Cairns:Merck Sharp and Dohme: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Striha:MSD: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Hockaday:Millenium: Research Funding; MSD: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Jones:Celgene: Honoraria, Other: Travel support, Research Funding. Kishore:Celgene: Honoraria; Takeda: Honoraria, Other: travel support. Garg:Amgen: Honoraria, Other: Travel Support; Takeda: Other: Travel Grant; Novartis: Other: travel support, Research Funding; Janssen: Honoraria. Williams:Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel Support, Speakers Bureau; Takeda: Honoraria, Other: Travel support; Amgen: Honoraria, Speakers Bureau. Karunanithi:Janssen: Other: Travel support, Research Funding; Celgene: Other: Travel support, Research Funding. Lindsay:Celgene: Honoraria, Other: Travel support; BMS: Consultancy, Other: Travel support; Takeda: Other: Travel support; Janssen: Consultancy; Novartis: Other: Travel support. Jenner:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau. Cook:Amgen, Bristol-Myers Squibb, GlycoMimetics, Celgene, Janssen and Takeda and Sanofi: Honoraria; Celgene, Janssen and Takeda: Research Funding. 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. Gregory:Janssen: Honoraria; Amgen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck Sharp and Dohme: Research Funding. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Jackson:Amgen: Honoraria; Celgene: Honoraria; Chugai: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Kaiser:Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel support; Takeda: Consultancy, Other: Travel Support; Amgen: Consultancy, Honoraria; Janssen: 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.

Introduction: Multiple myeloma (MM) evolves from precursor disorders such as monoclonal gammopathy of undetermined significance (MGUS) and SMM (Landgren O, et al. Blood 2009. 113[22]:5412-5417). Currently, there are no approved therapies for SMM, and guidelines recommend close monitoring of SMM patients (pts) and initiating treatment only upon progression to MM. However, therapeutic intervention at the SMM stage, especially in pts at higher risk of progression to MM, may yield clinical benefit and prevent the development of MM-associated complications. DARA is a CD38-targeting IgG1κ monoclonal antibody with on-tumor and immunomodulatory mechanisms of action. Based on the demonstrated efficacy and favorable safety profile of DARA monotherapy in pts with relapsed/refractory MM (RRMM; Usmani SZ, et al. Blood 2016. 128[1]:37-44), we hypothesized that DARA could delay progression from SMM to MM. A prespecified primary analysis (15.8-month median follow-up) of the phase 2 CENTAURUS study (NCT02316106) revealed that DARA monotherapy was active and well tolerated in pts with intermediate- or high-risk SMM (Hofmeister CC, et al. ASH 2017. Abstract 510). Here, we present updated data from CENTAURUS based on 10 months of additional follow-up. Methods: Eligible pts had had a confirmed diagnosis of high-risk or intermediate-risk SMM for Results: A total of 123 pts were randomized (41 pts per arm). The median (range) age was 61.0 (31-81) years, and the median (range) time from initial SMM diagnosis to randomization was 6.83 (0.40-56.0) months. In total, 73% of pts were of IgG subtype. Median treatment duration was 25.8 months in both the Long and Int arms and 1.6 months in the Short arm (Table 1). In the Long, Int, and Short arms, 17%, 22%, and 5% of pts, respectively, discontinued treatment; reasons included PD (7%, 10%, and 0%, respectively), adverse events (AEs; 7%, 2%, and 5%, respectively), refusal of further treatment (5% in Int), withdrawal of consent (2% each in Long and Int), and death (2% in Int). At a median (range) follow-up of 25.9 (0-33.2) months, overall response and ≥CR rates were higher in the Long and Int arms than in the Short arm (Table 2); in the combined Long and Int arms, the ≥CR rate was 7%. Median PFS based on SLiM-CRAB criteria was not reached in any arm; 24-month PFS rates were 90% (Long), 82% (Int), and 75% (Short; Figure 1A). PD/death rates indicate a median PFS of ≥24 months in all arms (Table 2). Median PFS based on BOD criteria was reached in the short arm only (14.8 months); 24-month PFS rates were 78% (Long), 70% (Int), and 27% (Short; Figure 1B). Safety results are summarized in Table 1. In all arms, no hematologic treatment-emergent AE was observed in ≥10% of pts, and the rates of grade 3/4 infections were ≤5%. Deaths occurred in 1 pt (2%) in the Int arm (due to heart failure not related to DARA) and 1 pt (2%) in the Short arm (due to PD); no deaths were observed in the Long arm. No deaths occurred within 30 days of the last DARA dose. Conclusions: After median follow-up of 25.9 months, a more pronounced BOD PFS benefit was observed in the Long and Int arms compared with the Short arm. The safety profile of DARA monotherapy in SMM remains consistent with other single-agent DARA studies, and no new safety signals were observed with longer follow-up. Because dose intensity was associated with efficacy in SMM pts, an extended, dose-intensive schedule was selected for an ongoing phase 3 study of DARA monotherapy versus active monitoring in SMM (AQUILA). Disclosures Landgren: Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Chari:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Research Funding; The Binding Site: Consultancy. Cohen:Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Voorhees:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Novartis: Consultancy, Other: served on an IRC; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Speakers Bureau. Estell:Janssen: Membership on an entity's Board of Directors or advisory committees. Sandhu:Bioverativ: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Jenner: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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Williams:Takeda: Honoraria, Other: travel support, Speakers Bureau; Celgene: Honoraria, Other: travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Other: travel support, Speakers Bureau; Novartis: Honoraria. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Beksac:Amgen,Janssen-Cilag,Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Chugai: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Amgen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuppens:Janssen Research & Development: Employment. Bandekar:Janssen Research & Development: Employment. Neff:Janssen Research & Development: Employment. Cortoos:Janssen Research & Development: Employment. Clemens:Janssen Research & Development, LLC: Employment. Qi:Janssen: Employment. Adams:Janssen Pharmaceutical R&D: Employment. Hofmeister:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

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 All regimens were well tolerated with no significant additional toxicity due to the quadruplet regimen. KCRD was administered for a median of 4 cycles, CRD 5 cycles and CTD 6 cycles. Grade 3+ neutropenia occurred in 16.4% KCRD, 22.3% CRD and 12.8% CTD patients and thrombocytopenia in 8.4% KCRD, 2.3% CRD and 1.2% CTD patients. A higher proportion of patients receiving KCRD induction were able to undergo ASCT than those who received response-adapted induction. In an analysis restricted to those who had completed ASCT, KCRD induction was still associated with a significantly longer PFS. An exploratory analysis compared the patients receiving KCRD to patients in the CTD/CRD arm who had received the optimum response-adapted approach (i.e. excluding those randomized to no CVD following MR/PR). The quadruplet was associated with significantly longer PFS than using a response adapted sequential triplet approach (HR 0.64, 95% CI 0.52, 0.78, p Conclusions This large randomized study of a carfilzomib containing quadruplet combination, KCRD, demonstrates that it is well tolerated and associated with deep responses both pre- and post-transplant and has a significant PFS and PFS2 benefit compared to triplet therapy. The benefit of upfront intensification of treatment persisted even compared to triplets administered sequentially and including exposure to both lenalidomide and bortezomib. On behalf of the NCRI Haem-oncology CSG Disclosures Jackson: Merck Sharp and Dohme: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau. Davies:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; ASH: Honoraria; MMRF: Honoraria; Janssen: Consultancy, Honoraria; TRM Oncology: Honoraria. Pawlyn:Janssen: Honoraria, Other: Travel support; Celgene Corporation: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy, Other: Travel support. Cairns:Merck Sharp and Dohme: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Striha:Amgen: Research Funding; Abbvie: Research Funding; MSD: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Hockaday:MSD: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Millenium: Research Funding. Collett:Amgen: Research Funding; Celgene: Research Funding; Merck Sharp and Dohme: Research Funding. Jones:Celgene: Honoraria, Other: Travel support, Research Funding. Kishore:Takeda: Honoraria, Other: travel support; Celgene: Honoraria. Garg:Novartis: Other: travel support, Research Funding; Amgen: Honoraria, Other: Travel Support; Janssen: Honoraria; Takeda: Other: Travel Grant. Williams:Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria, Other: travel support, Speakers Bureau; Takeda: Honoraria, Other: travel support, Speakers Bureau; Celgene: Honoraria, Other: travel support, Speakers Bureau. Karunanithi:Janssen: Other: Travel support, Research Funding; Celgene: Other: Travel support, Research Funding. Lindsay:Takeda: Other: Travel support; BMS: Consultancy, Other: Travel support; Janssen: Consultancy; Celgene: Honoraria, Other: Travel support; Novartis: Other: Travel support. Jenner:Celgene: 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; Takeda: 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. Cook:Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau. Russell:Jazz Pharma: Speakers Bureau; Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kaiser:Bristol-Myers Squibb: Consultancy, Other: travel support; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Other: travel support; Janssen: Consultancy, Honoraria; Chugai: Consultancy; 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; Janssen: Honoraria; Amgen: Research Funding; Merck Sharp and Dohme: Research Funding. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

To obtain a comprehensive genomic profile of presenting multiple myeloma cases we performed high-resolution single nucleotide polymorphism mapping array analysis in 114 samples alongside 258 samples analyzed by U133 Plus 2.0 expression array (Affymetrix). We examined DNA copy number alterations and loss of heterozygosity (LOH) to define the spectrum of minimally deleted regions in which relevant genes of interest can be found. The most frequent deletions are located at 1p (30%), 6q (33%), 8p (25%), 12p (15%), 13q (59%), 14q (39%), 16q (35%), 17p (7%), 20 (12%), and 22 (18%). In addition, copy number-neutral LOH, or uniparental disomy, was also prevalent on 1q (8%), 16q (9%), and X (20%), and was associated with regions of gain and loss. Based on fluorescence in situ hybridization and expression quartile analysis, genes of prognostic importance were found to be located at 1p (FAF1, CDKN2C), 1q (ANP32E), and 17p (TP53). In addition, we identified common homozygously deleted genes that have functions relevant to myeloma biology. Taken together, these analyses indicate that the crucial pathways in myeloma pathogenesis include the nuclear factor-κB pathway, apoptosis, cell-cycle regulation, Wnt signaling, and histone modifications. This study was registered at http://isrctn.org as ISRCTN68454111.

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 Conclusions. We would conclude that MRD is a particularly powerful predictor of outcome in the maintenance setting and is clearly a desirable therapeutic goal in this patient group. The hazard ratio of 0.2 demonstrated here appears superior to those demonstrated in previous studies examining post induction or ASCT time-points. Approximately one third of MRD-positive patients receiving maintenance became MRD-negative and maintenance therapy also results in a decrease in disease levels in those patients remaining positive. These results support the role of MRD monitoring in assessment of the efficacy of different maintenance/consolidation strategies within clinical trials. In the longer term, a stratified approach to treatment based on sequential MRD assessments is feasible. The predictive ability of MRD during maintenance will be assessed with respect to overall survival when the primary endpoint matures in September 2017 and presented at the meeting. Disclosures Rawstron: BD biosciences: Patents & Royalties; Gilead: Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Pawlyn: Celgene: Honoraria, Other: Travel support; Janssen: Other: Travel support; Takeda: Honoraria, Other: Travel support. Davies: Bristol-Myers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Jones: Celgene: Honoraria, Other: Travel Support, Research Funding. Kaiser: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy; BMS: Consultancy, Other: Travel expenses; Chugai: Consultancy. Drayson: Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jenner: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support , Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding, Speakers Bureau; Chugai: Membership on an entity's Board of Directors or advisory committees. Gregory: Janssen: Honoraria; Celgene: Consultancy, Honoraria. Jackson: Celgene: Honoraria; J&J: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Chugai: Honoraria. Morgan: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Myers: Consultancy, Honoraria. Owen: Takeda: Honoraria, Other: Travel Support; Janssen: Consultancy, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding.

Introduction. The outlook for myeloma patients who relapse after or become refractory to bortezomib and IMiDs is poor, with limited therapeutic options and a median survival (OS) of 9 months. In the phase 3 MM-003 study, pomalidomide plus low-dose dexamethasone resulted in a significant PFS (median 4 vs 1.9 months) and OS (median 13.1 vs 8.1 months) benefit, compared to high-dose dexamethasone. Information on real-world outcomes of pomalidomide therapy is limited. We carried out a retrospective analysis of patients receiving pomalidomide in the UK, to compare outcomes and tolerability with published clinical trial data, and focus on high risk subgroups. Methods. All patients treated with pomalidomide at 5 major UK centres between August 2013 and March 2016 were identified from chemotherapy records, and clinical data including toxicity and survival from patient records. Disease response and adverse FISH were defined as per IMWG. Survival was estimated using Kaplan-Meier, and correlations made using log-rank methods. Key subgroups: eGFR Results. A total of 85 patients were identified. Of these, 70 (82%) had measurable disease (IMWG criteria) and received ≥1 cycle so were included in response analyses. Baseline patient characteristics are reported in Table 1. 96.5% of patients were refractory to one or more IMiDs, and 72.9% were refractory to both IMiDs and bortezomib. 92.9% were refractory to their last treatment. The median dose of pomalidomide was 4mg (2-4). Grade 3-4 non-haematological toxicities occurred in 42.4%: pneumonia (16.5%), neutropenic sepsis (8.2%), and acute kidney injury (7.1%), were most common. Grade 3-4 neutropenia occurred in 38% and thrombocytopenia in 24%. Seven patients died on treatment, 6 during the first cycle (2 PD and sepsis, 2 neutropenic sepsis, 1 PD and AKI, 2 pneumonia). In the 70 patients assessable for response, ORR was 52.9% (5.7% VGPR, 47.1% PR, 38.6% SD). Median duration of response (DoR) was 4 months. With median follow-up of 13 months, median PFS was 5 months (95%CI 3.6-6.4), and median OS 13 months (95%CI 10.8-15.2). Patients with renal failure (eGFR 65yrs had similar outcomes to younger patients,(ORR 54.1 vs 51.5%, median PFS and OS comparable between groups). Rates of toxicity were also not influenced by renal impairment, adverse genetics, or older age. The most important predictors of PFS and OS were depth and durability of response. PFS was 6 months for patients achieving PR, 4 months for SD and 1 month for PD, while OS was 18 months in patients achieving PR, 13 months for SD and 3 months for PD. For patients with DoR >4 months, PFS was 11 months and OS 23 months. In contrast, in patients whose DoR was < 4 months or who did not respond, OS was 9 months. Conclusions. Our real-world data on the characteristics and outcomes of patients receiving pomalidomide for relapsed/refractory myeloma in the UK reflect results of published clinical trials. The ORR of 52.9% in our cohort is higher than in MM-003 and MM-010, but PFS (5 months) and OS (13 months) were remarkably similar. Rates of haematological toxicity and infections are low, confirming the good tolerability of pomalidomide in this patient group. Depth and sustainability of response were important predictors of survival: achievement of PR was associated with improved PFS and OS, while patients who achieved SD still derived a survival benefit. Patients who maintained a response for at least 4 months had an estimated survival of nearly 2 years. No difference in response, survival or tolerability was seen in key subgroups, including those with moderate renal impairment, adverse cytogenetics and older age. Our findings confirm the efficacy of pomalidomide in these heavily pre-treated patients and add to the evidence for the benefit of pomalidomide in high risk patient groups. Table Patient characteristics and comparison with MM003 trial Table. Patient characteristics and comparison with MM003 trial Figure 1 PFS and OS for the edited group of 70 patients Figure 1. PFS and OS for the edited group of 70 patients Disclosures Maciocia: Autolus: Equity Ownership, Patents & Royalties: TRBC1 and 2 Targeting for the Diagnosis and Treatment of T-cell Malignancies. Ramasamy:Celgene: Honoraria, Research Funding. Jenner:Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding. Schey:Celgene, Takeda: Honoraria; Celgene, Johnson & Johnson: Speakers Bureau; Celgene: Consultancy. Yong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: 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.

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 The benefit of lenalidomide maintenance on PFS persisted across risk subgroups and was independent of induction therapy and response. An exploratory analysis of 132 patients stopping lenalidomide treatment for reasons other than disease progression (91 toxicity, 28 patient choice and 13 clinician choice) shows that patients receiving greater than 12 months of treatment have an improved median PFS compared to those stopping earlier (HR 0.35 [95%CI 0.18-0.68], 49 vs 31 months, p At this time 445 patients continue to receive lenalidomide maintenance on study. Of patients who have stopped therapy, only 21.5% did so due to toxicity. Relevant grade 3/4 adverse events were: neutropenia 35%, thrombocytopenia 7.4%, anaemia 4.4%, peripheral neuropathy 1.4%. Venous thromboembolism occurred in 2.3%. Second primary malignancy (SPM) data was collected and the relationship with maintenance therapy reviewed. 72 SPM were observed (24 no maintenance, 48 lenalidomide). Haematologic malignancy crude incidence was 0.3% vs. 0.9%. While we found a slight excess of SPM in older patients these were mostly non-invasive and did not impact the outcome benefit demonstrated. Conclusion The use of maintenance lenalidomide treatment results in highly significant improvements in PFS for patients of all ages and should be standard of care. On behalf of the NCRI Haem-Onc CSG Disclosures Jackson: Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau. Davies:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Pawlyn:Takeda Oncology: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support. 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; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: 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; Takeda: Other: Travel support; BMS: Consultancy, Other: Travel support; Celgene: Honoraria, Other: Travel support. Jenner:Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau. Kaiser:BMS: Consultancy, Other: Travel Support; Takeda: Consultancy, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; 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:Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding.

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.

Introduction: Histone deacetylase inhibitors (HDACis) have demonstrated clinical efficacy in multiple myeloma, particularly in combination with proteasome inhibitors. CHR-3996 is a class 1 selective HDACi with potent anti-myeloma activity in vitro. Aminopeptidase inhibitors act downstream of the proteasome and prevent breakdown of proteasome generated peptides into amino acids. Synergistic cytotoxicity was observed in vitro when CHR-3996 was combined with the aminopeptidase inhibitor, tosedostat through rapid activation of NFkB followed by increased expression of the repressors IκBα, A20, CYLD, BIRC3. The MUK-three study was designed to translate these pre-clinical findings into a phase 1 clinical trial. This dose escalation study aimed to determine the maximum tolerated dose, safety and preliminary activity of CHR-3996 administered in combination with Tosedostat for patients with relapsed, refractory MM. Here we present the final study results. Methods: MUK-three was an open label multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had failed conventional treatments. Patients were permitted to meet the haematological entry criteria using growth factor and/or blood product support. During dose escalation subjects received CHR-3996 (20-40mg days1-28) and Tosedostat (0-60mg days 1-28) (Table 1) every 28 day cycle until disease progression or withdrawal. Dose limiting toxicities (DLTs) were evaluated during cycle 1 and dose escalation followed the 3+3 design. Responses were assessed using modified IMWG uniform response criteria, with the primary endpoint for the expansion phase of stable disease (SD) rate after 4 cycles of therapy. Toxicity was graded by CTCAE V4.0. Results: The trial was open to recruitment from July 2012 to December 2015. 20 patients were treated during dose escalation, including 8 at the recommended dose (RD) and 12 at dose levels (DL) 1-3. Only 1 DLT was observed at DL3 (grade 4 thrombocytopenia); however, this DL was deemed not tolerable due to the high incidence of low grade gastrointestinal toxicities. Hence the RD was determined as DL3b, CHR-3996 20mg and Tosedostat 60mg. A further 2 patients were treated at RD during dose expansion to make the required 10 patients for the protocol defined initial analysis at which point the trial closed. At the RD (n=10) median age was 63 years (range 47-73). 80% of patients had received at least 4 prior lines of therapy (median 4, range 2-9); 50% were ISS II, 30% ISS III; 4/6 patients with evaluable FISH data had 1q gain. The median time from diagnosis to treatment for the overall population was 85.3 months (27.5-198.8). The median number of cycles received was 2.5 (range 2-8) and 2 patients remain on treatment with 8 stopped due to disease progression. The 2 patients ongoing (received 5 & 9 prior lines) had their schedule adjusted to a 5 day a week dosing to further improve tolerability. Both had a clinical response (1MR, 1PR) and remained progression free at 6 months. 3/10 patients had SD after 4 cycles, the overall response rate (≥PR) was 1/10(10%) and the clinical benefit rate (≥MR) 2/10 (20%). Overall outcomes were: PR 10%, MR 10%, and SD 30%. Median time to maximum response was 1.84 months (95% CI [1.09, 8.65]). Toxicities at the RD were manageable, 30% of patients required a dose reduction. 22 serious adverse events were reported in 16 patients across all doses, mainly infections (10/22, 45.5%). The commonest grade 3-4 toxicities reported for all 22 patients were: platelet count decrease (12, 54.5%), white blood cell decreased (6, 27.2%), diarrhoea (5, 22.7%). The most frequent grade 1-2 toxicities were fatigue (15, 68.2%), nausea (14, 63.3 %), anorexia (14, 63.6%), anaemia (13, 59.1%). 1 patient withdrew due to toxicity, and there were no treatment related deaths. Conclusions: This study demonstrated that the novel combination of CHR-3996 and tosedostat was safe and tolerable in multiply relapsed, refractory myeloma patients many of which had poor bone marrow function. The recommended dose of the combination was 20mg and 60mg, respectively. Following further adjustment to an intermittent 5 day/ week dosing schedule, treatment was well tolerated and clinical benefit observed. This suggests that further evaluation of this novel combination is warranted. Acknowledgments: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 24989786. Disclosures 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. Yong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Cook:Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Jenner:Amgen: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: Travel support; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Univ of AR for Medical Sciences: Employment; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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.

Introduction. Minimal residual disease (MRD) is a powerful predictor of outcome in multiple myeloma (MM). We have previously demonstrated, in transplant eligible patients, that the level of MRD as a continuous variable independently predicts both PFS and OS, with approximately a one year median OS benefit per log depletion (J Clin Oncol 2013; 31:2540-7 and Blood 2015; 125:1932-5). The impact of MRD also appears to be independent of therapy received. There is more limited data on the applicability of MRD assessment in transplant ineligible patients, largely as a consequence of low rates of CR historically within this patient cohort. Patients and Methods. In this analysis we have assessed the impact of MRD on PFS amongst patients treated within the non-intensive arm of the NCRI Myeloma XI trial. Patients were randomised between thalidomide (CTDa) and lenalidomide (RCDa) based induction therapies with responding patients being subsequently randomised to maintenance with lenalidomide monotherapy, or no further therapy. Bone marrow aspirates were obtained at the end of induction and this analysis represents a subset of 297 patients (median age 74 years). MRD was assessed using flow cytometry (sensitivity 10-4) with a minimum of 500,000 cells evaluated with six-colour antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in additional cases as required. Results. Overall MRD-negativity was demonstrated in 41/297 (13.8%). When considered according to induction therapy received 25/154 (16.0%) of patients randomized to RCDa were MRD-negative compared to 16/143 (10.8%) of those randomized to CTDa (p=0.24; Fisher's exact test). MRD-negativity was associated with a significant outcome advantage as the median PFS was 34 months versus 18 months for MRD-positive patients (p/=10% were 34, 26, 16, 14 and 9 months respectively (p Conclusions. We would conclude that MRD is a powerful predictor of outcome in transplant ineligible patients and is a meaningful therapeutic goal in this patient group. In contrast to conventional CR it retains independent prognostic significance both as a quantitative and qualitative variable. This data further supports the role of MRD as a primary endpoint and surrogate marker for survival in future clinical trials. Figure. Figure. Disclosures Rawstron: Janssen: Research Funding; BD Biosciences: Other: Remuneration; Gilead: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Genzyme: Honoraria; AbbVie: Honoraria; Roche: Honoraria; Celegene: Honoraria. Pawlyn:Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support; Chugai: Consultancy. Jones:Celgene: Honoraria, Research Funding. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; 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. Jenner:Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: Travel support. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jackson: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; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, 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. Owen:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel support; Janssen: Consultancy, Other: Travel support.

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 ( Methods: In 2013, the TE pathway was amended to include KCRD: carfilzomib 36mg/m2 IV d1-2,8-9,15-16 (20mg/m2 #1d1-2), cyclophosphamide (cyclo) 500mg PO d1,8, lenalidomide (len) 25mg PO d1-21, dexamethasone (dex) 40mg PO d1-4,8-9,15-16). Patients are randomised to this up-front quadruplet or the sequential strategy of CRD: cyclo 500mg PO d1,8, len 25mg PO d1-21 PO daily, dex 40mg PO d1-4, 12-15 or CTD: cyclo 500mg PO d1,8,15 thalidomide 100-200mg PO daily, dex 40mg PO d1-4,12-15 given to max. response - patients with VGPR/CR proceed straight to ASCT, PR/MR are randomised to sequential CVD: cyclo 500mg d1,8,15, bortezomib 1.3mg/m2 IV/SC d1,4,8,11, dex 20mg PO d1,2,4,5,8,9,11,12 or nothing and SD/PD all receive sequential CVD. All treatments are given to max. response prior to ASCT, after which there is a maintenance randomisation. Patients: 1512 patients entered the TE pathway prior to amendment (756 CRD, 756 CTD). Of these, 201 patients with a suboptimal initial response went on to receive CVD, 142 following randomisation (initial response PR/MR) and 59 with NC/PD. 788 (of target n=1036) patients have been randomised post-amendment to date (394 KCRD, 197 CRD, 197 CTD). Results: TE patients receiving treatment prior to the amendment had response rates ≥VGPR: CRD 58% vs CTD 52%. For patients receiving the sequential triplet CVD due to a suboptimal response this was upgraded to ≥VGPR in 49% of those with initial MR/PR, 27% with NC/PD. This suggests the overall ≥VGPR rate to this treatment approach prior to ASCT would be approx. 75%. This now needs to be compared to the alternative approach of an upfront quadruplet. Comparing patients contemporaneously randomised to initial induction the patients receiving KCRD have completed a median 4 cycles (range 1-7), CRD 5 (range 1-10) and CTD 6 (range 1-9). Dose modifications have been required in 62% of patients receiving KCRD (56% to carfilzomib, 42% to lenalidomide) 44% CRD (40% to lenalidomide) and 65% CTD (59% to thalidomide). Data for study drug related toxicity in patients who have completed at least one cycle of initial induction are shown in table 1. Serious adverse events suspected to be due to trial medications have occurred in 37% on KCRD, 32% CRD and 35% CTD. Updated toxicity and preliminary response analysis on 23/09/15 will be presented at the meeting. This will include a response comparison at the end of initial induction regimen i.e. KCRD vs CRD vs CTD for an anticipated 700 contemporaneous patients who will have completed treatment. Updated response to the sequencing approach (with 250 patients having received sequential CVD) will also be presented and compared. Conclusions: In our study KCRD, an outpatient delivered 4-drug regimen combining second generation IMiD and PI drugs, is well-tolerated in TE NDMM patients, comparable to 3-drug regimens. Data will be presented at the meeting to compare the response rates achieved with the different regimens and treatment approaches. On behalf of the NCRI Haemato-oncology CSG Table 1. Comparative toxicities KCRD n=261 CRD n=143 CTD n=142 % (no. of patients) Peripheral neuropathy Sensory Gr II-IV 1.9 (5) 1.4 (2) 8.5 (12) Motor Gr II-IV 3.1 (8) 1 (1) 5.6 (8) VTE all grades 4.2 (11) 4.9 (7) 5.6 (8) Anaemia Gr III-IV 9.2 (24) 4.2 (6) 5.6 (8) Neutropenia Gr III-IV 14.9 (39) 16.1 (22) 13.3 (19) Thrombocytopenia Gr III-IV 8.4 (22) 1.4 (2) 1.4 (2) Infusion reaction Gr III-IV 0.4 (1) - - Disclosures Pawlyn: Celgene: Honoraria, Other: Travel support; The Institute of Cancer Research: Employment. Off Label Use: Carfilzomib as induction treatment for myeloma Lenalidomide and vorinostat as maintenance treatments for myeloma. Davies:University of Arkansas for Medical Sciences: Employment; Celgene: Honoraria; Onyx-Amgen: Honoraria; Takeda-Milenium: Honoraria. Jones:Celgene: Other: Travel support, Research Funding. Kaiser:Janssen: Honoraria; Chugai: Consultancy; Amgen: Consultancy, Honoraria; BristolMyerSquibb: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Jenner:Takeda: Honoraria; Amgen: Honoraria. Cook:Jazz Pharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Chugai: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Russell:Therakos: Other: shares. Owen:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Gregory:Janssen: Honoraria; Celgene: Honoraria. Jackson:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Morgan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; CancerNet: Honoraria; Weisman Institute: Honoraria; MMRF: Honoraria; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Weisman Institute: Honoraria; CancerNet: Honoraria.

Introduction: Bortezomib (Velcade) and dexamethasone is a standard combination for relapsed myeloma. Both in vitro data and initial clinical trials signalled the efficacy of the combination of intravenous bortezomib and the oral histone deacetylase inhibitor vorinostat. Although the randomised phase 3 VANTAGE 088 trial identified an improvement in progression free survival with the combination of bortezomib and vorinostat compared to bortezomib monotherapy in relapsed myeloma, 50% of patients in the vorinostat group had at least one dose reduction compared with 25% in the placebo group, with potential impact on clinical outcomes. Subcutaneous bortezomib has now become the standard route of administration because of lower rates of peripheral neuropathy. MUK four is a single arm phase 2 multi-centre UK trial to evaluate the toxicity profile and efficacy of an alternative dosing schedule of vorinostat in combination with subcutaneous bortezomib and oral dexamethasone. We report the final analysis of toxicity and response data. Methods: Patients with relapsed myeloma treated with 1-3 prior lines of therapy received up to 8 cycles of V2 D (bortezomib 1.3 mg/m2 subcutaneously days 1, 4, 8 and 11, vorinostat 400 mg orally days 1-4, 8-11 and 15-18 and dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21 day cycle). Following completion of a minimum of 3 cycles of V2 D, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28 day cycle) until disease progression, intolerance or participant withdrawal. Responses were assessed using the modified IMWG response criteria and toxicities graded using CTCAE v4.0. Results: Between August 2013 and November 2014, 16 participants were recruited to MUK four. Median age was 69.5 years (range 50.0-78.0) and median lines of prior treatment was 1 (1-3). Prior treatment included thalidomide-based combinations in 13/16 (81.3%), bortezomib-based in 7/16 (43.8%) and lenalidomide-based in 2/16 (12.5%). 9/16 (56.3%) participants had received prior high dose melphalan ASCT. Median time from diagnosis was 38.6 months (9.3-120.4). At analysis in June 2015 8/16 (50%) participants continued on maintenance vorinostat. All 16 patients were evaluable for response within the first 8 cycles of V2 D. Overall response rate was 81.3% (13/16, 95% CI [55.4-96.0]) consisting of CR in 4/16 (25.0%), VGPR 2/16 (12.5%) and PR in 7/16 (43.8%). The remaining 3/16 (18.8%) achieved MR giving a clinical benefit response rate of 16/16 (100%). Participants received a median of 6 cycles of initial treatment with 6/16 (37.5%) receiving all 8 cycles. Treatment was discontinued in 4/8 (50%) because of disease progression, in 2/8 (25%) because of toxicity and in 2/8 (25%) for clinician discretion. Overall 12/16 (75%) participants experienced a dose reduction of either vorinostat or bortezomib or terminated treatment early as a result of toxicity. 11/16 (68.8%) reduced vorinostat and 10/16 (62.5%) reduced bortezomib. The most frequent grade 2 toxicities during the first 8 cycles were fatigue in 8/16 (50%), anaemia in 7/16 (43.8%), diarrhoea in 5/16 (31.3%), nausea in 4/16 (25.0%) and peripheral neuropathy in 4/16 (25.0%). The most frequent grade 3-4 toxicities encountered during the first 8 cycles were thrombocytopenia in 8/16 (50%), anaemia in 1/16 (6.3%), diarrhoea in 1/16 (6.3%) and fatigue in 1/16 (6.3%). During maintenance vorinostat only 1 participant experienced an adverse reaction above grade 2 (grade 3 neutropenia). Conclusion: Bortezomib, vorinostat and dexamethasone is a highly effective combination in relapsed myeloma with good response rates. Maintenance vorinostat is well tolerated. Although toxicity and dose reductions are observed with combination therapy, this study demonstrates that the combination of proteasome inhibitor, HDAC inhibitor and dexamethasone offers promise. Further data on PFS will be presented. Disclosures Jenner: Amgen: Honoraria; Takeda: Honoraria. Off Label Use: Vorinostat for treatment of myeloma. Pawlyn:Celgene: Honoraria, Other: Travel support; The Institute of Cancer Research: Employment. Williams:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Davies:Array-Biopharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; Onyx-Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

We performed fluorescent in situ hybridization (FISH) for 16q23 abnormalities in 861 patients with newly diagnosed multiple myeloma and identified deletion of 16q [del(16q)] in 19.5%. In 467 cases in which demographic and survival data were available, del(16q) was associated with a worse overall survival (OS). It was an independent prognostic marker and conferred additional adverse survival impact in cases with the known poor-risk cytogenetic factors t(4;14) and del(17p). Gene expression profiling and gene mapping using 500K single-nucleotide polymorphism (SNP) mapping arrays revealed loss of heterozygosity (LOH) involving 3 regions: the whole of 16q, a region centered on 16q12 (the location of CYLD), and a region centered on 16q23 (the location of the WW domain-containing oxidoreductase gene WWOX). CYLD is a negative regulator of the NF-κB pathway, and cases with low expression of CYLD were used to define a “low-CYLD signature.” Cases with 16q LOH or t(14;16) had significantly reduced WWOX expression. WWOX, the site of the translocation breakpoint in t(14;16) cases, is a known tumor suppressor gene involved in apoptosis, and we were able to generate a “low-WWOX signature” defined by WWOX expression. These 2 genes and their corresponding pathways provide an important insight into the potential mechanisms by which 16q LOH confers poor prognosis.

Multiple myeloma is characterized by genomic alterations frequently involving gains and losses of chromosomes. Single nucleotide polymorphism (SNP)-based mapping arrays allow the identification of copy number changes at the sub-megabase level and the identification of loss of heterozygosity (LOH) due to monosomy and uniparental disomy (UPD). We have found that SNP-based mapping array data and fluorescence in situ hybridization (FISH) copy number data correlated well, making the technique robust as a tool to investigate myeloma genomics. The most frequently identified alterations are located at 1p, 1q, 6q, 8p, 13, and 16q. LOH is found in these large regions and also in smaller regions throughout the genome with a median size of 1 Mb. We have identified that UPD is prevalent in myeloma and occurs through a number of mechanisms including mitotic nondisjunction and mitotic recombination. For the first time in myeloma, integration of mapping and expression data has allowed us to reduce the complexity of standard gene expression data and identify candidate genes important in both the transition from normal to monoclonal gammopathy of unknown significance (MGUS) to myeloma and in different subgroups within myeloma. We have documented these genes, providing a focus for further studies to identify and characterize those that are key in the pathogenesis of myeloma.

To obtain a comprehensive genomic profile of presenting multiple myeloma cases we performed high resolution single nucleotide polymorphism (SNP) mapping array analysis to examine changes in DNA copy number and loss of heterozygosity in 115 cases with matched peripheral blood controls. Identification

Background: The optimal therapy for patients with relapsed/refractory multiple myeloma remains controversial. Lenalidomide, an oral immunomodulatory drug, has been shown to be an effective treatment in this setting, with in-vitro laboratory data suggesting that its effect is synergistic with a number of established chemotherapeutic agents. The primary objective of this study was to determine the maximum tolerated dose and toxicity of cyclophosphamide when used in combination with lenalidomide and dexamethasone for patients with relapsed/refractory myeloma. The secondary objective was to determine clinical response rates. Methods: Cyclophosphamide was given at increasing doses from 300 mg po in cohort 1, up to the maximum planned dose of 700 mg po in cohort 5 on days 1 and 8 of a 28 day cycle, in combination with dexamethasone (20mg po, daily on days 1–4 and 8–11) and Lenalidomide (25mg po, daily on days 1–21). Maximum tolerated dose (MTD) was established as one dose level below that at which 2 or more patients suffered dose limiting toxicity (DLT). DLT was defined as Grade 4 haematological toxicity or febrile neutropenia occurring during cycle 1 of treatment, or Grade 3/4 non-haematological toxicity during cycle 1, or a failure to start cycle 2 within 7 days of scheduled day due to toxicity. Once the MTD had been established, a further ten patients were enrolled at that dose. Safety assessments were performed weekly during cycle 1, and at the end of every cycle thereafter. Response data was collected on day 28 of each cycle. Results: Toxicity The most commonly observed adverse events were; neutropenia (grade 1–3), cramps (grade 1–2), somnolence (grade 1–2), constipation/diarrhoea (grade 1–2), minor infections (grade 1–2), and musculoskeletal aches and pains (grade 1). The most common reason for dosing delays and dose reductions was grade 3 neutropenia. Maximum tolerated dose No patients receiving doses of 300 to 600mg cyclophosphamide have experienced dose limiting toxicity during the first month of treatment. 2 patients receiving 700mg qualified as having dose limiting toxicity (One patient with febrile neutropenia, pneumonia and syncope (all grade 3)), and another with grade 4 pancytopenia). The maximum tolerated dose of cyclophosphamide in combination with lenalidomide and dexamethasone has therefore been established at 600mg daily on days 1 and 8 of a 28 day cycle. Response: A total of 31 patients were enrolled into the study. Median age at enrolment was 57 years (range 42–79). Median ISS at trial entry was 1 (range 1–3). Median time since last therapy was 7 months (range 1–84). To date, 36% of patients have achieved CR or VGPR, and 81% PR or better. Responses were assessed at the end of each cycle. 25 of the 31 patients have so far achieved PR or better. Of these 25 patients, 76% had achieved their maximum response by cycle 3 day 28. Patients had received 1–6 prior lines of therapy (median 3). 28/31 patients had previously received thalidomide, 20 had received autologous stem cell transplant, and 8 received velcade. 7 patients had received all 3 and, of these, 1 achieved SD, 3 PR, and 3 CR. This suggests that lenalidomide in combination with cyclophosphamide and dexamethasone is an effective therapy for heavily pre-treated patients. Conclusion: 600mg cyclophosphamide on days 1 and 8 of a 28 day cycle is well tolerated in combination with Lenalidomide and dexamethasone. The combination is a highly effective therapy for relapsed/refractory myeloma. The majority of patients achieved a maximal response during the first 4 courses of treatment. CRD is also an effective treatment for patients who have received extensive prior chemotherapy. Whether patients need to continue treatment to nine cycles remains to be tested. Figure Figure

The immunoglobulin production of myeloma plasma cells means they are dependent on the unfolded protein response process (UPR), which controls protein production and ensures its proper translation and folding. Knockout mouse studies have highlighted the importance of IRE1, a transducer of the UPR signal and XBP1 its downstream target, in B cell development. Gene expression studies show that XBP1 is highly expressed in myeloma plasma cells and it is consistently deregulated in clinical samples. XBP1s, the active moiety, is a known myeloma survival factor and IgVH-XBP1s transgenic mice develop myeloma. In this work we demonstrate that XBP1s levels correlate with survival of myeloma patients and that targeting it with small molecules may be a useful therapeutic strategy. We have re-sequenced IRE1 and determined the gene expression levels of IRE1, total XBP1, XBP1 unspliced (XBP1u), and XBP1 spliced (XBP1s) in a large series of myeloma patients (n=260), and correlated biological findings with clinical characteristics and patient outcome. To quantitatively assess the expression of XBP1s and XBP1u variants, we have designed a novel real time PCR method (Lux Technology, Invitrogen) capable of determining the ratio of these transcripts within a sample. These results show that total IRE1 and XBP1 are highly expressed in all patients. In addition all patients expressed higher levels of XBP1s, the active transcription factor which is anti-apoptotic, compared to the inactive precursor XBP1u. We correlated XBP1s/u gene expression levels with clinical parameters in 159 newly diagnosed patients. This group of patients contained 68 females and 91 males with a median age of 64 years (range 39–89), B2M median = 7.45mg/mL (range 1.1–30mg/mL), haemoglobin median = 10.2g/dL (range 5.7–14.7g/dL) and ISS status stage 1 = 21%, stage 2 = 36%, and stage 3 = 36%. The XBP1s/u ratio demonstrated a statistically significant effect on overall survival (OS) in patients with high B2M (B2M >5), with a cut-off ratio of 2.8 for the XBP1s/u expression (assigned using the quartile method). In this group of patients those with higher XBP1s/u have shorter survival (28 months) compared to those with lower XBP1s/u (not reached, 50+ months). (p = 0.033). The cause for the high and variable XBP1s levels is uncertain but could be mediated by IRE activity. Sequence analysis of the kinase and endoribonuclease domain of IRE1 identified 3/50 patients with an inactivating mutation in the endoribonuclease domain (G923V): patients with this mutation had a lower ratio of XBP1s to XBP1u and a longer survival. In conclusion, this study is the first to demonstrate the clinical significance of high XBP1s levels in myeloma and shows that patients with high levels of XBP1s have a shorter overall survival. Coupled with our previous study highlighting the critical role of the UPR in myeloma and the report of the XBP1s transgenic mouse model, the importance of the IRE1-XBP1 axis myeloma is now established, and its role as a therapeutic target needs to be explored.

Multiple Myeloma (MM) is a malignancy depicted by clonal expansion of plasma cells in the bone marrow. There are two broad genetic subtypes of multiple myeloma as defined as hyperdiploid multiple myeloma (H-MM), characterized by trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, and nonhyperdiploid multiple myeloma (NH-MM) associated with primary translocations involving the immunoglobulin heavy chain (IgH). These two subtypes of multiple myeloma have two different molecular pathogenesis given that characteristic changes of each have been already observed. In order to contribute to the understanding of this malignancy and to unveil the different molecular pathogenesis, our interest is focused on Human Multiple Myeloma Cell lines (HMCLs), as a model, and a broad but specific group of enzymatic proteins: the Kinases. Kinase hyperactivity or lack of it often results in disregulation of cellular pathways involved in proliferation and survival. In our study, we describe the patterns of genetic lesions and molecular pathogenesis of 11 HMCLs with Single Nucleotide Polymorphism (SNP)-based mapping arrays from Affymetrix Human Mapping 500K array set. This technique allows the examination and identification of copy number changes, bi-allelic deletions and the identification of loss of heterozygosity (LOH) due to loss and uniparental disomy, as well as gene localization and identification. The 11 HMCLs utilized are characterized for their structural alterations and not by hyperdiploidy. In addition, so as to fulfill the selection criteria, a minimum of 3 cell lines must present the alterations cited below. The most frequently identified alterations were located as follows: Previously described gains were observed in 1q, 7q, 8, 11q, 18, 19, and 20q; but also found at 4q. The bi-allelic deletions were ascertained on 3p. Similarly, we identified the regions of hemizygotic deletions on 1, 2q, 6q, 8q, 9p, 11q, 12, 13q, 14q, 17p, and 20p. In addition, described regions of homozygotic deletions were detected on 1p, 6q, 8p, 13q, 16q, and 22q, and furthermore located on 2q, 3, 4q, 9, 10q, 12p, and 20p. Finally, the uniparental disomies (UPDs) obtained were traced on 1q, 4q, 8q, 10q, and 22q. These identified alterations are affecting a series of enzymatic genes belonging to targeted pathways. Within the chromosomes 1, 10, 11, 14, and 16 we have localized kinases that are part of the PI3K/AKT pathway, which affect to a number of intracellular and extracellular myeloma growth cytokines. In the chromosomes 1, 6, 12, and 19 we identified a series of Cyclin-Dependent Kinases that are critical regulators of cell cycle progression and RNA transcription, since they regulate and control the cyclins, cell cycle regulatory proteins, which can provoke dysregulation and abnormally accelerated cell cycle progression. And finally on chromosomes 1, 2, 14, 21, and 22 we observed certain Aurora and related kinases, as another family of the cell cycle regulators and often aberrantly activated in human tumor cells, they facilitate transit from G2 through cytokinesis. These mutated kinases may be potential targets for therapeutics. Our data demonstrates the genomic complexity of multiple myeloma enhancing our understanding of the molecular pathogenesis of the disease and the importance of the HMCLs as a model.

Single nucleotide polymorphisms (SNPs) have been long regarded as being important in determining variation and disease predisposition. Recently, chromosomal structural variation in the form of deletions, insertions and duplifications have been identified frequently in the genome of the general population. Such copy number variations (CNVs) have been shown to contribute to a range of human diseases. In recent studies we have utilized Affymetrix 50K and 500K arrays to identify acquired copy number change in myeloma tumor samples. In those studies we had access to paired constitutional DNA and in the present study have been able to report for the first time a CNV map of the constitutional genome of myeloma patients. Affymetrix 500K mapping arrays were used to identify copy number changes in 63 paired samples using DNA from peripheral blood and CD138 selected plasma cells. Tumor samples were analyzed in CNAG using both a paired and unpaired analysis to distinguish between inherited and acquired copy number change. Constitutional DNA was analyzed by both CNAG and GEMCA using 90 Caucasian samples from the Hapmap database as a reference set. For maximum calling accuracy, only those regions identified by both algorithms were called as CNVs. As with similar studies, overlapping CNVs identified using this approach were merged to generate a list of CNV regions (CNVRs) characteristic of the constitutional DNA of these myeloma cases. Using this approach, we identified 292 CNVs across 63 cases, with a median of 4 regions per sample. There were 155 discrete CNVRs, of which 46 were recurrent. The recurrent CNVRs were found most frequently in the pericentric regions of chromosome 14 and 15 in keeping with other studies. We then compared these recurrent CNVRs with a comparable dataset of normal individuals generated using Affymetrix 500K arrays. In this analysis, 25/46 recurrent CNVRs in the myeloma cases were novel. The two most frequent novel CNVRs in the myeloma cases were gains on chromosome 21 and 15. We also compared the characteristics of the constitutional CNVs with the acquired copy number changes in the corresponding tumor samples and identified that the constitutional CNVs were generally considerably smaller. However, using unpaired analysis it was possible to determine the presence of the constitutional CNV in the tumor sample, providing validation of the CNVs. We were also able to demonstrate that acquired copy number change in the tumor cells can either exaggerate or ameliorate the effect of the inherited CNV in the tumor genome, such as cases with acquired trisomy 15 and deletion or gain of regions of 15q in the constitutional DNA. These findings also reinforce the need for paired non-tumor DNA when undertaking copy number analysis of tumor DNA using SNP arrays. In this study we have been able to identify for the first time the presence of CNVs in the constitutional genome of individuals with myeloma. We have been able to systematically catalogue these CNVRs. These results provide the basis for future studies aimed at identifying how this type of genomic variation may influence the development of and outcome of myeloma and a broad range of other hematological conditions.

Defining biologically relevant prognostic indices in myeloma is a challenge. The International Staging System (ISS) is important but based on simple clinical data. Cytogenetics, in particular switch translocations and 17p-, are more important biologically, being based on underlying genetic changes. However, these changes do not capture all of the important biological data and so signatures based on global expression analysis have been developed to address these shortcomings. Most signatures to date have been based on expression features correlated with outcome rather than using structural genetic change to define biologically relevant expression features and, as such, although predictive, they may be acting as “bystander” markers rather than being pathologically important themselves. We have used homozygous deletions (HD) to define relevant genes and gene signatures predictive of outcome in a large homogeneously treated set of myeloma patients.

Whilst gene expression signatures have been defined that correspond to poor overall survival, the mechanism for deregulation of such genes is often elusive. We and others have described acquired copy number change as one potential mechanism of gene deregulation in myeloma. Other potential mechanisms exist that may influence the expression of myeloma-associated genes such as inherited SNPs and copy number variation (CNV). We have therefore embarked upon an integrated pharmacogenomic strategy to determine the importance of acquired and inherited genetic changes in determining response to therapy. We have carried out gene expression analysis on CD 138 selected bone marrow plasma cells from 231 newly diagnosed myeloma cases using Affymetrix U133 Plus 2.0 expression arrays and copy number analysis using 500K Gene Mapping arrays on a subset of 90 cases. Peripheral blood DNA has been genotyped using Affymetrix 500K Gene Mapping arrays and the BOAC chips. Cytogenetics was available in the majority of cases. Younger, fitter patients received either cyclophosphamide, thalidomide and dexamethasone (CTD) or cyclohosphamide-VAD (C-VAD), followed by high dose melphalan (HDM). Older, less fit patients received attenuated dose CTD or MP. Response was assessed before and after HDM in the intensive group and on completion of therapy in the non-intensive group using EBMT criteria plus the category of VGPR. We used a supervised approach to define a gene expression signature corresponding to high level response (CR, VGPR or PR) against poor response (NC, PD or MR) overall and for each of the three induction strategies, CTD/CTDA, CVAD and MP. We have combined the data from expression arrays together with mapping data from tumor DNA and 2 different SNP arrays performed on germline DNA. We defined a poor response expression signature initially and then identified the genomic loci of these genes and how they were affected by acquired copy number change. For each candidate gene we also examined the constitutional DNA to see if each fell within a region of inherited CNV and how this could be affected by acquired copy number change. In a similar fashion, we used the BOAC chip to define genes and SNPs associated with response. This is different as it utilized mostly functional cSNPs in candidate genes. We then looked at how CNV affected these genes. Although not all genes in which functional cSNPs are present would necessarily be expected to be expressed in plasma cells, this approach is a vital step in identifying the clinical relevance of such cSNPs in myeloma. We also took the alternate approach and designed an algorithm able to correlate acquired copy number change with paraprotein response. We then identified differentially expressed genes in these loci and their impact on response, narrowing the candidate genes down to define a signature which could be validated. Using this approach has allowed us to identify genes important in determining response and their relation to tumor-associated copy number change and inherited CNV. Overall, this methodology provides significant insight in to the factors that predict response to different chemotherapy regimens. Preliminary data will be presented.

Previous data sets have defined deregulation of the RAS, RAF and MAPK pathway as being critical in Myeloma pathogenesis. More recently, the NFκB pathway has been identified as commonly deregulated. Combined with cytogenetic data these findings suggest that multiple events affecting common pathways lead to the initiation and progression of Myeloma. We employed a novel strategy to identify other deregulated pathways contributing to Myeloma progression. We hypothesize that gain of chromosome segments correlates with over-expression of genes contained within and losses result in a corresponding decrease in expression. For copy number (CN) 0, i.e. homozygous deletions, expression should be lost. Expression may not always be altered by other CN changes, e.g. hemizygous deletions (CN1) where a single copy of the gene may be sufficient to maintain the level of expression. Furthermore, the relationship between CN and expression is not expected to be linear, e.g. CN4 having twice the expression of the normal CN2, as steric interactions and feedback mechanisms play important roles in the expression of multiple copies. Our aim was to identify CN changes in Myeloma plasma cells and identify networks of gene expression altered as a consequence of CN changes. Dysregulation of one gene within a pathway can perturb the overall balance of the system, causing changes in the entire network that could contribute to tumour pathogenesis. Expression changes correlating with genes with CN changes should reflect the interactions of those genes and identify more genes that are co-regulated or directly influenced within the same networks. The CN0 and CN4 plus genes should have the largest downstream effects, i.e. complete ablation or large over-expression of a gene would perturb its networks the most. We analysed DNA and RNA from CD138+ plasma cells from 84 patients with Myeloma. The DNA was analysed using the Affymetrix 500k SNP GeneChip arrays and CN changes were assessed using DNA from paired samples of peripheral blood and inferred using dChip (2007 build). Gene expression was measured using RNA and Affymetrix HG-U133 +2 GeneChips with dChip to generate expression values. Correlation of expression was measured using the Pearson correlation coefficient and significance was assessed using permutation tests and a corrected p

Dexamethasone is an important drug in the treatment of myeloma and is widely used in novel combinations, however, resistance can develop and clinical intolerance is frequent. Novel regimens that are effective and dexamethasone sparing are therefore required. Bortezomib (Velcade), the first-in-class proteasome inhibitor, has shown to be effective for the treatment of relapsed refractory myeloma, and has been shown to enhance the antitumor efficacy of both Melphalan and Anthracyclines. Early clinical results have demonstrated the efficacy and tolerability of combinations of Velcade with either of these agents. We have carried out a dose-escalating phase 1 study is to assess the safety, tolerability and response rate of the Velcade/Idarubicin/Melphalan (VIM) combination. Patients with relapsed/refractory myeloma who were either resistant or intolerant to dexamethasone were recruited. The study aimed to recruit 6 cohorts of 3 patients with standard dose Velcade and increasing doses of Melphalan and Idarubicin. Velcade (1.3 mg/m2) was administered on days 1, 4, 8 and 11 on a 28-day cycle with total number of 3 cycles, with the single dose of Melphalan (10, 15 or 20 mg/m2, i.v.) on day 4 and Idarubicin (5 or 10mg/m2) on days 4,5,(6 and 7). NCI CTCAE v3.0 was used for toxicity assessment; DLT was defined as any grade 3 or 4 non-haem toxicity (excluding neuropathy) or any grade 4 haem toxicity (excluding neutropenia) which does not resolve to a grade 2 within 2 weeks of completing a course. As of July 2007, 14 patients were enrolled in cohorts 1–3 with a median age of 59 (range 36–68). The median number of prior therapies was 2.5 (range 1–5), including 10 pts with prior high dose therapy, 11 with Anthracyclines, and 13 with Thalidomide. In patients assessable for response 9/13 achieved a response with 2 CR, 5 PR and 2 MR according to EBMT criteria. The side effect profile was manageable and no unexpected toxicities were seen. Grade 3 toxicities were mostly related to myelosuppression with 79% thrombocytopenia and 71% neutropenia. 12 patients received GCSF to maintain their neutrophil count and 10 pts received platelet transfusions. Despite the myelosuppression no increase in infections or serious bleeding was observed. 5 patients required a dose reduction of Velcade and/or course delay due to low counts and 1 patient also required Melphalan dose reduction. Other side effects included upper respiratory tract infection (36%), peripheral neuropathy (29%) and shingles (14%), resulting in a recommendation of aciclovir prophylaxis for all patients. New/worsening neuropathy led to dose reduction of Velcade in 2 patients and discontinuation of treatment in 1 patient. One DLT of G3 respiratory tract infection was observed in cohort 3 (Mel 15 mg/m2, Idarubicin 5 mg/m2 on day 4–7), therefore another 3 patients will be enrolled to this cohort. The study indicates that VIM had a manageable toxicity profile with significant clinical activity in this dexamethasone refractory group of patients.

Homozygous deletions (HD) are important in cancer cell lines and have a non-random distribution in the genome. We have determined the frequency and distribution of HD, along with the genes affected, in 84 presenting multiple myeloma cases using the Affymetrix 500K SNP GeneChip mapping arrays. Initially we took a highly sensitive approach identifying regions with a copy number (CN)

Improving response rates represents an important way to improve PFS and OS in myeloma. In the MRC Myeloma VII study, now with a median follow up of 8 years, we showed the importance of achieving CR. The addition of thalidomide represents a way of increasing response rates. In the MRC Myeloma IX study, which has recruited 1800 patients, in two randomisations embracing younger and older patients, we have compared CTD with MP and CTD + HDM + ASCT with CVAD + HDM + ASCT. In addition to giving insight as to the impact of thalidomide on ORR and CR in both settings, we can assess the effects of HDM + ASCT following CTD induction. We have used a number of techniques to assess response in this study including protein electrophoresis, immunofixation and serum free light chain estimation combined with bone marrow aspiration and trephine assessment. This approach has been supplemented by sensitive multiparameter flow cytometry MRD analysis able to quantitate low levels of residual myeloma plasma cells. In a preliminary analysis, a thalidomide containing combination is associated with improved response rates. Post induction rates are CTD: ORR 95.7%, CR 20.3%; CVAD: ORR 83.4%, CR 11.7% and these differences are maintained at 100 days post HDM, CTD + HDM: ORR 98.7%, CR 58.2%; CVAD + HDM: ORR 95.7, CR 41%, showing that the ORR rate is higher and that the percentage of CR is doubled before HDM and 20% more following the HDM. The depth of CR is also greater in the cases receiving thalidomide. We are updating these results as well as the results from the MP vs CTD comparison and will present these data. There are some discrepancies between each of the disease monitoring approaches and optimally all should be used. At d+100 it is possible to have true CR measured by flow MRD assessment but still have detectable paraprotein. The opposite also occurs: apparent CR by paraprotein estimation with MRD positivity by flow. This has important implications for the definition of remission as well as for the assessment of new treatments and their use. Our findings suggest that thalidomide combinations significantly improve ORR, taking more patients to response levels which render them eligible for HDM + ASCT. CR rates are increased and there is a qualitative difference in the depth of CR obtained. The additive value of HDM + ASCT, even when thalidomide is used initially, is suggested by the further increase in the number of responses above that achieved by CTD alone. We await the follow up of patients entered into this large study to assess whether these increased and enhanced responses translate into improved PFS and OS.

We have previously shown that integration of gene expression and SNP based mapping arrays can identify genes dysregulated as a result of copy number loss and gain in multiple myeloma. Using FISH, it has been possible to identify that gain and loss frequently occurs in association with primary IgH translocations, such as loss of FGFR3 and gain of CCND1 in a proportion of t(4;14) and t(11;14) cases. The aim of this study was to determine the frequency and size of such copy number change associated with IgH translocations and to identify the genes dysregulated as a consequence of these. FISH was performed on CD138 selected plasma cells from 80 newly diagnosed myeloma cases to identify cases with primary IgH translocations. Affymetrix 500K mapping arrays were used to determine copy number change using paired tumor and constitutional DNA and Affymetrix U133 plus 2.0 expression arrays were used to determine global gene expression. Samples were analyzed in dChip and CNAG. Thirty eight of 80 cases (47.5%) had primary IgH translocations: 7 t(4;14), 1 t(6;14), 16 t(11;14), 3 t(14;16), 2 t(14;20) and 9 with an unknown translocation partner. Of 29 cases with a known translocation partner, 11 had gain or loss of all or part of the derivative chromosome. Three of 7 t(4;14) cases had loss of FGFR3 by FISH, confirmed by mapping array as being due to deletion of the derivative 14, with loss of 4p16.3-pter and the remainder of chromosome 14 excluding IgH. The region on 4p commenced at FGFR3 and extended to the telomere. Gene expression analysis showed that there was underexpression of FGFR3 and 4 other genes in the deleted region in the 4p16 deleted cases. In 6 of 16 t(11;14) cases, the translocation was associated with an additional copy of CCND1 by FISH. Mapping arrays revealed in all cases the gain commenced at the presumed translocation breakpoint: in 4 cases there was gain of 11q13.3-qter and in 2 there was gain of a small region of 11q13 only. In most cases there was isolated gain of a variable sized region of 14q32 suggesting a sequence whereby translocation was followed by gain then by deletion of a portion of the derivative chromosome. Gene expression analysis identified 4 genes overexpressed on 11q in t(11;14) cases with 11q gain. In a single t(6;14) case there was a complex rearrangement involving gain of 6p21.1-pter and IgH with loss of the derivative 6, again suggesting translocation followed by gain then loss. In one t(14;16) case there was UPD of 16q except for 16q23-qter with associated gain of IgH alone. This complex pattern suggests a sequence whereby deletion is followed by IgH translocation then by duplication of the untranslocated 16q. This study has shown that loss and gain of translocated regions is a frequent occurrence, present in 11/29 cases with known IgH translocations. Using mapping arrays it is possible to demonstrate that in the majority of cases, the translocation is the initial event, followed by subsequent gain or loss as a later event. We have shown the variable size of these regions and have identified genes dysregulated as a result of the deletions of 4p in t(4;14) cases and gains of 11q in t(11;14) cases. These findings provide evidence of collaborating mechanisms that may be responsible for disease progression in these cases.

We have shown that loss of heterozygosity (LOH) at 16q is an adverse prognostic marker when it occurs in combination with either t(4;14) translocation or del(17p). Using 500K Affymetrix mapping arrays we found that 16q was involved in translocations with the IgH locus, deleted, or had uniparental disomy (UPD). The deletion patterns led us to 2 regions at 16q12.1 and 16q21-q24.1, which contains 5 genes and is the location of the t(14;16) translocation. By integrating mapping and expression profiling data from presenting myeloma cases we were able to identify WWOX and CYLD as key genes deregulated in these regions. Both WWOX and CYLD are known tumor suppressor genes. WWOX is known to have a pro-apoptotic effect by participating in the TNF apoptotic pathway and via the direct physical interaction with p53 and p73. CYLD functions as a negative regulator of the NF-κB pathway as well as blocking the activation of cyclin D. WWOX is found to be methylated in other cancer tissues, whereas CYLD is frequently mutated. To determine mode of action of these genes in samples with LOH we performed mutation and methylation analysis on myeloma cell lines and pre-treatment patient samples. Variant transcripts of WWOX, which may act as dominant negatives to block the function of WWOX have been reported so we also determined the nature of these in the samples. Exons from WWOX and CYLD were PCR amplified from samples with LOH, as well as from samples with retention of heterozygosity, and sequenced directly. All differences to the consensus were checked against databases for known SNPs and mutations. Mutations in the tumor sample were confirmed by a repeat PCR, and mutations were also checked against peripheral blood DNA from the same patient to determine if these were acquired in the tumor. LOH of 16q was found in 2 out of 9 myeloma cell lines and additionally homozygous deletion of WWOX exons 5-8 in KMS11 cells was observed. cDNA analysis from these cell lines showed that KMS11 cells expressed variant 3, as could be expected, whereas the dominant transcript in other cell lines is variant 1. However, 2 cell lines also expressed an additional transcript (variant 4), which has previously been shown to act as a dominant-negative transcript. All pretreatment samples expressed the variant 1 transcript. 16 pretreatment samples with LOH were screened for mutations revealing 2 mutations in exon 9, one of which was non-synonymous. Methylation analysis of the WWOX locus is underway. Analysis of CYLD showed frequent mutation in cell lines with many synonymous and non-synonymous mutations, including several frame-shifts resulting in truncated products. Screening of 14 pretreatment samples with LOH at the CYLD locus revealed 2 mutations including a C>TT mutation in exon 11, which results in a frameshift and premature termination of translation. Alternative transcripts of CYLD are formed through splicing of exons 3 and 7. Both exon 3 variants were present but only the variant lacking exon 7 was present in myeloma cell lines. These data suggest that dysregulation of both WWOX and CYLD may be important in the pathogenesis of myeloma and contribute to the effect of del(16q) on patient survival.

Dexamethasone, thalidomide, etoposide and an antracycline have formed part of regimens such as DT-PACE which have demonstrated efficacy in previously treated patients with multiple myeloma. They are inpatient regimens which limit their usage in a palliative setting. We have designed an oral regimen incorporating these agents. The toxicity and efficacy data of this novel treatment are presented. Between October 2004 and May 2007 patients who had progressive myeloma or were intolerant of DT-PACE were treated with 100–200mg of thalidomide on days 1–21 and four days (D1–4) of 10mg/m2 idarubicin, 40mg dexamethasone and 50mg/m2 etoposide twice daily (TIDE). All agents were administered orally on a 21 day cycle for a maximum of 5 cycles. Aciclovir, co-trimoxazole and Lansoprazole were administered routinely and G-CSF was administered in the event of neutropenic fever and as secondary prophylaxis. Thromboembolism prophylaxis was not specified. Response was assessed using the international uniform response criteria for multiple myeloma. Toxicity was assessed using the CTCAE version 3.0. Efficacy data is presented as intention to treat. Nineteen patients received TIDE chemotherapy with a median age of 60 (range 36–70) and a male to female ratio of 11:8. Patients had a median of 3 (range 1–6) previous cycles and 18/19 patients had previous thalidomide. Patients received a median of 3 cycles (range 1–5) of TIDE. The most common grade 3/4 non-haematological toxicities were infection (8 patients), thromboembolism (3 patients), nephrotoxicity (2 patients), diarrhoea (1 patient) and peripheral neuropathy (1 patient). Grade 3–4 haematological toxicity occurred in 17/19 patients but 10/19 patients had grade 1–2 ‘toxicity’ at baseline. There were no recorded toxic deaths. Out of the 8 patients that suffered neutropenic fever, 7 experienced this on their 1st cycle resulting in treatment cessation in 3 patients. With prophylactic G-CSF or dose reduction, 3 of the remaining 4 patients did not get further neutropenic sepsis. In total 6 patients required a dose reduction and 17/19 patients had G-CSF. Seven patients were anti-coagulated from the beginning of this study; 2 were on Erythropoetin, 2 had previous thromboembolism and 3 were commenced at the clinicians discretion. None of the anti-coagulated patients went on to have a thromboembolic event. 18/19 patients were evaluable for response. The overall response rate was 42% (1CR, 7PR, 9SD and 1PD). The response rate to TIDE in patients who were intolerant of inpatient DT-PACE was the same as those that were treated with TIDE alone (50% vs 45%). The median progression free survival was 4 months (range 1–12) and the median overall survival was 8 months (range 1–31). In patients who responded to TIDE the median progression free survival was 7 months (range 3–12) and the median overall survival was 10 months (range 4–23). The TIDE regimen is able to induce responses in heavily pre-treated myeloma patients, including those taking thalidomide at the time of disease progression. Toxicities are acceptable but primary prophylactic G-CSF and anticoagulation should be contemplated. Consideration should also be given to using the TIDE regimen at an earlier stage in the disease process.

Lenolidamide (Revlimid®) is an oral immunomodulatory drug that has been shown to be effective for the treatment of relapsed refractory myeloma, and in-vitro laboratory studies suggest that its action may be synergistic with a number of conventional chemotherapeutic agents. The aim of this study is to assess the efficacy and toxicity profile when lenolidamide is used in combination with cyclophosphamide and dexamethasone for patients with relapsed refractory disease. Multiply relapsed patients were given Revlimid 25mg po on days 1–21, dexamethasone 40mg po days 1–4 and days 12–15, and cyclophosphamide 500 mg po days 1, 8, 15 and 21 of a 28 day cycle for a maximum of 6 cycles of treatment. Prophylaxis with acyclovir, septrin and proton pump inhibitors was routinely used, 1 high risk patient received prophylactic anticoagulation. Toxicity profiles and response were assessed every 4 weeks. To date 18 patients have been included in the study with median age of 60.5 years (range 34–76). All were heavily pre-treated with a median of 4 previous lines of therapies (range 2–8). 12 patients had received high dose melphalan, 18 patients thalidomide and 16 patients bortezomib. One case had undergone an allogeneic BMT. The median time from diagnosis to treatment initiation was 55.5 months (range 11–122). To date 81 complete courses of therapy have been given to 18 patients with median number of 5 courses (range 1–6). 8 patients experienced neutropenia with the neutophil count falling below 0.5×109/L in a total number of 14 cycles, which resulted in a dose reduction or stopping of cyclophosphamide in 8 patients. 12 patients received GCSF to maintain their neutrophil count. 5 patients required dose reduction/omit of Revlimid. 4 patients required intravenous antibiotics for neutropenic fever. The side effect profile was manageable, importantly no patient experienced sedation, constipation or worsening of peripheral neuropathy. 2 patients with a heavy myeloma load suffered a DVT, but continued on therapy achieving a PR once anti-coagulation had been commenced. 14 of the 17 patients assessable for response achieved a response with 1 CR, 3 VGPR, 8 PR and 2 MR according to EBMT criteria. The median time to response was prompt at 32 days (range 21–68). To date only 2 patients have discontinued therapy because of a failure to respond to therapy and 1 stopped due to liver toxicity. 13 patients have completed treatment and 5 still remain on treatment. The combination of CRD is effective in heavily pretreated myeloma patients and has a manageable toxicity profile. In view of the neutropenia further studies using this combination are currently being investigated using cyclophosphamide on days 1 and 8 only.