ALBERT

Description: Background: Polycythemia vera (PV) is characterized by erythrocytosis, thrombocytosis, and/or leukocytosis and a broad range of disease-related symptoms. In high-risk patients, the most common first-line treatment is hydroxyurea (HU). The open-label RESPONSE trial demonstrated that ruxolitinib (RUX), a JAK1/JAK2 inhibitor, provided superior efficacy compared with best available therapy in patients with PV who were resistant to or intolerant of HU according to modified European LeukemiaNet (ELN) criteria. This study (RELIEF) was conducted in patients receiving a stable dose of HU and who were generally well controlled but reporting disease-associated symptoms, comparing the change in PV-related symptom burden in patients continuing their HU therapy with those switching to RUX treatment. Methods: RELIEF was a randomized, multicenter, double-blind, double-dummy, phase 3b study of patients with PV aged ≥18 years on a stable dose of HU monotherapy and reporting PV-related symptoms. Patients were required to be receiving HU for ≥12 weeks prior to enrollment and on the same dose level for the last 4 weeks, and have a score ≥8 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) cytokine total symptom score (TSS-C). The TSS-C comprised symptoms of itching, tiredness, muscle ache, night sweats, and sweats while awake; each symptom was rated on a scale of 0=absent to 10=worst imaginable, with a maximum TSS-C score of 50. Patients also had to meet one of the following: ≤1 phlebotomy in the previous 6 months or no palpable splenomegaly. Those eligible were randomized 1:1 to receive RUX 10 mg BID and HU-placebo, or HU at the same dose/schedule and RUX-placebo. Dose adjustments were permitted for safety and efficacy. After Week 16, patients could receive open-label RUX until Week 48. The primary endpoint was the proportion of patients with a ≥50% reduction in TSS-C at Week 16; secondary endpoints included proportion of patients with a ≥50% reduction in individual TSS-C symptoms and safety. Results: Overall, 54 and 56 patients were randomized to RUX and HU, respectively; 87.0% and 89.3% remained on treatment through Week 16. At baseline, the median age (range) was 64 (36-87) in the RUX group and 66 (19-85) in the HU group; 44% and 61% were men. The majority of patients in the RUX and HU groups did not have baseline platelet counts or WBC above ELN thresholds: platelets 〉400 and ≤600 x 109/L (RUX 31.5%, HU 28.6%), 〉600 x 109/L (3.7%, 8.9%); WBC 〉10 and ≤15 x 109/L (16.7%, 16.1%), 〉15 x 109/L (11.1%, 14.3%). In the RUX and HU groups, the mean TSS-C at screening (22.4, 23.1) was higher than that at baseline (16.7, 18.0); the ratio of screening to baseline TSS-C was 1.7 and 1.6. The proportion of patients achieving a ≥50% reduction from baseline in TSS-C at Week 16 (primary endpoint) was 43.4% in the RUX group and 29.6% in the HU group (P=0.139; OR, 1.82; 95% CI, 0.82-4.04). The proportions of patients in the RUX vs HU groups achieving a ≥50% reduction in scores for itching and tiredness at Week 16 were 40.0% vs 26.4% and 54.2% vs 32.0%, respectively. Median percentage changes in individual TSS-C symptoms are shown in Table 1. Additional analyses found no correlation between individual changes in HU dose from baseline to Weeks 13-16 and percentage change in TSS-C in the HU arm (r2=0.030). Even patients maintaining the same HU dose from prior to study entry through Week 16 reported symptom improvement: 12/35 (34.3%) with no dose change, 4/12 (33.3%) with a dose increase, and 0/9 (0%) with a dose decrease had a ≥50% reduction in TSS-C. The most common nonhematologic adverse events in the RUX arm on randomized treatment were fatigue (20.4% RUX vs 10.7% HU), headache (16.7% vs 5.4%), and dizziness (13.0% vs 8.9%). The most common adverse events on HU were diarrhea (9.3% RUX vs 19.6% HU) and constipation (7.4% vs 12.5%); most events were grade 1 or 2. Grade 3 or 4 anemia or thrombocytopenia (lab values) were not reported in the RUX group; two patients in the RUX group had grade 3 or 4 neutropenia. Conclusion: In generally well controlled PV patients receiving a stable dose of HU, there was a positive trend in symptom improvement for patients switched to RUX therapy versus those continuing on HU therapy, although this was not statistically significant. The 34% response rate among patients who continued to receive a stable HU dose suggests a placebo effect that led to an underpowered study. Further analyses are required to better interpret these findings. Disclosures Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yacoub:Alexion Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees. Koschmieder:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne:Novartis Pharmaceuticals: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Hunter:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Morozov:Novartis Pharmaceuticals: Employment, Equity Ownership.

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

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

Description: Introduction Current treatment options for myelofibrosis (MF) are diverse; apart from rare patients who are eligible for allogeneic transplantation, active treatments are focused on controlling MF-related symptoms and are not disease modifying. Patients who are initially asymptomatic and those at low risk for progression are usually observed without active treatment (watch and wait) until the appearance of symptoms or progression. There are limited real-world data on the management of patients with MF in the United Kingdom (UK). The REALISM UK study documented the early management pathways for patients with MF in routine clinical practice. Method REALISM UK was a multi-centre, retrospective, non-interventional study in 15 UK secondary care centres. Eligible patients were those aged ≥18 years at diagnosis of MF, with diagnosis 〉6 months and ≤5 years prior to data collection and with ≥1 follow-up visit. Data on patient demographics, clinical characteristics, MF management strategies and outcomes were collected from patients' medical records; the observation period was from the date of MF diagnosis until data collection. The primary endpoint was the time from diagnosis to active treatment. Watch and wait strategies included supportive therapies (blood transfusions, erythropoiesis-stimulating agents, and steroids). Results A total of 200 patients were recruited (63% [n=126/200] with primary MF (PMF); 37% [n=74/200] with secondary MF). The median age at MF diagnosis was 69.7 years (interquartile range [IQR] 63.5-75.7) and 71% (n=141/200) had a JAK2 mutation. At diagnosis, 52% (n=104/200) of patients had International Prognostic Scoring System (IPSS) categories of intermediate-2 (Int-2) or high. Common documented features of disease at diagnosis included an enlarged spleen (47%, n=94/200), anaemia (44%, n=88/200), and constitutional symptoms (e.g. night sweats, unexplained fever, or weight loss [30%, n=60/200]). The median (IQR) time to first active treatment was 46 days (range 0-350) in the total population; patients with higher risk disease were prescribed active treatment sooner: IPSS low, 136.5 days (range 0-625; n=26); IPSS Int-1, 90 days (range 0-494; n=70); IPSS Int-2, 0 days (range 0-252; n=65); IPSS high: 0 days (0-216; n=39). The choice of first management strategy by IPSS at diagnosis is shown in Table 1. During the study period, watch and wait was the first management strategy for 54% (n=107/200) of patients, with the median (IQR) time from diagnosis to active treatment in this group being 322 (130-610) days. Constitutional symptoms were recorded in 20% (n=21/107) of patients for whom watch and wait was the first management strategy. Active treatment was started at diagnosis for 47% (n=93/200) of patients, with the most commonly used medications being hydroxycarbamide (22.5% [n=45/200]) and ruxolitinib (17.5% [n=35/200]). The median (IQR) treatment duration during the study observation window was 346 days (range 121-768) for hydroxycarbamide and 375 days (range 172-691) for ruxolitinib. In total, 5.5% (n=11/200) of patients were recorded as having undergone allogenic stem cell transplantation during the observation period. Conclusion Clinicians in the UK apply a broad range of management strategies for the treatment of patients with MF. Many patients were observed without active treatment following diagnosis, despite having symptomatic disease. The most common active treatments as first management strategies were hydroxycarbamide and ruxolitinib. Disclosures Mead: Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Consultancy. Somervaille:Novartis: Consultancy, Honoraria. Butt:Novartis: Consultancy, Honoraria, Speakers Bureau. Whiteway:Novartis: Consultancy, Honoraria, Speakers Bureau. Kirkpatrick:Novartis: Consultancy, Honoraria. Roughley:Novartis: Consultancy, Honoraria. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . Garg:Novartis: Consultancy, Honoraria. Harrison:Promedior: Honoraria; Shire: Speakers Bureau; Sierra Oncology: Honoraria; Celgene: Honoraria, Speakers Bureau; Roche: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; Gilead: Speakers Bureau; CTI: Speakers Bureau; AOP: Honoraria; Janssen: Speakers Bureau. Bains:Novartis: Employment. Chiu:Novartis: Employment. Hickey:OPEN VIE: Employment.

Description: Background The benefit of single agent maintenance is largely established from studies in newly diagnosed patients, while extended therapy combination regimens are more commonly used in relapsed disease. Extended therapy on combination protocols may be limited by tolerability and safety, as well as patient compliance. Fixed duration combination treatment followed by single agent maintenance may provide better long term disease control. Such benefit may correlate with depth of response, measured as minimal residual disease (MRD). Prognostic significance of MRD negativity in the relapsed setting is increasingly recognised, but the utility of single agent maintenance in achieving this is unknown. Aims The MUKfive phase 2 trial studied the safety and activity of carfilzomib, cyclophosphamide and dexamethasone (KCd) for patients at first relapse or refractory to one prior line, and compared activity and safety of maintenance K vs observation after fixed duration KCd. Here we provided updated results of the maintenance randomization, including the effect on MRD and interaction with genetic risk. Methods The first part of the study compared KCd with VCd as fixed duration therapy for patients at first relapse, or primary refractory to one line of treatment. Inclusion criteria included Hb〉80g/L, neutrophils〉1.0x109/L, platelets≥50x109/L and GFR〉30ml/min. Participants with ≥SD after KCd were randomised (R2) 1:1 to receive maintenance K (36mg/m2 days 1, 2, 15, 16 for 6m, then days 1, 2 for 12m) or no further treatment, minimization factors: disease response (≥VGPR vs

Description: Introduction Daratumumab (DARA) is a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumor and immunomodulatory mechanism of action. In combination with standard of care (SOC) regimens, DARA has consistently demonstrated a doubling of complete response (CR) rates, tripling of minimal residual disease (MRD)-negative rates, and reduction in the risk of progression or death by ≥50% vs SOC alone in relapsed/refractory MM and NDMM pts. In the prespecified interim analysis of ALCYONE, a phase 3 study of D-VMP versus VMP in transplant ineligible NDMM (Mateos MV, N Engl J Med 2018. 378[6]:518-528), significant progression-free survival (PFS) benefit (median not reached [NR] vs 18.1 mo; hazard ratio [HR], 0.50; P

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

Description: Background Triplet combination therapies are the preferred treatment choice for RRMM, however, high-cost-high-cost drug combinations pose significant barriers for health technology assessments (HTA) and access in many public healthcare systems, including the UK. Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1), thereby forcing the nuclear retention of key tumour suppressor proteins (TSPs), leading to MM cell death. Recently, the FDA has granted accelerated approval to selinexor for MM on the basis of results from the STORM trial, which tested selinexor in doublet combination with dexamethasone in RRMM. Several trials exploring triplet combinations are ongoing, but most are with high-cost combination partners. In the Myeloma UK Twelve (MUKTwelve) trial Selinexor is combined with low-dose cyclophosphamide and prednisolone in a randomized phase II design, exploring a triplet regimen that could potentially be more accessible for wider patient population. Study design and methods MUKtwelve is a randomized, controlled, open, parallel group, multi-centre phase II trial designed to evaluate clinical efficacy of selinexor in combination with cyclophosphamide and prednisolone (SCP) in patients with RRMM (ISRCTN15028850). The primary objective is to determine whether the addition of selinexor to cyclophosphamide and prednisolone (CP) may lead to increased progression free survival (PFS) compared to historic CP data. A calibration arm of patients will receive CP alone, and will be used to evaluate the validity of the outcome in the experimental arm in comparison to historical control data. Participants who experience disease progression on the CP arm may, if deemed eligible receive SCP. Eligible participants are those with RRMM who have received ≥ 2 prior anti-myeloma treatments including a proteasome inhibitor and lenalidomide. Entry criteria are inclusive to allow for a real-world RRMM population, including GFR 〉=20, no limitation regarding pre-existing polyneuropathy and allowance of growth factor and transfusion support. A maximum of 60 participants will be recruited (45 participants in the SCP arm, and 15 in the CP arm) from 10 UK NHS hospitals. Participants are randomized on a 3:1 basis to receive either SCP or CP. The trial opened on 20th July 2018 and as of 23rd July 2019 16 patients have been randomized. Trial treatment is as shown in Table 1 (28 day cycle). Metronomic, continuous doses of cyclophosphamide and intermittent doses of prednisolone in conjuncture with proactive, prophylactic side effect management, in particular nausea and kachexia, have been chosen to make the trial more accessible for a wider RRMM population. The primary endpoint is proportion of patients alive and progression-free at 6 months (PFS6m). Secondary endpoints include response, response duration, safety and toxicity, PFS and treatment compliance. A three outcome statistical design is used based on the SCP arm only. The trial is designed to test the hypothesis PFS 6m ≤0.28 vs. PFS 6m ≥0.44 (equivalent to median PFS 3.3 vs. 5.1 months). With 90% power, 1-sided 10% significance level, a total of 45 patients are required in the SCP arm. Cut-off values and conclusions for the three outcome design: ≤14/45 patients PFS6m, SCP does not warrant further study≥17/45 patients PFS6m, sufficient evidence for further study of SCP15 or 16/45 patients PFS6m, decision uncertain and can be based upon other secondary endpoints. This approach provides more realistic decision-making compared to those where success of failure is hinged on a difference of a single primary endpoint event. Discussion The MUKtwelve trial is the first trial to assess the clinical efficacy of selinexor with low-dose cyclophosphamide and prednisolone in RRMM, a triplet regimen that, if found to be effective, is likely to be accessible to a wider patient population. Disclosures Brown: Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Kendall:Karyopharm: Other: Research funding to Institution. Ingleson:Karyopharm: Other: Research funding to Institution. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Auner:Karyopharm: Consultancy; Takeda: Consultancy; Amgen: Other: Consultancy and Research Funding. Boyd:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Garg:Janssen: Honoraria; Janssen, Takeda, Novartis: Other: Travel expenses; Novartis, Janssen: Research Funding. Kaiser:Celgene, Janssen: Research Funding; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy.

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

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