INTRODUCTION: Significantly improved response, time to progression and overall survival with lenalidomide plus high dose dexamethasone (Len+Dex) vs Dex alone was demonstrated in two pivotal trials (MM-009/010) (Weber et. al., NEJM2007, 357:21 and Dimopoulos et. al., NEJM2007, 357:21). Grade 3 or 4 adverse events (AEs) were reported in 83% of patients receiving Len+Dex and 70% with Dex alone. The risk of AEs was not constant over the course of treatment, however. AE rates in the two groups over time are reported here, along with the percentage of dose modifications (interruptions or reductions) of lenalidomide in response to AEs. METHODS: Data on patients from the MM-009/010 trials were pooled for these analyses. Monthly hazard rates of grade 3 or 4 neutropenia, thrombocytopenia (TCP) and deep-vein thrombosis (DVT) were calculated as the ratio of events observed to person-time accrued each month. Patients alive at the start of a month were included in that month’s calculation. Patients alive and followed through the month contributed a full month to the denominator; patients whose follow-up ends during the month only contributed the fraction of time followed. Rates were calculated at three-month intervals. Similarly, treatment interruptions and dose modifications were quantified in each cycle (28 days) by counting person-days without medication (i.e., interrupted) on each dose of Len. RESULTS: Of the 353 patients randomized to Len+Dex, 35% experienced neutropenia, 13% TCP and 8% DVT. With Dex alone (N=351), the corresponding percentages were 5%, 7%, and 4%. The hazard rates were highest during the first three months of treatment, and declined thereafter. For example, with Len+Dex, the rate of grade 3 neutropenia was 38 per 1000 person-months, but dropped to 21 per 1000 person-months during months 10–12. The corresponding rates with Dex alone were 4 and 0 per 1000 person-months. The reduction in rates was more pronounced for grade 3 TCP and DVT: from 25 per person-months during months 1–3 to 3 per 1000 person-months during months 10–12 for TCP with Len+Dex, and from 15 to 0 per 1000 person-months for Dex alone. Grade 4 AEs occurred much less frequently but followed a similar pattern. Treatment interruptions were highest during the in first 4 cycles, with patients off treatment between 5 and 8% of follow-up days in this period, compared to 2 to 5% in the subsequent period. Similarly, dose reductions occurred more frequently during the initial cycles and decreased subsequently. CONCLUSIONS: Exploring AE rates over time revealed that these events were most likely to occur in the initial cycles of treatment. Hazard rates declined thereafter, possibly due, in part, to observed dose modifications. Similarly, patients more susceptible to AEs may have discontinued from the study earlier. Further analyses linking AEs to dose modifications are underway. Figure Figure Month AE Group 1–3 4–6 7–9 10–12 13–15 16–18 19–21 Neutropenia Len-Dex (Grade 3) 0.038 0.035 0.035 0.021 0.025 0.009 0.011 Dex (Grade 3) 0.004 0.002 0.003 0.000 0.002 0.000 0.000 Len-Dex (Grade 4) 0.008 0.006 0.001 0.000 0.002 0.000 0.000 Dex (Grade 4) 0.001 0.000 0.000 0.000 0.000 0.000 0.000 Thrombocytopenia Len-Dex (Grade 3) 0.025 0.007 0.003 0.006 0.002 0.000 0.000 Dex (Grade 3) 0.015 0.002 0.000 0.000 0.000 0.000 0.000 Len-Dex (Grade 4) 0.001 0.002 0.000 0.000 0.000 0.000 0.005 Dex (Grade 4) 0.002 0.000 0.000 0.000 0.000 0.000 0.000 DVT Len-Dex (Grade 3) 0.013 0.011 0.001 0.004 0.000 0.003 0.000 Dex (Grade 3) 0.005 0.006 0.001 0.000 0.000 0.000 0.000 Len-Dex (Grade 4) 0.001 0.000 0.000 0.000 0.000 0.000 0.000 Dex (Grade 4) 0.001 0.000 0.000 0.000 0.000 0.000 0.000

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INTRODUCTION: Lenalidomide combined with high-dose dexamethasone (Len+Dex), yields improved time-to-progression (TTP) and survival compared to Dex alone in previously treated patients with multiple myeloma (Weber et. al., NEJM2007, 357:21 and Dimopoulos et. al., NEJM2007, 357:21). It is also effective in patients previously treated with thalidomide. This study aimed to estimate long-term health and cost consequences of Len+Dex versus Dex in patients with multiple myeloma (MM) previously treated with at least two prior therapies, including prior thalidomide. METHODS: A discrete event simulation of a patient’s disease-course following initiation of Len+Dex or Dex was developed. The model uses patient’s response (complete response, partial, stable disease or progression) and estimates corresponding TTP and subsequent survival based on Weibull functions derived from pooled data from two phase III trials (MM-009/MM-010). Long-term results from the UK MRC MM IV, V, VI, and VIII trials were used to estimate Dex survival, as 47% of Dex patients crossed-over to lenalidomide treatment in MM-009/MM-010. Time-dependent adverse event rates were derived from pooled MM-009/MM-010 data and associated management costs reflecting UK NHS practice were applied. Health utilities by response level were obtained from the literature. Patients remained on treatment until disease progression. Disease management costs were reflective of clinical practice in the UK NHS. As recommended by the UK treasury, costs and health outcomes were discounted at 3.5% per annum in order to adjust to present values. A life-time horizon was used to model costs and health outcomes, including survival and quality adjusted life-years (QALYs). RESULTS: Use of Len+Dex is associated with a substantial improvement in survival and QALYs. Although estimated incremental costs are large, the improvements in health outcomes yield incremental cost-effectiveness ratios (ICERs) below £30,000 per QALY. Len/Dex is similarly cost-effective when used to treat patients previously treated with thalidomide. Undiscounted ICERs are lower because survival benefits are not fully realized until end-of-life and so are subject to a higher degree of compound discounting than the costs which are incurred relatively early. Univariate and probabilistic sensitivity analyses showed that results remain consistent through broad changes in model parameters. CONCLUSIONS: Lenalidomide in combination with high-dose dexamethasone in patients with at least two prior therapies delivers substantial improvements in quality-adjusted survival in a life-limiting orphan disease and yields an estimated incremental cost per QALY which falls within a cost-effective range. ≥2 prior therapies Undiscounted Discounted Len+Dex Dex Len+Dex Dex Life Years (projected mean) 5.92 1.08 4.76 1.05 Quality Adjusted Life Years (QALYs) 3.98 0.79 3.23 0.77 Average Cost (per patient) £63,809 £707 £61,171 £694 Incremental cost per Life Year Gained £13,038 £16,301 Incremental cost per QALY Gained £19,781 £24,584 ≥2 prior therapies (including thalidomide) Undiscounted Discounted Len+Dex Dex Len+Dex Dex Life Years (projected mean) 5.42 1.03 4.43 1.01 Quality Adjusted Life Years (QALYs) 3.60 0.72 2.96 0.70 Average Cost (per patient) £53,719 £706 51,745 694 Incremental cost per Life Year Gained £9,727 £14,927 Incremental cost per QALY Gained £18,407 £22,589

INTRODUCTION: Thalidomide (Thalomid®/Thalidomide Pharmion®) combined with melphalan and prednisone (MPT) yields improved progression-free and overall survival compared to MP alone (Facon et. al., Lancet2007; 370:1191). This study was designed to estimate the life-time health and cost consequences of MPT versus MP in Scottish patients with previously untreated multiple myeloma. METHODS: A Markov model was developed to determine cost and health outcomes for a cohort of patients receiving a course of MPT or MP. The disease course was conceptualized by 4 mutually exclusive health states: pre-progression without adverse events, pre-progression with adverse event, progressive disease, and death. Probabilities of moving between these states (i.e. natural progression plus efficacy and safety of the treatments) were derived from a long-term randomized clinical trial, IFM 99-06 (Facon et. al., Lancet2007; 370:1191). Both patient cohorts remained on the assigned treatment for a maximum of twelve 6-week cycles, until progression or treatment-limiting toxicity. Treatment duration and the average daily dose were modelled to match IFM 99-06. During treatment, each cohort was exposed to adverse event risks associated with therapy estimated from IFM 99-06. Health state utilities associated with adverse events and disease states were obtained from the literature. Thalidomide cost was set at UK list price; routine disease-management costs by disease-state (progressive disease and remission state) reflect clinical practice in Scotland. As recommended by the UK treasury, costs and health outcomes were discounted at 3.5% per annum to adjust to present values. Univariate and multivariate sensitivity analyses were performed around key model parameters. RESULTS: The model estimated improvements in health outcomes with MPT with a median time to progression of 25 months vs. 12 months with MP. Estimated median overall survivals were 4.03 years vs. 2.88 years with MP. These results translate to a gain of 0.91 (3.24 vs. 2.32) quality-adjusted life-years (QALYs). MPT is associated with higher overall costs (£25,199 per patient) compared with MP (£8,935), over the modeled life-time, leading to an incremental cost-effectiveness ratio of £17,847 per QALY and £14,803 per life-year gained. Sensitivity analyses showed that results remained consistent through broad changes in model parameters including the addition of thromboembolic prophylaxis. CONCLUSIONS: MPT delivers improvements in progression-free and overall survival in a life-limiting orphan disease compared to MP and economic results fall within a range considered cost-effective in Scotland.

Introduction. Hematopoietic stem cell donors (HSCD) frequently suffer from anxiety and feelings that are usually unnoticed by the physician o their relatives. The origin is multifactorial: fear of pain, fear of the procedure, adverse effects of growth factor, feelings of responsibility regarding the success of the transplant, family pressure, etc. HSCD could show ambivalence of feelings about the donation, which may be related to the moral obligation to help a sick relative and fear of the donation procedure, thus originating anxiety and moral distress (MD). We evaluated the incidence of MD, anxiety, and other symptoms in a group of HSCD regarding donor related allogeneic transplantation. Materials and methods. A prospective observational study was carried out through a survey applied to 60 consecutive HSCD from April, 2014 to January, 2017. Protocol was approved by Institutional Ethics Review Committee and was carried out according to the Declaration of Helsinki. HSCD completed 3 written self-answered questionnaires (Questionnaire to assess moral distress (MDQ) elaborated by the researcher, State Trait Anxiety Index (STAI®) and Edmonton Symptom Assessment System (ESAS)) in three stages: right before initiating stem cell mobilization, immediately before the apheresis procedure, and 24 hours after the donation. Cell mobilization was done with granulocyte colony-stimulating factor (G-CSF) 10 µg/kg/day/4 days while the apheresis collection was performed on the fifth day as an outpatient basis in all cases. Results. Sixty donors, 36 male and 24 female with a mean age of 38.2 years (SD = 13.6) were included. HSCD was a brother/sister of the patient in 39 cases (65%), and one parent in 21 cases. Regarding donor educational level, only 24 (40%) donors had university level. MDQ: Most donors felt happy to be the donor (97%), but 28% said they were not given the opportunity to accept or refuse being the donor, 10% would have preferred that another person had been the donor, and 5% mentioned that donation worsened their family relationship and they would not donate cells again if necessary. The number of donors with negative feelings regarding the donation decreased through the 3MD questionnaires (Table 1). STAI: In the first, second, and third questionnaire, the mean score for the state of anxiety was 12.1 (SD = 7.6), 10.3 (SD = 6.6), and 7.9 (SD = 5.7), respectively. In first STAI, mild to moderate anxiety was observed in 33% of the donors and severe anxiety was observed in 7%, observing a higher score in the first questionnaire, just before starting cell mobilization; however, that score gradually decreased in the following questionnaires. ESAS: In the first questionnaire, although no procedure was still performed, all donors had symptoms, including insomnia (33%), anxiety (33%), and tiredness (30%). In the second ESAS questionnaire, symptoms worsened, mainly pain (78%), tiredness (63%), and insomnia (55%), which was probably related to G-CSF. In the third ESAS questionnaire, there was a significant decrease in the symptoms: pain (60%), tiredness (50%), and discomfort (40%). The average global score for 10 symptoms evaluated was 10.5 (SD = 14.2), 20.1 (SD = 16.0), and 12.3 (SD = 14.4) for the first, second, and third ESAS questionnaires, respectively. According to the score given to each symptom, the most frequent disabling symptoms in each questionnaire were hyporexia (10%), pain (23%), and discomfort (15%) in ESAS questionnaire 1, 2, and 3, respectively. Higher scores for MD correlated with higher scores in STAI questionnaires as well as with lower levels of education (r=0.456, p< .005). Conclusions MD in the donor can manifest both clinically and socially through insomnia, fatigue, loss of appetite, anxiety, and ambivalence of feelings (happy to be the donor but feel morally obligated to donate) which may affect family relationships. Although there is no instrument to measure the MD before performing any procedure in the present study, the donors had different symptoms, such as negative feelings, anxiety, tiredness, difficulty to sleep, and even pain; all of them without an apparent physical reason. It is desirable that donors receive bioethical counseling and psychological guidance before the donation process in order to provide them with the necessary information regarding the experience they are about to endure. Disclosures Gomez-Almaguer: Amgen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.