19 th Congress of the European Hematology Association who received bortezomib or lenalidomide as a primary therapy for AL amyloi - Myeloma and other monoclonal gammopathies - dosis. Furthermore, in order to reduce early mortality and retain the rapid activ - Clinical 2 ity of bortezomib, three years ago we implemented a risk-adapted approach for bortezomib dose and schedule, based on cardiobiomarkers, age and systolic blood pressure. P365 Methods: We analyzed the outcomes of 85 consecutive patients, who received primary therapy with bortezomib (N=49) or lenalidomide (N=36)(maximum 12 ACTIVITY OF MV-NIS IN A PHASE I TRIAL FOR PATIENTS WITH cycles – no maintenance). Standard bortezomib/dexamethasone was given in RELAPSED, REFRACTORY MULTIPLE MYELOMA (MM) 26 patients and risk-adapted bortezomib in 23 patients (of which N=11 received A Dispenzieri 1,* MQ Lacy 2, KM Laumann 3, B LaPlant 3, D Dingli 1, MA Gertz 1, full dose/schedule bortezomib/dexamethasone and N=12 weekly (attenuated) F Buadi 1, V Lowe 4, M O’Connor 4, N Leung 1, SV Rajkumar 1, SK Kumar 1, bortezomib/ dexamethasone), based on cardiac biomarkers, systolic blood C Tong 5, A Birgin 1, KW Peng 5, MJ Federspiel 5, SJ Russell 5 pressure, presence of neuropathy and age. 1Division of Hematology, 2Mayo Clinic, Rochester, United States, 3Division of Results: On intent to treat, 67% of patients achieved a hematologic response Biostatistics, 4Department of Radiology, 5Molecular Medicine, Mayo Clinic, (24% hemCRs and 8% VGPRs) and 34% an organ response; both were more fre - Rochester, United States quent with bortezomib vs lenalidomide. Onset of hematologic remission was sig - nificantly more rapid with bortezomib. Median survival is 47 months. An early Background: MV-NIS is an Edmonston-lineage measles virus that expresses death occurred in 20%: in 36% of patients treated with standard bortezomib, in the human sodium-iodide symporter (hNIS). The virus is oncolytic to primary 22% of lenalidomide-treated patients (p=0.940); but only in 4.5% of patients treat - myeloma cells and cell lines, and its activity can be monitored by noninvasive ed with the risk-adapted bortezomib approach. Activity, in terms of hemPR/hem - imaging of radioiodine uptake by hNIS. CD46, the receptor for MV, is overex - CR and NTproBNP response, was similar for bortezomib regimens. In patients with pressed in myeloma cells. a minimal follow up of 3 years, 19% of patients with Mayo stage-3 disease remain Aims: To conducted a Phase I study to determine the safety and efficacy of MV- alive, the survival of patients with stage-2 disease is 28 months and has not been NIS in patients with relapsed, refractory MM. reached for patients with Mayo stage-1 disease (the 3-year survival is 88%) but Methods: The trial is a standard 3+3 dose escalation design but with two is similar for patients treated with bortezomib or lenalidomide. patient cohorts. Cohort 1 included single agent intravenous MV-NIS adminis - Summary and Conclusions: long term follow up indicates that remissions tered at TCID50 titers of: 10 6, 10 7, 10 8, 10 9, 10 10 , and 10 11 . Cohort 2 patients obtained with lenalidomide or bortezomib may be durable. There was no dif - started treatment with cyclophosphamide 10 mg/kg 2 days prior to MV-NIS at ference in the survival of patients treated with bortezomib vs lenalidomide, MTD/100. Antibody response to measles was tested pre and post therapy. although bortezomib acts faster and induces deeper responses. A risk-adapt - Bone marrow myeloma (CD138+) and non-myeloma cells (CD138-) were test - ed treatment strategy based on bortezomib may reduce early mortality and ed for CD46 expression and MV infectivity. PK and biodistribution were fol - preserve activity but longer follow up is needed in order to evaluate whether lowed, respectively, by MV-N by Q-RT-PCR in blood, urine, and gargle sam - this strategy improves other outcomes. ples and by serial nuclear imaging. Eligible patients had adequate bone mar - row and organ reserve and had explored all other myeloma treatment options. Results: Thirty-one patients have been treated. Two patients were replaced for P367 lack of protocol completion. Cohort I initially enrolled 13 patients receiving one dose 10 6, 10 7 10 8 or 10 9 TCID50 of MV-NIS. Since no DLT was observed, per proto - BORTEZOMIB COMBINATION THERAPY, AND SUBSEQUENT BORTE - col Cohort 2 began accrual, recruiting 8 patients. At trial conception, manufactur - ZOMIB RE-TREATMENT, IS A USEFUL TREATMENT STRATEGY FOR MUL - ing allowed doses only up to 10 9, but technology improvements subsequently TIPLE MYELOMA PATIENTS WITH RAS MUTATIONS 10 11 D Smith 1,* L Percy 1, M Kumar 2, E Armenteros 2, A Lach 3, G Herledan 3, allowed for two higher dose levels (10 and 10 ). Therefore, Cohort 2 accrual 1 2 1 was suspended, and Cohort 1 accrual was resumed to test these 2 higher levels M Stubbs , J Downward , K Yong 1Haematology, University College Hospital, London, 2London Research Insti - (11 additional patients). Grade 3-4 AEs deemed at least possibly related to proto - 3 col therapy in both cohorts at all dose levels were: neutropenia (n=8); thrombocy - tute, University College London, London, United Kingdom topenia (n=4); anemia (n=3); and lymphopenia (n=1). One patient treated in cohort 2, dose level 3 ( e.g. CTX and TCID50 9x10 7) had a grade 3 left ventricular failure Background: Mutations of the RAS gene family are prevalent in MM. A syn - possibly related to therapy. In Cohort 1, MTD has not been reached, and TCID50 thetic lethality screen in RAS mutant cells identified genes encoding for pro - 10 11 , will be the dose used in an upcoming Phase II trial of single agent MV-NIS. teasome subunits, suggesting that MM tumours bearing RAS mutations may Grade 1-2 AEs seen in at least 5 patients were: nausea (n=11); chills (n=9); fever be particularly sensitive to bortezomib. (n=6); and rash, neutropenia, thrombocytopenia, and vomiting (each n=5). Most Aims: To investigate if MM disease response to bortezomib is linked to patients had low baseline anti-IgG MV titers which boosted by six weeks post MV- NRAS/KRAS mutational status. NIS treatment. MV-N RNA sequences were amplified from gargle specimens, Methods: 70 patients treated at a single centre with bortezomib for relapsed dis - blood and urine. The most dramatically positive 123 I scan was seen in 1 patient at ease were analysed for RAS mutation status to correlate with clinical outcomes. the 10 11 demonstrating proof of principle of NIS. One patient treated at TCID50 Results: Patients were mainly relapsed/refractory (92.8%), had received a medi - 10 11 , achieved a CR that persists for more than 8 months. Transient drops in an of 4 prior lines of therapy and 97% were bortezomib naïve. Pre-treatment bone serum FLCs were seen in other patients. marrow samples were obtained with informed consent and RAS mutation analy - Summary and Conclusions: Intravenous administration of MV-NIS is feasi - sis performed on RNA extracted from CD138 selected cells. RAS mutations were ble and produced a CR in one patient at top dose level. The virus is capable detected in 31 patients (44.3%). 22 patients (31.4%) had mutations in NRAS and of replicating before being cleared by the immune system. The Phase II trial 10 patients (14.3%) in KRAS (1 patient had mutations in both). NRAS mutations will open in a month using the 10 11 , dose. Oncolytic viruses offer a promising were found in codons 61 (n=12), 13 (n=5), 12 (n=4) and 64 (n=1). KRAS muta - new modality for the targeted infection and destruction of disseminated can - tions were detected in codons 61 (n=6), 12 (n=3) and 117 (n=1). There was no cer. This work was supported by funds from the NIH/NCI (R01CA125614, association between RAS mutation and high risk FISH.[KY1] All patients were R01CA168719), Al and Mary Agnes McQuinn, the Richard M Schulze Family treated with bortezomib regimens: single agent bortezomib (4 patients), borte - Foundation. The NCI (RAID Program) supported cGMP virus manufacture and zomib/dexamethasone (23), bortezomib/dexamethasone/cyclophosphamide (31), toxicology/pharmacology studies. bortezomib/dexamethasone/doxorubicin (9) and bortezomib/dexamethasone/ thalidomide (3), with an even split between patient groups. 86.7% of patients with RAS mutations responded to treatment compared to 72.2% with WT RAS. No dif - P366 ference in PFS was observed between the two groups (8.0 months WT vs 8.0 RAS). OS was shorter in patients with RAS mutations (27.0 months vs 40.7, NS). OUTCOMES OF PRIMARY SYSTEMIC LIGHT CHAIN (AL) AMYLOIDOSIS Analysis of NRAS and KRAS mutations separately showed response rates (≥PR) IN PATIENTS TREATED UPFRONT WITH BORTEZOMIB OR LENALIDO - were similar (85.7% NRAS vs 88.9% KRAS). Patients with KRAS mutations had MIDE AND THE IMPORTANCE OF RISK ADAPTED STRATEGIES a trend to shorter OS (24.8 KRAS vs 28.2 NRAS vs 40.7 WT). At relapse post ini - E Kastritis 1,* M Roussou 1, M Gavriatopoulou 1, M Migkou 2, C Pamboucas 1, tial exposure to bortezomib a similar percentage of patients in each group received E Kaldara 3, A Ntalianis 3, E Psimenou 4, S Toumanidis 1, E Terpos 1, MA Dimopoulos 1 further therapy (6/8 KRAS, 16/19 NRAS, 31/33 WT). Median OS from date of 1Department of Clinical Therapeutics, National and Kapodistrian University of relapse was shorter in patients with RAS mutations (11.7 months KRAS vs 22.1 Athens, 2Department of Clinical Therapeutics, National and Kapodistrian Uni - NRAS VS 33.8 WT, p=0.04 for KRAS vs WT).