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). Patients with RAS mutations had versity of Athens,, 3National and Kapodistrian University of Athens, School of similar PFS and OS whether treated with repeat bortezomib or lenalidomide (PFS Medicine, 4Nephrology Unit, Alexandra Hospital, Athens, Greece 8.5 months bortezomib vs 7.0 lenalidomide, OS 28.67 vs 33.67). In contrast in patients with WT RAS PFS was significantly shorter with bortezomib re-treatment Background: Bortezomib and lenalidomide are increasingly used in patients compared to lenalidomide (5.67 months vs 10.5, p=0.015), as was OS (25.6 with AL amyloidosis, but long-term data of their use as first line therapy in AL months with bortezomib vs 46.6 with lenalidomide, NS). amyloidosis are lacking. Furthermore, despite the use of these effective ther - Summary and Conclusions: Although RAS mutation status had no impact on apies early death remains a significant complication of AL and new startegies the outcome of initial bortezomib therapy, at disease progression patients with are neede in order to reduce early mortality KRAS mutations fared worse. This may reflect the association of KRAS muta - Aims: We report our experience after long follow up of the outcomes of patients tions with advanced disease, but also suggests tumours with mutant KRAS are
114 | haematologica | 2014; 99(s1) Milan, Italy, June 12 – 15, 2014 relatively more sensitive to bortezomib combination therapy than other subse - Summary and Conclusions: Patterns of thromboprophylactic medication in quent therapy. In contrast to a recent report on the resistance of NRAS mutant the big 5 EU countries were comparable and highest in Italy and Spain, inter - tumours to single agent bortezomib, we found no impact of NRAS mutations mediate in the UK and France and lowest in Germany. ASA was the most fre - on sensitivity to combination bortezomib regimens. Patients with WT RAS fared quently prescribed Tx. In RRMM pts treated with LEN, there was sustained worse when retreated with bortezomib than if they received lenalidomide but compliance to thromboprophylaxis during the first 6 months. The incidence of those with RAS mutations had similar outcomes with either therapy, suggest - VTE during LEN Tx was 5%. Further analyses will examine the incidence by ing RAS mutation status may confer added bortezomib sensitivity. Although type of prophylaxis used as well as other risk factors. our findings await confirmation in a larger patient cohort they suggest that borte - zomib combination therapy, and bortezomib re-treatment, is a useful strategy for MM patients with RAS mutations. P369 RANDOMIZED PHASE 2 STUDY OF BORTEZOMIB, THALIDOMIDE, AND P368 DEXAMETHASONE WITH OR WITHOUT CYCLOPHOSPHAMIDE AS INDUCTION THERAPY IN PREVIOUSLY UNTREATED MULTIPLE MYELO - EUROPEAN POST-APPROVAL SAFETY STUDY (PASS) OF RELAPSE/ MA (MM): LONG-TERM FOLLOW-UP RESULTS REFRACTORY MULTIPLE MYELOMA (RRMM): PATTERNS OF ANTITHROM - H Ludwig 1,* R Greil 2, T Masszi 3, I Spicka 4, O Shpilberg 5, R Hajek 6, A Dmoszynska 7, BOTIC PROPHYLAXIS IN A LARGE COHORT OF MM PATIENTS TREATED B Paiva 8, MB Vidriales 9, G Esteves 10 , AM Stoppa 11 , D Robinson Jr , WITH LENALIDOMIDE 12 S Chaturvedi 13 , O Ataman 14 , C Enny 13 H Feng 13 , H van de Velde 15 B Gamberi 1,* J Caers 2, J Parreira 3, M Haenel 4, GM Bos 5, F Escalante 6, 1Wilhelminen Cancer Research Institute, c/o First Department of Medicine, P Bacon 7, B Rosettani 7, E Kueenburg 7, M Ramos Rodriguez 7, N Brandenburg 8, Center for Oncology, Haematology and Palliative Care, Wilhelminenspital, Vien - N Minton 8, B Andreasson 9 na, 2Universitätsklinik für Innere Medizin III, Landeskrankenhaus, Salzburg, 1Arcispdedale S. Maria Nuova, Reggio Emilia, Italy, 2CHU, Liege, Belgium, Austria, 3Department of Haematology and Stem Cell Transplantation, St István 3Instituto Português de Oncologia Francisco Gentil de Lisboa, Lisboa, Portu - and St László Hospital, Budapest, Hungary, 4First Faculty of Medicine, 1st Med - gal, 4Klinikum Chemnitz, Chemnitz, Germany, 5UMC Maastricht, Maastricht, ical Department, Clinical Department of Haematology, Charles University in Netherlands, 6Hospital de León, Leon, Spain, 7Celgene International, Boudry, Prague, Prague, Czech Republic, 5Rabin Medical Center, Institute of Hematol - Switzerland, 8Celgene Corporation, Summit, United States, 9Uddevalla ogy, Petah-Tiqva, Israel, 6Department of Internal Medicine and Hematooncol - Sjukhus, Uddevalla, Sweden ogy, FN Brno and IHOK and BMG DPP Faculty of Medicine, Masaryk Univer - sity, Brno, Czech Republic, 7Medical University of Lublin, Lublin, Poland, 8Clin - Background: EU PASS is an observational, non-interventional post-authoriza - ica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), tion study designed to investigate the safety of lenalidomide (LEN) and other Pamplona, 9Hospital Universitario Salamanca, CIC, IBMCC (USAL-CSIC), agents in the treatment of RRMM patients (pts) in a real-world setting. Venous Salamanca, Spain, 10 Hospital de Santa Maria, Hospital de Dia de Hematolo - thromboembolic events (VTE) are common among cancer pts (7%) and recog - gia, Lisbon, Portugal, 11 Institut Paoli-Calmettes, Marseille, France, 12 Janssen nized as a possible adverse event (AE) associated with the administration of Global Services, LLC, 13 Janssen Research & Development, LLC, Raritan, NJ, LEN+dexamethasone (DEX) therapy (Tx). Among RRMM pts treated with LEN United States, 14 Janssen Research & Development, a division of Janssen- and high-dose DEX, grade (Gr) 3–4 VTE was experienced by 11-14% of pts Cilag Limited, High Wycombe, United Kingdom, 15 Janssen Research & Devel - (Dimopoulos, NEJM 2007; Weber, NEJM 2007). Recommendations for throm - opment, Division of Janssen Pharmaceutica NV, Beerse, Belgium boprophylactic Tx based on the number of VTE risk factors have been pub - lished. Larocca (Blood 2012) reported that the incidence of VTE was similar in Background: Bortezomib in combination with thalidomide and dexametha - NDMM pts treated with LEN+low dose DEX, who were randomized to receive sone (VTD) is an effective regimen in patients (pts) with previously untreated either acetylsalicylic acid (ASA) 100 mg/day (2%) or low-molecular-weight- MM. We conducted an open-label phase 2 study to evaluate the efficacy and heparin (LMWH) enoxaparin 40 mg/day (1%). safety of VTD and VTD plus cyclophosphamide (VTDC) as induction therapy Aims: To investigate the frequency and patterns of thromboprophylactic med - prior to high-dose therapy plus stem cell transplant (HDT/SCT) (NCT00531453). ication used in LEN-treated pts, and describe the proportion of pts who expe - Primary results showed that both VTD and VTDC are active induction regi - rienced a VTE while receiving RRMM Tx. mens resulting in bone marrow confirmed complete response (CR) rates of Methods: RRMM pts who had received ≥1 prior Tx were enrolled at the inves - 29% and 31% post-induction, and 57% and 61% post-HDT/SCT, respectively tigator’s discretion into a LEN- or background cohort (other regimens). This (Ludwig et al. JCO 2012). There were no significant differences in efficacy analysis will focus only on pts who were treated within the LEN cohort. Throm - between the 2 regimens, indicating no benefit from the addition of cyclophos - boprophylactic medication was administered as per local standard practice. phamide. AEs were graded according to NCI-CTCAE (v3). Patterns of thromboprophy - Aims: To assess any differences in long-term outcomes between the 2 regi - lactic usage were examined using descriptive statistics. mens, this long-term extension follow-up phase of the study evaluated final Results: As of November 2013, a total of 3,520 pts across 269 institutions in time-to-event data: updated post-treatment results are reported. 17 European countries were enrolled; of those, 62% received LEN (n=2,166). Methods: Adult pts were randomized (1:1) to receive i.v. bortezomib (1.3 mg/m 2), Pts in the LEN cohort had a median age of 68 years (range 25–95) and 54% thalidomide (100 mg), and dexamethasone (40 mg), with or without cyclophos - were male. Median number of prior RRMM Tx was 2 (range 0–6); 18% had 1 phamide 400 mg/m 2 for 4x21-day cycles, followed by HDT/SCT. This long-term prior, 57% had 2 prior, and 24% had ≥3 prior Tx; 12% of pts had a history of extension study assessed time-to-event endpoints, including time-to-next thera - prior VTE. A total of 71% (n=1527) of pts were receiving thromboprophylactic py (TTNT), progression-free survival (PFS) and overall survival (OS). Tx prior to starting LEN; 81% (n=1558) received Tx on commencing LEN and Results: 98 pts (49 VTD, 49 VTDC) were included in the intent-to-treat and this number increased to 84% (n=871) for those remaining on LEN by month safety populations. At the final analysis, median duration of follow-up was 64.8 6. On commencing LEN, thromboprophylaxis included 42% (n=800) ASA, 31% months (65.3 months VTD, 64.7 months VTDC). Median TTNT was 51.8 (n=589) LMWH, 5% (n=90) warfarin, and 8% (n=149) other agents. The pro - months (95% CI 31.9, NE) and 47.9 months (95% CI 28.7, NE) in the VTD and portion of pts receiving prophylaxis at 6 months was 91-93% in Italy and Spain, VTDC treatment groups, respectively. The type of subsequent therapy was 75–76% in UK and France, and 60% in Germany (Table 1). A total of 5% (n=117) similar in both treatment groups; dexamethasone (41.8%), lenalidomide out of the 2,166 pts in the LEN cohort developed VTE while on Tx; among (33.7%), bortezomib (31.6%) and thalidomide (17.3%) were the most common - these 59% (n=69) occurred within the first 6 months. The occurrence of VTE ly used agents. In a sensitivity analysis (10 pts starting subsequent therapy after Gr 3-4 was 3% (n=56). ‘relapse from CR’ or ‘clinical relapse’ but without IMWG criteria-based progres - sion were considered to have progressed), PFS and TTP were similar in the Table 1. Percent of patients receiving any form of thromboprophylaxis in VTD and VTDC groups: median PFS was 34.1 months (95% CI 23.5, NE) and the first 6 months of LEN treatment by country and by month. 34.2 months (95% CI 23.5, 48.2), and median TTP was 34.7 months (95% CI 23.9, NE) and 34.5 months (95% CI 23.5, 50.6), respectively. The 3-year and 5-year OS rates were similar for both treatment groups: 79.6% (95% CI 65.4, 88.5) vs 83.7% (95% CI 70.0, 91.5) at 3 years, and 69.1% (95% CI 54.1, 80.1) vs 65.3% (95% CI 50.1, 76.8) at 5 years for the VTD and VTDC treatment groups, respectively (Figure 1A). Of pts with bone-marrow-confirmed CR avail - able for MRD analysis, 34 were MRD-negative and 8 MRD-positive by multi - parameter flow cytometry. When analyzed by MRD status, OS was longer in MRD-negative vs MRD-positive pts (hazard ratio [HR] 3.66, p=0.0318) (Figure 1B). Although not significant, a similar trend was seen for PFS (HR 2.29, p=0.0849). During this follow-up period, no new adverse events and no second primary malignancies were reported. Summary and Conclusions: The VTD induction regimen followed by HDT/SCT provides long-term disease control (median TTNT 51.8 months, 5- year OS 69.1%). Consistent with the primary analysis results, there was no sig - nificant difference in long-term outcomes between the VTD and VDTC groups.
haematologica | 2014; 99(s1) | 115 19 th Congress of the European Hematology Association
Analysis of OS and PFS by MRD status confirms the importance of achieving most common adverse events (AEs) being transient, non-cumulative myelosup - an immunophenotypic CR after treatment. pression: based on laboratory data, Grade (Gr) 3-4 neutropenia was observed in 38% of pts and Gr3-4 thrombocytopenia in 27% of pts. A low overall rate of non-hematological toxicity was observed: no Gr3-4 non-hematologic AEs were observed in more than 9% of patients. Among all 29 pts treated at doses of ≥1.25 mg/m 2/D filanesib+1.3 mg/m 2/D BTZ, treatment-emergent neuropathy (Gr2) was observed in only 1 pt. In the 19 pts in Schedule 1 who received ≥1.25 mg/m 2/D filanesib+1.3 mg/m 2/D BTZ, the overall response rate (ORR, ≥PR) was 42% (8/19) and the clinical benefit rate (CBR, ≥MR) was 58%. In the subset of pts with BTZ-sensitive disease, an ORR of 56% (5/9) and a CBR of 89% was observed. In pts with PI-refractory disease, an ORR of 30% (3/10) was observed. The median time on treatment in Schedule 1 has been 12 months (range 1, 14.3+). The observed duration of response to-date ranged from 3.1+ to 11.4+ months. The 10 pts in Schedule 2 had received a median of 1 cycle of treatment at the time of data cutoff and 8 pts remained on study with 2 MR observed to date. High pre-dose levels of alpha 1-acid glycoprotein (AAG) are a potential marker of lack of response to filanesib. To date in PI- refractory pts, responses occurred only in pts with low AAG levels. Summary and Conclusions: Filanesib combined with weekly BTZ, dex, and prophylactic G-CSF appears well tolerated with manageable AEs in heavily pretreated pts. This combination has shown promising activity both in BTZ-sen - sitive (ORR=56%; CBR=89%) and in PI-refractory MM (ORR=30%). In addi - tion, a more convenient schedule of filanesib on D1, 15+weekly BTZ, is feasi - ble. Expansion cohorts of 21 pts of both schedules are ongoing in pts with BTZ-sensitive disease who received 1-3 prior therapies. These data will be updated at time of presentation and will include pts in the expansion cohorts.
P371 A COMPARISON BETWEEN NEXT-GENERATION SEQUENCING AND ASO-QPCR FOR MINIMAL RESIDUAL DISEASE DETECTION IN MULTI - PLE MYELOMA: THE CLINICAL VALUE IN ASCT SETTING H Takamatsu 1, R Murata 2, S Ito 3, J Zheng 4, M Moorhead 4, Y Terasaki 5, T Yoshida 6, M Faham , 4,* S Nakao 1 1Kanazawa University, 2NTT West Kanazawa Hospital, Kanazawa, 3Iwate Med - ical University School of Medicine, Morioka, Japan, 4Sequenta, Inc., South San Francisco, United States, 5Toyama City Hospital, Toyama, 6Shizuoka City Shimizu Hospital, Shizuoka, Japan
Background: Although molecular complete remission (mCR) in multiple myelo - ma (MM) can be assessed by allele-specific oligonucleotide (ASO)-PCR, this technique requires preparation of clonotype-specific primers for each individ - ual which is laborious and time-consuming. We utilized a sequencing method, Figure 1. termed the LymphoSIGHT™ platform, which employs consensus primers and high-throughput sequencing to amplify and sequence all rearranged immunoglobulin gene segments present in a myeloma clone. Aims: We compared the LymphoSIGHT™ method with ASO-qPCR for MRD P370 detection in autografts in the autologous peripheral blood stem cell transplan - A PHASE 1 STUDY OF FILANESIB (ARRY-520) WITH BORTEZOMIB (BTZ) tation (ASCT) setting. AND DEXAMETHASONE (DEX) IN RELAPSED OR REFRACTORY MULTI - Methods: Forty-four Japanese patients with newly diagnosed MM who PLE MYELOMA (RRMM) received various induction regimens prior to ASCT were retrospectively ana - A Chari 1,* M Htut 2, J Zonder 3, J Fay 4, A Jakubowiak 5, B Harrison 6, K Lau 1, lyzed. All patients had achieved a partial response (PR) or complete response S Burt 3, B Hilder 7, AM Ptaszynski 8, S Rush 7, J Kaufman 9 (CR) after ASCT. BM slides from 29 MM patients and fresh BM cells from 15 1Hem/Onc, Mt Sinai, New York, 2City of Hope National Medical Center, Duarte, MM patients at diagnosis as well as autografts were obtained for DNA extrac - 3Karmanos Cancer Inst, Detroit, 4Baylor Medical Center, Dallas, 5University of tion. IGH-based ASO-qPCR was performed as described previously (van der Chicago Medical Centre, Chicago, 6MMRC, Norwalk, 7Array BioPharma, Velden et al. , Methods Mol Biol 2009). We performed next-generation Raleigh, 8Array BioPharma, Boulder, 9Emory University School of Medicine, sequencing (NGS) using the LymphoSIGHT method (Faham et al. , Blood Atlanta, United States 2012). Using universal primer sets, we amplified IGH variable (V), diversity (D), and joining (J) gene segments, IGH-DJ, and IGK from genomic DNA. Background: Filanesib is a novel KSP inhibitor with encouraging activity in Amplified products were subjected to deep sequencing using NGS. Reads patients (pts) with RRMM. In preclinical models, the activity of filanesib is syn - were analyzed using standardized algorithms for clonotype determination. ergistic with BTZ, providing a rationale to combine these drugs in the clinic. Myeloma-specific clonotypes were identified for each patient based on their Aims: ARRAY-520-111 is a Phase 1 study to identify the maximum tolerated high frequency in BM samples. The presence of the myeloma clonotype was dose of filanesib, BTZ and dex. then assessed in follow-up samples. Methods: Eligible pts have RRMM with ≥2 prior lines of therapy, including a Results: MRD in autografts could be assessed in 44 of 44 patients (100%) proteasome inhibitor (PI) and an IMiD. Filanesib is administered intravenous - by NGS and 36 of 44 patients (82%) by ASO-qPCR. MRD in autografts was ly (IV) on days (D) 1, 2, 15, 16 (Schedule 1) or on D1, 15 (Schedule 2); BTZ is detected in 35 of 44 (80%) by NGS and 16 of 36 (44%) by ASO-qPCR. Two administered IV or subcutaneously weekly on D1, 8, 15; and 40 mg oral dex, cases where MRD was not detected by NGS (MRD NGS (-)) and 19 MRD - if given, is taken on D 1, 8, 15 in a 28D cycle. G-CSF is given for 5-7D starting NGS (+) cases received post-ASCT therapy using novel agents such as borte - D3 or 4 and again D17 or 18. The safety of filanesib+BTZ in the early portion zomib/lenalidomide/thalidomide while 7 MRD NGS (-) cases and 16 MRD - of dose escalation has been reported previously. This abstract will focus on the NGS (+) cases were followed without post-ASCT therapy. The MRD NGS (-) cas - safety and activity of higher doses of filanesib in this dose escalation study es without post-ASCT therapy showed a significantly better PFS than those (≥1.25 mg/m 2/D filanesib+1.3 mg/m 2/D BTZ). MRD NGS(+) cases without post-ASCT therapy ( P=0.025) although overall Results: In Schedule 1, 19 pts have been treated at filanesib doses of 1.25 and survival rates were comparable among the three groups (Figure 1A). To inves - 1.5 mg/m 2/D with 1.3 mg/m 2/D BTZ, without and with dex. Pts received a medi - tigate the value of sensitive detection by NGS, we compared PFS in 7 MRD - an of 5 prior therapies and 42% were BTZ refractory. The maximum planned NGS (-) cases (Group 1) with the 6 MRD NGS (+) cases where MRD was not dose in this schedule has been established as 1.5 mg/m 2/D filanesib and 1.3 detected by ASO-qPCR (MRD ASO (-)) (Group 2). The patients in both groups mg/m 2/D BTZ+40 mg dex. In Schedule 2, 10 pts have been treated at doses did not receive any post-ASCT therapy. Group 1 tended to show a better of 2.25 and 3.0 mg/m 2/D filanesib with 1.3 mg/m 2/D BTZ+dex. Pts had received PFS than Group 2 ( P=0.091) (Figure 1B). Additional patients and samples are a median of 4 prior therapies. The recommended Phase 2 dose (RP2D) in this being analyzed and results will be presented. schedule has been established as 3.0 mg/m 2/D filanesib and 1.3 mg/m 2/D Summary and Conclusions: Detection of MRD in the post-ASCT setting is a BTZ+40 mg dex. Both schedules have shown acceptable tolerability, with the significant predictor of PFS, and MRD-negativity in autografts revealed by NGS
116 | haematologica | 2014; 99(s1) Milan, Italy, June 12 – 15, 2014 may be more closely associated with durable remission of MM than that revealed by ASO-qPCR.
Figure 1. Comparison between NGS and ASO-qPCR for MRD detection in MM. PFS according to MRD in autograft by NGS (A), and PFS comparison between NGS and ASO-qPCR in cases without post-ASCT Tx.
P372 Figure 1. A)VBDD-treatment schedule; B) DLT in dose levels 0,+1 and +2; C) best response (n=25) and EOT (n=20) according to IMWG and EBMT cri - VORINOSTAT (V) IN COMBINATION WITH BORTEZOMIB (B), DOXORU - teria and D) HDAC activity (before cycle 1, d1 and under VBDD treatment, BICIN (D) AND DEXAMETHASONE (D) (VBDD) IN PATIENTS WITH cycle 2, d8) after VBDD initiation demonstrated HDAC-downregulation in REFRACTORY OR RELAPSED MULTIPLE MYELOMA (RRMM): AN INTER - 7/10 (70%) patients. IM PHASE I/II ANALYSIS M Kleber 1,* D Wider 1, K Keller 2, B Groß 1, H Reinhard 1, D Jakobs 1, M Burbeck 1, M Pantic 1, A May 3, J Duyster 1, M Jung 2, R Waesch 1, M Engelhardt 1 P373 1Department of Hematology, Oncology and Stem Cell Transplantation, Univer - 2 sity of Freiburg Medical Center, Institute of Pharmaceutical Sciences, Albert- A PHASE IB DOSE ESCALATION TRIAL OF SAR650984 (ANTI-CD-38 MAB) 3 Ludwigs-University Freiburg, Institute of Pathology, University Medical Center, IN COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE IN Albert-Ludwigs-University, Freiburg, Germany RELAPSED/REFRACTORY MULTIPLE MYELOMA T Martin 1,* R Baz 2, D Benson 3, N Lendvai 4, R Vij 5, E Charpentier 6, K Hsu 6 Background: The combination of bortezomib, doxorubicin and dexametha - 1Hematology, University of California San Francisco, San Francisco, 2Hema - sone (BDD) is well tolerated and induces a high overall response rate (ORR). tology, Moffitt cancer center, Tampa, 3Hematology, Ohio state university med - Preclinical studies have demonstrated that vorinostat, a histone deacetylase ical center, columbus, 4Hematology, Memorial Sloan-Kettering Cancer Center, inhibitor, is synergistic with bortezomib and doxorubicin. New York, 5Hematology, Washington University Medical School, St Louis, Aims: The aim of this phase I/II study was to determine the tolerability and activ - 6Sanofi Oncology, Sanofi, Cambridge, United States ity of the combination of BDD with vorinostat (VBDD) in RRMM. Methods: Patients received escalated vorinostat-doses (provided by MSD) at Background: SAR650984 (SAR) is a humanized IgG1 monoclonal antibody 100mg (dose level [DL] 0), 200mg (DL +1) and 300mg (DL +2) on days 1-4, 8- that binds selectively to a unique epitope on human CD38 receptor. SAR kills 11, 15-18, combined with bortezomib 1.3mg/m 2 day 1,8,15 (provided by tumor cells via antibody-dependent cellular-mediated cytotoxicity, complement- Janssen-Cilag GmbH), dexamethasone 40mg day 1,8,15,22 and doxorubicin dependent cytotoxicity, direct apoptosis induction without secondary crosslink - on 9mg/m 2 day 1+8 (Figure 1A). The primary objective was the maximum tol - ing and allosteric inhibition on CD38 enzymatic activity. We present data on the erated dose (MTD; 3+3 dose escalation design). Secondary objectives were dose escalation phase of the study (NCT01749969) safety, response assessed by EBMT and IMWG criteria, progression-free sur - Aims: To determine the safety profile of SAR650984 in combination with Leno - vival and overall survival. ORR (>PR) was assessed every 4 weeks and at dis - lidomide and dexamethasone in heavily pretreated patients with refractory and continuation or end of treatment (EOT). Correlative endpoints include prognos - relapsing multiple myeloma tic MM-parameters, organ function, QoL-, comorbidity-assessments and trans - Methods: Three dose levels (DL) of SAR 3, 5 and 10 mg/kg were evaluated in lational studies ( e.g. HDAC-activity decrease in PB MNCs, global acetylation combination with lenalidomide (LEN) and dexamethasone (Dex). LEN 25 mg and gene expression analysis). Dose limiting toxicities (DLTs) were defined as was given on days (d) 1 – 21 and D 40 mg on d 1, 8, 15 and 22 every 28 d’s. any possibly drug related adverse events (AEs) ≥grade 3 (CTCAE) within the SAR was given IV on d 1 and 15 and escalated using the classic 3+3 design. 1st cycle. After completion of 6 cycles, patients could continue with bortezomib All patients signed an IRB approved informed consent. maintenance or proceed to (most often 2nd) ASCT. Results: 13 patients (pts) with RRMM were treated; median age 61 yrs (48 - 73); Results: To date, 26/30 patients have been enrolled (median age: 63 years median prior treatment regimens 6 (2 - 12), 100% had received prior LEN (23% [range 54-78], 58% males). Median prior therapy lines were substantial with 3 prior pomalidomide) and 92.3% previously received bortezomib (38.5% prior carfil - (range 1-8): bortezomib, thalidomide or lenalidomide had been given in 81%, zomib). The median time from diagnosis to first SAR dosing was 4.5 yrs (3 - 11). 23% and 31%, respectively; 84% of patients had undergone prior SCTs. Cyto - The maximum tolerated dose was not reached. The most frequent adverse events genetic abnormalities included del(17p) (n=4), t(4;14) (n=2), gain(1q) (n=4), included nausea, cough (n=6 each); fatigue, muscle spasm, infection (n=5 each); t(11;14) (n=4) and hyperdiploidy (n=7). The median Karnofsky Performance vomiting, diarrhea, dehydration and insomnia (n=4 each). Grade (G) ≥3 hemato - Status was 90% (range 70-100%). No DLTs have been observed to date; with logic abnormalities were neutropenia (n=4) and thrombocytopenia (n=3). One pt 3 patients each being included in DL 0 and DL +1, the following patients safe - discontinued therapy (cycle 1, d 1) due to an infusion reaction (bronchospasm G ly proceeded to DL +2 (Figure 1B). Nine SAEs occurred in 7/26 patients (27%): 3). The ORR (≥PR), according to IMWG criteria, among 12 evaluable pts was bacteraemia (n=1) and herpes zoster reactivation (n=1) were suspected to be 58%. Responses occurred at each DL of 3mg/kg (1PR), 5mg/kg (1PR, 1 VGPR) related to all VBDD-drugs. No causal relationship to study drugs was suspect - and 10 mg/kg (1PR, 3 VGPR). Clinical benefit response (≥MR) was 67% with 1 ed for pneumonia (2), syncope (1), pathological fracture (1), respiratory infec - MR at 3 mg/kg. Median time on treatment was 20.6 weeks (0 - 35) and 7 pts tion (1) and 2 death due to PD with persisting plasma cell leukemia (PCL) or remain on therapy. PK showed non linearity at select dose levels, SAR plasma refractory disease. Best response and response at EOT defined by ORR was trough levels were above target for tumor eradication from preclinical data. 60% and 45%, and the clinical benefit rate (CR, PR, SD) 92% and 90%, respec - Summary and Conclusions: The combination of SAR with LEN/Dex was toler - tively (Figure 1C). At a median follow-up of 12 months (range 1-28), there have ated and no DLT’s were reported at any DL. SAR+LEN/Dex demonstrated encour - been only 2 patients with PD (1 with RRMM and 1 with PCL). The analysis of aging efficacy in pts with heavily pretreated RRMM. An expansion cohort of 18 pts HDAC activity (before cycle 1, d1 and under VBDD treatment, cycle 2, d8) after recently enrolled on the trial and the results will be reported at the meeting. VBDD initiation demonstrated HDAC-downregulation in 7/10 (70%) patients (Figure 1D). Further analyses will determine whether HDAC activity and treat - ment response may correlate and whether this HDAC downregulation may pre - P374 cede and/or indicate depth of response. Summary and Conclusions: VBDD is a well tolerated and effective regimen IDENTIFICATION OF REVERSIBLE RENAL DAMAGE AND EARLY MARK - in heavily pretreated RRMM patients. There have been no observed DLT and ERS OF RESPONSE TO CHEMOTHERAPY IN AL AMYLOIDOSIS: A STUDY the MTD of vorinostat was set at 300mg, with all reported SAEs being in line ON 732 PATIENTS with the known safety profile of the investigated drugs. Our alternative vorino - G Palladini 1,* U Hegenbart 2, P Milani 1, C Kimmich 2, A Foli 1, A Ho 2, M Vidus stat-schedule (dosing of 4 days on and 4 days off) induced excellent tolerabil - Rosin 1, R Albertini 3, R Moratti 4, G Merlini 1, S Schönland 2 ity and seems to enhance the antimyeloma response, warranting completion 1Department of Molecular Medicine, University of Pavia, Pavia, Italy, 2Department of this study. of Internal Medicine V, Division of Hematology / Oncology / Rheumatology, Uni -
haematologica | 2014; 99(s1) | 117 19 th Congress of the European Hematology Association versity of Heidelberg, Heidelberg, Germany, 3Clinical Chemistry Laboratory, 4Sci - years). Among individuals with MGUS, 53.7% were male, compared to 50.2% entific Direction, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy of individuals with FLC-MGUS and 40.9% of individuals with no MGUS. Of vis - ible M-protein bands on SPEP, IgG was the most common isotype (56.5%), fol - Background: The kidney is involved in 70% of patients with AL amyloidosis, lowed by IgM (30.7%), IgA (10.5%), free kappa/lambda only (1.9%) and IgD but little is known on factors affecting progression and potential reversibility of (0.3%). After a median follow-up time of 8 years, we found that individuals with renal damage, and the criteria for renal response have never been validated. MGUS had a significantly higher risk of death (HR=1.3, 95% CI 1.1-1.5) than Aims: To identify prognostic factors, response and progression criteria for renal individuals with no MGUS, whereas individuals with FLC-MGUS did not involvement in AL amyloidosis. (HR=1.1, 95% CI 0.9-1.2) (Figure 1). Methods: We systematically searched the databases of the Pavia and Heidel - berg amyloidosis canters for previously untreated patients with renal AL amy - loidosis diagnosed between 2004 and 2012. Italian patients (n=461) were used as testing cohort and German patients (n=271) as validation cohort. All the patients gave written informed consent. The study endpoint was time from diagnosis to dialysis initiation (renal survival). Patients who died off-dialysis were censored. Results: Seventy-one (15%) patients required dialysis in the Italian group and 84 (31%) in the German series after a median time of 85 and 69 months, respec - tively. Baseline proteinuria >5 g/24 hours and estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m 2 were associated with poorer renal survival. Patients with proteinuria below and eGFR above the thresholds were at low-risk of dialysis (0 and 4% at three years in the testing and validation cohorts, respec - tively), whereas subjects with both high proteinuria and low eGFR were at high- risk (60% at three years in the Italian and 85% in the German series). Patients with either proteinuria above the cutoff or eGFR below the threshold were at intermediate-risk of progression (18% and 31% at three years in the testing and validation cohorts, respectively). The difference in renal survival between the three stages was significant (P<0.001 in both groups). Response and progres - sion were assessed at three and six months. A decrease in eGFR by ≥25% was Figure 1. associated with poor renal survival in both cohorts and was adopted as the cri - terion for renal progression. A decrease in proteinuria by ≥30% or below 0.5 g/24 hours in the absence of renal progression was the criterion for renal response, Summary and Conclusions: In this large, population-based cohort screening being associated with longer renal survival in both series. Hematologic very good study, we found that compared to individuals without MGUS, individuals with partial or complete remission improved renal outcome. MGUS have a 30% increased risk of dying at a median of 8 years of follow-up. Summary and Conclusions: We identified and validated a staging system for This is in contrast to previous, hospital-based studies. Our findings also sug - renal involvement and criteria for early assessment of renal response and pro - gest that MGUS is perhaps even more common than previously assumed. gression in AL amyloidosis which should be used in routine clinical practice and Attention should be directed towards characterizing causes of death as well as clinical trial design. finding the underlying reasons for inferior survival in MGUS.
P375 P376 MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE INTERIM RESULTS FROM A PHASE IIA STUDY OF THE ANTI-CXCL12 (MGUS) IS ASSOCIATED WITH A 30% INCREASED RISK OF DYING AT 8 SPIEGELMER OLAPTESED PEGOL (NOX-A12) IN COMBINATION WITH YEARS OF FOLLOW-UP: RESULTS FROM A SCREENED CROSS-SEC - BORTEZOMIB AND DEXAMETHASONE IN PATIENTS WITH MULTIPLE TIONAL POPULATION-BASED STUDY MYELOMA EK Lindqvist 1,* SH Lund 2, R Costello 3, D Burton 3, N Korde 3, S Mailankody 3, H Ludwig 1,* K Weisel 2, M T Petrucci 3, X Leleu 4, A M Cafro 5, M Kropff 6, R Greil 7, M Björkholm 1, V Gudnason 2, 4, G Eiriksdottir 4, LJ Launer 5, TB Harris 5, N Zojer 8, T Dümmler 9, A Kruschinski 9, K Riecke 9, R Foa 3, I Yakoub-Agha 4, M Hultcrantz 1, O Landgren 1, 3, SY Kristinsson 1, 2 M Engelhardt 10 1Department of Medicine, Division of Hematology, Karolinska University Hos - 11. Medizinische Abteilung Zentrum für Onkologie, Hämatologie und Pallia - pital and Karolinska Institutet, Stockholm, Sweden, 2Faculty of Medicine, Uni - tivmedizin, Wilhelminenspital, Vienna, Austria, 2Internal Medicine II, Oncology and versity of Iceland, Reykjavik, Iceland, 3Center for Cancer Research, National Hematology, University of Tübingen, Tübingen, Germany, 3Department of Cellu - Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, United lar Biotechnologies and Hematology, “Sapienza” University of Rome, Rome, Italy, States, 4Icelandic Heart Association, Kopavogur, Iceland, 5National Institute on 4Hematology, CHRU de Lille, Lille, France, 5Department of Oncology and Hema - Ageing, National Institutes of Health (NIH), Bethesda, United States tology, Niguarda Ca’ Granda Hospital, Milan, Italy, 6University of Münster, Mün - ster, Germany, 7IIIrd Medical Department with Hematology and Medical Oncol - Background: Multiple myeloma (MM) is a hematological malignancy where ogy,, Paracelsus Medical University Salzburg, Salzburg, 81. Medizinische abnormal plasma cells proliferate and accumulate in the bone marrow. All cas - Abteilung Zentrum für Onkologie, Hämatologie und Palliativmedizin, Wilhelminen - es of MM are preceded by the asymptomatic condition monoclonal gammopa - spital, Vienna, Austria, 9NOXXON Pharma AG, Berlin, 10 Internal Medicine I, thy of undetermined significance (MGUS), where an M-protein is present in the Oncology and Hematology, University of Freiburg, Freiburg, Germany blood but there are no other signs of hematologic malignancy. The prevalence of MGUS increases with age, and has been estimated to be 3-4% in a popu - Background: Olaptesed pegol (NOX-A12) is a novel L-stereoisomer RNA lation aged 65 years or above. However, since MGUS by its nature is asymp - aptamer (Spiegelmer ®) that binds and neutralizes the chemokine CXCL12 with tomatic and likely to remain undiscovered, there is there is limited information high affinity. CXCL12, through interaction with the chemokine receptors CXCR4 on prevalence and survival in MGUS. and CXCR7, is responsible for homing and trafficking of healthy and malignant Aims: This study aims to determine the prevalence of MGUS in a screened, blood cells to the bone marrow (BM) stroma. Preclinical studies have shown elderly population, and to evaluate the effect of MGUS on survival. synergistic activity of CXCL12-targeting and anti-myeloma agents, specifical - Methods: The cohort under study was the longitudinal AGES-Reykjavik Study. ly bortezomib, suggesting that targeting of the myeloma niche may enhance The participants were men and women born 1907-1934 in Iceland, who were treatment efficacy. examined up to six times by the Icelandic Heart Association. Blood samples Aims: Here we aim to assess the activity and safety of olaptesed in combina - from all participants, collected in 2002-2006, were screened for M-protein using tion with bortezomib and dexamethasone in patients with relapsed/refractory serum protein electrophoresis (SPEP) as well as free light chain (FLC) analy - multiple myeloma (MM). sis. Information on outcome was supplemented by matching hospital, nursing Methods: Twenty-nine patients with relapsed or refractory MM were enrolled. home, and mortality records to the cohort. The survival of individuals with At this time, data from 20 patients (10 males and 10 females) are evaluable. MGUS versus those without was compared by calculating hazard ratios (HRs) Median (range) age was 65 years (48-79). Patients had received 2 (1-6) prior and confidence intervals (CIs), based on a Cox proportional hazard model treatment lines. Pre-treatment consisted of dexamethasone in 19, lenalido - adjusting for age and gender, and by using Kaplan Meier analysis. mide in 15, bortezomib in 10 and carfilzomib in 1 patient. Seven patients under - Results: Out of 5,784 participants, 313 participants (5.4%) had 1, 2 or 3 M-pro - went stem cell transplantation. Four patients presented with ISS stage I, 8 with tein bands on SPEP. A total of 464 participants (8.0%) had a pathological FLC stage 2 and 8 with stage III. Twelve patients had IgG, 2 presented with IgA and ratio (reference interval 0.26-1.65), but normal SPEP. Due to missing informa - 6 with light chain myeloma. Thirteen patients had “high-risk” cytogenetic aber - tion, 36 observations were excluded from the analyses, and 2 were excluded rations, defined by the presence of t(4;14) or del17p. Six patients were refrac - because of conflicting results on SPEP and FLC. The median age at inclusion tory to their last prior treatment, 10 were progressing during or shortly after in the cohort was 77 years (range 66-98). Individuals with MGUS and with maintenance therapy, mostly lenalidomide-dexamethasone. Patients were FLC-MGUS were older (78.5 years) than individuals without MGUS (76.8 treated using a dose titration design with intravenous olaptesed at doses
118 | haematologica | 2014; 99(s1) Milan, Italy, June 12 – 15, 2014 increasing from 1 mg/kg to 2 mg/kg and 4 mg/kg at cycles 1, 2 and 3, respec - sequenced and analyzed using standardized algorithms for clonotype determi - tively, at 1 hour prior to bortezomib administration. During cycles 4 to 8, nation. Tumor-specific clonotypes were identified for each patient based on olaptesed was dosed at the highest individually titrated dose. Bortezomib (1.3 their high-frequency (>5%) within the B-cell repertoire. Following identification mg/m 2) was given on days 1, 4, 8 and 11 as intravenous injection. Oral dexam - of the myeloma-specific clonotypes, we assessed each of the cell preparations ethasone (20 mg) was added on the day of and the day after bortezomib admin - for the presence of the myeloma clonotype(s). istration. Response was evaluated based on the uniform response criteria of Results: The sequencing assay detected the presence of a myeloma-specific the IMWG (Rajkumar SV et. al. Blood 2011; 117: 4691-5). To study PK/PD, a clonal gene rearrangement in 22 of 23 (96%) of patients with MM. Applicabili - pilot dose of 1 to 4 mg/kg olaptesed alone was administered to the initial 10 ty rates were 17/18 (94%) in BMA slides and 18/19 (95%) in RBC lysis cell patients before the start of the regular treatment regimen. preparations. These applicability rates are consistent with previous reports of Results: The median number of completed cycles was 7.5 (0-8). The overall sequencing applicability in MM patients. In thirteen patients, we investigated the response rate was 70% with 6 patients achieving VGPR and 8 PR. Minimal potential loss of myeloma-specific clonotypes due to Ficoll cell preparation. response was noted in 1 patient, and 3 patients had progressive disease. Lev - The variation in myeloma cell loss was typically low but ranged from essential - els of circulating CD138 +/CD38 +, plasma cells were studied for 72 hours in the ly no loss to the loss of more than 90% of the myeloma cells in the PBMC of pilot phase and for 24 hours at cycles 1 and 4. A 2-fold increase of plasma cells one patient compared to the RBC lysis preparation. The myeloma cells were compared to baseline was noted already after one hour and an increased mobi - detected in the typically discarded lower layer of the Ficoll preparation which lization persisted throughout the observation period (Figure 1). Treatment with explained the loss. olaptesed in combination with VD was safe and well tolerated without a signif - Summary and Conclusions: These results suggest that sequencing based icant increase in adverse events compared to VD-treated MM patients. The MRD analysis is applicable in >95% of patients with MM. Further evaluation and dose of olaptesed was titrated up to 4 mg/kg in all 15 patients treated beyond optimization of sample processing methods is ongoing to enable application of cycle 3. the sequencing method for clinical MRD assessment in MM patients.
P378 MULTIPLE MYELOMA PATIENTS THAT DEVELOP SECOND PRIMARY MALIGNANCY HAVE A WORSE PROGNOSIS THAN MULTIPLE MYELO - MA PATIENTS TREATED BEFORE THE INTRODUCTION OF NOVEL AGENTS: A POPULATION BASED-STUDY G Jónsdóttir 1,* SH Lund 1, O Landgren 2,3, M Björkholm 2, I Turesson 4, A Wahlin 5, C Blimark 6, M Hultcrantz 2, A Porwit 7, S Y Kristinsson 1,2 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland, 2Department of Medicine, Division of Hematology, Karolinska University Hospital and Karolin - ska Institutet, Stockholm, Sweden, 3Center for Cancer Research, NCI, NIH, Bethesda, United States, 4Department of Hematology and Coagulation Disor - ders, Skåne University Hospital, Malmö, 5Department of Radiation Sciences, University of Umeå, Umeå, 6Department of Medicine, Section of Hematology and Coagulation, Sahlgrenska University Hospital, Gothenburg, Sweden, 7Uni - versity Health Network, Department of Laboratory Medicine and Pathobiology, Toronto General Hospital, Toronto, Canada Figure 1. Background: The survival of patients with multiple myeloma (MM) has signif - icantly improved over the last decades due to increasingly effective therapies. The analysis of 20 evaluable patients document - Summary and Conclusions: With this improvement the incidence of second primary malignancies (SPM), ed an ORR of 70%, which is comparable to published data of the VD regimen. including acute myeloid leukemia (AML) and myelodysplastic syndromes Considering that the study population included patients retreated with borte - (MDS), has become a concern. In a recent meta-analysis, exposure to lenalido - zomib and a marked proportion of patients with unfavorable cytogenetics, these mide plus melphalan significantly increased hematological SPM. However, the results support the further development of olaptesed pegol in MM. effect of SPM on survival in patients with MM has not been established. Aims: The aim of this population-based study was to assess the effect of SPM on survival in patients with MM. P377 Methods: All MM patients diagnosed in Sweden 1958-2011 were identified IDENTIFICATION OF MYELOMA-SPECIFIC CLONOTYPES IN DIAGNOS - from the Swedish Cancer Registry. We identified information on all subsequent TIC SAMPLES FROM PATIENTS WITH MULTIPLE MYELOMA USING NEXT- SPM diagnoses among patients in the MM cohort. For each MM patient with GENERATION SEQUENCING METHOD SPM, two controls without SPM from the MM cohort were selected and matched S Maheo 1, M Klinger 2, M Faham 2, H Avet-Loiseau 3,* by year of birth, sex, and date of MM diagnosis. Survival was estimated from 1University Hospital Toulouse, Toulouse, France, 2Sequenta, Inc., South San SPM diagnosis (and corresponding date for controls) until death, with follow- Francisco, United States, 3University Hospital Toulouse, Toulouse, France up to 2012. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs), adjusting for gender, age at MM diagnosis, and cal - Background: Recent reports support the prognostic importance of minimal endar period. residual disease (MRD) levels in multiple myeloma (MM) patients and suggest Results: Among 26,627 patients diagnosed with MM in Sweden 1958-2011, a that novel methods for MRD assessment can play a role in the evolving MM total of 1,812 developed SPM and 5,132 MM patients were matched controls. treatment paradigm. The application of next-generation sequencing-based MRD Median age at MM diagnosis was 70 years and 74 years at SPM diagnosis. Of assessment has been previously demonstrated in multiple lymphoid malignan - the 1,812 patients that developed SPM, 25% were gastrointestinal, 12% hema - cies (Faham et al. Blood 2012, Ladetto et al. Leukemia 2013). This quantita - tological, 13% non-melanoma skin cancer, 3% malignant melanoma, 5% respi - tive method, termed the LymphoSIGHT™ platform, relies on amplification and ratory, 3% nervous system tumors, 15% male reproductive system, 6% breast, sequencing of immunoglobulin gene segments using consensus primers, with 3% female reproductive system, 8% kidney and urinary tract, and 6% unspeci - a demonstrated applicability higher than 90% in MM patients (Vij et al. , Clin Lym - fied. Overall patients with SPM had a statistically significant 1.8-fold (95% CI 1.7- phoma Myeloma Leukemia 2013). 1.9) increased risk of death in comparison to control MM group. Median survival Aims: This technical study is aimed at assessing optimal sample type and was 0.9 years after SPM diagnosis and 2.5 years after corresponding date for preparation techniques. Previous experience suggested that myeloma cells controls. MM patients with SPM diagnosed 2001-2011 had a significant 1.2-fold may be diminished in a PBMC preparation. In this study, we evaluated this (1.01-1.42) increased risk of death in comparison to MM patients without SPM hypothesis by comparing the myeloma level in PBMC preparations and sam - diagnosed 1958-2000 (Figure). MM patients with SPM 1958-2000 had a signif - ples following RBC lysis. In addition, we evaluated the effectiveness of identi - icant 1.6-fold (1.4-1.9) increased risk of death in comparison to MM patients fying myeloma clonotypes using DNA obtained from Bone Marrow Aspirate with SPM 2001-2011. There was a statistically significant increased risk of death (BMA) slides. in MM patients with the following cancer groups (compared to without): gas - Methods: Baseline samples were collected from 23 patients with MM. The fol - trointestinal (HR=2.3; 2.1-2.5), hematological (2.9; 2.5-3.3), non-melanoma skin lowing samples were provided at baseline: BMA slides, BMA cell preparations cancer (1.2; 1.0-1.3), respiratory (3.7; 3.0-4.5), nervous system tumors (3.9; 3.0- using a Ficoll protocol, and BMA cell preparations using an RBC lysis protocol. 5.1), male reproductive system (1.3; 1.2-1.6), female reproductive system (2.0; The Ficoll BMA cell preparations were divided into the mononuclear cell frac - 1.5-2.7), kidney and urinary tract (1.9; 1.6-2.3), and unspecified tumors (2.5; tion and the lower Ficoll fraction which is typically comprised of granulocytes 2.1-3.1). There was no significant effect on survival in patients with malignant and erythrocytes. Identification of myeloma cells was performed using Sequen - melanoma (1.1; 0.8-1.5) and breast cancer (1.3; 1.0-1.6) (Fig ure 1). ta’s LymphoSIGHT™ platform. Briefly, using universal primer sets, we ampli - Summary and Conclusions: In this large population-based study including fied immunoglobulin heavy chain (IGH) and light chain (IGK) variable, diversi - more than 25,000 MM patients, we found that despite the improvement in MM ty, and joining gene segments from genomic DNA. Amplified products were survival in recent years, patients diagnosed with SPM in the last decade have
haematologica | 2014; 99(s1) | 119 19 th Congress of the European Hematology Association an increased risk of death compared to MM patients without SPM before the sis, that included different therapies, along with baseline and treatment-relat - introduction of the novel agents. Although MM patients in general benefit from ed features as prognostic factors. Variables significantly related to extended the new therapies, the prognosis in patients with SPM is a concern. Clearly, TTP and PFS included novel agent-based ASCT (P=0.006 and P=0.003), ISS there is need to clarify the underlying biological mechanisms and risk factors 1 vs 2 and 3 (P=0.03 and P=0.01) and receiving a bortezomib-based therapy for SPM in the clinical setting to be able to provide effective MM treatment followed or not by ASCT (P=0.02 and P=0.03). Prolonged OS was significant - without increasing SPM. ly related to attainment of CR as a best response and ISS 1 (P=0.005 for both). Summary and Conclusions: This analysis suggests that ASCT is feasible and well tolerated in selected MM pts aged >65. With the limitations of a retrospec - tive case-match analysis and different treatments, novel agents incorporated into ASCT seem to offer better outcomes in comparison with novel agent-based treat - ments alone and should be considered a valid option for fit elderly pts.
P380 CAN 24-HOUR URINE COLLECTION BE REPLACED BY AN EARLY MORN - ING SAMPLE FOR BENCE JONES PROTEIN DETECTION AND QUANTIFI - CATION? P Milani 1,* G Palladini 1, C Klersy 2, V Valentini 1, F Lavatelli 1, M Nuvolone 1, L Zanolla 3, G Righetti 4, V Meneghini 5, MS Graziani 4, G Merlini 1 1Department of Molecular Medicine, University of Pavia, 2Scientific Direction, Fondazione IRCCS Policlinico San Matteo, Pavia, 3Cardiology Department, 4Clinical Chemistry Laboratory, 5Hematology Department, Ospedale Civile Maggiore, Verona, Italy
Figure 1. Background: Detection and quantification of Bence Jones protein (BJP) is necessary in multiple myeloma, AL amyloidosis, and other monoclonal gam - mopathies. For BJP quantification a 24h urine collection is required; however, this can be inconvenient and subject to errors, particularly in the outpatient P379 setting. Total protein excretion can be measured in an early morning void (EMV) BORTEZOMIB OR THALIDOMIDE INCORPORATED INTO AUTOLOGOUS and expressed as protein-to-creatinine ratio. STEM CELL TRANSPLANTATION VERSUS NOVEL AGENT-BASED Aims: In the present study we tested if an EMV sample could be used to detect TREATMENTS FOR ELDERLY PATIENTS WITH NEWLY DIAGNOSED MUL - and quantify BJP in 337 outpatients from two hematology Clinics. TIPLE MYELOMA: A CASE-MATCH COMPARISON Methods: Two-hundred four had AL amyloidosis, 56 MGUS, 51 MM, 17 SMM, P Tacchetti 1,* S Bringhen 2, E Zamagni 1, L Pantani 1, A Pezzi 1, B Zannetti 1, 9 WM. All the patients gave written informed consent. Patients were asked to P Tosi 3, A Larocca 2, A Brioli 1, K Mancuso 1, F Patriarca 4, S Rocchi 1, N Testoni 1, provide the 24h urine collection and the early morning void (EMV) obtained at V Montefusco 5, B Gamberi 6, G Marzocchi 1, C Terragna 1, A Palumbo 2, M Cavo 1 the end of the collection. The BJP was detected by agarose gel immunofixa - 1Bologna University School of Medicine, Seràgnoli Institute of Hematology, tion. The BJP quantification was performed by densitometric scanning of the Bologna, 2Torino University, Hematology Unit, Department of Oncology and electrophoretic monoclonal peak. Hematology San Giovanni Battista, Torino, 3Rimini Hospital, Hematology Unit, Results: In 132 patients BJP was detected in both samples, in 13 only in the Rimini, 4Udine University, Hematologic Clinic, Department of Experimental and EMV, and in 1 only in the 24h sample (agreement 96%, Kappa-statistic 0.91 in Clinical Medical Sciences, Udine, 5Fondazione IRCCS Istituto Nazionale dei the overall population). When the BJP was visible at electrophoresis (68 pairs Tumori, Division of Hematology, Milano, 6Azienda Ospedaliera ASMN, IRCCS, of samples) it was quantified by densitometric scanning of the peak and Hematology Unit, Department of Oncology, Reggio Emilia, Italy expressed in mg/24h or mg/g-creatinine. There was very good agreement between BJP expressed as mg/24h and mg/g-creatinine in the 24h samples Background: In the novel agent era, the role of autologous stem cell transplan - (Lin’s correlation coefficient [cc] 0.95), mg/g-creatinine in the 24h and EMV tation (ASCT) for newly diagnosed multiple myeloma (MM) patients (pts) over samples (cc 0.95), and mg/24h in the 24h sample and mg/g-creatinine in the 65 years of age still remains an open issue. EMV (cc 0.91). In 25 patients with ≥2 measurements, agreement between Aims: We aimed at exploring the role of novel agents incorporated into ASCT changes in BJP expressed in mg/24h in the 24h sample and in mg/g-creatinine in comparison with novel agents alone in elderly MM pts. in the EMV was suboptimal (cc 0.72). However, agreement between BJP Methods: We retrospectively analyzed 63 pts with a median age of 68 years changes expressed in mg/g-creatinine in the 24h sample and in the EMV was (range 66-72) who were considered eligible to receive up-front novel agents plus better (cc 0.85). ASCT, and we performed a case-match comparison with a series of pts who Summary and Conclusions: An EMV can be used for BJP detection and were enrolled in two GIMEMA trials for elderly pts and were treated with melpha - measurement. The better agreement in BJP changes between the 24h and lan-prednisone plus thalidomide (MPT) (78 pts) or bortezomib (MPV) (111 pts). EMV samples when BJP is expressed in mg/g-creatinine probably reflects Results: At diagnosis, 50% of ASCT-eligible pts had ISS stage 2-3 and 24% patients’ errors in timed urine collection. had renal impairment. Cytogenetic abnormalities were evaluable in half of the pts: t(4;14) was detected in 19% of them and 17p deletion in 15%. Induction therapies were bortezomib-based (37 pts) or thalidomide-based (26 pts) (medi - P381 an number of cycles received: 4) and affected at least a VGPR in 57% and 36% of the pts, respectively. A median of 7.2x10 6 CD34+ cells/kg (IQR 5.8-10.9) was PHASE II TRIAL OF LENALIDOMIDE, DEXAMETHASONE AND collected following cyclophosphamide plus G-CSF (58 pts) or G-CSF alone (5 CYCLOPHOSPHAMIDE (LENDEXAL) FOR PREVIOUSLY UNTREATED pts). Melphalan dose prior to ASCT was 200 mg/m 2, in 39/63 pts, and 140 PATIENTS WITH LIGHT-CHAIN AMYLOIDOSIS mg/m 2 in the remaining pts due to impaired renal function; 16 pts received a MT Cibeira 1,* A Oriol 2, JJ Lahuerta 3, M V Mateos 4, J de la Rubia 5, M Hernández 6, tandem ASCT. Hematologic recovery occurred at day 12 both for platelets and M Granell 7, C Fernández de Larrea 8, JF San Miguel 4, J Bladé 8 neutrophils (range 7-16 and 10-15). No transplant-related mortality was 1Hematology, Hospital Clinic of Barcelona, 2Hospital Universitari Germans observed at 100 days. Two pts experienced grade 4 mucositis, and 13 pts Trias i Pujol, Barcelona, 3Hospital Universitario Doce de Octubre, Madrid, 4Hos - (20%) presented grade 3 toxicities, mainly mucositis and infections. Overall, pital Universitario de Salamanca, Salamanca, 5Hospital Universitario La Fe, 98% of the pts achieved at least PR, including 79% at least VGPR and 51% Valencia, 6Hospital Universitario de Canarias, Canarias, 7Hospital de la San - CR. With a median follow up of 48 months, 4-years OS was 77%, median TTP ta Creu i Sant Pau, 8Hospital Clinic of Barcelona, Barcelona, Spain and PFS were 42 and 43.4 months, respectively. Case matching was per - formed with a 1:3 ratio, with respect to age (+/-2 years), ISS stage and year of Background: Oral melphalan and dexamethasone is the standard treatment treatment; ASCT-eligible pts who had received bortezomib-based induction for newly diagnosed patients with immunoglobulin light chain (AL) amyloidosis therapy were matched with pts treated with MPV, whereas pts who had received not eligible for high-dose melphalan and stem cell transplantation (HDM/SCT). thalidomide-based induction were matched with pts treated with MPT. Base - However, new treatment options are still needed for this patient population. line characteristics were similar between pts who received or not ASCT. The Aims: Based on the activity of IMiDs® (immunolodulatory drugs) in median number of MPT or MPV cycles actually received was 6. Novel agent- relapsed/refractory AL amyloidosis, we designed a prospective and multicen - based ASCT significantly increased the probability to achieve CR as a best ter phase II trial with lenalidomide, dexamethasone and cyclophosphamide for response (51% vs 29%, P=0.002), and extended TTP (43 vs 25 months, newly diagnosed patients not eligible for autologous transplant (clinicaltrials.gov P=0.0013), PFS (43 vs 24 months, P=0.0007) and time to next treatment (33 identifier: NCT01194791). vs 23 months, P=0.0077), in comparison to the control group. OS was similar Methods: The main inclusion criteria were newly diagnosed AL amyloidosis between the two groups (66% at 48 months), as well post relapse OS (41% at confirmed by biopsy, significant organ involvement, cardiac ejection fraction 48 months in both groups). We performed a multivariate Cox regression analy - over 50%, serum creatinine below 3 mg/dL, and not being eligible for autolo -
120 | haematologica | 2014; 99(s1) Milan, Italy, June 12 – 15, 2014 gous transplant. Treatment schedule consisted of 6 cycles of lenalidomide at Aims: The aim of this stud is to investigate the characteristics of cytogenetic 15 mg orally (po) on days 1 to 21, dexamethasone at 20 mg po on days 1 to 4 abnormaliteis found in AL amyloidosis as compared with other plasma cell neo - and 9 to 12, and cyclophosphamide at 300 mg/m 2 intravenously (iv) on days 1 plasms, and to determine the significance of proportions of abnormal clones and 8 every 28 days, followed by 6 more cycles of lenalidomide at the same measured by the cIg FISH method. dose, dexamethasone at 20 mg po on days 1 to 4 and cyclophosphamide 300 Methods: A total of 230 patients was enrolled; 25 cardiac AL, 25 MUGS, and mg/m 2 iv on day 1. After these 12 cycles, maintenance with lenalidomide (10 180 MM patients. Plasma cell Sorting was performed by cIg-FISH targeting mg po on days 1 to 21) and dexamethasone (20 mg po on days 1 to 4) was IGH, RB1, TP53, 1p25/1q32, CEP 9/p16. planned until discontinuation due to intolerance or disease progression. All Results: Of 25 amyloidosis patients, 16 (61.5%) presented at least one cyto - patients received prophylaxis of thromboembolic events with oral aspirin (100 genetic abnormalities. IGH rearrangement was most frequent in 13 (50%; 13/16, mg) or subcutaneous low-molecular-weight heparin. The primary end-point was 81.3%) patients, followed by RB1 deletions in 3. Eleven AL amyloidosis patients hematologic response. with ≤30% BM plasma cells showed only IGH rearrangements without other Results: From September 2010 to December 2012, 28 patients were includ - cytogenetic abnormalities and% of clonal cells with IGH among among total ed in the study. Twenty-three patients had cardiac involvement, with cardiac plasma cells in BM ranged from 16% to 100%. In 5 patients with >30% BM plas - stage 3 in 13 of them. The overall hematologic response rate was 46%, includ - ma cells showed multiple abnormalities. In these patients, cIg-FISH revealed ing 14% complete responses. The organ response rate was 32%. In 5 patients abnormalities in >90% of plasma cells. The 6-month mortality rate of AL amy - lenalidomide was reduced or discontinued due to toxicity. A therapy-related loidosis patients with single IGH rearrangements were 27.3% (3/11), which serious adverse event was reported in 7 patients. So far, 11 patients remain on higher than those of amyloidosis patients with multiple abnormalities (0/5). the study and 17 have been discontinuated mostly due to death secondary to Among 25 MGUS patients, 8 (32%) patients showed cytogenetic abnormalities. AL-related cardiac or renal events (8 patients), progression or lack of response Of note, the most frequent abnormality was trisomy 9, which was found in 7 (4), and toxicity (3). (28%; 7/8, 87.5%) patients. Five MGUS patients presented trisomy 9 as single Summary and Conclusions: In agreement with previous reports, our results abnormality and the% clonal plasma cells ranged from 55% to 90%. Among 180 support the efficacy and tolerability of the combination lenalidomide/dexam - MM patients, 150 (83.3%) presented ≥2 cytogenetic abnormalities, 110 (61.1%) ethasone/cyclophosphamide in this poor prognostic population of patients with patients presented IGH rearrangements, 91 (50.6%) had trisomies or tetra - AL amyloidosis. somies of chromosome 9, and 37 (20.6%) patients presented both abnormali - ties. The% clonal plasma cells ranged from 12-100%. The difference in% clon - al plasma cells in BM was not significantly between AL amyloidosis and MGUS P382 (mean, 63.8% vs 71.9%, P=0.971), and higher in MM (mean, 91%; P <0.001). Summary and Conclusions: AL amyloidosis patients presented IGH THE ADDITION OF BORTEZOMIB TO STANDARD MELPHALAN/DEXAM - rearrangement as a most frequent single cytogenetic abnormality. The percent - ETHASONE IMPROVES THE QUALITY OF RESPONSE BUT DOES NOT age of clonal plasma cells in BM by Ig-FISH was not significantly different REDUCE THE RATE OF EARLY DEATHS IN AL AMYLOIDOSIS: A among AL amyloidosis and MGUS. The clinical presentation of cardiac amyloi - MATCHED CASE CONTROL COMPARISON 1,* 1 1 1 1 1 dosis was not dependent of the plasma cell burden or the clone size harboring G Palladini P Milani , M Vidus Rosin , M Basset , F Lavatelli , A Foli , cytogenetic abnormalities. G Merlini 1 1Department of Molecular Medicine, University of Pavia, Pavia, Italy
Background: Oral melphalan and dexamethasone (MDex) is standard treat - ment in patients with AL amyloidosis who are not eligible for stem cell transplan - tation. Following encouraging reports on the activity of bortezomib combined with alkylators and dexamethasone, these combinations are being moved to frontline therapy. Aims: We compared the outcome of 87 patients treated with bortezomib plus MDex (BMDex) with that of 87 controls treated with MDex. Methods: Patients and controls were matched for all known prognostic factors, including age, cardiac and renal function and clonal burden. All the patients gave written informed consent. Results: There was no significant difference in the rate of severe adverse events (17% in the MDex cohort and 22% in the BMDex group, P=0.444). Most common were fluid retention and cytopenia (9% and 7% in both cohorts, respec - tively). Peripheral neuropathy was observed only in BMDex patients (5%). A higher rate of complete responses was observed with BMDex (42% vs. 19%, P=0.002), but this did not result in a survival improvement. However, when patients with class III or IV heart failure and N-terminal pro-natriuretic peptide type-B >8500 ng/mL where excluded, a significant survival advantage for BMDex appeared (median survival 61 months vs. not reached, P=0.014). Patients treated with full-dose dexamethasone (40 mg) had similar response rates and survival whether they received bortezomib or not. Summary and Conclusions: The addition of bortezomib to MDex does not overcome the poor prognosis of advanced cardiac amyloidosis. Intermediate- risk patients, who are not deemed eligible for high-dose dexamethasone, are likely to take the greatest advantage from combinations of bortezomib, alkyla - tors and dexamethasone.
P383 THE PERCENTAGE OF CLONAL PLASMA CELLS IN BONE MARROW BY CIG-FISH: COMPARISON AMONG LIGHT CHAIN CARDIAC AMYLOIDO - SIS, MONOCLONAL GAMMOPATHY OF UNDERMINED SIGNIFICANCE AND MULTIPLE MYELOMA SY Kim 1,* K Im 2, SN Park 2, J Kwon 2, JA Kim 1, Q Choi 1, SM Hwang 3, SS Yoon 4, DS Lee 1 1Department of Laboratory Medicine, 2Cancer Research Institute, Seoul Nation - al University College of Medicine, 3Department of Laboratory Medicine, Seoul National University Bundang Hospital, 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, Republic Of
Background: Amyloid light chain (AL) amyloidosis is a disease of clonal plas - ma cells synthesizing structurally abnormal light chain. Since infiltration of plas - ma cells in in bone marrow (BM) is minimal in amyloidosis and mature plasma cells have low proliferative activity, classic cytogenetic analysis is hampered. Thereon, we performed immunofluorescence detection of cytoplasmic light- chain (cIg FISH) in AL amyloidosis, monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM).
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