Greeting. Grußwort. 2 nd Heidelberg Myeloma Workshop. Dear colleagues,

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1 Greeting Dear colleagues, We are pleased to welcome you to the. This continues the series of annual events dealing with new developments and new therapeutic strategies for treating multiple myeloma. Myeloma patients profit from the diverse and substantial innovations in diagnostics and treatment that have been made in recent years. On average patients live longer than previously and their quality of life has improved. Increasingly, the influence of genetic modifications on diagnosis, prognosis, and treatment of multiple myeloma is being discussed. New imaging procedures provide additional information to that supplied by the currently established diagnostic tools used for patients with multiple myeloma. In terms of therapy, two approaches are being debated. The combination of old substances with the new medications Thalidomid, Lenalidomid, and Bortezomib represses the myeloma with a significant increase in complete remissions. Through escalation of the therapy, a complete remission of the myeloma is even achieved in up to 80% of patients. Within the scope of the, these developments are being discussed and various possibilities for treating multiple myeloma critically juxtaposed with each other. Furthermore, current aspects regarding myeloma therapy, in particular new substances as well as treatment recommendations and new viewpoints concerning affectation of the liver and bisphosphonate therapy, constitute main focal points for the seminar. Both German myeloma study groups will present on their activities. We hope that the Myeloma Workshop in Heidelberg will provide you with extensive information about the progress being made in the treatment and diagnosis of multiple myeloma and that it will contribute in the long-term to improving successful treatments for myeloma patients. We look forward to welcoming you in Heidelberg! Grußwort Sehr geehrte Kolleginnen und Kollegen, wir freuen uns, Sie zum begrüßen zu können. Dieser setzt die Reihe von jährlichen Veranstaltungen zu neuen Entwicklungen und neuen Therapiestrategien beim Multiplen Myelom fort. Myelompatienten profitieren von vielfältigen grundlegenden Neuerungen in Diagnostik und Therapie der letzten Jahre. Sie leben im Durchschnitt länger als früher, zudem ist ihre Lebensqualität besser geworden. Vermehrt wird der Einfluss von genetischen Veränderungen auf Diagnose, Prognose und Behandlung des Multiplen Myeloms erörtert. Neue Bildgebende Verfahren liefern zusätzliche Informationen zu den bisher etablierten diagnostischen Werkzeugen bei Patienten mit Multiplem Myelom. Bei der Therapie werden zwei Vorgehensweisen diskutiert. Die Kombination von alten Substanzen mit den neuen Medikamenten Thalidomid, Lenalidomid und Bortezomib bewirkt ein Zurückdrängen der Myelomerkrankung mit einer signifikanten Zunahme der kompletten Remissionen. Durch die Eskalation der Therapie wird sogar bei bis zu 80% der Patienten eine komplette Remission der Myelomerkrankung erzielt. Im Rahmen des 2 nd Heidelberg Myeloma Workshops werden diese Weiterentwicklungen besprochen und verschiedene Möglichkeiten der Behandlung des Multiplen Myeloms einander kritisch gegenübergestellt. Weiterhin sind aktuelle Aspekte der Myelom-Therapie, insbesondere neue Substanzen sowie Therapieempfehlungen und neue Gesichtspunkte bei Nierenbeteiligung und Bisphosphonat- Therapie Schwerpunkte des Seminars. Die beiden deutschen Myelom-Studiengruppen stellen ihre Aktivitäten vor. Wir hoffen sehr, dass der Myeloma Workshop in Heidelberg Sie umfassend über die Fortschritte in der Behandlung und Diagnostik des Multiplen Myeloms informieren und langfristig dazu beitragen wird, die Therapieerfolge bei Myelompatienten zu verbessern. Herzlich willkommen in Heidelberg! Privatdozent Dr. Kai Neben Prof. Dr. Hartmut Goldschmidt 3

2 Program Friday, May 15 th 2009 Meeting Language English Seminarsprache Englisch Until 12:15 p.m. Arrival 12:15 p.m. 12:45 p.m. Registration, Lunch 12:45 p.m. 1:15 p.m. Welcome, Introduction Hartmut Goldschmidt, Heidelberg, Anthony D. Ho, Heidelberg, Otmar Wiestler, Heidelberg 1:15 p.m. 4:45 p.m. Diagnosis of Multiple Myeloma CV Abstract Slides 1:15 p.m. 2:50 p.m. Session I Imaging methods for diagnosing Multiple Myeloma standard and new approaches Chairmen: Stefan Delorme, Heidelberg, Hanno Glimm, Heidelberg 1:15 1:30 Current issues Stefan Delorme, Heidelberg /11 1:30 1:45 Computed tomography Marius Horger, Tübingen /15 1:45 2:00 Magnetic resonance imaging Andrea Baur-Melnyk, München /19 2:00 2:15 Functional MR-imaging and prognosis Jens Hillengass, Heidelberg /23 2:15 2:30 Positron emission tomography Ludwig Strauss, Heidelberg /27 2:30 2:50 Questions and answers 2:50 p.m. 3:10 p.m. Key note lecture CV Abstract Slides The biology of Multiple Myeloma Bernard Klein, Montpellier 28 3:10 p.m. 3:30 p.m. Coffee break CV Abstract Slides 3:30 p.m. 4:45 p.m. Session II Monitoring Multiple Myeloma Chairmen: Dirk Hose, Heidelberg, John D. Shaughnessy Jr., Little Rock 3:30 3:45 Serum free light chain tests for Myeloma Arthur R. Bradwell, Birmingham /33 3:45 4:00 FACS (flow cytometry) Andy C. Rawstron, Leeds /37 4:00 4:15 PCR-based MRD diagnostics Paolo Corradini, Milano /41 4:15 4:30 Is there a Role for Genomics in the Diagnosis, Prognosis and Treatment of Multiple Myeloma? John D. Shaughnessy Jr., Little Rock 42 4:30 4:45 Questions and answers 5:00 p.m. 7:45 p.m. Therapy of Multiple Myeloma CV Abstract Slides 5:00 p.m. 6:20 p.m. Session III Is autologous stem cell transplantation the therapy of choice for the treatment of Multiple Myeloma patients? Chairmen: Gösta Gahrton, Stockholm, Hartmut Goldschmidt, Heidelberg 5:00 5:05 Introduction Hartmut Goldschmidt, Heidelberg 5:05 5:35 Pro Bart Barlogie, Little Rock 44 5:35 6:05 Contra Morie A. Gertz, Rochester, Minnesota /49 6:05 6:15 Debate All 6:15 6:20 Summary Hartmut Goldschmidt, Heidelberg 6:20 p.m. 6:45 p.m. Refreshments CV Abstract Slides 6:45 p.m. 7:45 p.m. Session IV New therapeutic approaches Chairmen: Bart Barlogie, Little Rock, Morie A. Gertz, Rochester, Minnesota 6:45 7:10 Significance of allogeneic transplantation in Multiple Myeloma Gösta Gahrton, Stockholm /53 7:10 7:35 New standards of care for elderly patients with Multiple Myeloma Federica Cavallo, Torino /57 7:35 7:45 Questions and answers 8:30 p.m. Dinner 4:45 p.m. 5:00 p.m. Coffee break 4 5

3 Programm Samstag, 16. Mai 2009 Seminarsprache Deutsch Meeting Language German CV Abstract Slides 08:30 09:30 Uhr Sitzung V Neues aus den Studiengruppen Vorsitzende: Wolfgang Knauf, Frankfurt a.m. Ralph Naumann, Koblenz 08:30 08:50 DSMM (Deutsche Studiengruppe Multiples Myelom) Stefan Knop, Würzburg /61 08:50 09:00 Fragen zum Vortrag 09:00 09:20 GMMG (German-Speaking Myeloma Multicenter Group) Hartmut Goldschmidt, Heidelberg /65 09:20 09:30 Fragen zum Vortrag 09:30 09:45 Uhr Kaffeepause CV Abstract Slides 09:45 11:45 Uhr Sitzung VI Neue Aspekte zur Therapie des Multiplen Myeloms: Neuigkeiten vom Welt-Myelomkongress in Washington Vorsitzende: Igor Wolfgang Blau, Berlin, Dirk Jäger, Heidelberg 09:45 10:05 Lenalidomid Kai Neben, Heidelberg /69 10:05 10:15 Fragen zum Vortrag 10:15 10:35 Bortezomib Wolfgang Knauf, Frankfurt a. M /73 10:35 10:45 Fragen zum Vortrag 10:45 11:05 Thalidomid Ralph Naumann, Koblenz /77 11:05 11:15 Fragen zum Vortrag 11:15 11:35 Neue Phase - I/II- Substanzen Marc Raab, Heidelberg /81 11:35 11:45 Fragen zum Vortrag 13:30 14:30 Uhr Mittagessen CV Abstract Slides 14:30 15:30 Uhr Sitzung VIII Bisphosphonate beim Multiplen Myelom: neue Aspekte Vorsitzende: Anthony D. Ho, Heidelberg, Hans Salwender, Hamburg 14:30 14:50 Bisphosphonate beim Multiplen Myelom: warum, wann, wie lange, bei wem? Markus Munder, Heidelberg /95 14:50 15:00 Fragen zum Vortrag 15:00 15:20 Häufigkeit und Pathophysiologie von Osteonekrosen beim Multiplen Myelom Igor Wolfgang Blau, Berlin /99 15:20 15:30 Fragen zum Vortrag 15:30 Uhr Resümee Hartmut Goldschmidt, Heidelberg 11:45 12:00 Uhr Kaffeepause CV Abstract Slides 12:00 13:30 Uhr Sitzung VII Myelom und Niere Vorsitzende: Kai Neben, Heidelberg, Martin Zeier, Heidelberg 12:00 12:20 Pathophysiologie der Nierenerkrankung Martin Zeier, Heidelberg 12:20 12:30 Fragen zum Vortrag 12:30 12:50 Myelom und Niere aus der Sicht des Internisten Orhan Sezer, Berlin /87 12:50 13:00 Fragen zum Vortrag 13:00 13:20 Neue Dialyseverfahren Nils Heyne, Tübingen /91 13:20 13:30 Fragen zum Vortrag 6 7

4 Curriculum vitae Stefan Delorme Imaging in Multiple Myeloma: Current issues Stefan Delorme, Heidelberg, Germany 1987 Graduated from Medical School in Hannover, Approbation, Assumed German citizenship Resident in Internal Medicine, I. Medizinische Universitätsklinik Heidelberg 1988 Medical Dissertation (Dr. med.) Resident in Radiology, DKFZ Working group leader in CT and Ultrasonography Resident, Department of Radiology, Heidelberg University Resident in Radiology, DKFZ 1996 Board certification in Radiology, supervising physician and research fellow, DKFZ since.1998 Deputy chairman of the Derpartment of Radiology, DKFZ 1999 Habilitation and appointment as Associate Professor in Radiology (Heidelberg University) 1999 Appointment as Senior Teacher in the German Society of Ultrasound in Medicine (DEGUM) Working group leader in MRI Acting chairman of the Department of Oncological Diagnostics and Therapy, DKFZ Since 2003 Working group leader in Body and Musculoskeletal imaging Chairman of the Radiological section of the German Society of Ultrasound in Medicine (DEGUM) Since 2008 Acting chairman of the Department of Radiology, DKFZ Since 2008 President elect of the German Society of Ultrasound in Medicine (DEGUM) Still, the most widely used staging system is the one introduced by Durie and Salmon in 1975, where, besides blood and urine values, skeletal x-ray surveys (plain films) are used. From blood hemoglobin, immunoglobins, albumin and creatinine, and in urine the daily excretion of Bence-Jones protein are measured. The chief imaging criterion for staging is whether one or no lytic bone lesion is seen, or whether multiple lesions are present. Once more than one lesion are found, the patient will be stage III. With the International Staging System (ISS), beta-2 microglobulin and albumin are measured, but imaging plays no role. New imaging techniques whole-body computed tomography (CT), whole-body or spinal magnetic resonance imaging (MRI), positron emission tomography (PET) with 18-F-deoxyglucose (FDG) - have proven advantageous for imaging multiple myeloma: 1. All lesions leading to bone destructions visible on plain films will also be seen with CT or MRI. 2. CT and MRI will also show lesions which have not yet caused a destruction of mineralized bone, which extend beyond the confines of the bone, or which are primarily extraskeletal. While MRI will show intraosseous lesions irrespective of their location, CT will detect lesions mainly if they lie within fatty but not hematopoietic bone marrow. 3. MRI but not CT or plain films will reliably show a diffuse myeloma infiltration in the bone marrow, even if the cancellous bone is still preserved. This will only be depicted by CT if the bone is very osteoporotic. 4. CT of the entire skeleton can be performed within one minute in low-dose technique without effort for the patient and with a radiation dose comparable to plain films. 5. MRI is highly sensitive to any lesion and a normal MRI excludes lytic lesions, which could possibly be detected with CT or plain films. However, once a lesion is found with MRI, additional CT or plain films may be needed to assess alterations of mineralized bone and their impact on its stability. 6. FDG-PET is insensitive to diffuse bone marrow involvement but shows solid nodules if they are metabolically active. Despite its low sensitivity its value may lay in the detection of mainly active nodules, i.e. clinically relevant ones. A treatment response is mirrored in a reduction in FDG uptake which occurs earlier than a morphological shrinkage of lesions. It can be anticipated that plain films will be obsolete in near future, and it has already been replaced by whole-body CT in some centers. Nevertheless, new open questions have arisen. First, the imaging criteria for staging are still divergent. Second, there is disagreement which imaging techniques be used in future, and in which combination. Third, using more sensitive techniques will inevitably cause patients to be staged higher than they would if only plain films were used, but the consequences with regard to treatment are unclear. In particular, the relevance of diffuse infiltration patterns seen with MRI only is open. 8 9

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6 Curriculum vitae Marius Horger Imaging methods for diagnosing Multiple Myeloma standard and new approaches: Computed tomography Marius Horger, Tübingen, Germany Studies Human medicine study Universities Bucharest ( ) and Temeschburg ( ) 1982 Exam and licensure Professional training to General Practitioner (1 year Surgery, year Internal Medicine, 1 2 year Pediatrics) at the University Hospital Temeschburg Clinical activity Practice as General Practitioner Internal Medicine at the University Tübingen Professional training as a Radiologist: General Hospital Waiblingen Specialist for Radiology 2000 Job change to Department of Radiology of the Eberhard-Karls-University Hospital Tübingen (Chairman: Prof. C.D. Claussen) Areas of responsibility as Senior Physician 2001 Conventional and Digital Roentgen Diagnostic, Ultrasound, Colour/Power Doppler, Contrast-Enhanced Ultrasound, Angiography, CT, MRI, interventional Radiology, SPECT/CT Responsible for Radiologic Diagnostic -Internal Medicine Division- at the University Hospital Tübingen (Hematology&Oncology, Gastroenterology, Endocrinology, Cardiology, Emergency Unit, Medical Care, Transplantation Unit), SPECT/CT and PET/CT Multiple myeloma is a malignant hematologic disease which usually involves the bone marrow leading secondary to bone destruction. An optimal imaging tool should therefore provide information about both: extent of bone marrow infiltration and bone lysis. With the advent of multidetector row CT (MDCT) standardized investigational protocols using nonenhanced low-dose techniques are now available and suitable for staging, follow up and long-term response monitoring in patients with multiple myeloma (MM). What are the advantages of using CT-imaging over conventional X-ray- and MR-imaging? First of all, CT enables, contrary to MRI, assessment of bone destruction and/or remineralisation/remodelling in a way that is much more accurate compared to the current state of the art on this field (conventional X-ray technique). Thereby, the use of thin-collimation and sharp spatial reconstruction algorithms increases sensitivity of CT for detection of lytic bone lesions and allows depiction of sub millimeter tiny osteolysis. However, not all MM patients develop lytic bone lesions, and the occurrence of bone destruction is usually delayed compared to that of medullary lesions. Especially in patients presenting primarily with extramedullary disease or those with nonsecretory myeloma, this information is highly relevant for diagnosis. For this purpose, CT can also be used similarly to MRI for assessment of both medullary and extramedullary MM involvement. Whereas extramedullary myelomas are easily assessed even by nonenhanced CT, visualization of medullary myeloma is optimal particularly in the bony canals of the appendicular skeleton, being comparable with MRI. Moreover, due to age-dependent and osteoclasts-induced bony rarefaction in MM patients, even pelvic bones and the spine allow generally visualisation of their bone marrow cavities including myeloma cell infiltration, however, at the prise of a lower sensitivity compared with MRI. Recent developments of post processing software applications have made possible volumetric measurements of target medullary or extramedullary myeloma lesions as well as determination of their mean CT-attenuation values. Can assessment of statics be accomplished in a one-stop procedure together with myeloma monitoring? Accurate assessment of skeletal stability, fracture, or risk of fracture is given by every staging or monitoring whole-body nonenhanced low-dose CT investigation. What are the pros and the cons for the use of CT? The strengths of CT are: wide accessibility, short acquisition time (less than 30s) with consequently higher patient s acceptance, high reproducibility, easy appraisal, no need for IV contrast media administration, no contraindications and comparably low cost whereas the main limitation of CT in comparison with MRI is a slightly lower sensitivity for detection of myeloma lesions in the axial skeleton. How sensitive has myeloma imaging to be? At this point the importance of medullary lesions detected at staging by cross-sectional imaging techniques, contrary to that of lytic bone lesions, has yet to be ascertained. Can myeloma monitoring be reduced to assessment of only few target lesions analogous to RECIST? Knowing, that the evolutionary trends of all medullary lesions detected are always alike, even if growth and/or resolution kinetics sometimes prove slightly time-delayed, judgement of myeloma response to therapy could be accomplished by monitoring of few medullary target lesions. Unfortunately, the need for whole-body investigational protocols remains stringent, as according to our experience discrepant evolutions of extramedullary myeloma manifestations, especially during treatment with novel agents, is seen in up to 20% of the patients. Is joint (hematologic + imaging) monitoring in patients with MM beneficial? At this time, international guidelines do not recommend the routine use of cross-sectional imaging for follow up and response monitoring in MM patients. However, according to our experience, joint (hematologic + CT-imaging) monitoring yields more accurate results compared to each of these methods alone. Thus, the demand for available, payable imaging tools for more confident diagnosis of MM is expected to increase in the next future, particularly for monitoring effects of novel antimyeloma drugs

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8 Curriculum vitae Andrea Baur-Melnyk MR Imaging in multiple myeloma Andrea Baur-Melnyk, Munich, Germany Multiple myeloma is a typical bone marrow neoplasia of the elderly. In x-rays it is often difficult to detect the typical osteolyses in early stages or in regions where overlying structures hamper image analysis. Osteoporosis may be a sign of tumor infiltration, however it is difficult to distinguish from senile osteoporosis. Therefore more and more cross sectional methods replace the skeletal survey, which has been the standard imaging method for a long period of time Medical School, Ludwig-Maximilians-University of Munich 1996 MD thesis: Infiltration patterns of multiple myeloma in MRI with clinical and histopathological correlation. (magna cum laude) Residency and fellowship; Dept. of Clinical Radiology, University of Munich-Grosshadern 1999 Internship, Dept. of Hemato-Oncology, University of Munich-Grosshadern 2000 Continued Fellowship, Dept. of Clinical Radiology, University of Munich-Grosshadern 2003 Associate Professor Thesis: The Role of MRI for the diagnosis and prognosis in patients with multiple myeloma Section Chief - Dept. of Clinical Radiology, University Hospitals Munich- Campus Grosshadern In MRI 5 different infiltration patterns can be found: a normal looking bone marrow signal is found in patients with low grade interstitial infiltration with plasma cells (< 20 Vol % in bone marrow biopsy). In cases with significant infiltration in bone marrow a focal, a diffuse or a combined focal and diffuse infiltration pattern can be noted. In some patients a so called salt&pepper pattern can be detected. This is due to focal fat accumulations in bone marrow beside normal marrow with only sparse interstitial infiltration with myeloma cells. Contrast media can help in grading diffuse infiltration. A cutoff value of 40% signal increase has been found to be associated with significant myeloma infiltration. Perfusion imaging may detect early hypervascularisation. The most sensitive imaging method for multiple myeloma is MRI. With new scanners and coil devices a whole body Imaging approach can be made feasible within an acceptable scanning time. Whole body MRI is superior to conventional skeletal survey and whole body MDCT. This is explained by the fact that in MRI tumor accumulations can be displayed before any bony destructions have appeared. On the other hand, MDCT is the method of choice for displaying osteolyses and determining the fracture risk. Whole body MDCT can be performed with a low dose protocol using 120 KV and mas. The images should be reconstructed in the axial, in the coronal plane and the sagittal plane for the spine. It is mandatory to look at the pelvis and long bones in the bone and the soft-tissue window in order not to overlook infiltrates within the marrow cavity without cortical destructions. Durie and Salmon staging system created in 1975 is the most widely used clinical staging system. It combines laboratory and imaging data (x-rays). In 2003 the Durie and Salmon PLUS staging system has been released, which includes Whole body MRI and or PET-CT data. A grading of diffuse infiltration should be given and the focal infiltrations should be counted up to number of 20. The cut-off value for stage I versus stage II is > 5 lesions, the cut-off value for stage II versus stage III is 20 lesions

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10 Curriculum vitae Jens Hillengass Functional MR-imaging and prognosis Jens Hillengass, Heidelberg, Germany Education primary school (Pestalozzischule Liedoldsheim) grammar school (Gymnasium Neureut) Community service at the Diakonissenkrankenhaus (Hospital) Karlsruhe, Germany including 1 year training in nursing studies of medicine at the University of Heidelberg Professional experience 1999 Doctoral thesis in the laboratory of T.M. Moehler, M.D. (supervisor Prof H. Goldschmidt) at University of Heidelberg Dept. of Hematology/ Oncology/ Rheumatology, In cooperation with German Cancer Research Centre, Dept. of Radiology The thesis deals with the measuring of proangiogenic cytokines and local microcirculation in multiple myeloma since 2002 Internship at the Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Germany since 2007 Principle investigator (Heidelberg) of the OPTIMUM-Study since 2008 Gerok-Scholarship: Department of radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany Conventional magnetic resonance imaging (MRI) of the axial skeleton (spine and sacral bone) can be performed within reasonable time on all current MR-tomographs and has therefore found its way into routine examination of patients with multiple myeloma. In these patients plasma cell infiltration in bone marrow leads to diffuse, focal or variegated patterns in MRI. While focal lesions can be counted and measured easily in conventional MRI a diffuse infiltration pattern eludes objective quantification. So far only descriptive categories as mild or severe diffuse infiltration have been used in the classification of diffuse bone marrow involvement. Functional MRI techniques permit to gain more precise and, to a certain degree, quantifiable information of the examined tissue. Diffusion-weighted imaging (DWI) is a MRI technique which is sensitive to random water movements at spatial scales at a sub-millimeter range. The motion of water molecules is more restricted in tissues with a high cellular density associated with numerous intact cell membranes (e.g., tumor tissue). The lipophilic cell membranes act as barriers to motion of water molecules in both the extracellular and intracellular spaces. By contrast, in areas of low cellularity or where the cellular membranes have been breached, the motion of water molecules is less restricted. Experience has been gained for differentiating benign from pathologic vertebral compression fractures. Thereby diagnosis is based on the contrast to normal bone marrow. Hypo- or isointensity reflects acute benign collapse, whereas hyperintensity is indicative of the tumorous nature of a fracture. Apparent diffusion coefficients (ADC) acquired by DWI are significantly lower in metastatic disease than in bone marrow edema and bone marrow cellularity can be estimated. These two attributes make this imaging technique an excellent tool for patients with multiple myeloma. Currently investigations of DWI of the bone marrow in healthy controls as well as in patients with different stages of plasma cell disease are under way. First results show significant differences between these groups. Dynamic contrast-enhanced MRI (DCE-MRI) is a noninvasive technique for the detection of microcirculation in malignant tissues. It determines and visualizes changes of contrast enhancement after a constant flow-controlled intravenous infusion of Gadolinium-DTPA. Pharmacokinetic signal time curves are used to calculate microcirculation parameters amplitude A and exchange rate constant kep which serve as semi-quantitative parameters for blood volume and vascular permeability in the investigated tissue. To visualize the distribution of microcirculation parameters in the examined area a color coded pharmacokinetic map is superimposed onto the static MR image. High amplitude A is correlated with an increased micro vessel density in bone marrow and both DCE-MRI parameters are significantly increased in patients with active multiple myeloma compared to healthy controls. Furthermore it has been shown that a high level of amplitude A is an adverse prognostic factor in advanced multiple myeloma. Correlations with chromosomal aberrations revealed that several adverse cytogenetic abnormalities go along with increased microcirculation parameters. These new functional imaging techniques contribute to the assessment of disease activity in multiple myeloma and allow the investigation of pathophysiological mechanisms in vivo

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12 Curriculum vitae Ludwig G. Strauss Imaging methods for diagnosing multiple myeloma standard and new approaches: PET Ludwig G. Strauss, Heidelberg, Germany Academic Education Medical School, Justus-Liebig-Universität, Gießen Student of Mathematics, Justus- Liebig- Universität, Gießen 1976 Approbation 1978 M.D Board certified: Nuclear Medicine 1986 Board certified: Radiology 1986 Habilitation (Assistant Professor of Radiology) 1992 Appointment as Full Professor of Radiology Positions held Intern Resident, Internal Medicine, Medizinische Klinik (Clinic of Internal Medicine), St. Marien-Krankenhaus, Ludwigshafen Research Fellow, Institut für Nuklearmedizin (Institute of Nuclear Medicine), Deutsches Krebsforschungszentrum (German Cancer Research Center), Heidelberg Resident, Radiology, Institut für Klinische Radiologie (Institute of Clinical Radiology), Klinikum Mannheim, Ruprecht-Karls-Universität Heidelberg 1986 Supervising Physician, Institut für Klinische Radiologie (Institute of Clinical Radiology), Klinikum Mannheim, Ruprecht-Karls-Universität Heidelberg 1986 veni legendi (Assistant Professor), Ruprecht-Karls-Universität, Heidelberg Director, Medical PET Group - Biological Imaging, Associate Director, Abteilung für Onkologische Diagnostik und Therapie (Department of Oncologic Diagnosis and Therapy), Deutsches Krebsforschungszentrum (German Cancer Research Center), Heidelberg 2002 Director, Medical PET Group - Biological Imaging, Clinical Cooperation Unit Nuclear Medicine 1992 Full Professor of Radiology Positron emission tomography (PET) has found widespread use in the last twenty years for tumor diagnostics and treatment planning in oncological patients. The most frequently used radiopharmaceutical for PET is F-18-Deoxyglucose (FDG). FDG is transported into the cells and phosphorylated, but then trapped due to a very low dephosphorylation rate. If dynamic PET studies are performed, the tracer kinetics can be quantified by applying a two tissue compartment model: The model provides the transport constants k1, k2, the phosphorylation/dephosphorylation rates k3, k4 and vb, the fractional blood volume, also named vessel density. Besides the accurate quantification of the tracer kinetics state-of-the-art PET systems provide additionally static whole body images and PET/CT systems facilitate the comparison of morphology and function very easily. The use of PET and FDG in myeloma was reported first by Sasaki et al., who compared FDG PET with the conventional bone scanning (Sasaki et al 1993). The authors demonstrated that negative lesions in bone scan may be FDG positive in PET. Only a limited number of studies are published focusing on the application of PET in myeloma patients. Adam et al. applied PET with FDG in 49 patients primarily during the initial staging procedure and for the assessment of therapy response (Adam et al 2007). Overall, the authors emphasize the complementary role of FDG PET for the biological assessment of a lesion. A negative FDG PET was highly predictive for response to treatment. Only one patient with a negative FDG PET relapsed 12 months after the PET examination (Adam et al 2007). The aspect of the biological assessment of a lesion was also investigated by Durie et al (Durie et al 2002). The evaluation of 66 PET studies with FDG demonstrated, that FDG scans without a significant tracer accumulation significantly predicted response to treatment in more than 90 % of the patients (Durie et al 2002). MRI and PET/CT was investigated by Lin et al (Lin et al 2007). In conclusion, the authors emphasize that both methods contribute to the improvement of tumor diagnostics. Generally, MRI was more accurate regarding the bone marrow assessment, while PET/CT enhances the detection of extra osseous lesions. FDG PET/CT, Tc- 99m-MIBI, and MRI were compared by Fonti et al (Fonti et al 2008). Interestingly, PET identified slightly more lesions than MRI. However, MRI was performed in the pelvic region and the spine and not as a whole body examination. Based on the majority of studies reported in the literature, whole body MRI is the method of choice to assess patients with myeloma in order to obtain morphological information. PET with FDG should find additional use to assess the biological properties of lesions identified with MRI. In our own study in 19 patients (56 lesions) with myeloma we evaluated the predictive value of dynamic FDG PET using the progression free survival for reference. Patients with FDG uptake values with less than 4 SUV had a significantly longer progression free survival than patients with higher uptake values. The analysis of the compartment data revealed a comparable result for k3. Patients with a k3 of less than 0.07 had a longer progression free survival. The data show, that the intracellular phosphorylation of FDG, as represented by the compartment parameter k3, plays a key role regarding prognosis. Besides FDG other tracers have been used in myeloma patients to obtain specific information. Initial studies with C-11- choline direct to a higher sensitivity as compared to FDG (Nanni et al 2007). Other tracers are in development, which are directed to surface proteins or receptors. Overall, the combination of accurate morphological imaging followed by functional imaging to assess the biological aspects of lesions will help to improve both, tumor diagnostics and therapy management

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14 Curriculum vitae Bernard Klein Key note lecture The biology of Multiple Myeloma Bernhard Klein, Montpellier, France notes Diploma 1974 Engineer of the School of Mines of Paris 1980 PhD in Biomathematics, University Paris VII 1984 PhD in Biological Sciences, University Paris XI Professional qualifications Researcher INSERM Director of Research INSERM 2000 Professor of University-Hospital Practitioner in Haematology Professional activity Researcher at the Institute of Cancer and Immunogenetic (Villejuif, France) Researcher at the INSERM U236, then U291, Montpellier, France Director the Oncogenesis Laboratory, University of Nantes, Nantes Group leader, Institute of Molecular Genetics, Montpellier 1995 Head of the Unit for Cellular and Gene therapy, University Hospital of Montpellier Director of INSERM U Director of the Institute of Research In Biotherapy INSERM-CHU-University 2007 Director of INSERM U847 Committee Member of the Federation of Oncology Member of the Cellular Therapy Committee of French FDA Member of the national committee for cell and gene therapy 28 29

15 Curriculum vitae Arthur R. Bradwell Clinical evidence for monitoring of MM with serum free light chain assays Arthur R. Bradwell, Birmingham, United Kingdom I am currently honorary professor of Immunology at the University of Birmingham and the University Hospital and chairman of a university, spin-out, biotechnology company. My research interests are in cancer immunology, immunoassays and renal medicine. I have published over 300 papers, 5 books, each with 2 or more editions and hold several patents. I trained as a doctor at the University of Birmingham from 1963 to 1968, qualifying at the age of 22. I then progressed through a series of junior hospital jobs, with the intention of becoming a general physician. I obtained the board exams in internal medicine (MRCP) in 1971 and then spent three years in a research laboratory, investigating the new subject of plasma protein measurements in disease. This resulted in a life-long interest in antibodies, immunoassays and serum proteins. I returned to full-time hospital medicine and endocrinology, in 1975, as university lecturer to Sir Raymond Hoffenberg (who later became President of the Royal College of Physicians). Endocrinology was a rapidly developing subject in the 1970 s and my contribution was the development of the first immunoassay for thyroxine binding globulin. This was made using a novel technique and I took out a patent on the process. The University saw the value of the patent and set up a research unit within the Department of Immunology to develop novel antibodies and immunoassays with me as director and senior lecturer. This allowed me to expand my interest in immunology and coincided with the first studies on tumour imaging using radio-labelled antibodies (radio-immunodetection). Over 10 years, I ran a team of scientists investigating the use of antibodies for tumour detection and developed a variety of novel techniques including the first indium labelling of antibodies and the first antibody positron emission scans in collaboration with the physics department. In 1983, the university allowed my research unit to seek private funding and a spin-out biotechnology company was founded (The Binding Site Ltd). This has since grown from 3 people to over 500 world-wide with branches in California, Germany, France and Spain, while retaining close links with the department of immunology and the University hospital. During this period I developed the clinical immunology department into a regional service and one of the largest in the UK. Over the past few years I have developed novel clinical immunoassays using immune knock-out animal models that can produce high affinity, epitope-specific antibodies. This technology has been harnessed for making serum free light chain assays that are replacing Bence Jones protein tests in urine. These assays give better assessment of patients with myeloma kidney, allowing the use of protein leaking dialysers to prevent permanent renal failure. Tumour immunology has been a long term interest, commencing with detection of solid tumours using radio-labelled antibodies. From animal experiments, it was apparent that amino-acid substitutions in known peptide sequences could be used to break immune tolerance. This has lead to the successful treatment of patients with parathyroid tumours using modified human peptides. Successful collaboration with colleagues around the world, and particularly Professor Albert Beckers at the University of Liege, in Belgium, has allowed treatment of many patients. I have been at Birmingham University throughout my career. This has allowed close friendships with numerous colleagues, included some interested in mountaineering. I have organised and led a series of expeditions to the Himalayas and Andes to investigate the problems of acute mountain sickness and human adaptation to altitude. Results of these studies culminated in three papers in The Lancet, including the first controlled trial of acetazolamide in the successful prevention of mountain sickness. Future studies include expansion of the current immunotherapy studies to other tumour types and improved detection of monoclonal gammopathies using immunoassays. I have a team of more than 100 research and development scientists and lecture extensively at national and international meetings. Serum free light chains (FLCs), κ and λ are rapidly cleared through the renal glomeruli with a serum half-life of 2 6 hours and are then metabolised in the proximal tubules of the nephrons. Under normal circumstances, therefore, little protein escapes to the urine which remains negative when serum FLC concentrations have increased many-fold. Plasma cell tumours produce a monoclonal excess of only one of the FLC types, often with bone marrow suppression of the alternate FLC, so that κ/ λ ratios become highly abnormal. Accurate measurement of κ/ λ ratios underpins the utility of the serum FLC immunoassays and provides a numerical indicator of clonality. Early clinical studies were in patients with Bence Jones (light chain) MM. In studies, on 270 sera taken at the time of clinical presentation, highly abnormal serum FLC concentrations were found in every case. 3 4% of patients with MM have so called nonsecretory disease. Nevertheless, several studies showed that FLC tests identified monoclonal proteins in % of patients. Most patients with MM produce intact monoclonal immunoglobulins (IMIgs), yet FLCs are also abnormal in 95% of such patients at disease presentation. Interestingly, the serum concentrations of FLCs and IMIgs are not correlated (R = <0.02). Monoclonal serum FLCs are, therefore, independent markers of the disease process. This is of clinical importance when the tumour produces large amounts of FLCs and small amounts of IMIgs. Patients who are in apparent remission, as judged by study of their IMIgs, may still have residual disease as judged by elevated monoclonal FLCs. Using a similar argument, when these patients relapse, FLC concentrations may increase first. Free light chain, breakthrough, is thought to occur in up to 15% of patients who relapse after modern, intensive treatment. An additional feature of serum FLCs is that, in contrast to IMIgs, they are frequently nephrotoxic. In many patients with IMIgs the serum FLC concentrations are >1,000mg/L ( times normal). This is characteristic of patients with IgD MM but is also apparent in 10 15% of IgG and IgA producing patients. The assays now allow assessment of the prerenal load of monoclonal light chains. There is early evidence that in some patients, treatment should be aimed at normalising serum FLC concentrations in order to prevent renal damage. Furthermore, recent report documented recovery of 12/17 patients with myeloma kidney (cast nephropathy) and dialysis dependent acute renal failure following FLC removal by high cut-off hemodialysis. All patients who recovered renal function were alive 20 months after the commencement of the study, whereas the 5 who did not recover renal function all died, with a median survival of less than six months (P<0.02). The high sensitivity of serum FLC immunoassays for tumour detection suggests they have a role in screening for B cell dyscrasias. Currently, symptomatic patients are assessed using serum and urine protein electrophoretic tests. Since urine is frequently unavailable, it is logical to add serum FLC analysis to current test protocols. Several studies have now shown that the combination of serum FLC analysis with serum protein electrophoretic analysis removes the need for urine tests for Bence Jones protein. Indeed, if the choice is between serum FLCs and serum or urine IFE, then FLC tests are more useful. There is little, if any role for urine FLC analysis

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17 Curriculum vitae Andy C. Rawstron Monitoring Multiple Myeloma by Flow Cytometry (FACS) Andy C. Rawstron, Leeds, United Kingdom Andy Rawstron initially trained as an immunologist at Edinburgh University, before joining the Haematological Malignancy Diagnostic Service at Leeds. The HMDS laboratory is a multi-disciplinary unit that serves a population of 4 million, analysing approximately 20,000 specimens from leukaemia and lymphoma patients each year. Dr Rawstron developed and directs an outreach service to provide monitoring for individuals with haematological malignancies not requiring immediate treatment and heads the flow cytometry section for the diagnosis monitoring of mature B-cell disorders. He is a lead investigator for laboratory diagnostics on the MRC UK Myeloma IX trial and several UK CLL trials. His primary research area is the development of minimal disease detection assays for follow-up of patients and for diagnosis of early stages of disease and has been centrally involved in the identification and characterisation of MBL, a pre-cursor syndrome of CLL analogous to MGUS. The increasing efficacy of treatment for myeloma has led to improved complete remission (CR) rates and the need for more sensitive outcome measures. The concept of a stringent CR requires that the bone marrow plasma cells are polyclonal. Immunohistological approaches for clonality assessment are difficult to interpret and more objective approaches using flow cytometry or PCR are preferable. These can be sub-divided into qualitative and quantitative assays. The qualitative approaches, i.e. plasma cell Kappa:Lambda ratio by flow cytometry and consensus-primer IgH-PCR, are simple and cheap but highly dependent on the relative levels of neoplastic and normal B-cells. In a sample with no normal B-cells, qualitative techniques can detect residual disease at the level of 0.01%. However, in most individuals after effective treatment the regenerative normal B-cells and plasma cells represent 5-10% of leukocytes. In this setting qualitative approaches are unlikely to detect residual disease below the 0.5% level. Studies in other disorders, particularly CLL, have demonstrated that it is essential to use a quantitative approach. For flow cytometry this requires development of a disease-specific phenotype and for PCR the design of a specific primer for each patient (ASO-PCR). The key advantages of disease-specific flow cytometry are: i) Rapid and direct measurement of current tumour burden ii) High sensitivity, directly comparable to ASO-PCR to 0.01% iii) Improved prediction of outcome compared to immunofixation iv) Standard panel of markers applicable to >99% of patients v) Pre-treatment sample not essential to enable monitoring vi) Quantitative technique that also provides data on sample quality Quantitative PCR approaches can detect disease below the 0.01% level, although this is not necessarily clinically relevant. Patient-specific PCR approaches will also detect clonally-related B-cells. As it is still debatable whether these B-cells can contribute to disease relapse, it is not clear whether classifying such cells as residual disease increases or decreases prognostic power. The disadvantage of both flow cytometry and PCR is the potential for sampling error and the reduced disease levels in aspirate samples compared to trephine biopsy, although the current results clearly demonstrate better prediction of outcome than other response measures. Perhaps an optimal approach to monitoring myeloma would use sflc and measurement for early response assessment, flow cytometry and/or PCR to confirm and to assess efficacy after induction, consolidation and maintenance treatment cycles, with sflc plus paraprotein assessment for post-treatment monitoring. We have found the most cost-effective approach is to assess first by flow cytometry and confirm by PCR in cases with low levels of residual disease. The advent of six or more colours has greatly simplified flow cytometry analysis by allowing several plasma cell markers to be combined with disease-specific markers in a single tube. Basic clonality assessment can also be performed within the same test, although the most effective approaches is to maximise the numbers of disease-specific markers. In our experience MRD monitoring in myeloma has changed from being one of the most complex flow cytometry assays to a simple and readily reproducible test. Consensus approaches for analysis have been reported although further standardisation of MRD assessment would be beneficial to improve reproducibility across different clinical trials

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19 Curriculum vitae Paolo Corradini PCR-based diagnostics for minimal residual disease monitoring Paolo Corradini, Milano, Italy Education 1987 Medical Doctor degree, School of Medicine, University of Torino, Torino Italy 1992 National Board of Hematology, School of Medicine, University of Torino, Torino Italy Professional record Internal medicine training, Department of Internal Medicine, University of Torino 1988 Fellowship on Cancer Research, A. Bossolasco, University of Torino Italy 1989 Fellowship on Cancer Research, A. Bossolasco, University of Torino Italy Post-doctoral research fellow at Molecular and Cellular Biology Division, Department of Pathology, Columbia University, New York 1993 Fellowship on Minimal Residual Disease in Lymphoid Malignancies, European School of Hematology, Hopital Saint Louis, Paris France 1994 Visiting physician at the Bone Marrow Transplantation Unit, Dana-Farber Cancer Institute, Harvard Medical School, Boston Staff member, Department of Hematology and Bone Marrow Transplantation, University of Torino Italy Head, Hematological Malignancy Program, Dept. of Hematology and Bone Marrow Transplantation, Istituto Scientifico H.S. Raffaele Secretary, Chronic Leukemia Working Party, EBMT Head, Autologous Transplantation Section, Gruppo Italiano Trapianto di Midollo (GITMO) Associate Professor of Hematology, University of Milano 2001 present - Director, Division of Hematology and Bone Marrow Transplantation, Although multiple myeloma (MM) remains an incurable disease, there is no doubt that the panorama is rapidly changing. The recent discoveries of the pathogenetic mechanisms and novel therapeutic targets have enabled the design of new drugs that are being evaluated in clinical trials. Conceptually, achieving complete remission (CR) seems to be the first step to cure (Kyle et al, 1998; Lahuerta et al, 2000; Martinez-Lopez et al, 2007). Nonetheless, the present definition of CR in myeloma does not seem to be adequate. The classic method for establishing response is protein electrophoresis (EF) and the current criteria for defining CR is based on negative serum immunoglobulin immunofixation (IF) (Blade et al, 1998). Recently, the serum free light-chain (FLC) assay has been incorporated into the response criteria in patients with oligo-secretory or non-secretory myeloma (Durie et al, 2006). Improvements in MM patient treatment due to better transplantation strategies and the emerging novel therapies have led to the need for sensitive methods to detect the remaining tumor load or minimal residual disease (MRD), as well as methods which are easily applicable in large clinical studies. However, the definition of the best technique to detect the MRD and its clinical utility are still unresolved issues. There are preliminary evidences that MRD results are better predictors of outcome in myeloma than the presently used definition of hematologic CR. Stringently defined molecular CR can be obtained in a relatively high proportion of MM patients receiving allogeneic stem cell transplantation and in a smaller fraction of patients after undergoing autograft procedures (Corradini et al, 1999, Martinelli et al, 2000), a finding that suggests the existence of a beneficial immunological effect exerted by donor T cells present in the allograft. Real-time molecular follow-up can be used to monitor the graft versus myeloma (GVM) effect and that can be employed in the clinical setting to tailor post transplant immunomodulation (Voena et al 2003). Whether molecular CR actually represents a goal of the new treatments for MM and whether achieving a molecular CR correlates with the clinical outcome still remains to be formally demonstrated. Studies on larger series of patients are needed in order to confirm the prognostic relevance of MRD monitoring. Finally, in patients who remain persistently PCR+, a quantitative monitoring could be of value to identify a threshold level above which there is a significantly higher risk of clinical relapse and modulate immunotherapeutic approaches. So far, molecular MRD studies in MM have used the Ig heavy chain gene (IGH) rearrangements. Molecular tests based on ASO-PCR of the Ig heavy chain gene (IGH) rearrangements are methodologically complex, laborious and expensive and therefore difficult to apply as a routine MM patient follow-up technique (Billadeau et al, 1992; Raab et al, 2005; Sarasquete et al, 2005). In recent years, the study of MRD by multi-parametric flow cytometry (MFC) has proven to be of value in predicting outcome for different haematological malignancies including MM. It is still to assess whether MFC could be an optimal option for MRD evaluation in the practical patient management. MRD studies in the field of novel drugs are ongoing and will hopefully define the most appropriate methodology. Moreover prospective correlation of molecular results, flow cytometry, cytogenetics and clinical data, are required. Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy 2004 present - Chairman, Department of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy 2007 present - Full Professor of Hematology, University of Milano 2008 present - Director PhD School of Experimental Hematology, University of Milano 2008 present - President of the Italian Society for Experimental Hematology 38 39

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