1. Fifty Years of Progress and the Future of Myeloma CP1123175-1 Myeloma Research Roundtable Scottsdale, Arizona March 21, 2014 Robert A. Kyle, MD Scottsdale, Arizona Rochester, MinnesotaJacksonville, Florida

2. Disclosures for Robert A. Kyle None Related to this presentation.

4. Multiple Myeloma Cecil Textbook of Medicine 7 th Ed., 1948

5. CP1143748-20 Lancet 2:388, 1947

6. CP1143748-23

7. Survival from Onset of Treatment of Multiple Myeloma Surviving (%) Months Placebo Blood 27(3):335, March 1966 Urethane CP1143748-24

8. Electrophoresis Discovered 4 bands in horse serum, 1937 – albumin, α, β, γ Rejected by Biochemical Journal Published in Transactions of the Faraday Society Arne Tiselius

9. Electrophoresis Cost: $5,000 One technician, 1 day, 1 patient 1951 Kunkel & Tiselius – filter paper electrophoresis

10. Studies on Conditions Associated with Disturbed Gammopathies Globulin Formation CP1118008-5 Jan Waldenström Department of Medicine, University of Lund General Hospital, Malmõ, Sweden Jan Waldenström Department of Medicine, University of Lund General Hospital, Malmõ, Sweden One of the important happenings in clinical, chemical pathology, and thus in medicine generally, has been the introduction of better methods for the fractionation of serum proteins. The old method of electrolyte precipitation was followed by the free electrophoresis of Tiselius (1937) in Uppsala, permitting… Harvey Lectures 56:211, 1961

11. Gammopathy Concept Monoclonal – Malignant or potentially malignant Polyclonal – Reactive or inflammatory

12. CP1222613-1 so easy it seemed Once found, which Yet unfound most Would have thought Impossible. so easy it seemed Once found, which Yet unfound most Would have thought Impossible.

13. Jan Waldenström and Robert Kyle

14. Treatment of Multiple Myeloma CP1143748-22 L-sarcolysin (L-phenylalanine mustard) (Melphalan) (Alkeran) Blokhin et al, 1958 Bergsagel et al, 1962 Blokhin et al, 1958 Bergsagel et al, 1962

15. Multiple Myeloma Single (M/P) vs Combination Chemotherapy (CCT) CP1123175-33 TherapyResponse (%) M/P53 CCT60 P<0.00001 No difference in survival No subsets with benefit TherapyResponse (%) M/P53 CCT60 P<0.00001 No difference in survival No subsets with benefit n=4,930 (20 trials)

16. Novel Agents High Dose Therapy with stem cell transplant High Dose Therapy with stem cell transplant Thalidomide Thalidomide Bortezomib (Velcade) Bortezomib (Velcade) Lenalidomide (Revlimid) Lenalidomide (Revlimid)

17. Multiple Myeloma Novel Agents Pomalidomide (Pomalyst)CC-4047 Carfilzomib (Kyprolis)PR-171

18. Multiple Myeloma Novel Agents Proteosome inhibitor (oral/IV)MLN-9708 Proteosome inhibitor (oral)NPI-0052 ElotuzumabBendamustine Histone deacetylase inhibitorVorinostat (SAHA) Histone deacetylase inhibitorPanobinostat

19. CP1315995-1 Multiple Myeloma 1971-2006 n=2,981 Proportion surviving Time from diagnosis (months) Kumar et al: Blood 111:2516, 2008 Diagnosis after 1996 Diagnosis during/ before 1996 P<0.001 Survival, med 44.8 mo Survival, med 44.8 mo Survival, med 29.9 mo Survival, med 29.9 mo

20. Multiple Myeloma Mayo Patients 2001-2005 2006-2010 47% 66% P < 0.0001 S. Kumar, 2012

21. Future Imperfect RightWrong Correct population estimate Underwater homes Nuclear powerCars and boats on compressed air Household robotsMoon colonies Missed the internet Boredom from lack of work Scientific American, March 2014 Isaac Asimov 1964 Predictions

22. Pneumococcal Pneumonia 1939 Lobar pneumonia Lobar pneumonia High fever, cough High fever, cough Resolution of fever or death Resolution of fever or death Need more potent Pneumococcal antisera Need more potent Pneumococcal antisera

24. Fleming and Penicillin Contaminated Petrie dish by Staphylococcus and fungusContaminated Petrie dish by Staphylococcus and fungus Fleming identified PenicillinFleming identified Penicillin Unable to successfully extractUnable to successfully extract adequate quantities adequate quantities

25. Discovery of Penicillin “I had noticed the anti-bacterial effect of fungi by chance but Duchesne did so by methodic investigations.” Sir Alexander Fleming Kyle RA and Shampo MA. JAMA 241:1886, 1979.

27. Discovery of Penicillin Professor Gabriel Roux advised the study of competition of cultures of bacteria and fungi. Duckett S. Lancet 354:2068, 1999.

28. Discovery of Penicillin Guinea pigs inoculated with E. coli or S. typhi Saline injectionDeath Penicillin glaucum Survival Kyle RA and Shampo MA. JAMA 248:847, 1978. 1896

29. Discovery of Penicillin “ We hope that the pursuit of these studies on the vital competition for life between fungi and microbes that we have only begun here, and for which we do not pretend to have made more than a small contribution, may result in the discovery of other facts useful and applicable to prophylactic hygiene and therapy.” “ We hope that the pursuit of these studies on the vital competition for life between fungi and microbes that we have only begun here, and for which we do not pretend to have made more than a small contribution, may result in the discovery of other facts useful and applicable to prophylactic hygiene and therapy.” Ernest Duchesne Ernest Duchesne Duckett S. Lancet 354:2068, 1999. 1897

30. kyle.robert@mayo.edu