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Fifty Years of Progress and the Fifty Years of Progress and the Future of MyelomaFuture of Myeloma
CP1123175-1
Myeloma Research RoundtableMyeloma Research RoundtableScottsdale, ArizonaScottsdale, Arizona
March 21, 2014March 21, 2014Robert A. Kyle, MDRobert A. Kyle, MD
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida
Disclosures for Robert A. KyleDisclosures for Robert A. Kyle
None Related to this presentation.None Related to this presentation.
Multiple Myeloma
Cecil Textbook of Medicine 7th Ed., 1948
CP1143748-20
Lancet 2:388, 1947Lancet 2:388, 1947
CP1143748-23
Survival from Onset of Treatment of Survival from Onset of Treatment of Multiple MyelomaMultiple Myeloma
0
20
40
60
80
100
0 10 20 30 40 50
Surviving(%)
Surviving(%)
MonthsMonths
PlaceboPlacebo
Blood 27(3):335, March 1966Blood 27(3):335, March 1966
UrethaneUrethane
CP1143748-24
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
Electrophoresis
• Cost: $5,000
• One technician, 1 day, 1 patient
• 1951 Kunkel & Tiselius – filter paper electrophoresis
Studies on Conditions Associated with Disturbed Gammopathies Globulin Formation
CP1118008-5
Jan Waldenström
Department of Medicine, University ofLund General Hospital, Malmõ, Sweden
Jan Waldenström
Department of Medicine, University ofLund 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…
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, 1961Harvey Lectures 56:211, 1961
Gammopathy Concept
• Monoclonal – Malignant or potentially malignant
• Polyclonal – Reactive or inflammatory
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.
Jan Waldenström and Robert Kyle
Treatment of Multiple MyelomaTreatment of Multiple Myeloma
CP1143748-22
L-sarcolysin (L-phenylalanine mustard) (Melphalan) (Alkeran)L-sarcolysin (L-phenylalanine mustard) (Melphalan) (Alkeran)
Blokhin et al, 1958Bergsagel et al, 1962Blokhin et al, 1958Bergsagel et al, 1962
Multiple MyelomaMultiple MyelomaSingle (M/P) vs CombinationSingle (M/P) vs Combination
Chemotherapy (CCT)Chemotherapy (CCT)
CP1123175-33
Therapy Response (%)
M/P 53
CCT 60
P<0.00001
No difference in survival
No subsets with benefit
Therapy Response (%)
M/P 53
CCT 60
P<0.00001
No difference in survival
No subsets with benefit
n=4,930 (20 trials)n=4,930 (20 trials)
Novel AgentsNovel Agents
• High Dose Therapy with High Dose Therapy with stem cell transplantstem cell transplant
• ThalidomideThalidomide
• Bortezomib (Velcade)Bortezomib (Velcade)
• Lenalidomide (Revlimid)Lenalidomide (Revlimid)
Multiple Myeloma Multiple Myeloma Novel AgentsNovel Agents
Pomalidomide (Pomalyst)Pomalidomide (Pomalyst) CC-4047CC-4047
Carfilzomib (Kyprolis)Carfilzomib (Kyprolis) PR-171PR-171
Multiple Myeloma Multiple Myeloma Novel AgentsNovel Agents
Proteosome inhibitor (oral/IV)Proteosome inhibitor (oral/IV) MLN-9708MLN-9708
Proteosome inhibitor (oral)Proteosome inhibitor (oral) NPI-0052NPI-0052
ElotuzumabElotuzumab
BendamustineBendamustine
Histone deacetylase inhibitorHistone deacetylase inhibitor Vorinostat Vorinostat (SAHA)(SAHA)
Histone deacetylase inhibitorHistone deacetylase inhibitor PanobinostatPanobinostat
CP1315995-1
Multiple Myeloma 1971-2006Multiple Myeloma 1971-2006n=2,981n=2,981
0.0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80 100 120 140
Pro
po
rtio
n s
urv
ivin
gP
rop
ort
ion
su
rviv
ing
Time from diagnosis (months)Time from diagnosis (months)
Kumar et al: Blood 111:2516, 2008Kumar et al: Blood 111:2516, 2008
Diagnosis after 1996Diagnosis after 1996
Diagnosis during/before 1996
Diagnosis during/before 1996
P<0.001P<0.001
Survival, med44.8 mo
Survival, med44.8 mo
Survival, med29.9 mo
Survival, med29.9 mo
Multiple MyelomaMayo Patients
2001-2005
2006-2010
47%
66%P < 0.0001
S. Kumar, 2012
Future ImperfectFuture Imperfect
Right Wrong
• Correct population estimate
• Underwater homes
• Nuclear power • Cars and boats on compressed air
• Household robots • Moon colonies
• Missed the internet
• Boredom from lack of work
Scientific American, March 2014
Isaac Asimov 1964 Predictions
Pneumococcal PneumoniaPneumococcal Pneumonia19391939
• Lobar pneumoniaLobar pneumonia
• High fever, coughHigh fever, cough
• Resolution of fever or deathResolution of fever or death
• Need more potent Pneumococcal Need more potent Pneumococcal antiseraantisera
Fleming and PenicillinFleming and Penicillin
• Contaminated Petrie dish byContaminated Petrie dish byStaphylococcus and fungusStaphylococcus and fungus
• Fleming identified Penicillin Fleming identified Penicillin • Unable to successfully extract Unable to successfully extract
adequate quantitiesadequate quantities
Discovery of PenicillinDiscovery of Penicillin
““I had noticed the anti-bacterial effect I had noticed the anti-bacterial effect of fungi by chance but Duchesne didof fungi by chance but Duchesne did
so by methodic investigations.”so by methodic investigations.”
Sir Alexander FlemingSir Alexander Fleming
Kyle RA and Shampo MA. JAMA 241:1886, 1979.Kyle RA and Shampo MA. JAMA 241:1886, 1979.
Discovery of PenicillinDiscovery of Penicillin
Professor Gabriel Roux advised the Professor Gabriel Roux advised the study of competition of cultures of study of competition of cultures of
bacteria and fungi.bacteria and fungi.
Duckett S. Lancet 354:2068, 1999.Duckett S. Lancet 354:2068, 1999.
Discovery of PenicillinDiscovery of Penicillin
Guinea pigs inoculated with E. coli or S. typhiGuinea pigs inoculated with E. coli or S. typhi
Saline injectionSaline injection DeathDeath
Penicillin glaucum Penicillin glaucum Survival Survival
Kyle RA and Shampo MA. JAMA 248:847, 1978.Kyle RA and Shampo MA. JAMA 248:847, 1978.
1896
Discovery of PenicillinDiscovery of Penicillin
“ “ We hope that the pursuit of these studies on the We hope that the pursuit of these studies on the vital competition for life between fungi and vital competition for life between fungi and microbes that we have only begun here, and for microbes that we have only begun here, and for which we do not pretend to have made more which we do not pretend to have made more than a small contribution, may result in the than a small contribution, may result in the discovery of other facts useful and applicable to discovery of other facts useful and applicable to prophylactic hygiene and therapy.”prophylactic hygiene and therapy.”
Ernest DuchesneErnest DuchesneDuckett S. Lancet 354:2068, 1999.Duckett S. Lancet 354:2068, 1999.
1897
kyle.robert@mayo.edu
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