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