MIELOMA MULTIPLO tumore delle plasmacellule producono immunoglobuline vivono nelle ossa DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI

MIELOMA MULTIPLOMIELOMA MULTIPLO

tumore delle plasmacelluletumore delle plasmacellule

producono immunoglobulineproducono immunoglobuline

vivono nelle ossavivono nelle ossa

DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY

Multiple myeloma• uncontrolled proliferation of Ig secreting plasma cells

– most commonly IgG (57%), IgA (21%) or light chain only (18%)• twice as common in men as women• and in blacks as whites• 1% of all cancers

– 2% in african americans• incurable• median survival 3 years

• few therapeutic advances since the introduction of melphalan (Bergsagel, 1962)

Myeloma bone pathology

Multiple Myeloma (MM)

• B-cell neoplasia, characterized by the expansion of plasma cells producing an abnormal monoclonal immunoglobulin

• 21,500 new cases yearly in Europe

• Median age at diagnosis: 65 years

• incurable disease

MM – Impact for PatientsConsequences of MM include:

• Painful osteolytic bone lesions

• Bone marrow infiltration, causing anemia, fatigue, and immunodeficiency, with an increased risk of serious infections

• The abnormal proteins may cause renal dysfunction or kidney failure

Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004

IL-1IL-1

OAFOAF

IL-6IL-6


hepatocytehepatocyte

CRPCRP

OSTEOCLASTOSTEOCLAST

DIVISIONE UNIVERSITARIA DI DIVISIONE UNIVERSITARIA DI EMATOLOGIAEMATOLOGIAAZIENDA OSPEDALIERA S. GIOVANNI AZIENDA OSPEDALIERA S. GIOVANNI BATTISTABATTISTATORINO, ITALYTORINO, ITALY


malattia dell'anzianomalattia dell'anziano

5/100.000/pazienti/anno5/100.000/pazienti/anno

350 pazienti/anno in Piemonte350 pazienti/anno in Piemonte

età media alla diagnosi 70 annietà media alla diagnosi 70 anni


Serum protein electrophoresis (SPEP)

albumin

Elevated total protein suggests hypergammaglobulinemia

Total protein= Albumin + Globulins


albumin

Elevated total protein suggests hypergammaglobulinemia

Total protein= Albumin + Globulins

Quantitative immunoglobulins

measures amount of IgM, IgG and IgA

in myeloma, typically see “reciprocal depression” of uninvolved Igs


albumin

Immunoeletrophoresis


albumin

Immunoeletrophoresis

SP

Immunofixation


SP

Immunofixation

IgG 57%IgA 21%IgD 1%IgM or IgE almost neverLight chain only 18%


SP

Immunofixation


M-spike stands for Monoclonal, not IgM


SP

Immunofixation



IgM, IgG and IgA are all gamma-globulins


SP

Immunofixation



Light chains (Bence-Jones proteins) are not detected in the serum, because of their low molecular weight, they are secreted in the urine

IgM, IgG and IgA are all gamma-globulins

Table 1 Multiple myeloma* Diagnostic criteria

1 Monoclonal plasma cells in the bone marrow 10% and/or presence of a biopsy-proven plasmacytoma2 Monoclonal protein present in the serum and/or urinea3 Myeloma-related organ dysfunction (1 or more)

[C] Calcium elevation in the blood (serum calcium >10.5 mg/l or upper limit of normal)[R] Renal insufficiency (serum creatinine >2mg/dl)[A] Anemia (hemoglobin o10 g/dl or 2 gonormal)[B] Lytic bone lesions or osteoporosisc

Myeloma - clinical features

bone pain - often with loss of height

constitutional - weakness, fatigue and weight loss

anemia - responds to erythropoeitin

renal disease -renal tubular dysfunction

susceptibility to infections - neutropenia, hypogammaglobulinemia)

hypercalcemia - myeloma cells secrete osteoclast activating factors

hyperviscosity - 2 % with myeloma, 50 % with macroglobulinemia

neurologic dysfunction - spinal cord or nerve root compression

Myeloma staging system cells x 10 /m

12 2

MedianSurvival(months)

Stage I No anemia >60 <0.6No hypercalcemiano more than one bony lesionlow M protein

Stage II in between I and III 41 0.6-1.2

Stage III Anemia 23 >1.2hypercalcemiaadvanced lytic bone diseasehigh M protein

Principles of treatment• no evidence that early treatment prolongs survival• wait for symptoms, or evidence of disease

progression to start treatment• supportive measures are critically important

– drink 3l of fluids daily– treat infections promptly– prophylactic bisphosphonates reduce skeletal cmplications– anemia responds to erythropoeitin

Causes of death in multiple myeloma

• Progressive myeloma 45%

• Sepsis 25%

• Renal failure 10%

• Other (old age) 20%

Treatment course

Asymptomatic

MGUSStable MM

Years Months Days

Treatment course

Asymptomatic

MGUSStable MM

Symptomatic

Years Months Days

Treatments

M protein

Treatment course

Asymptomatic

MGUSStable MM

Symptomatic Acute

PancytopeniaPlasma cell leukemia

Years Months Days

Treatments

M protein


trattato con blande chemioterapietrattato con blande chemioterapie

parzialmente chemiosensibileparzialmente chemiosensibile

il tumore si riduce ma dopo breve il tumore si riduce ma dopo breve intervallo riprende a crescereintervallo riprende a crescere



chemioterapiachemioterapia

Melphalan e Prednisone (MP)Melphalan e Prednisone (MP)

(Alexanian, 1969)(Alexanian, 1969)



100100

5050

36 mesi36 mesi

sopravvivenzasopravvivenza


MULTIPLE MYELOMAMULTIPLE MYELOMA

DOSEDOSE

RE

SP

ON

SE

RE

SP

ON

SE

Melphalan dose-response curveMelphalan dose-response curve

DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY


relazione dose-rispostarelazione dose-risposta

ALTA-DOSE =ALTA-DOSE = + risposte complete+ risposte complete

+ lunga sopravvivenza+ lunga sopravvivenza


RIDUZIONE DELLA TOSSICITA'RIDUZIONE DELLA TOSSICITA'DELLE TERAPIE AD ALTE DOSIDELLE TERAPIE AD ALTE DOSI

FATTORI DI CRESCITAFATTORI DI CRESCITA

CELLULE STAMINALI PERIFERICHECELLULE STAMINALI PERIFERICHE

tossicità comparabile alla terapia tossicità comparabile alla terapia convenzionaleconvenzionale

possibilità di trattare pazienti anzianipossibilità di trattare pazienti anziani

alte percentuali di risposte completealte percentuali di risposte complete

A PROSPECTIVE, RANDOMIZED TRIAL OF A PROSPECTIVE, RANDOMIZED TRIAL OF AUTOLOGOUS BONE MARROW AUTOLOGOUS BONE MARROW

TRANSPLANTATION AND CHEMOTHERAPY TRANSPLANTATION AND CHEMOTHERAPY IN MULTIPLE MYELOMAIN MULTIPLE MYELOMA

Sopravvivenza a 5 anniSopravvivenza a 5 anni 52% trapianto52% trapianto

12% convenzionale12% convenzionale

Attal, et al., NEJM, 1996Attal, et al., NEJM, 1996

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50 60 70

EFS TOT

MEL100

MP

Months

% o

f p

atie

nt s

p<0.001


0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50 60 70 80

OS TOT

Months

% o

f p

atie

nt s MEL100

MP

p<0.005


5555 6060 6565 7070

MULTIPLE MYELOMAMULTIPLE MYELOMAMULTIPLE MYELOMAMULTIPLE MYELOMA


AGEAGE

AGE AT DIAGNOSISAGE AT DIAGNOSIS


5555 6060 6565 7070

MULTIPLE MYELOMAMULTIPLE MYELOMAMULTIPLE MYELOMAMULTIPLE MYELOMA


AGEAGE

AGE AT DIAGNOSISAGE AT DIAGNOSIS

HIGH-DOSEHIGH-DOSE CONVENTIONALCONVENTIONAL

survivalsurvival%%

yearsyears

100100


MALATTIA INCURABILEMALATTIA INCURABILE

Relapsed Disease• Transient Response to Therapy• Survival 1-3 years

Multiple myelomaMultiple myeloma

Diagnosis• Survival 3-5 yrs

Relapsed andRefractory

• Resistant to all therapy• Universally fatal • Survival 6-9 months

Unmet

Medical Need


Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004


Advancing Treatment Options in MM

Melphalan From 1990sMyeloablation +

ASCT

1999First reportthalidomide

1962 Prednisone +

melphalan

Thalidomide Pharmion licence

Aus/NZ 2003


VELCADE® US licence 2003VELCADE® EU positive

opinion 2004

scenario

MULTIPLE MYELOMA

+


ThalidomideThalidomide

Originally developed in 1950s as a Originally developed in 1950s as a treatment for insomnia and morning treatment for insomnia and morning sickness in pregnancysickness in pregnancy

Thalidomide is an immunomodulatory Thalidomide is an immunomodulatory agentagent

– Precise mechanism of action not yet understoodPrecise mechanism of action not yet understood

– Multiple actions, including anti-angiogenic effectsMultiple actions, including anti-angiogenic effects

• Anti-angiogenic effects of thalidomide provide the rationale for its use in MM

• Angiogenesis in bone marrow supports growth and development of MM cells


Antitumor activity of thalidomide

in refractory multiple myeloma.Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P,

Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B.

N Engl J Med 1999 Nov 18;341(21):1565-71Myeloma and Lymphoma Program, South Carolina Cancer Center, University of South Carolina, Columbia, USA.

BACKGROUND: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. RESULTS: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the

mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively.

CONCLUSIONS: Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy

Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004, in Press DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIA

AZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY

Thalidomide: mechanism of action ??

Humanmyeloma

Humanliver

Thal

Thal

Humanmyeloma

~

reduced

unchanged

Yaccoby et Al, Blood, 2002

“Thal metabolism required for its anti-myeloma efficacy”


MELPHALAN, PREDNISONE + MELPHALAN, PREDNISONE + THALIDOMIDE (MPT)THALIDOMIDE (MPT)

versus

MELPHALAN PREDNISONE (MP)MELPHALAN PREDNISONE (MP)

GRUPPO ITALIANO PER LO STUDIO DEL MIELOMA GRUPPO ITALIANO PER LO STUDIO DEL MIELOMA MULTIPLOMULTIPLO

INTERIM ANALYSIS INTERIM ANALYSIS

PROSPECTIVE RANDOMIZED TRIALPROSPECTIVE RANDOMIZED TRIAL

NEWLY DIAGNOSED PATIENTS, NEWLY DIAGNOSED PATIENTS, AGE > 65 YEARSAGE > 65 YEARS


ADVERSE EVENTS

Hematologic (%)

Constipation (%)

Neurologic (%)

Cardiac (%)

Cutaneous (%)

Infection (%)

Thromboemb.(%)

Early death (%)

3-4 1-2 WHO (grade)MPTMPT MPMP

3-4 1-2

29

28

32

17

15

14

18

7

9

3

2

10

35

-

11

3

3

12

25

-

-

4

-

1

19

5

4

5DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY

RESPONSE TO THERAPYRESPONSE TO THERAPY

Dept. Hematology, University of Torino

0

20

40

60

80

100

MPT MP

PR (50-74)

PR (75-99)

CR + nCR

27.7%27.7%5.4%5.4%

33.8%33.8%

15.6%15.6%

13.3%13.3%

28%28%

77.1%77.1%

46.7%46.7%

% o

f R

esp

on

se%

of

Res

po

nse

EVENT-FREE SURVIVALEVENT-FREE SURVIVAL(median follow up 13.6 months)(median follow up 13.6 months)

0

0,2

0,4

0,6

0,8

1

0 5 10 15 20 25 30 35

MonthsMonths

Pro

po

rtio

nP

rop

ort

ion

p<0.001p<0.001

MPTMPT

MPMP


RESPONSE TO THERAPYRESPONSE TO THERAPY

10

20

30

% CR

MP Thal MP +Thal

27.7%27.7%


5% 3-5%

Revlimid ™ (lenalidomide)

(CC-5013)

Actimid™ (CC-4047)

NNHO O

O

NH2

NNH

O

O O

O

NH2

NNHO

O

O

O

Thalomid®

(thalidomide)

Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004, in Press

The Proteasome: A Target for Novel Therapies


TNFR

TNF

IkBp65

p50

IkBp65

p50

PP

PUb

IkBp65

p50

PP

P

p50

p65IkB

PP

PUb

Protein kinases

NFkB-IkB complex

IkBP

P

PUb

Degradation of IkB by 26S proteasome

TNFR

TNF

IkBp65

p50

IkBp65

p50

PP

PUb

IkBp65

p50

PP

P

p50

p65IkB

PP

PUb

IkBP

P

PUb

NFkB binding site

Protein kinases

NFkB-IkB complex

p65p50

NFkB Nuclear translocation

NFkB Induced proteins

Block of programmed cell death

Increase in Cytokine production

Increase in adhesion molecules


PS 341

TNFR

TNF

IkBp65

p50

IkBp65

p50

PP

PUb

IkBp65

p50

PP

P

p50

p65IkB

PP

PUb

NFkB binding site

Protein kinases

NFkB-IkB complex

p65p50







PS 341

TNFR

TNF

IkBp65

p50

IkBp65

p50

PP

PUb

IkBp65

p50

PP

P

p50

p65IkB

PP

PUb

NFkB binding site

Protein kinases

NFkB-IkB complex







PS 341p50

p65IkB

PP

PUb

p50

p65IkB

PP

PUb

TNFR

TNF

IkBp65

p50

IkBp65

p50

PP

PUb

IkBp65

p50

PP

P

p50

p65IkB

PP

PUb

Protein kinases

NFkB-IkB complex






PS 341p50

p65IkB

PP

PUb

p50

p65IkB

PP

PUb


TNFR

TNF

IkBp65

p50

IkBp65

p50

PP

PUb

IkBp65

p50

PP

P

p50

p65IkB

PP

PUb

Protein kinases

NFkB-IkB complex






PS 341p50

p65IkB

PP

PUb

p50

p65IkB

PP

PUb

Antimyeloma effect


SUMMIT (025):SUMMIT (025):A Phase II Study of VELCADEA Phase II Study of VELCADE™ (bortezomib) for ™ (bortezomib) for InjectionInjection in Patients With Relapsed and Refractory in Patients With Relapsed and Refractory Multiple MyelomaMultiple Myeloma

Paul G. Richardson,Paul G. Richardson,11 Bart Barlogie, Bart Barlogie,22 James Berenson, James Berenson,33 Seema Singhal, Seema Singhal,44 Ann Traynor, Ann Traynor,44 Sundar Sundar Jagannath,Jagannath,5 5 David Irwin,David Irwin,66 Vincent Rajkumar, Vincent Rajkumar,77 Gordan Srkalovic, Gordan Srkalovic,8 8 Melissa Alsina,Melissa Alsina,9 9 Raymond Alexanian,Raymond Alexanian,1010 David Siegel,David Siegel,1111 Robert Orlowski, Robert Orlowski,1212 David Kuter, David Kuter,13 13 Steven Limentani,Steven Limentani,1414 Dixie Esseltine, Dixie Esseltine,1515 Gretchen Gretchen Richards,Richards,1515 Michael Kauffman,Michael Kauffman,1515 Julian Adams, Julian Adams,1515 David P. Schenkein, David P. Schenkein,1515 and Kenneth C. Anderson and Kenneth C. Anderson11

11Dana-Farber Cancer Institute, Dana-Farber Cancer Institute, 22University of Arkansas, University of Arkansas, 33Cedars-Sinai Medical Center, Cedars-Sinai Medical Center, 44Northwestern University Medical Northwestern University Medical Center, Center, 55St Vincent’s Comprehensive Cancer Center, St Vincent’s Comprehensive Cancer Center, 66Alta Bates Cancer Center, Alta Bates Cancer Center, 77Mayo Clinic, Mayo Clinic, 88Cleveland Clinic Cleveland Clinic Foundation, Foundation, 99H. Lee Moffitt Cancer Center, H. Lee Moffitt Cancer Center, 1010M.D. Anderson Cancer Center, M.D. Anderson Cancer Center, 1111Carol G. Simon Cancer Center, Carol G. Simon Cancer Center, 1212University of University of North Carolina at Chapel Hill, North Carolina at Chapel Hill, 33Massachusetts General Hospital, Massachusetts General Hospital, 1414Charlotte Medical Clinic, Charlotte Medical Clinic, 1515Millennium Pharmaceuticals, Millennium Pharmaceuticals, IncInc

Median number of lines of Median number of lines of prior therapy = 6 (range prior therapy = 6 (range 2-15)2-15)

92% of patients received 92% of patients received at least 3 of the drug at least 3 of the drug therapies listed here therapies listed here (excluding stem cell (excluding stem cell transplant) transplant)

91% of patients were 91% of patients were refractory to the last prior refractory to the last prior therapytherapy

SUMMIT – Prior TherapySUMMIT – Prior Therapy

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%99.5%

92%

64%

81%83%

SUMMIT – Response Rates with SUMMIT – Response Rates with VELCADEVELCADE®® Alone Alone

35% response rate35% response rate

10% CR (IF+ and IF-)10% CR (IF+ and IF-)

28% CR+PR28% CR+PR

59% of patients SD59% of patients SDor betteror better

Mean duration of Mean duration of response 12 monthsresponse 12 months

4%

6%

18%

7%

24%

0%

5%

10%

15%

20%

25%35%

+-CR IF- CR IF+ PR MR SD

Prior treatment had no significant effect on response ratePrior treatment had no significant effect on response rate DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY

Treatment plan Treatment plan –– APEX APEX

273 treatment days 280 treatment days

1.3 mg/m2 IV pushDays 1, 4, 8, 11 Q3W cycle

8 cycles

1.3 mg/m2 IV pushDays 1, 8, 15, 22 Q5W cycle

4 cycles

3 cycles 5 cycles

40 mg po Days 1–4, 9–12, 17–20 Q5W cycle

40 mg po Days 1–4 Q4W cycle

Randomization

Bortezomib Dexamethasone

Induction

Maintenance

Richardson et al. NEJM 2005Richardson et al. NEJM 2005

APEX: Time to Progression (n=669)APEX: Time to Progression (n=669)78% improvement in median TTP with bortezomib78% improvement in median TTP with bortezomib

Median TTP: Bortezomib 6.2 months vs dexamethasone 3.5 monthsRichardson et al. NEJM 2005Richardson et al. NEJM 2005

APEX: Response rates (CR, PR)APEX: Response rates (CR, PR)

Median time to response (TTR)– 43 days in both armsDuration of response– Bortezomib 8.0 months– Dexamethasone 5.6 months– Median follow-up ~8.3 months

<1% nCR 25% PR

16% PR7% nCR6% CR

Bortezomib Dexamethasone

Res

po

nse

(%

)

38%

18%

P<.0001

0

10

20

30

40

50

60

70

80

90

100

<1% CR


APEX: 1-year survival (n=669)APEX: 1-year survival (n=669)

41% decreased risk of death with bortezomib41% decreased risk of death with bortezomib

80%

66%


APEX: Overall survival (n=669)APEX: Overall survival (n=669)

Median duration of follow-up 8.3 months


ConclusionConclusion

Phase III APEX:Phase III APEX:

Bortezomib demonstrated superior efficacy to high-Bortezomib demonstrated superior efficacy to high-dose dexamethasone in relapsed MMdose dexamethasone in relapsed MM

– Significant TTP benefit (Significant TTP benefit (PP<.0001)<.0001)

– Response rate advantage (Response rate advantage (PP<.0001)<.0001)

– Superior 1-year survival (Superior 1-year survival (PP=.0005, HR=.53)=.0005, HR=.53)

– Superior overall survival (Superior overall survival (PP=.0013, HR=.57)=.0013, HR=.57)


Most common adverse events from Most common adverse events from Phase I, SUMMIT, CREST and APEX trialsPhase I, SUMMIT, CREST and APEX trials

Adverse eventAdverse event Phase IPhase I11 SUMMITSUMMIT22 CRESTCREST33 APEXAPEX44

(%)(%) (%)(%) (%)(%) (%) (%)

Thrombocytopenia Thrombocytopenia 7474 4040 3030 35 35

FatigueFatigue 5959 4141 7070 42 42

NauseaNausea 5252 5555 5454 57 57

DiarrheaDiarrhea 3737 4444 4444 57 57

Constipation Constipation 3030 1616 3737 42 42

VomitingVomiting 3030 2727 NRNR 35 35

Peripheral neuropathyPeripheral neuropathy 1919 3131 4141 36 36

NR = not recorded11Orlowski Orlowski et alet al. . J Clin OncolJ Clin Oncol 2002;20:4420; 22Richardson Richardson et alet al. . N Engl J MedN Engl J Med 2003;348:2609; 2003;348:2609;

33Jagannath Jagannath et alet al. . Br J HematolBr J Hematol 2004;127:165; 2004;127:165; 44Richardson Richardson et alet al. ASH 2004 (abstract 336.5). ASH 2004 (abstract 336.5)

Toxicities were predictable and manageableToxicities were predictable and manageable

Combinations therapiesCombinations therapies in Multiple Myeloma in Multiple Myeloma

Bortezomib + Thalidomide Bortezomib + Thalidomide +/- cytotoxic drugs+/- cytotoxic drugs

M-C

OM

PO

NE

NT

induction

High dose

relapse

remission

Dana FarberDana FarberRichardsonRichardsonPhase II VELCADE alone in 1st linePhase II VELCADE alone in 1st line tx tx

CHU de CHU de NantesNantes

HarousseauHarousseauPhase II VELCADE + high-dose Phase II VELCADE + high-dose dexamthasone 1st line, pre-transplantdexamthasone 1st line, pre-transplant

LocationLocationPIPIStudyStudy

ECOG/CTEPECOG/CTEPDispenzieriDispenzieriPhase II VELCADE in high risk myeloma, 1st Phase II VELCADE in high risk myeloma, 1st lineline

U. MarylandU. MarylandBadrosBadrosPhase I/II VELCADE + DT-PACE, 1st linePhase I/II VELCADE + DT-PACE, 1st line

CALGBCALGBOrlowskiOrlowskiPhase II VELCADE + DoxilPhase II VELCADE + Doxil

U. ArkansasU. ArkansasBarlogieBarlogiePhase II VELCADE + Total Therapy III in high Phase II VELCADE + Total Therapy III in high risk myeloma 1st linerisk myeloma 1st line

Salick GroupSalick GroupJagannathJagannathPhase II VELCADE Phase II VELCADE monotxmonotxDex after 2 cycles for less than optimal Dex after 2 cycles for less than optimal responseresponse

Multiple Myeloma Studies in Development:Multiple Myeloma Studies in Development:Front LineFront Line

AUTOLOGOUS FIRST STEP

Thalidomide

Proteasomeinhibitors

MULTIPLE MYELOMA

Mini allo


Thalidomide Proteasomeinhibitors

MULTIPLE MYELOMA


Chemo LanilomideLanilomide

Documents

MIELOMA MULTIPLO tumore delle plasmacellule producono immunoglobuline vivono nelle ossa DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI