Federica Cavallo Divisione di Ematologia, Universita’ di Torino Terapia nei pazienti non candidati...

Federica CavalloDivisione di Ematologia, Universita’ di Torino

Terapia nei pazienti non candidati a trapianto

The Mediterranean School ofOncology

LLC e MM oggi: un paradigma per nuovi standard nelle patologie ematologiche

Orvieto, 20-21 Novembre, 2009

Multiple MyelomaMultiple Myeloma

ASL TORINO: 902.000 peopleASL TORINO: 902.000 people

INCIDENCE:INCIDENCE: 1974: 1974: 5.9/100.0005.9/100.000

2002: 2002: 8.9/100.0008.9/100.000

Median age at diagnosis: Median age at diagnosis: 69.4 years69.4 years

31%31%

33%33%

36%36%

65-75 years65-75 years25-64 years25-64 years

75-101 years75-101 yearsRegione Piemonte, Assessorato Sanità 2006,15

Survival outcomes for multiple myelomaSurvival outcomes for multiple myeloma

Age at diagnosis

Years Mortality Ratio Increased ratio

0-40 1.00 (ref.)

41-50 1.27 27%

51-60 1.50 18%

61-70 1.96 31%

71-80 2.42 23%

81 3.40 40%Kristinsson SY, et al. J Clin Oncol. 2007;25:1993-9.

60 years 60 years 4-year survival 4-year survival 70 years70 years 3-year survival3-year survival

OS From Time of Diagnosis in 6-yr Intervals Based on Date of Diagnosis

Kumar SK et al. Blood. 2008; 111: 2516

1971–76

1994–00

1989–94

1977–82

2001–06

1983–88

TimeTime0 20 40 60 80 100 120 140

Su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al

Facon T et al. Blood. 2006; 107:1292

MP vs Dexamethasone-Based Regimens MP vs Dexamethasone-Based Regimens (IFM 95-01 Trial) (IFM 95-01 Trial)

488 patients aged 65-75 yr (median 70) randomized to MP, MD, D, or D-IFN (12 courses at 6-wk intervals)

FU 82.8 mo, OS 35.0 mo (415/488), EFS 18.3 mo (473/488) for whole series

Standard MP gold standard for treatment of older pts

Regimen MP MD D D-IFN

n 109 110 109 101

≥PR↓ (P<0.001) 51%51% 74%74% 40%40% 42%42%

CR (P=NS) 1%1% 3%3% 1%1% 1%1%

EFS (mo) 21.1 21.1 ± 1.7± 1.7 22.9 22.9 ± 2.0± 2.0 12.2 12.2 ± 1.0*± 1.0* 15.2 15.2 ± 2.7*± 2.7*

OS (mo) 34.0 34.0 ± 3.6± 3.6 39,6 39,6 ± 3.1± 3.1 33.4 33.4 ± 2.0± 2.0 32.0 32.0 ± 5.3± 5.3

*P<0.001 for pts not receiving Melphalan

Thal/Dex vs MP Thal/Dex vs MP in newly diagnosed MMin newly diagnosed MM

274 patients, median age 72 yr

Median follow-up: 28.1 monthsMedian follow-up: 28.1 months

Thal 200 mg/d, Dex 40 mg (odd: d 1–4, 15–18; even: d 1–4), Thal 200 mg/d, Dex 40 mg (odd: d 1–4, 15–18; even: d 1–4),

Melphalan 0.25 mg/kg/d (d 1–4) + prednisone 2 mg/kg, d 1–4, q 4–6 Melphalan 0.25 mg/kg/d (d 1–4) + prednisone 2 mg/kg, d 1–4, q 4–6 wkswks

0.074325PFS (months)

0.4551%68%> PR

58

15%

MP

(n=138)

0.02945OS (months)

0.00131%CR/nCR

P valueThal/Dex

(n=136)Results

Ludwig H, et al. Blood. 2009 13(15):3435-42.

RegimenRegimen nn CR+PR (%)CR+PR (%) CR (%)CR (%) PFS/EFSPFS/EFS OSOS ReferenceReference

Thal/MPThal/MP vs vs MP MP

129129

126126

76 76

4848

16 16

44

21.821.8

14.514.5

45m 45m

47.6m47.6m

Palumbo Palumbo et alet al..Blood Blood 2008; 2008; 112112:3107-14:3107-14

Thal/MP vs Thal/MP vs MP vs MP vs

MEL 100MEL 100

191191

124124

121121

76 76

35 35

6565

1313

22

1818

27.5m27.5m

17.8m17.8m

19.4m19.4m

51.6m51.6m

33.2m33.2m

38.3m38.3m

Facon,Facon, et al. et al.LancetLancet 2007; 2007; 370:1209–18370:1209–18

Thal/MP vsThal/MP vs

MP (>75y)MP (>75y)

113113

116116

6262

3131

77

11

24.1m24.1m

19m19m

45.3m45.3m

27.7m27.7m

Hulin, Hulin, et alet al..J Clin Oncol 2009; J Clin Oncol 2009;

27:3664-7027:3664-70

Thal/MP*Thal/MP* vs vs MPMP

363 363 totaltotal

4242

2828

66††

33††

20m20m

18m18m

29m29m

33m33m

Gulbrandsen et Gulbrandsen et al. EHA 2008 al. EHA 2008

(Abstract 209)(Abstract 209)

Thal/MPThal/MP vs vs MPMP

152152

149149

6666

4747

22

22

EFS EFS 13m13m vs 9m vs 9m

PFS PFS 13m13m vs 10m vs 10m

37m37m

30m30m

Wijermans Wijermans et alet al. . ASH 2008 ASH 2008

(Abstract 649)(Abstract 649)

*Thal doses: 200–400 mg †CR + nCR

Summary of MPT phase 3 trials in the upfront settingSummary of MPT phase 3 trials in the upfront setting

In 5/5 studies, MPT was superior to MP in terms of PFS and/or TTP.In 2/5 studies, MPT was superior to MP in terms of OS.

Grade 3-4 Grade 3-4 Adverse Events Adverse Events

0 10 20 30

Early deaths*

Dermatologic

Cardiac

Infection

Neurologic

Thrombosis

Hematologic

Patients (%)

MPT (n=167) MP (n=164)

PP = .0002 = .0002

PP = .0001 = .0001

PP = .03 = .03

PP = .009 = .009

PP = .006 = .006

*MPT: 4 infection, 2 cardiac, 3 progression

MP: 1 infection, 1 progression

MRC Myeloma IX studyMRC Myeloma IX study

– Non-intensive arm: Non-intensive arm: MP vs. attenuated CTD prior to MP vs. attenuated CTD prior to maintenance randomizationmaintenance randomization

– Thalidomide maintenanceThalidomide maintenance: : •initiated at the end of induction in the non-intensive initiated at the end of induction in the non-intensive arm; 100mg daily until relapsearm; 100mg daily until relapse • median age 73 non-intensivemedian age 73 non-intensive

Morgan et al. ASH 2008 (abstract 656)

CTDaCTDa

(n=120)(n=120)

MPMP

(n=113)(n=113)

CRCR 22.5%22.5% 6%6%

≥≥VGPRVGPR 47.5%47.5% 9.5%9.5%

≥ ≥ PRPR 82.5%82.5% 49%49%

Morgan et al. ASH 2007 (Abstract 3593)

Intensive pathway: significant benefit of maintenance in patients with less than a VGPR post initial induction (p=.007)

PFS difference did not translate into survival benefit because survival after progression in PR patients receiving maintenance thalidomide was poor (p=.002)

Non-intensive pathway: similar but less pronounced effect of thalidomide maintenance on PFS

Although thalidomide maintenance may improve PFS, there is no demonstrable benefit on OS

EfficacyEfficacy

VISTA:VISTA: VVELCADE as ELCADE as IInitial nitial SStandard tandard TTherapy in multiple myeloma: herapy in multiple myeloma: AAssessment with melphalan and prednisonessessment with melphalan and prednisone

• Randomized, international, phase III trial of VMP vs MP in previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT due to age (≥65 yrs) or co-morbid conditions

• Stratification: β2-microglobulin, albumin, region

VMPCycles 1–4Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

Cycles 5–9Bortezomib 1.3 mg/m2 IV: d 1,8,22,29Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

MPCycles 1–9 Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

RANDOMIZE

9 x 6-week cycles (54 weeks) in both arms

• Primary end point: TTP

• Secondary end points: CR rate, ORR, time to response, DOR, time to next therapy (TNT), OS, QoL (PRO)

San Miguel et al. N Engl J Med 2008;359:906–17

VISTA: New Engl J Med dataVISTA: New Engl J Med data

VMPVMPn=337n=337

MPMPn=331n=331 p-valuep-value

ORR (≥PR)ORR (≥PR) 71%71% 35%35% <10<10-6-6

CRCR 30%30% 4%4% <10<10-6-6

PRPR 40%40% 31%31%

MRMR 9%9% 22%22%

SDSD 18%18% 40%40%

1. Bladé et al. Br J Haematol 1998;102:1115-23. San Miguel et al. N Engl J Med 2008;359:906–17

Responses according to EBMT criteria1

VMPVMP MPMP p-valuep-value

Median time to response, monthsMedian time to response, months

Time to first response*Time to first response* 1.41.4 4.24.2 <10<10-10-10

Time to CR*Time to CR* 4.24.2 5.35.3 <10<10-10-10

Median DOR, monthsMedian DOR, months

All respondersAll responders 19.919.9 13.113.1

Patients achieving CRPatients achieving CR 24.024.0 12.812.8*Medians shown for responding patients; p-values based on total study population

Time to response and duration of response Time (months)

0102030405060708090

100

VMP: 24.0 months (83 events)MP: 16.6 months (146 events)HR=0.483, P<0.000001

0 3 6 9 12 15 18 21 24 27

VMPMP

Time to progression

VISTA: Overall SurvivalVISTA: Overall Survival~36% reduced risk of death on VMP~36% reduced risk of death on VMP

San Miguel et al. ASH 2008 (abstract 650)

Median follow-up 16.3 monthsVMP: not reached (45 deaths)MP: not reached (76 deaths)HR = 0.607, p = 0.0078

VMPMP

UPDATE AT ASH 2008

Median follow-up 25.9 months

VMP: median OS not reached (75 deaths); 3-year OS rate = 72%

MP: median OS not reached (111 deaths); 3-year OS rate = 59%

HR = 0.644, p = 0.0032

VISTA Update – ASH 2008VISTA Update – ASH 2008

Subsequent therapy:Subsequent therapy:

Patients can be successfully treated with subsequent immunomodulatory-Patients can be successfully treated with subsequent immunomodulatory-based therapy and can also be retreated with bortezomib (CR 4-10%; PR 44-based therapy and can also be retreated with bortezomib (CR 4-10%; PR 44-55%)55%)

VMPVMP MPMP

BortezomibBortezomib 16%16% 43%43%

ThalidomideThalidomide 49%49% 44%44%

LenalidomideLenalidomide 19%19% 6%6%


VMPVMP MPMP

Time to next therapyTime to next therapy 28.1 months28.1 months 19.2 months19.2 months HR=0.53, HR=0.53, P<0.000001P<0.000001

Treatment-free intervalTreatment-free interval 16.6 months16.6 months 8.4 months8.4 months HR=0.54, HR=0.54, P<0.00001P<0.00001

VISTA: Adverse eventsVISTA: Adverse events

Herpes zoster more frequent with VMP (14% vs 4%)Herpes zoster more frequent with VMP (14% vs 4%)– Rate with VMP only 3% among patients receiving antiviral prophylaxisRate with VMP only 3% among patients receiving antiviral prophylaxis

Peripheral neuropathy was manageable and reversible Peripheral neuropathy was manageable and reversible – 79% of PN events improved (≥1 grade), median of 1.9 months 79% of PN events improved (≥1 grade), median of 1.9 months

– 60% of PN events completely resolved, median of 5.760% of PN events completely resolved, median of 5.7 monthsmonths

VMP (n=340)VMP (n=340) MP (n=337)MP (n=337)

AE, %AE, % Grade 3Grade 3 Grade 4Grade 4 Grade 3Grade 3 Grade 4Grade 4

NeutropeniaNeutropenia 2929 1111 2323 1515

ThrombocytopeniaThrombocytopenia 2020 1818 1616 1515

AnemiaAnemia 1616 33 2020 88

GIGI 1919 11 55 00

Peripheral sensory neuropathyPeripheral sensory neuropathy 1313 <1<1 00 00

FatigueFatigue 77 11 22 00

AstheniaAsthenia 66 <1<1 33 00

PneumoniaPneumonia 55 22 44 11

Herpes zosterHerpes zoster 44 00 22 00


VMP vs VTP in newly diagnosed elderly patients with MMVMP vs VTP in newly diagnosed elderly patients with MMPETHEMA/GEM studyPETHEMA/GEM study

• Randomized, phase III trial of VMP vs VTP in previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT

• age ≥65 yrs, N=260 pts

VMPCycle 1 (6-week cycle)Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

Cycles 2-6 (5-week cycles)Bortezomib 1.3 mg/m2 IV: d 1,8,15,22Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4

RANDOMIZE

VTPCycle 1 (6-week cycle)Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32Thalidomide 100 mg/d and prednisone 60 mg/m2: d 1–4

Cycles 2-6 (5-week cycles)Bortezomib 1.3 mg/m2 IV: d 1,8,15,22Thalidomide 100 mg/d and prednisone 60 mg/m2: d 1–4

Mateos et al. ASH 2008 (abstract 651)

Mateos et al. ASH 2008 (abstract 651)

VMP (n=130)VMP (n=130) VTP (n=130)VTP (n=130)

ORRORR 81%81% 81%81%

CR IF-CR IF- 22%22% 27%27%

CR IF+CR IF+ 19%19% 10%10%

PRPR 40%40% 44%44%

Median time to first responseMedian time to first response 1.6 months1.6 months 1.6 months1.6 months

Median time to CRMedian time to CR 4.4 months4.4 months 4.9 months4.9 months

2-year TTP2-year TTP 72%72% 68%68%

2-year OS2-year OS ~~90%90% ~~90%90%


ConclusionsConclusions

Similar efficacy in the two armsSimilar efficacy in the two arms

Modified VMP regimen (weekly schedule after cycle 1; only six cycles) is well toleratedModified VMP regimen (weekly schedule after cycle 1; only six cycles) is well tolerated– Reduced incidence of PNReduced incidence of PN

Thalidomide may not be the partner of choice for combination with bortezomibThalidomide may not be the partner of choice for combination with bortezomibMateos et al. ASH 2008 (abstract 651)

≥≥G3 Adverse eventsG3 Adverse events VMP (n=80)VMP (n=80) VTP (n=87)VTP (n=87) PP

NeutropeniaNeutropenia 34%34% 19%19% 0.0090.009

ThrombocytopeniaThrombocytopenia 21%21% 9%9% 0.010.01

Non-hematological AEsNon-hematological AEs 25%25% 32%32% 0.040.04

Cardiac toxicityCardiac toxicity 00 7%7%

Thromboembolic eventsThromboembolic events <1%<1% 4%4%

Peripheral neuropathyPeripheral neuropathy 5%5% 9%9%

Treatment discontinuationTreatment discontinuation 8%8% 17%17%

DeathsDeaths 4%4% 4%4%


VMPCycles 1-9Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

VMPTCycles 1-9Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4Thalidomide 50 mg/day continuously

RANDOMIZE

9 x 5-week cycles in both arms

511 patients (older than 65 years) randomized from 58 Italian centers

Patients: Symptomatic multiple myeloma/end organ damage with measurable disease

≥65 yrs or <65 yrs and not transplant-eligible; creatinine ≤ 2.5 mg/dL

MAINTENANCEBortezomib 1.3 mg/m2 IV: days 1,15Thalidomide 50 mg/day continuously

NO MAINTENANCE

Until relapse

* 61 VMP patients and 70 VMPT patients were treated with biweekly infusions of Bortezomib

VMPT vs VMP in elderly patients with newly diagnosed MMVMPT vs VMP in elderly patients with newly diagnosed MMGIMEMA studyGIMEMA study

Palumbo et al. ASH 2008 (abstract 652)

VMPT vs VMP in elderly patients with newly diagnosed MMVMPT vs VMP in elderly patients with newly diagnosed MMGIMEMA studyGIMEMA study


VMPT VMPT (N=177)(N=177)

VMP VMP (N=177)(N=177) P valueP value

CRCR 35%35% 21%21% 0.060.06

>> VGPR VGPR 51%51% 42%42% < 0.0001< 0.0001

TTNT @ 3 yearsTTNT @ 3 years 80%80% 78%78% 0.300.30

PFS @ 3 yearsPFS @ 3 years 71%71% 56%56% 0.130.13

OS @ 3 yearsOS @ 3 years 90%90% 89%89% 0.810.81

VMP vs VMPTVMP vs VMPTGrade 3-4 Hematologic Adverse EventsGrade 3-4 Hematologic Adverse Events

0 5 10 15 20 25 30 35

Anaemia

Thrombocytopenia

Neutropenia

% of patients

VMPT VMP


0 5 10 15

Thrombosis

Fatigue

Cardiologic

Gastrointestinal

Infections

Sensoryneuropathy

% of patients

VMPTVMP

VMP vs VMPTVMP vs VMPTGrade 3-4 Non Hematologic Adverse EventsGrade 3-4 Non Hematologic Adverse Events

Overview of planned and actual bortezomib doses in phase 3 trialsOverview of planned and actual bortezomib doses in phase 3 trials

StudyStudy Bortezomib scheduleBortezomib schedule Planned Planned treatmenttreatment

Actual bortezomib Actual bortezomib treatment receivedtreatment received

Responses in VMP Responses in VMP groupsgroups

VISTAVISTASan Miguel San Miguel et alet al. . N Engl J MedN Engl J Med 2008;359:906–172008;359:906–17

Four 6-week cyclesFour 6-week cycles1.3 mg/m1.3 mg/m22, d 1, 4, 8, , d 1, 4, 8, 11, 22, 25, 29, 3211, 22, 25, 29, 32Five 6-week cyclesFive 6-week cycles1.3 mg/m1.3 mg/m22, d 1, 8, 22, , d 1, 8, 22, 2929

54 weeks:54 weeks:52 bortezomib 52 bortezomib injectionsinjections

Median number of Median number of treatment cycles treatment cycles administered: 8 (46 administered: 8 (46 weeks) in VMP group: weeks) in VMP group: 48 injections48 injections

CR (IF-): 30%CR (IF-): 30%CR + PR: 71%CR + PR: 71%

VMPT vs VMPVMPT vs VMPPalumbo Palumbo et alet al. . ASH 2008 ASH 2008 (abstract 652)(abstract 652)

Four 6-week cyclesFour 6-week cycles1.3 mg/m1.3 mg/m22, d 1, 4, 8, , d 1, 4, 8, 11, 22, 25, 29, 3211, 22, 25, 29, 32Five 6-week cyclesFive 6-week cycles1.3 mg/m1.3 mg/m22, d 1, 8, 22, , d 1, 8, 22, 2929


Not reported in abstractNot reported in abstract

All patients:All patients:CR (IF-): 21%CR (IF-): 21%CR + PR: 82%CR + PR: 82%

Subgroup – Subgroup – bortezomib weekly:bortezomib weekly:CR (IF-): 20%CR (IF-): 20%

(CR + PR: not reported)(CR + PR: not reported)

From March 2007From March 2007::Nine 5-week cycles Nine 5-week cycles Bortezomib 1.3 mg/mBortezomib 1.3 mg/m22, , d 1, 8, 15, 22d 1, 8, 15, 22


VMP vs VTPVMP vs VTPMateos Mateos et alet al. . ASH 2008 ASH 2008 (abstract 651)(abstract 651)

One 6-week cycleOne 6-week cycle1.3 mg/m1.3 mg/m22, days 1, 4, 8, , days 1, 4, 8, 11, 22, 25, 29, 3211, 22, 25, 29, 32Five 5-week cyclesFive 5-week cycles1.3 mg/m1.3 mg/m22, days 1, 8, , days 1, 8, 15, 2215, 22


Not reported in abstractNot reported in abstract CR (IF-): 22%CR (IF-): 22%CR + PR: 81%CR + PR: 81%

Phase I/II trial of MPR in newly diagnosed MMPhase I/II trial of MPR in newly diagnosed MM

Cohort Lenalidomide, mg/day

Melphalan, mg/kg/day

Prednisone, mg/kg/day

1 (n = 6)1 (n = 6) 55 0.180.18 22

2 (n = 6)2 (n = 6) 55 0.250.25 22

3 (n = 6 + 15)3 (n = 6 + 15) 1010 0.180.18 22

4 (n = 6 + 15)4 (n = 6 + 15) 1010 0.250.25 22

Every 4–6 weeks for maximum of 9 cycles.Aspirin (100 mg/day) given as DVT prophylaxis.

1 2 3 4 21

LenalidomideLenalidomide

MelphalanMelphalan

PrednisonePrednisone

Day

Median age 71 years (range, 57–77)

Palumbo A, et al. J Clin Oncol. 2007:25: 4459

MTD = Mel 0.18 mg/kg + Lenalidomide 10 mg/dayMTD = Mel 0.18 mg/kg + Lenalidomide 10 mg/day

*Historical control – Palumbo et al, Lancet 2006 *Historical control – Palumbo et al, Lancet 2006 5.4% of response not available5.4% of response not available

Newly Diagnosed MM PatientsNewly Diagnosed MM PatientsMPR vs MPT: Response Rates MPR vs MPT: Response Rates

MPT MPT Best ResponseBest Response

n=129*n=129*

16

21

40

5 58

0

10

20

30

40

50

60

70

CR VGPR PR MR SD PD

Pro

po

rtio

n o

f p

atie

nts

Pro

po

rtio

n o

f p

atie

nts

37%37%

MPR MPR Cohort 3 (0.18-10)Cohort 3 (0.18-10)

Best ResponseBest Responsen=21n=21

Pro

po

rtio

n o

f p

atie

nts

Pro

po

rtio

n o

f p

atie

nts

48%48%

24 24

33

19

0 00

10

20

30

40

50

60

70

CR VGPR PR MR SD PD


0

0,25

0,5

0,75

1

0 5 10 15 20 25

0

0,25

0,5

0,75

1

0 5 10 15 20 25

MPT: median follow-up 17.6 months (0.23-44.3) [N=129]*MPT: median follow-up 17.6 months (0.23-44.3) [N=129]*

R-MP: median follow-up 14.6 months (10.8-21.8) [N=53]R-MP: median follow-up 14.6 months (10.8-21.8) [N=53]

p=0.046p=0.053

EFSEFS OSOS

Pro

po

rtio

n o

f p

atie

nts

Months Months

MPT

RMP

Pro

po

rtio

n o

f p

atie

nts

MPT

RMP

*Historical control – Palumbo et al, Lancet 2006 *Historical control – Palumbo et al, Lancet 2006

Newly Diagnosed MM PatientsNewly Diagnosed MM PatientsMPR vs MPT: EFS and OS MPR vs MPT: EFS and OS


0 10 20 30 40 50 60

% of patients% of patients

MPR [n=21]MPR [n=21]MPT [n=129]*MPT [n=129]*

Grade 3–4 Adverse EventsGrade 3–4 Adverse EventsCohort 3 (0.18-10) vs MPTCohort 3 (0.18-10) vs MPT

*Historical control, Lancet 2006 *Historical control, Lancet 2006

Neutropenia

Thrombocytopenia

Anemia

Infections

Thrombosis

Cutaneous

Cardiac

Early deaths

• Novel agents are changing the scenario in elderlyNovel agents are changing the scenario in elderly

• MPT and VMP have been shown to be superior over MP (and MPT and VMP have been shown to be superior over MP (and MEL100)MEL100)

• Initial results suggest a high efficacy for MPR Initial results suggest a high efficacy for MPR

• Response rates with novel agents in elderly patients are Response rates with novel agents in elderly patients are comparable to previous outcomes with ASCT in younger comparable to previous outcomes with ASCT in younger patientspatients

• Role of maintenance needs further studiesRole of maintenance needs further studies

ConclusionsConclusions

PAD induction plus reduced-intensity ASCT plus lenalidomide PAD induction plus reduced-intensity ASCT plus lenalidomide consolidation/maintenance in elderly patientsconsolidation/maintenance in elderly patients

PatientsPatients ( (n=102)n=102)

– aged 65aged 65––75 years75 years

TreatmentTreatment– InductionInduction ( (four 21-day PAD cycles)four 21-day PAD cycles)

• Bortezomib 1.3 mg/mBortezomib 1.3 mg/m22 days 1, 4, 8, 11 days 1, 4, 8, 11• Pegylated-lyposomal-doxorubicin 30 mg/m2 day 4Pegylated-lyposomal-doxorubicin 30 mg/m2 day 4• Dexamethasone 40 mg days 1-4, 8-11, 15-18Dexamethasone 40 mg days 1-4, 8-11, 15-18

– Intensification: Intensification: tandem Melphalan 100 mg/mtandem Melphalan 100 mg/m22 (MEL100) + ASCT (MEL100) + ASCT

– Consolidation: Consolidation: 4 28-day LP cycles (Lenalidomide 25 mg days 1-21 4 28-day LP cycles (Lenalidomide 25 mg days 1-21 plus, Prednisone 50 mg every other day)plus, Prednisone 50 mg every other day)

– Maintenance: Maintenance: Lenalidomide (10 mg days 1-21 every 28 day)Lenalidomide (10 mg days 1-21 every 28 day)

Palumbo et al. JCO 2009 (in press)

ResultsResults

Median follow-up: 14 monthsMedian follow-up: 14 months

– 1-year PFS 92%1-year PFS 92%

– 1-year TTP 97%1-year TTP 97%

– 1-year OS 92%1-year OS 92%

PFS not significantly affected by β2-microglobulin levels (p=0.10), PFS not significantly affected by β2-microglobulin levels (p=0.10), presence of chromosome 13 deletion (p=0.5) or t(4;14) (p=0.61)presence of chromosome 13 deletion (p=0.5) or t(4;14) (p=0.61)

After PADAfter PAD After tandem After tandem MEL100 + ASCTMEL100 + ASCT

After LP After LP ConsolidationConsolidation

CRCR 13%13% 41%41% 53%53%

≥ ≥ VGPRVGPR 59%59% 88%88% 88%88%

≥ ≥ PRPR 94%94% Not availableNot available 100%100%


ResultsResults

During PAD:During PAD:

thrombocytopenia (13%)thrombocytopenia (13%)

neutropenia (11%)neutropenia (11%)

infections (18%)infections (18%)

gastrointestinal toxicities gastrointestinal toxicities (12%)(12%)

peripheral neuropathy (11%)peripheral neuropathy (11%)

deep vein thrombosis (6%)deep vein thrombosis (6%)

During LP consolidation:During LP consolidation:

neutropenia (18%)neutropenia (18%)

thrombocytopenia (6%)thrombocytopenia (6%)

infections (6%)infections (6%)

deep vein thrombosis (6%)deep vein thrombosis (6%)

PAD induction regimen followed by reduced-intensity ASCT, Lenalidomide as consolidation and maintenance is a highly

effective regimen in elderly patients

Most frequent grade 3/4 adverse events


Therapeutic AlgorithmTherapeutic AlgorithmLevel of Evidence 1b (Level of Evidence 1b (>> 1 Randomized Trial) 1 Randomized Trial)

MPMP

DiagnosisDiagnosis

TDTD

> 65 years> 65 years

MPVMPV

MPTMPT

MPRMPR

MPMP

MPMP

MPMP

=

>>

1 randomized trial

5 randomized trials

1 randomized trial

under evaluation

Factors Affecting Preference for Factors Affecting Preference for MPMP––Novel Combination*Novel Combination*

*Duration of treatment: 6 cycles

San Miguel JF. Presented at: 11th International Myeloma Workshop; June 25–30, 2007; Kos, Greece

Consolidate data ............................................ MPT

Antecedent or risk of DVT........................... MPV

Antecedent PN ................................................ MPR

Renal insufficiency ....................................... MPV

Distance from hospital ................................ MPR or MPT

Poor patient accomplishment .................. MPV

Cost ..................................................................... MPT

INDUCTIONINDUCTION

660 pts660 pts

ARM A (220 pts)

Rd X 9 courses

ARM B (220 pts)

MPR X 9 courses

ARM C (220 pts)

CPR X 9 courses

Maintenance

ARM A1

R

ARM A2

RP

Maintenance Maintenance

ARM B1

R

ARM B2

RP

ARM C1

R

ARM C3

RP

Newly diagnosed symptomatic MM patients ≥ 65 years of age or younger not eligible for SCT

EMN01EMN01

Federica Cavallo Divisione di Ematologia, Universita’ di Torino Terapia nei pazienti non candidati...

Documents

Transcript of Federica Cavallo Divisione di Ematologia, Universita’ di Torino Terapia nei pazienti non candidati...