treatment paradigms... · randomization. induction (three 21-d cycles) vel-thal-dex • vel...

New Treatment Paradigms in Transplant-Eligible Myeloma Patients

Michele Cavo

Seràgnoli Institute of Hematology, Bologna University School of Medicine, Italy

Turkey, March 1st 2013

NEW TREATMENT PARADıGM FOR PATıENTS WHO ARE ELıGıBLE FOR AUTOTRANSPLANTATıON (ASCT)

Novel agents

InductionASCT1 ± 2

Consolidation Maintenance

GOALS OF NOVEL-AGENT-BASED ASCT(s)

• To enhance tumor reduction and increase the rate of CR

- Induction

- ASCT, either single or double

- Post-ASCT consolidation therapy

• To reduce the risk of relapse and sustain durable CR

− Post-ASCT maintenance therapy

To extend PFS and OS

Achievement of at least nCR prognosticates for extended PFS

Multivariate analysis

Variable Relative risk (95% CI) p

t(4;14) ± del(17p) 1.8 (1.4-2.5) <0.001

Β2-m > 3.5 mg/l 2.0 (1.5-2.6) <0.001

Failure to achieve at least nCR 1.6 (1.1-2.3) 0.018

IMPORTANCE OF ACHıEVıNG HıGH-QUALıTY RESPONSETO VTD OR TD ıNDUCTıON THERAPY

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36Months

nCR+CR

< nCR

p=0.0106

Progression-free survival

Cavo et al, unpublished data

Thalidomide-based

Lenalidomide-based

Bortezomib-based

Bortezomib + IMiD-based

TD RDRd

VD2-drug combinations

TADCTD

RADRCDBiRD

PADVCD

VTDVRD

VTDCRVDC

NOVEL AGENT-BASED INDUCTION THERAPIES

3-drug combinations

4-drug combinations

Cavo et al. Blood 2011;117:6063-6073

Rajkumar. Blood 2005;106:2-3

Cavo et al. Blood 2005;106:35-39

INDUCTION N° INDUCTION FIRST ASCT

REGIMEN CYCLES % CR % ≥ VGPR % CR % ≥ VGPR

TAD1 3 3 37 14 54

VAD 3 2 18 12 44

CTD2 6 13 43 50▲ 74▲

C-VAD 6 8 27.5 37▲ 62▲

▲ per-protocol analysis1.Lokhorst et al. Blood 2010;15(6):1113-1120.2.Morgan et al. Haematologica 2012;97(3):442-450.

PHASE 3 STUDIES OF THALIDOMIDE-BASED INDUCTION REGIMENS



VD1 4 6 38 16 54

VAD 4 1 15 9 37

PAD2 3 not rep. 42 not rep. 61

VAD 3 not rep. 15 not rep. 36

▲ per-protocol analysis1.Harosseau et al. J Clin Oncol 2010;28(30):4621-4629.2.Sonneveld et al. Blood 2010;116(21)Abstract40

PHASE 3 STUDIES OF BORTEZOMIB-BASED INDUCTION REGIMENS



VTD1 3 19 62 38 79

TD 3 5 28 23 58

VTD2 6 35 60 46 65

TD 6 14 29 24 40

vTD3 4 13 49 29 74

VD 4 12 36 31 58

1.Cavo et al. Lancet 2010;379(9758):2075-2085.2.Rosiñol et al. Blood 2010;116(21). Abstract 307.3.Moreau et al. Blood 2011;117(11):3041-3044.

PHASE 3 STUDIES OF BORTEZOMIB-THALIDOMIDE-BASED INDUCTION REGIMENS

INDUCTION N° INDUCTION ASCT


VRD1 8 37 74 ▲ not reported

VRD2 4 7 32 not reported

VRD3 3 28 54 35 68

1.Richardson et al. Blood 2010; 116: 679-6862.Kumar et al. Blood 2012; 119(19):4357-43823.Roussel et al. Blood 2010; 116(21); Abstract 624

▲ best response

PHASE 2 STUDIES OF BORTEZOMIB-LENALIDOMIDE-BASED PRIMARY THERAPIES

INDUCTION N° INDUCTION ASCT


VCD1 3 14.6(+nCR) 36.6 not reported

CyBorD2 4 39(+nCR) 61 70

(+nCR) 74

VCD3 6 3▲ 13▲ not reported

VCD-mod3 6 12▲ 41▲ not reported

1.Einsele et al. Blood 2009; 114(22); Abstract 1312.Reeder et al. Leukemia 2009; 23(7:1337-1341)3.Kumar et al. Blood 2012; 119(19):4375-4382

▲ response evaluated after 4 cycles

PHASE 2 STUDIES OF BORTEZOMIB-CYCLOPHOSPHAMIDE-BASED PRIMARY THERAPIES

4 cycles Best response

REGIMEN CR (%) ≥ VGPR (%)

AEs grade ≥

3 (%)

EARLY DEATH

(%)

CR (%) ≥ VGPR (%)

PFS OS

RD vs NR 42 52 5 13 46 NR 87% (2-yr)

Rd 1 NR 24 35 1 10 36 NR 75% (2-yr)

1.Rajkumar et al. Lancet Oncol. 2010;11(1):29-37.

LENALIDOMIDE-DEXAMETHASONE UP-FRONT THERAPY± AUTOLOGOUS TRANSPLANTATION

DESIGN OF PHASE III TRIALS INCORPORATING NOVEL AGENTS INTO ASCT

STUDY INDUCTION N° ASCT CONSOLIDATION MAINTENANCE

HOVON-50 TADVAD 1 --

--ThalIFN

MRC IX CTDCVAD 1 --

-- +/- Thal

IFM 2005-02 VDVAD 1 or 2 Len +/- Len

HOVON 65/GMMG-HD4 PADVAD 1 or 2 --

--Vel

Thal

GIMEMA MMY-3006 VTDTD 2 VTD

TDDexDex

PETHEMA/GEMVTDTD

VBMCP/VBAD/Vel1 --

--

IFN-α2b vsThal vs

Vel+Thal

IFM 2007-02 vTDVD 1 +/- Len

or vTD +/- Thal or Len

IMPACT OF NOVEL AGENTS INCORPORATED INTO ASCT(s) ON CLINICAL OUTCOMES

• Rate of high-quality responses (≥VGPR, CR-nCR) to ASCT

• PFS and OS

• Novel agents have been also incorporated after ASCT as

consolidation and/or maintenance therapy

The contribution of different treatment phases to clinical

outcomes cannot be easily evaluated

TREATMENTINDUCTION ASCT

PFS OS% CR % ≥ VGPR % CR % ≥ VGPR

TAD1 + Thal maint. 3 37 14 54 34 mo 73 mo

VAD + IFN maint. 2 18 12 44 25 mo 60 mo

CTD2

± Thal maint.13 43 50▲ 74▲ 27 mo not reach.

C-VAD 8 27.5 37▲ 62▲ 25 mo 63 mo

VD3 + Len cons. 6 38 not rep. 68 36 mo 81% (3 yr)

VAD ± Len maint. 1 15 not rep. 47 30 mo 77% (3 yr)

PAD4 + Vel maint. not rep. 42 not rep. 61 36 mo not reach.

VAD + Thal maint. not rep. 15 not rep. 36 27 mo not reach.

PHASE 3 STUDIES OF NOVEL AGENTS INCORPORATED INTO AUTOTRANSPLANTATION

▲ per-protocol analysis

1.Lokhorst et al. Blood 2010;15(6):1113-1120 2.Morgan et al. Haematologica 2012;97(3):442-450

3.Harosseau et al. J Clin Oncol 2010;28(30):4621-4629.4.Sonneveld et al. Blood 2010;116(21)Abstract40

TREATMENTINDUCTION ASCT

PFS OS% CR % ≥ VGPR % CR % ≥ VGPR

VTD1 + VTD cons. 19 62 38 79 68% (3-yr) 86% (3-yr)

TD + TD cons. 5 28 23 58 56% (3-yr) 84% (3-yr)

VTD2+ IFN vs

VT vs Thal maint.

35 60 46 65 Not reach. Not reach.

TD 14 29 24 40 27 mo Not reach.

vTD3+ Len or vTD cons and Thal or Len maint.

13 49 29 74 26 mo Not reach.

VD 12 36 31 58 30 mo Not reach.

PHASE 3 STUDIES OF NOVEL AGENTS INCORPORATED INTO AUTOTRANSPLANTATION

1.Cavo et al. Lancet 2010;379(9758):2075-2085.2.Rosiñol et al. Blood 2010;116(21). Abstract 307.3.Moreau et al. Blood 2011;117(11):3041-3044.


Novel agents

InductionASCT 1 ± 2

Consolidation Maintenance

AıMS OF CONSOLıDATıON AND MAıNTENANCE THERAPY

Consolidation

• To improve the rate and depth

of response achieved following

therapy

– by administration of

treatment for limited

period

Maintenance

• To maintain response

achieved following therapy


treatment for prolonged

period

Overall goal: prolong survival

GIMEMA MMY-3006 PHASE 3 STUDY DESIGNRANDOMIZATION

INDUCTION (three 21-d cycles)VEL-THAL-DEX• Vel 1.3mg/m2 twice weekly• Thal 100 200mg/day• Dex 320mg/cycle

TRANSPLANTATION• MEL 200

• Thal 100md/day• Dex 160mg/cycle

• MEL 200

MAINTENANCE• DEX

PBSC COLLECTION• CTX

INDUCTION (three 21-d cycles)THAL-DEX

• Thal 100 200mg/day• Dex 320mg/cycle

CONSOLIDATION (two 35-d cycles)VEL-THAL-DEX• Vel 1.3mg/m2 once weekly• Thal 100mg/day• Dex 320mg/cycle

CONSOLIDATION (two 35-d cycles)THAL-DEX

• Thal 100mg/day• Dex 320mg/cycle

GIMEMA MMY-3006 PHASE 3 STUDY:IMPACT OF VTD CONSOLıDATıON ON OUTCOMES

VTD TD p

CR before consolidation 48.7% 40.4 0.131

CR post-consolidation 60.6% 46.6% 0.012

Upgrade to CR post-consolidation 30.5% 16.7% 0.029

Landmark analysis from start of consolidation (30 months median follow up)

3-yr PFS 60% 48% 0.042

Cavo et al. Blood. Prepublished online April 12, 2012

Per-protocol analysis: 321 patients

• Frequency of grade 3/4 AEs comparable in both groups– 10.6% VTD, 9.3% TD

• PN with VTD: 0.6%• Skin rash, DVT: 0.6% in each group• VTD arm: patients received 93% of planned doses of bortezomib and thal

KAPLAN-MEIER CURVES FOR PFS FROM THE LANDMARK OF STARTING CONSOLIDATION THERAPY


COX REGRESSION ANALYSIS OF PFS FROM START OF CONSOLIDATION THERAPY


UNIVARIATE ANALYSIS

High-risk subgroups

N° pts

Hazard ratio 95% CI P-valueVTD TD

t(4;14) and/or del(17p) positive 38 38 0.37 0.19–0.70 .002

del(13q) positive 71 63 0.48 0.29–0.81 .006

LDH >190 U/L 137 144 0.59 0.40–0.86 .007

β2-microglobulin >3.5 mg/L 59 67 0.56 0.34–0.92 .022

ISS stage 2–3 80 86 0.58 0.36–0.93 .023

MULTIVARIATE ANALYSIS

Variable Hazard ratio 95% CI P-value

β2-microglobulin <3.5 mg/L 0.42 0.29–0.61 < .0001

Absence of t(4;14) and/or (17p) 0.49 0.34–0.73 < .0001

Consolidation with VTD 0.61 0.42–0.89 .010

AGENT / REGIMEN

N°CYCLES

PROBABILITY TO UPGRADE RESPONSE (%) PFS OS

Bortezomib vs 6 ≥ VGPR*: 71 27 mos*(median)

no consolidation 1 / ≥ VGPR*: 57 20 mos*(median)

VTD 2 4 CR: 15% → 49% 60 mo (median)

89% (3-yr)

molecular CR: 3% → 18% > PFS > OS

Lenalidomide 3 2 CR: 14% → 20% not eval. not eval.≥ VGPR: 58% → 67% not eval. not eval.

* P value statistically significant

1.Mellqvist et al. Haematologica 2011; 96(suppl 1). Abstract 0112.Ladetto et al, J Clin Oncol 2010;28:2077-2084.3.Attal et al. Blood 2010;116. Abstract 310.

NOVEL-AGENT-BASED CONSOLıDATıON THERAPIES

AıMS OF CONSOLıDATıON AND MAıNTENANCE THERAPY

Consolidation

• To improve the rate and depth

of response achieved following

therapy


treatment for limited

period

Maintenance

• To maintain response

achieved following therapy


treatment for prolonged

period

Overall goal: prolong survival

PHASE 3 STUDIES OF THALIDOMIDE MAINTENANCE AFTER ASCT(s)

TreatmentInductionwith thal ASCT Maintenance

durationThal+pamidronate vs

No Double ASCT until PDPamidronate vsNone 1

Thal + pred vsNo Single ASCT 12 months

Pred2

Thal vs® Yes/No Double ASCT until PD

No Thal3

Thal vs® Yes/No Single or double ASCT until PD

IFN 4

Thal vs® Yes/No Single ASCT/

Non-intensive Tx until PDNone 5

Thal+pred vsNo Single ASCT until PD

None 6

1.Attal et al. Blood 2006;108:3289–32942.Spencer et al. J Clin Oncol 2009;27:1788–17933.Barlogie et al. N Engl J Med 2006;354:1021–1030; Blood 2008;112:3115–3121; J Clin Oncol 2010;28:1209–12144.Lokhorst et al. Blood 2010;115:1113–205.Morgan et al. Blood 2012; 119(1):7-156.Stewart et al. Blood 2010; 116(21). Abstract 39

Induct with Thal Improved PFS Improved OS Survival after relapse

NO 1 Yes Yes @ 39 m,Not @ 5.7 yr Similar in all groups

NO 2 Yes Yes(3 yrs follow up) Similar in all groups

YES 3 Yes Yes(7.2 yrs follow-up) Reduced OS after thal exposure

YES 4 Yes No Reduced OS after thal exposure

YES 5 Yes No Reduced OS after thal exposure

YES 6 Yes No Not reported

PHASE 3 STUDIES OF THALIDOMIDE MAINTENANCE AFTER ASCT(s)

1.Attal et al. Blood 2006;108:3289–32942.Spencer et al. J Clin Oncol 2009;27:1788–17933.Barlogie et al. N Engl J Med 2006;354:1021–1030; Blood 2008;112:3115–3121; J Clin Oncol 2010;28:1209–12144.Lokhorst et al. Blood 2010;115:1113–205.Morgan et al. Blood 2012; 119(1):7-156.Stewart et al. Blood 2010; 116(21). Abstract 39

OS BENEFıT WıTH THALIDOMIDE MAINTENANCE:META-ANALYSıS OF RANDOMIZED STUDıES

Morgan et al. Blood 2012; 119: 7-15

THALIDOMIDE MAINTENANCE AFTER ASCT(s) : CAVEATS

In ASCT setting, benefit with thal maintenance seen in

terms of PFS but not always of OS 1

• Toxicity, particularly neurological, leading to

discontinuation rates up to 60% 2

• Shorter survival following relapse in patients with

prior exposure to thal

− Selection of resistant clones?

• No benefit in patients with del(13q) and worse

outcome in patients with high-risk cytogenetics 2,3

1. Cavo et al. J Clin Oncol 2009; 27(32): e186-1872. Attal et al. Blood 2006;108:3289–32943. Morgan et al. Blood 2012; 119(1);7-15.

Study Treatment Medianfollow-up PFS OS

Len 41 mo 73% (4 yrs)

IFM 2005-021 Len consolid - R 45 mo

Placebo 23 mo 75% (4 yrs)

(p<0.001)

Len 46 mo 88% (3 yrs)

CALGB 1001042 R 34 mo

Placebo 27 mo 80% (3 yrs)

(p<0.001) (p=0.03)

PHASE 3 STUDIES OF LENALIDOMIDE MAINTENANCE AFTER ASCT(s)

1. Attal et al. NEJM 2012;366(19):1782-17912. McCarthy et al. NEJM 2012;366(19):1770-1781

IFM 2005-02: EFS and OS (as of October 2011)

PROGRESSION-FREE SURVIVAL OVERALL SURVIVAL

41 mos median*

23 mos median*

*40 vs 23 months after including SPM as an event

Lenalidomide: 73% at 4 yrs

Placebo: 75% at 4 yrs

Attal et al. NEJM 2012;366(19):1782-1791

STOP LEN

Age < vs ≥ 55 yr

Gender

β2-m ≤ vs > 3mg/L

Del(13q) neg vs pos

Induction VAD vs VD

< VGPR vs ≥ at ®

IFM 2005-02: HR FOR PFS BY PATIENT SUBGROUP

Attal et al. NEJM 2012;366(19):1782-1791

CALGB 100104: PFS and OS (as of October 2011)

PROGRESSION-FREE SURVIVAL OVERALL SURVIVAL

46 mo. median

27 mo. median Lenalidomide: 88% at 3 yrs

Placebo: 80% at 3 yrs

McCarthy et al. NEJM 2012;366(19):1770-1781

*43 vs 27 months after including SPM as an event

86 out of 128 patients without PD in the placebo group crossed over to lenalidomide maintenance after study unblinding

Attal et al. NEJM 2012;366(19):1782-1791

SECOND PRIMARY MALIGNANCIES

IFM 2005-02(as of Oct 2011)

CALG 100104(as of Feb 2012)


Attal et al. NEJM 2012;366(19):1782-1791

CUMULATIVE INCIDENCE OF SPMs

IFM 2005-02(as of Oct 2011)

CALG 100104(as of Feb 2012)


Secondary Cancers in Myeloma Potential Factors

Leukemogenic potential of conventional therapy• Alkylating agents

o Latency 5-10 yearso Often with loss of all/part of chromosomes 5 and/or 7

• Topoisomerase II inhibitors (doxorubicin, etoposide) o Latency 1-5 years.o Often with translocation of 11q23.

• Concomitant XRT increases risk

Potential contribution of high-dose therapy + ASCT• Low incidence MDS/AML with VAD induction and ASCT1

• FISH studies in Hodgkin’s and non-Hodgkin’s lymphoma indicate MDS changes present before ASCT in most cases2,3

1Govindarajan R, et al. Br J Haematol 1996; 95: 349-353; 2 Abruzzese E, et al. Blood 1999; 94: 1814-1819;

3 Lillington DM, et al. J Clin Oncol 2001; 19: 2472-2481.

Secondary Cancers in Myeloma Potential Factors

Increased risk appears intrinsic to plasma cell disorders• Higher risk of MDS/AML and non-melanoma skin cancer

in patients with myeloma and MGUS1

1Mailankody W, et al. Blood 2011; 118: 4086-4092.

Randomization

MM Stage II or III, Age 18–65

CAD + GCSF

3 x VAD

CAD + GCSF

3 x PAD

MEL 200 + PBSCT

GMMGMEL 200 + PBSCT

MEL 200 + PBSCT

GMMGMEL 200 + PBSCT

Thalidomide 50 mg/day for 2 years maintenance

Allogeneic Tx

Bortezomib 1.3 mg/m2 / 2 weeks for 2 years maintenance

HOVON 65/GMMG-HD4 MM STUDY DESIGN

HOVON 65/ GMMG-HD4 STUDY: PFS FROM ASCT

Sonneveld et al. Blood. 2010;116:[abstract 40].

A: VADB: PAD

N282303

F171165

A: VADB: PAD

10 Nov 2010-15:15:14

At risk:282303

215257

138167

5350

8

12

A: VAD

B: PAD

0

25

50

75

100

months0 12 24 36 48

Cum

ulat

ive

perc

enta

ge

HR = 0.82 (0.66-1.02), P=0.08

ALLOGENEIC SCT IN THE NOVEL AGENT ERA

• Over the last 10 years a reduced-intensity conditioning (RIC)

regimen in preparation for allo-SCT preceded by ASCT (tandem

AUTO-ALLO) has become a widely accepted procedure

• The role of ALLO-SCT as part of up-front therapy for MM

continues to remain controversial in the novel agent era

− higher risk of relapse/progression in comparison with that

previously reported with myeloablative treatments

− relatively high TRM and morbidity, particularly cronic GVHD

Lokhorst et al. JCO 2010;28:4521

COMPARISONS OF DOUBLE ASCT WITH AUTO-ALLO SCT

Bjorkstrand et al. JCO 2011;29:3016

EBMT STUDY

PFS OS

Krishnan et al. Lancet Oncol. 2011;12:1195

BMT CTN 0102 STUDYPFS / STANDARD RISK OS / STANDARD RISK

PFS / HIGH-RISK OS/ HIGH-RISK

CONCLUSIONS

• INDUCTION THERAPY

- Novel-agent-based induction regimens affect unprecedentedrates of CR that rival those previously seen with ASCTpreceded cy conventional CHT.

- A triplet bortezomib-based regimen is likely to yield thehighest rate of high-quality responses and should beconsidered a standard of care

- 3 to 6 cycles represent a reasonable balance between efficacyand toxicity

- BiPN is an issue: it may adversely influence patient’s QoL, butgenerally does not have a major impact on patient’s ability tocomplete the induction therapy and to receive subsequentASCT

- Neurological toxicity might be significantly reduced by use ofs.c. bortezomib

CONCLUSIONS

• ASCT

- Outside clinical trials comparing early vs late ASCT,the preferred approach should continue to be ASCT up-front

- High-dose therapy further enhances tumor reduction even inface of high CR rates affected by novel-agent-based inductionregimens

- The role of single vs. double ASCT in the novel agent eraneeds to be prospectively addressed in the context ofrandomized clinical trials

CONCLUSIONS

• CONSOLIDATION THERAPY

- Provided an increase in the rate of high-quality responses, upto the deepest level of molecular CR after ASCT and in severalstudies was associated with extended PFS, thus contributing tothe better outcome seen with the entire treatment program

- Its impact on long-term clinical outcomes needs to be confirmed in prospective, randomized trials

NOVEL AGENTS ALONE VERSUS NOVEL AGENTS + INTENSIVE THERAPY: EMN 02 TRIAL

CONCLUSIONS

• MAINTENANCE THERAPY

- Thalidomide has not been widely accepted

- Lenalidomide dramatically reduced the relative risk of progression (50% range) and significantly prolonged TTP/PFS in comparison with placebo

- Benefits with lenalidomide wee seen regardless of β2 m, priorexposure to any of the novel agents as part of induction,disease status at randomization and del (13q)

- The risk of SPMs associated with lenalidomide maintenance is outweighed by improved clinical outcomes

CONCLUSIONS

• ALLOGENEIC SCT

- Convincing evidence is lacking that tandem AUTO-ALLO (RIC-ALLO) as part of up-front therapy for MM improves the outcome compared with (double) ASCT, particularly in high-risk patients

- Novel agents incorporated into the entire treatment program(before and after AUTO-ALLO SCT) and more effectiveconditioning regimens in preparation for ALLO SCT to reducethe risk of relapse are warranted

- as up-front therapy for patients with “ultra-high-risk” disease

- as salvage therapy at first early relapse (sensitive-treatment patients)

in the context of controlled clinical trials

SUMMARYAlthough it is difficult to assess the impact of different treatment strategies(induction, ASCT, consolidation, maintenance) on clinical outcomes, PFShas been improved with “new” ASCT compared with “old” ASCT 1

1 Cavo et al. Blood. 2011;117(23):6063-73

“New” ASCT “Old” ASCT

Treatment PFS Treatment PFS

TAD + ASCT 1 + thal maint. 34 mos VAD + ASCT 1 + IFN maint. (Attal, 1996) 27 mos

PAD + ASCT 1/2 + bort maint. 36 mos VAD + ASCT 1 + IFN maint. (Child, 2003) 30 mos

VD + ASCT 1/2 + len cons. and maint. 36 mos VAD + ASCT 1 + IFN maint. (Cavo, 2007) 23 mos

VTD + ASCT 1 + IFN/thal/bort+thal maint.

60% at 3 yrs

VTD + ASCT 2 + VTD cons + dex maint.

68% at 3 yrs

VAD + ASCT 2 + IFN maint. (Attal, 2003) 30 mos

VAD + ASCT 2 + IFN maint. (Cavo, 2007) 35 mos

WHAT SHOULD BE THE TREATMENT GOAL ıN MM PATıENTS?

To achieve conventionally defined CR (not enough!)

To eradicate the tumor clone or reduce it at the lowest

detectable level

To achieve immunophenotypic or molecular CR

To achieve cure or at least long-term survival

(>10–15 years) with good quality of life

Progressive reduction in tumor cell mass throughout induction, ASCT, consolidation and maintenance therapy

Time

Tum

or c

ells

1 kg

0

1x1012

1x106

Detection limit ofImmunophenotyping andPolymerase chain reacdtion

Indu

ctio

n

Tran

spla

nt

Con

solid

atio

nMaintenance

FISH cytogenetics and immunophenotypic CR for the prediction of early relapse of patients in CR after ASCT

TTP OS

Paiva B et al. Blood 2012;119:687-691

Impact of MRD detection by flow cytometry on clinical outcomes after high-dose tx and ASCT

MRD negative (n=94) MRD positive (n=53)

Median: 71 months

0 20 40 60 80 100 120 140

0

20

40

60

80

100

P=0.009

0 25 50 75 100 125

0

20

40

60

80

100

P<0.001

Median: 37 months

5 years

30%

62%

5 years

59%

87%

PFS OS

Months Months

Paiva et al. Blood. 2008;112:4017–4023

Medians: not reached

PROGNOSTıC ıMPACT OF MAıNTAıNıNG MOLECULAR REMıSSıON 6 MONTHS AFTER CONSOLıDATıON THERAPY

0.00

0.25

0.50

0.75

1.00

33 32 28 24 19 6 431 31 31 28 18 6 3

Number at risk

0 6 12 18 24 30 36analysis time

PFS

p = 0.0023

H.R. 0.18 95% CI (0.05-0.62) p = 0.007

MCR positive

MCR negative

MCR positiveMCR negative

Terragna C et al unpublished data

PFS ACCORDING TO POST-ASCT PET/CT IN PATIENTS ACHIEVING CR

Zamagni et al. Blood. 2011;118:5989-95.

PFS ACCORDING TO POST-ASCT PET/CTIN PATIENTS ACHIEVING CR

Zamagni et al. Blood. 2011;118:5989-95.

0.00

0.25

0.50

0.75

1.00

33 32 28 24 19 6 431 31 31 28 18 6 3

Number at risk

0 6 12 18 24 30 36analysis time

PFS

p = 0.0023

H.R. 0.18 95% CI (0.05-0.62) p = 0.007

MCR positive

MCR negative

MCR positiveMCR negative

Terragna C et al , EHA 2011, oral presentation

Impact of MRD detection by PCR techniqueson clinical outcomes after high-dose tx and ASCT

Thalidomide maintenance and OS: Meta-analysis of randomized studies

Morgan GJ, et al. Blood. 2012;119:7-15.

Number of patients with at least one SPM (10/2011)Lenalidomide

(N= 306)

Placebo

(N= 302)

Total

(N= 608)

Hematologic malignancies (%) 13 (4.2) 5 (1.7) 18 (3.0)

AML/MDS 5 4

ALL 3 0

Hodgkin lymphoma / Non-HL 4 / 1 0 / 1

Solid tumours (%) 10 (3.3) 4 (1.3) 14 (2.3)

Esophageal / Colon 4 0

Breast 2 0

Lung / Sinus 1 1

Kidney / Prostate 3 2

Melanoma 0 1

Non-Melanoma skin cancers (%) 5 (1.6) 3 (1.0) 8 (1.3)

Total (%) 26* (8.5) 11** (3.6) 37 (6.1).Attal et al N Engl J Med 2012

IFM 2005-02: Risk Factors for SPM

Factors (Multivariate Analysis) P valueTreatment (Placebo vs Len) 0.03

Age (<=55 y vs >55 years) 0.02

Sex (M vs F) 0.03

ISS (I +II vs III) 0.002

Cumulative dose of Len• Consolidation only• < 12 m• 12 - 24 m• >24 m

HR1

1.82.43.6

P

0.20.0550.015

Courtesy by M. Attal

Secondary Cancers with Lenalidomide Maintenance: Considerations

• Small increase in incidence, but.....o IFM study included skin cancerso CALGB study had several cases even before starting drug

• EMA released statement in Sept 2011o “The benefit-risk balance for lenalidomide remains positive

within its approved patient population but advises doctors of the risk of new cancers as a result of treatment with the medicine”x 3.98 new cancers per every 100 patient-years with lenalidomide compared with

1.38 cases without lenalidomide in the approved populationx Risk of secondary cancers was increased four-fold with the use of lenalidomide

in newly diagnosed individuals

• Other factors likely contribute to these observations

1Press Release 23 Sept 2011, European Medicines Agency, www.ema.europa.eu

http://www.ema.europa.eu/

MDS-Associated Cytogenetic Abnormalities (CA) after High-Dose Melphalan and ASCT for Myeloma

105/3077 developed MDS CA • Transient in 72• MDS in 21; AML in 5

Predictors• Age• Lower CD34+ cell yields

Predictors for TT2 and TT3• Early onset MDS CA-- longer

time from dx and lower platelet count before ASCT

• Late onset MDS CA– post-ASCT consolidation chemotherapy

• No effect of thalidomide

1Barlogie B, et al. Blood 2008; 111: 95-100.

Secondary Malignancies Potential Factors

Possible relationship to immunomodulatory effects of

lenalidomide:• Meta-analysis of 74 RCTs of anti-TNFα monoclonal antibody therapy showed

relative risk of 2.09 for non-melanoma skin cancers and 0.99 for all other

cancers1

• Risk of skin cancers and lymphoma is higher in organ transplant recipients2

Updated analyses of secondary cancers in myeloma patients treated

with ASCT, IMiDs and bortezomib

ASH 2011 abstracts #’s 678, 823, 996, 2933, 4087

1 Askling J, et al. Pharmoepidemilo Drug Saf 2011; 20: 119-1302 Metcalfe MJ, et al. Can Resp J 2010; 17: e7-13

AGENT / REGIMEN

N°CYCLES

PROBABILITY TO UPGRADE RESPONSE (%) PFS OS

Bortezomib vs 6 ≥ VGPR*: 71 27 mos(median)

no consolidation 1 / ≥ VGPR*: 57 20 mos(median)

VTD 2 4 CR: 34 60 mo (median)

89% (3-yr)

molecular CR: 15 > PFS > OS

Lenalidomide 3 2 CR: 6 not eval. not eval.≥ VGPR: 10 not eval. not eval.

VTD 4,5 2 CR: 33 >PFS not sign.molecular CR: yes


1.Mellqvist et al. Haematologica 2011; 96(suppl 1). Abstract 0112.Ladetto et al, J Clin Oncol 2010;28:2077-2084.3.Attal et al. Blood 2009;114(22). Abstract 529.4.Cavo et al. Blood 2010;116(21). Abstract 42.5.Terragna et al. Blood 2010;116(21). Abstract 861.

NOVEL-AGENT-BASED CONSOLıDATıON THERAPY

RESPONSE TO DIFFERENT TREATMENT PHASES IN THE PER-PROTOCOL POPULATION, ACCORDING TO CENTRAL ASSESSMENT

Cavo et al. Blood 2012; in press

VTD (n=160) TD (n=161) P-value

After second ASCT

CR 78 (48.7%, 41.0–56.5) 65 (40.4%, 32.8–47.9) .131

CR/nCR 101 (63.1%, 55.6–70.6) 88 (54.7%, 47.0–62.3) .123

After consolidation therapy

CR 97 (60.6%, 53.0–68.2) 75 (46.6%, 38.9–54.3) .012

CR/nCR 117 (73.1%, 66.2–80.0) 98 (60.9%, 53.3–68.4) .020

CRUDE INCIDENCE OF SPM

IFM CALGB

n (%) Len(n = 306)

PBO(n = 302)

Len(n = 216)

PBO(n = 210)

Median follow-up 35 months 25 monthsAML 3 (1.0) 2 (0.7) 4 (1.9) 0MDS 2 (0.7) 0 3 (1.4) 0MDS to AML 0 0 0 0

B-ALL & Hodgkin lymphoma 6 (2.0) 0 2 (0.9) 0

Other hematol. malignancies 0 0 0 0

Total* hematol. malignancies 11 (3.6) 2 (0.7) 9 (4.2) 0

Solid tumors 6 (2.0) 1 (0.3) 8 (3.7) 4 (1.9)

Total* invasive SPMs 17 (5.6) 3 (1.0) 17 (7.9) 4 (1.9)

Non-melanoma skin malignancies 4 (1.3) 2 (0.7) 2 (0.9) 2 (1.0)

Total* all SPMs 19 (6.2) 5 (1.7) 19 (8.8) 6 (2.9)

TREATMENT PARADıGM FOR PATıENTS WHO ARE ELıGıBLE FOR AUTOTRANSPLANTATıON (ASCT)

Induction therapy

Autograft 1 ± 2 Maintenance

• VAD• DEX

• DEX• IFN


Novel agents

Induction therapy

Autograft 1 ± 2 Consolidation Maintenance

GOALS OF NOVEL-AGENT-BASED ıNDUCTıON THERAPıES

• To enhance the depth of response up to the VGPR,

nCR and CR level

• To quickly reverse disease-related complications,

such as hypercalcemia, renal failure and anemia

• To ameliorate patient’s symptoms

• To enable successful collection of PBSCs

• To minimize toxicities precluding subsequent ASCT

Cavo et al. Blood 2011;117:6063-6073




t(4;14) ± del(17p) 1.8 (1.4-2.5) <0.001

Β2-m > 3.5 mg/l 2.0 (1.5-2.6) <0.001



0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36Months

nCR+CR

< nCR

p=0.0106


Cavo M et al, unpublished data




t(4;14) ± del(17p) 1.9 (1.5-2.6) <0.001

Β2-m > 3.5 mg/l 1.8 (1.4-2.4) <0.001



nCR+CR

< nCR

p=0.0106


Cavo et al, unpublished data NUOVA

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36Months

< nCR

nCR+CR

p=0.0021


REGIMEN CYCLES % ≥ CR % ≥ VGPR % ≥ CR % ≥ VGPR

TD1 4 not rep. 35 not rep. 60

VAD 4 not rep. 13 not rep. 30.5

TD2 4 not rep. 25 not rep. 44

VAD 4 not rep. 7 not rep. 42

PHASE 3 STUDIES OF THALIDOMIDE-BASED INDUCTION REGIMENS

1.Cavo et al. J Clin Oncol 2009;27(30):5001-5007.2.Macro et al. Blood 2006;108. Abstract 57

% INDUCTION % ASCTREGIMEN CR ≥ VGPR CR ≥ VGPR PFS OS

TT2 + Thal vs NR NR 59 (3-yr)* NR 56% (5-yr)* 67% (5-yr)*TT2 no Thal 1 NR NR 42 (3-yr)* NR 45% (5-yr)* 65% (5-yr)*TAD + Thal vs 3 37* 14 54* 34 mo* 73 moVAD + IFN 2 2 18* 12 44* 22 mo* 60 moVD+Len±Len vs 6 38* 16* 54* 36 81% (3-yr)VAD+Len±Len 3 1* 15* 9* 37* 30 77% (3-yr)PAD+Bort vs NR 42* NR 61* 36 mo* HR = 0.73*VAD+Thal 4 NR 15* NR 36* 27 mo* Not reach.

PHASE 3 STUDıES OF NOVEL AGENTS ıNCORPORATED ıNTO AUTOTRANSPLANTATıON


1.Barlogie et al. N Engl J Med. 2006;354(10):1021-1030.2.Lokhorst et al. Blood 2010;115(6):1113-1120.3.Harousseau et al. J Clin Oncol. 2010;28(30):4621-4629.4.Sonneveld et al. Blood 2010;116(21). Abstract 40

% INDUCTION % ASCTREGIMEN CR ≥ VGPR CR ≥ VGPR PFS OS

TT2 + Thal vs NR NR 59 (3-yr)* NR 56% (5-yr)* 67% (5-yr)*TT2 no Thal 1 NR NR 42 (3-yr)* NR 45% (5-yr)* 65% (5-yr)*TAD + Thal vs 3 37* 14 54* 34 mo* 73 moVAD + IFN 2 2 18* 12 44* 22 mo* 60 mo

VD+ Len ± Len vs 6 38* 16* 54* 36 81% (3-yr)

VAD+ Len ± Len 3 1* 15* 9* 37* 30 77% (3-yr)

PAD + Bort vs NR 42* NR 61* 36 mo* HR = 0.73*VAD + Thal 4 NR 15* NR 36* 27 mo* Not reach.VTD + VTD vs 19* 62* 42* 82* 68% (3-yr)* 86% (3-yr)*TD + TD 5 5* 28* 30* 64* 56% (3-yr)* 84% (3-yr)*VTD vs 35* 60* 46* 65* Not reach.* Not reach.TD 6 14* 29* 24* 40* 27 mo* Not reach.vTD vs 13* 51* 30* 61* Not reach. Not reach.VD 12* 35* 33* 54* Not reach. Not reach.


1.Barlogie et al. N Engl J Med. 2006;354(10):1021-1030.2.Lokhorst et al. Blood 2010;115(6):1113-1120.3.Harousseau et al. J Clin Oncol. 2010;28(30):4621-4629.4.Sonneveld et al. Blood 2010;116(21). Abstract 40

5.Cavo et al. Lancet 2010;379(9758):2075-2085.6.Rosiñol et al. Blood 2010;116(21). Abstract 307.7. Harousseau et al. Blood 2009;114(22). Abstract 354.

PHASE 3 STUDıES OF NOVEL AGENTS ıNCORPORATED ıNTO AUTOTRANSPLANTATıON

EFFECT OF NOVEL AGENTS ON STEM CELL COLLECTION

Thalidomide• Adequate collection of stem cells 1,2

1. Breitkreutz et al. Leukemia 2007;21:1294–12992. Cavo et al. Blood 2005;106:35-393. Kumar et al. Blood 2009;114:1729-17354. Moreau et al. Leukemia 2010;24:1233-12355. Cavo et al. Lancet 2010;376:2075-2085

Bortezomib• Not cytotoxic to bone marrow

• Successful mobilization and adequate collection of PBSC with variety of induction regimens 3-5

REGIMEN Priming therapy Collected CD34+ (x106/kg)

VD4 G-CSF 6.8

VTD5 CTX + G-CSF 9.7

Kumar et al. Blood 2009;114:1729-1735

Lenalidomide

• Cytotoxic effect on bone marrow

• Evidence of decreased stem cell yield after lenalidomide exposure

• Recommendation:

- Collection of PBSC within 4 months of initiation of therapy

- Mobilization with G-CSF + cyclophosphamide after 4 months of

therapy and/or in patients aged ≥ 65 years

EFFECT OF NOVEL AGENTS ON STEM CELL COLLECTION

PROBABILITY TO UPGRADE FROM < CR TO CR

WITH VTD AND TD AS CONSOLIDATION THERAPY AFTER ASCT

TD: 17% VTD: 31%

p = 0.030*

*Pearson χ2 significance probability

Attal et al. NEJM 2012;366(19):1782-1791

IFM 2005-02: EFS (as of October 2011)

Avet-Loiseau et al. JCO 2010;28:4630-4634

treatment paradigms... · randomization. induction (three 21-d cycles) vel-thal-dex • vel...

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