Should Alkylators be used Upfront in Transplant-Ineligible Patients?

NO!!

Lymphoma-Myeloma

October 2013

Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida

Joseph Mikhael, MD, MEd, FRCPC, FACPStaff Hematologist, Mayo Clinic Arizona

Objectives

1. Review the emerging data regarding replacing “MP” as backbone in upfront therapy

2. Provide practical advice as to initiating therapy in older patients with myeloma

3. Unequivocally defeat my friend Antonio in this debate

4. Concede that cyclophosphamide may be an exception to this general rule

Summary Points – Why Melphalan is no longer standard

of initial care in elderly patients

1. Novel agents are equivalent if not superior to MP+novel agent

2. MP+ results in greater short term toxicity

3. As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity

4. Melphalan can lead to increased second primary malignancies

mSMART 2.0: Classification of Active MM

FISH Del 17p t(14;16) t(14;20)

GEP High risk

signature

All others including: Hyperdiploid t(11;14) t(6;14)

FISH t(4;14)*

Cytogenetic Deletion 13 or hypodiploidy

PCLI >3%

High-Risk 20% Intermediate-Risk 20% Standard-Risk 60%

3 years 4-5 years 8-10 years

Mikhael et al Mayo Clinic Proceedings April 2013

mSMART – Off-StudyTransplant Ineligible

Observation

Intermediate Risk Standard Risk*

MP + weekly Bortezomib or weekly CyBorD

Bortezomib maintenance

Rd

Mikhael et al Mayo Clinic Proceedings April 2013

High Risk

VRd

Argument #1

Novel agents are equivalent if not superior to MP+novel agent

MPT1

N = 129VMP2

N = 337MPR3

N = 153MPR-R4

N = 152VTP5

N = 130

CR 16% 30% 11% 16% 27%

> VGPR 29% Not reported 33% 32% 37%

> PR 69% 71% 68% 77% 81%

PFS 21.8 mo TTP: 24.0 mo 14 mo 31 mo 23 mo

Median follow-up

31.8 mo 36.7 mo 25 mo 25 mo 22 mo

1Palumbo A, et al. Blood. 2008;112:3107-3114; 2Mateos MV, et al. Blood. 2009;114(22). Abstract 3859;

3,4Palumbo A, et al. Blood. 2010;116(21). Abstract 622 and Abstract 566; 5Mateos MV, et al. Blood. 2009;114(22). Abstract 3.

MPT: melphalan, prednisone, thalidomide; VMP: bortezomib, melphalan, prednisone; MPR: melphalan, prednisone, lenalidomide; MPR-R: MPR with maintenance lenalidomide; VTP: bortezomib, thalidomide, prednisone.

Newly Diagnosed, Patients SCT Ineligible

Primary Study SchemaPrimary Study Schema

RANDOMIZATION

445 patients

RDx 4 cycles

Rdx 4 cycles

Less than PR

CR/PR

Thal + Dexx 4 cycles

Patients can go off and proceed to SCT

CR/PR/stable

Rajkumar et al

lenalidomide plus RD versus lenalidomide plus Rd in newly diagnosed MM

BEST RESPONSE: > PR*

RD [n] Rd [n] Odds

Ratio

Fisher's

Exact

Overall 81.3% [214] 70.2% [208] 1.85 p=0.009

< 65 85.4% [103] 66.0% [103] 3.02 p=0.002

> 65 77.5% [111] 74.3% [105] 1.19 p=0.634

> 70 74.6% [71] 73.8% [65] 1.04 p=1.000

> 75 77.8% [36] 70.4% [27] 1.47 p=0.566

*Same observations with VGPR except age > 70 42.3% vs 47.7%

ResultsResultsSecond Interim Analysis RD vs. RdSecond Interim Analysis RD vs. Rd

Rajkumar et al, 2010.

RD RdCR + PR 79% 68%

1 year OS 87% 96%

Grade 3 or worse AE

52% 35%

RD did not result in superior TTP, PFS, or OS compared to Rd

OS at 1-year was significantly better with Rd than RD, resulting in early closure of the trial

Overall Survival-ITT

Age > 65 yrs

Age > 65

Age > 70Age < 65

Age > 75

Status

RD

N=223 (%)

Rd

N=220 (%)

Total*

N=443Treatment End by Mandatory Crossover

Yes 195 (87.4) 169 (76.8) 364No 28 (12.6) 51 (23.2) 79

Survival Rate by AgeN 12 month

survival probability (95%CI)

24 month

survival

probability

(95%CI)

Age <65

Len-High Dex 104 0.92 (0.87-0.98) 0.86 (0.79-0.93)

Len-Low Dex 108 0.96 (0.93-1.00) 0.92 (0.87-0.97)

Age ≥65

Len-High Dex 119 0.84 (0.78-0.91) 0.72 (0.64-0.81)

Len-Low Dex 114 0.95 (0.91-0.99) 0.85 (0.79-0.92)

650 patients (older than 65 years) randomized from 5 countries

Patients: Symptomatic disease, organ damage, measurable disease

Treatment schedule

RdNine 28-day coursesR: 25 mg, d 1-21d: 40 mga or 20 mgb, d 1,8,15,22

CRPNine 28-day coursesC: 50 mg/daya or 3 times wkb

P: 25 mg, 3 times wkR: 25 mg, d1-21

1°RANDOMIZATION

2°RANDOMIZATION

MAINTENANCE 28-day course until relpaseR: 10 mg/day, days 1-21 P: 25 mg; 3 times wk

MAINTENANCE28-day courses until relapseR: 10 mg/day, days 1-21

MPRNine 28-day coursesM: 0.18 mg/kga or 0.13 mg/kgb, d 1-4P: 1.5 mg/kg, d 1-4R: 10 mg, d1-21

a Pts ≤ 75 yrs; b Pts > 75 yrs; C, cyclophosphamide; R, lenalidomide; M, melphalan; P, prednisone

Rd vs MPR vs CRPRd vs MPR vs CRPProgression Free Survival

Median follow-up 21 months

Rd CPR MPRvs. vs.Rd CPR MPRvs. vs.

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20 25 30 35 40

Larocca A, et al. IMW 2013

months

Pro

port

ion

of p

atie

nts

Rd, lenalidomide-dexamethasone; CPR, cyclophosphamide-prednisone-lenalidomide; MPR, melphalan-prednisone-lenalidomide;

Vsc, subcutaneous bortezomib; C, cyclophosphamide; M, melphalan; P, prednisone

VPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22P: 50 mg, 3 times wk

VCPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22C: 50 mg, 3 times wkP: 50 mg, 3 times wk

1°RANDOMIZATION

MAINTENANCE 28-day course until relpaseVsc: 1.3 mg/sqm, d 1, 15 P: 25 mg; 3 times wk

150 patients (> 75 years) randomized from 3 countries

Patients: Symptomatic disease, organ damage, measurable disease

Treatment schedule

VMPNine 35-day coursesVsc: 1.3 mg/sqm, d 1,8,15,22M: 2 mg, 3 times wkP: 50 mg, 3 times wk

MAINTENANCE 28-day course until relpaseVsc: 1.3 mg/sqm, d 1, 15 P: 25 mg; 3 times wk

MAINTENANCE 28-day course until relpaseVsc: 1.3 mg/sqm, d 1, 15 P: 25 mg; 3 times wk

Larocca A, et al. Gr. Emat. Milano 2012Larocca A, et al. Gr. Emat. Milano 2012

SubcutaneousVP vs VMP vs VCP

SubcutaneousVP vs VMP vs VCP

Progression Free Survival

Median follow-up 14 months

CVP VMP VPvs. vs.CVP VMP VPvs. vs.

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20 25

months

Pro

port

ion

of p

atie

nts

CVP, cyclophosphamide-bortezomib-prednisone; VMP, bortezomib-melphalan-prednisone; VP, bortezomib-prednisone; VD, bortezomib-dexamethasone;

Conclusion #1

• MP is not necessary

• Lenalidomide-dexamethasone and bortezomib-dexamethasone are effective and viable options

Argument #2

MP+ results in greater short term toxicity

Discontinuation reduces dose-intensityDiscontinuation reduces dose-intensity

3-drug 2-drug

Discontinuation %

65 - 75 years 17 10

> 75 years 34 16

Cumulative dose intensity %

65 - 75 years 88 97

> 75 years 56 97

3-drug 2-drug

Discontinuation %

65 - 75 years 17 10

> 75 years 34 16

Cumulative dose intensity %

65 - 75 years 88 97

> 75 years 56 97

Palumbo A, et al. EHA 2011;96:0514

Melphalan-prednisone-lenalidomide: MPR-R vs MPR vs MP

Melphalan-prednisone-lenalidomide: MPR-R vs MPR vs MP

R1:1:1

N = 459

•Newly diagnosed•Transplant-ineligible MM•Stratified by

– age (65–75 vs> 75 years)

– disease stage (ISS I/II vs III)

MPR-R (n = 152)M: 0.18 mg/kg, days 1–4P: 2 mg/kg, days 1–4R: 10 mg/day p.o., days 1–21

MPR (n = 153)M: 0.18 mg/kg, days 1–4P: 2 mg/kg, days 1–4R: 10 mg/day p.o., days 1–21

MP (n = 154)M: 0.18 mg/kg, days 1–4P: 2 mg/kg, days 1–4PBO: days 1–21

Dis

eas

e pr

ogre

ssio

n

Lena

lidom

ide

25 m

g/da

y ±

Dex

Double-blind treatment Open-label

Cycles (28-day) 1–9 Cycles 10+

Maintenance

Lenalidomide10 mg/day; days 1–21

Placebo

Placebo

* All patients received thromboprophylaxis during induction; thromboprophylaxis could be continued during maintenance at physician’s discretion.

Palumbo A, et al. N Engl J Med. 2012;366:1759-69.

MPR-R, melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; MPR, melphalan-prednisone-lenalidomide; MP, melphalan-prednisone; PBO, placebo

MPR-R: landmark PFS analysis by ageMPR-R: landmark PFS analysis by age

Palumbo A, et al. Haematologica. 2011;S238:[abstract 514; presented at EHA 2011].

> 75 years of age

INDUCTION MAINTENANCE

Disc. for AEs

%

*Dose intensity - % Disc. for AEs

%

*Dose intensity - %

Len Mel Pred Len

28 76 85 89 17 87

INDUCTION MAINTENANCE

Disc. for AEs

%

*Dose intensity - % Disc. for AEs

%

*Dose intensity - %

Len Mel Pred Len

28 76 85 89 17 87

INDUCTION MAINTENANCE

Disc. for AEs

%

*Dose intensity - % Disc. for AEs

%

*Dose intensity - %

Len Mel Pred Len

12 88 91 94 8 92

INDUCTION MAINTENANCE

Disc. for AEs

%

*Dose intensity - % Disc. for AEs

%

*Dose intensity - %

Len Mel Pred Len

12 88 91 94 8 92

65-75 years of age

* Median relative dose

* Median relative dose

100 5 15 20 250

25

50

75

100

100 5 15 20 25100 5 15 20 250

25

50

75

100

0

25

50

75

100

HR 0.297p = 0.030

MPR-R

MPR

Lenalidomide continuous therapyMPR Lenalidomide continuous therapyMPR

Time (months)Cycle 10

HR 0.349p < 0.001

MPR-R

MPR

Time (months)Cycle 10

0 5 10 15 20 25 300

25

50

75

100

0 5 10 15 20 25 300 5 10 15 20 25 300

25

50

75

100

0

25

50

75

100

Lenalidomide continuous therapyMPR Lenalidomide continuous therapyMPR

New treatment algorithm for elderly MM

PATIENT STATUS ASSESSMENT

- Age

- ADL

- IADL

- Charlson co-morbidity score

FIT UNFIT FRAIL

Age <80 yr

ADL 6

IADL 8

Charlson 0

Fit >80 yr

ADL 5

IADL 6-7

Charlson 1

Unfit >80 yr

ADL ≤4

IADL ≤5

Charlson ≥2

Full-dose regimensDose level 0

Reduced-dose regimensDose level -1

Reduced-dose Palliative approach

Dose level -2

PATIENT STATUS ASSESSMENT

- Age

- ADL

- IADL

- Charlson co-morbidity score

FIT UNFIT FRAIL

Age <80 yr

ADL 6

IADL 8

Charlson 0

Fit >80 yr

ADL 5

IADL 6-7

Charlson 1

Unfit >80 yr

ADL ≤4

IADL ≤5

Charlson ≥2

Full-dose regimensDose level 0

Reduced-dose regimensDose level -1

Reduced-dose Palliative approach

Dose level -2

Go-go moderate-go slow-go

ADL, Activity of Daily Living; IADL, Instrumental Activity of Daily Living; ASCT, autologous stem cell transplantation

PATIENT STATUS ASSESSMENT

- Age > 80 years

- ADL, , Activity of Daily Living

- IADL, Instrumental Activity of Daily Living

- Charlson co-morbidity score

PATIENT STATUS ASSESSMENT

- Age > 80 years

- ADL, , Activity of Daily Living

- IADL, Instrumental Activity of Daily Living

- Charlson co-morbidity score

Rd Lenalidomide Dex; Vd Bortezomib Dex ; CCd Carfilzomib Cyclophosphamide Dex

MPVdMPVdMPRdMPRdlower frequency of SAE

better outcome in frail patients

• lower doses• 2 drug combination• 2 drugs 3 drugs or higher doses

CCdCCd

ConclusionConclusion

Conclusion #2

• 3 drug regimens that include melphalan are more toxic (and not necessarily more effective)

• Dose reduction is critical in the elderly

Argument #3

As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity

CP1315995-1

Multiple Myeloma 1971-2006n=2,981

0.0

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80 100 120 140

Pro

port

ion

surv

ivin

gP

ropo

rtio

n 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 1996Diagnosis during/before 1996

P<0.001P<0.001

Survival, med44.8 moSurvival, med44.8 mo

Survival, med29.9 moSurvival, med29.9 mo

Multiple MyelomaMayo Patients

2001-2005

2006-2010

47%

66%P < 0.0001

S. Kumar, 2012

Argument #4

Melphalan can lead to increased second primary malignancies

Solid SPMs

Cumulative incidence (95% CI)

Lenalidomide onlyLenalidomide + cyclophosphamideLenalidomide + melphalan

Melphalan only

36 months 60 months

0.3 (0.0-0.07) 1.3 (0.0-2.7)0.3 (0.0-0.09) -1.8 (1.0-2.6) 3.9 (2.3-5.5)

0.4 (0.0-0.09) 1.4 (0.0-3.6)

Cumulative incidence (95% CI)

Lenalidomide only

Lenalidomide + cyclophosphamideLenalidomide + melphalan

Melphalan only

36 months 60 months

2.2 (0.7-3.7) 2.6 (0.9-4.3)

3.5 (0.0-8.3) -2.7 (1.8-3.7) 4.4 (2.9-5.8)

2.9 (1.4-4.4) 3.4 (1.6-5.2)

Cumulative incidence of SPMsDifferent lenalidomide combinations

Months

Hematologic SPMs

Months

0 20 40 60

Melphalan only

Lenalidomide only

Lenalidomide + cyclophosphamide

Lenalidomide + melphalan

Melphalan only

Lenalidomide only

Lenalidomide + cyclophosphamide

Lenalidomide + melphalan

HR 3.8 (95% CI 2.11-6.86), p<0.001

0

0.05

0.10

0.04

0.03

0.02

0.01

0.09

0.08

0.07

0.06

0

0.05

0.10

0.04

0.03

0.02

0.01

0.09

0.08

0.07

0.06

0 20 40 60 80

HR 1.09 (95% CI 0.73-1.63), p=0.67

0

0.05

0.10

0.04

0.03

0.02

0.01

0.09

0.08

0.07

0.06

0

0.05

0.10

0.04

0.03

0.02

0.01

0.09

0.08

0.07

0.06

Melphalan only

Lenalidomide only

Lenalidomide + cyclophosphamide

Lenalidomide + melphalan

Melphalan only

Lenalidomide only

Lenalidomide + cyclophosphamide

Lenalidomide + melphalan

Incidence rate per 100 per yearDifferent lenalidomide combinations

Hematologic SPMs

0 0,5 1 1,5 2

Melphalan only

Hematologic SPMs

0 0,5 1 1,5 2

Melphalan only

Lenalidomide + melphalanLenalidomide + melphalan

Lenalidomide + cyclophosphamideLenalidomide + cyclophosphamide

Lenalidomide onlyLenalidomide only

Lenalidomide + melphalanLenalidomide + melphalan

Lenalidomide + cyclophosphamideLenalidomide + cyclophosphamide

Lenalidomide onlyLenalidomide only

Solid SPMs

0 0,5 1 1,5 2

Melphalan only

Incidence Rate per 100 per year

Solid SPMs

0 0,5 1 1,5 2

Melphalan only

Incidence Rate per 100 per year

Cumulative incidence (95% CI) 36 months 60 months

Oral melphalan 2.8 (1.3-4.3) 7.2 (3.0-11.4)

IV melphalan (ASCT) 1 (0.1-1.8) 2 (0.5-3.5)

Cumulative incidence (95% CI) 36 months 60 months

Oral melphalan 2.8 (1.3-4.3) 7.2 (3.0-11.4)

IV melphalan (ASCT) 1 (0.1-1.8) 2 (0.5-3.5)

Cumulative incidence of hematologic SPMsOral versus high-dose intravenous melphalan

Len, lenalidomide; Mel, melphalan; IV, intravenous; ASCT, autologous stem cell transplantation

0 20 40 60 80

0

0.05

0.10

0.15

Months

Cu

mu

lativ

e In

cide

nce

Len + oral melphalan

Len + IV melphalan (ASCT)

HR: Oral Mel vs IV Mel 3.3 (1.46-7.46), p=0.004

Melphalan only

Lenalidomide only

0 20 40 60 80

0

0.05

0.10

0.15

Months

Cu

mu

lativ

e In

cide

nce

Len + oral melphalan

Len + IV melphalan (ASCT)

HR: Oral Mel vs IV Mel 3.3 (1.46-7.46), p=0.004

Melphalan only

Lenalidomide only

Incidence rate per 100 per yearOral versus high-dose intravenous melphalan

Solid SPMs

0 0,5 1 1,5 2

Melphalan only

Lenalidomide + IV melphalan (ASCT)

Lenalidomide + oral melphalan

Lenalidomide only

0 0,5 1 1,5 2

Melphalan only

Lenalidomide + IV melphalan (ASCT)

Lenalidomide + oral melphalan

Lenalidomide only

Incidence Rate per 100 per year

Hematologic SPMs

0 0,5 1 1,5 2

Melphalan only

Lenalidomide + IV melphalan (ASCT)

Lenalidomide + oral melphalan

Lenalidomide only

Melphalan only

Lenalidomide + IV melphalan (ASCT)

Lenalidomide + oral melphalan

Lenalidomide only

The “NEW” CyBorD• All three drugs given weekly

• Cyclophosphamide 300mg/m2 PO• Bortezomib 1.5 mg/m2 IV or SQ• Dexamethasone 40mg PO

• We consider one cycle a 4 week course

• No “week off”

• Less neuropathy, more convenience, equal efficacy

• Always give viral prophylaxis

Comment – I see CyBorD as a slight modification to VMP

Summary Points – Why Melphalan is no longer standard

of initial care in elderly patients

1. Novel agents are equivalent if not superior to MP+novel agent

2. MP+ results in greater short term toxicity

3. As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity

4. Melphalan can lead to increased second primary malignancies

Quote – ASCO 2013 – Dr. Antonio Palumbo

“Gli Americani avevano ragione: non dobbiamo usare melphalan come terapia iniziale nei pazienti anziani”

“The Americans were right – we should not use melphalan upfront in elderly patients”