Treatment of Transplant Ineligible/Elderly MM Patients

Treatment of Transplant Ineligible/Elderly MM Patients

Ruben Niesvizky Department of Medicine, Division of Hematology/Oncology,

Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA

[email protected]

Disclosures

•Speaker’s bureau: Celgene, Millennium, Onyx

Case

• 65 year-old Hispanic male– Presents to emergency room with chest pain, fatigue;

found with:• Creatinine: 5.0• Hemoglobin: 8.9• Multiple lytic lesions• Total urine protein: 20 gm/24 hr• UPEP: 19.4 gms kappa light chain• SPEP: 0.1 monoclonal peak

• β2M: 15.0

• BM: 50% plasma cells

Case Discussion

As you discuss with him his disease and his prognosis, he is concerned that his age precludes him from aggressive therapy. You advise him:

1. He is a “young person with lots of experience,” and his age should not preclude him from receiving aggressive therapy with the intent of changing the natural history of his disease

2. Patients over the age of 65 should not be considered for aggressive therapies

• Nearly half of multiple myeloma patients are considered elderly

• Current distinction of elderly based on transplant eligibility (European and North American trials)

Patients under 65 years of age, 35% Older patients from 65 to 75 years of age, 28%Elderly patients over 75, 37%

The Elderly Patient

The median age at diagnosis is 70 years

.

Eld

erly

Old

er

37%

28%

35%

Palumbo A, et al. Hematology Am Soc Hematol Educ Program. 2009:566-577.; Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5 Version 2.0. Lyon: IARC Press; 2004.; Ries LAG, et al. National Cancer Institute. SEER Cancer Statistics Review. Source: SEER 13. Accessed August 24, 2010 at: http://seer.cancer.gov/faststats

< 65 years >65 years

Myeloma: 5-year Relative Survival Rates

42.9% 25.2 %

SEER 1995-2001

Novel Agent Limitations in the Aging Population

Median OS<65 60 m

Median OS>65 32 m

Kumar et al. Blood 2007

What is the goal of treatment (does CR matter)?

What is the best induction treatment?

Is it possible to individualize the treatment?

Can novel drugs improve outcome

Treatment of Elderly MM PatientsLeading Questions




Median not available, OS calculated from 2yr (San Miguel), 3yr (Palumbo) and 5yr (Zervas) estimates

Keldsen 1993

Hulin 2007

Facon 2006

Facon 2007

Palumbo 2006

Osterborg 1993

Oken 1999

San Miguel 2007

Zervas 2001

Hernandez 2004

Ludwig 2007

Joshua 1997

Waage 2007

MEAN

-20 -15 -10 -5 0 5 10 15 20 25 30 35 40

Percent Improvement in Survival

• 5 of 13 studies failed to show association: primarily due to the confounding effect of a therapy that generates high CR and is simultaneously too toxic

• Two polarizing impact of a therapy on survival (higher CR leading to longer survival vs higher toxicity leading to shorter survival) confounds analysis

Mean = 3.6%

ΔCR/nCR OS ΔOS

+10% 35m +12.6m

+10% 50m +18m

• Medline/OVID search from 1980 – Mar 2008• 13 studies (4396 patients) meeting the criteria: randomized comparative trials in newly

diagnoses MM reporting CR or CR/nCR and survival (either median survival or survival rate)

• Percent improvement in survival for each percent increase in the CR/nCR rate was calculated for each study

CR in Non-Transplant Settingvan de Velde et al. Haematologica 2007

Hematologic CR Correlates with Long-term PFS and OS in Elderly Patients Treated with Novel Agents

Gay et al. Blood 2011; 117(11):3025-31

PFS OS

P<0.001 P<0.001

CR

VGPR

PR

CR

VGPR

PR

Pro

bab

ility

Pro

bab

ility

• Retrospective analysis: 3 randomized European trials of GIMEMA and HOVON groups (N=1175)

• First-line treatment

MP (n=332), MPT (n=332), VMP (n=257), VMPT-VT (n=254)

•Significant benefit also seen when analysis is restricted to patients >75 years old

6050403020100

100

80

60

40

20

0

Months

P =0.001

PFS

Immunophenotypic CR 90% at 3y

“Stringent CR” 38% at 3y

Conventional CR 57% at 3y

PR (≥70% reduction) 28% at 3y

Paiva et al; J Clin Oncol. 2011;29(12):1627-33.

The Better the Quality of the Response the Longer the Survival (Immunophenotypic CR): GEM2005>65y

PFS

Sequential Approach NDMM Patients

PAD, bortezomib-pegylated doxorubicin-dexamethasone; MEL100, Melphalan100 mg/m2; Len-Pdn, lenalidomide-prednisone; Len, lenalidomide; PFS, progression-free survival; OS, overall survival; CR, complete response; VGPR, very good partial response; PR, partial response; NDMM, newly diagnosed multiple myeloma

TransplantMEL100two courses

Median follow-up 66 months Median age 70 years

OS according response

monthsmonths monthsmonths monthsmonths

InductionPAD

four 21-day courses

ConsolidationLen-Pdn

four 28-day courses

MaintenanceLen

until progression

0.00

0.25

0.50

0.75

1.00

20 40 60 80 100

CRCR

VGPRVGPR

PRPR

12

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60 70 80

Median 47 moMedian 47 mo

Gay F, et al. Gr. Emat. Milan 19 November 2012Gay F, et al. Gr. Emat. Milan 19 November 2012

CR

PR

P<0.0010.00

0.25

0.50

0.75

1.00

10 20 30 40 50 60

PFS according response

VGPRVGPR

Important Aim of Treatment: Achievement of high-quality, sustained CR

balanced with acceptable toxicity

CR Should Be an Important Objective in Elderly MM Patients



THALIDOMIDE

MPT vs. MP : Efficacy in Newly Diagnosed Elderly Myeloma Patients

3 trials (IFM991, IFM012, HOVON3)………. > RR, PFS & OS 2 trial (GIMEMA4, TURKISH5)………………. > RR, PFS 1 trial (Nordic6 )…………………………….. > RR

RR : 59% vs. 37 % (>22%)

CR : 10% vs. 2,5% (>8 %)

PFS : 20,4 vs. 15 m ( 6 m)………… HR 0,67

OS : 39,3 vs. 32,7 m (>6 m)…………HR 0,83

• Thal maintenance in Italian, Nordic, Hovon

1.Facon et al. Lancet 2007;370:1209–1218; 2. Hulin et al. JCO 2009; 27(22):3664-70 ; 3. Wijermans JCO 2010; 28: 3160-6; 4. Palumbo et al. Blood 2008; 112:

3107–3114; 5. Beksac M et al. Eur J Haematol 2010; 86:16-22; 6. Waage et al Blood 2010;116(9):1405-12; Fayers PM et al. Blood 2011; 118(5): 1239-47

MPT vs. MP : Toxicity

Palumbo A. Haematologica 2012; Epub ahead on August 8Palumbo A. Haematologica 2012; Epub ahead on August 8

*Appropriate thromboprophylaxis is required** p of significant value

MPT MP

Grade 3-4 hematologic Aes 32% 29%

Grade 3-4 non-hematologic Aes 40%** 18% -Infection 13%** 9%

-Peripheral Neuropathy 15%** 3%

-Deep Venous Thrombosis 6%** 2%

-Toxicity-related discontinuations 35%** 5%

Other Thalidomide-based Combinations in Front-line

Study Results Reference

Phase 3

Thal/dex vs MP

• In patients > 75 years, OS longer with MP (41 vs 20m)• In patients <75 years, similar OS • Higher mortality during 1st y with thal/dex vs MP (28 vs 16, p=0.02)

Ludwig et al. Blood,2009 ;113:3435-43

Phase 3

CTDa vs MP

Morgan et al. Blood 2011; 118(5): 1231-8

CTDa MP

≥ PR 64% 33%

CR 13% 3%

OS 33m 31m

Thal/

Dex*MP

≥ PR 73% 42%

TTP 21m 29m

OS 41m 49m

Thal: 200 mg daily; Dex: 40 mg days 1-4; 9-12

LENALIDOMIDE

Secondary Comparison MPR-R vs. MPRAddition of MPR arm per EMEA advice

MPM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4PBO: days 1-21

Primary Comparison MPR-R vs. MP

MPRM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day po, days 1-21

Placebo

Placebo

Lenalidomide(R) +/- MP: MPR-R vs. MPR vs. MP

Phase III Study Scheme N=459 patients > 65years

M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo.

MPR-RM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day po, days 1-21

RA

ND

OM

ISA

TIO

N

Double-Blind Treatment Phase

Diseaseprogression

LenalidomideContinued Tx

Lenalidomide (25 mg/day) +/- dexamethasone

Open-Label Extension/Follow-Up Phase

Stratified by age (≤ 75 vs. > 75 years) and stage (ISS 1,2 vs. 3)

10 mg/day,days 1-21

Cycles (28-day) 1-9 Cycles 10+

Response & PFS: MPR-R vs. MP vs. MPR

%RR (%CR): 77(10) vs. 50(3) vs. 68(3)

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

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

Median follow-up 30 months

HR 0.49 P < .0000001

Time (months)0 5 10 15 20 25 30 35 40

0

25

50

75

100

HR 0.40P = .153

OS: MPR-R vs. MPR vs. MP

Median follow-up 30 months


MPR-R(N = 150)

MPR(N = 152)

MP(N = 153)

Hematological, % G3 G4 G3 G4 G3 G4

Neutropenia 67 35 64 32 29 8

Thrombocytopenia 35 11 38 14 12 4

Non-hematological, %

Infections 9 1 13 2 7 -

DVT 1 - 4 - 1 -

SPM, n 12 9 4

- AML 5 2 -

- MDS 2 3 1

- Non-hematologic SPM 5 4 3DVT, deep vein thrombosis; SMP: Second primary malignancy; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome

AEs During Induction: MPR-R vs. MP vs. MPR


BORTEZOMIB

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

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

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

RANDOMIZE

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

• Stratification: β2-microglobulin, albumin, region

Primary end point: TTPSecondary end points:

CR rate, ORR, time to response, DOR, time to next therapy, OS, PFS, QoL (PRO)

VISTA: Bortezomib (V) as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and

Prednisone

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

disease– ≥ 65 years or < 65 years and not transplant-eligible; KPS ≥ 60%

Bortezomib+MP (VMP) vs. MP: Efficacy Data (682 patients)

San Miguel et al. N Engl J Med 2008;359:906–917; Updated by Mateos et al JCO 2010

ORR: VMP 71%, MP 35%, CR: VMP 30%, MP 4%

0 3 6 9 12

Time (months)

15 18 21 24 27

0

20

40

60

80

100

VMPMP

Pat

ient

s w

ithou

t ev

ent

(%)

Time (months)0 4 8 12 16 20 24 28 32 36 40

0

20

40

60

80

100VMPMP

Pat

ient

s w

ithou

t ev

ent

(%)

Time to progression Overall survival

52% reduced risk of progression on VMP ~36% reduced risk of death on VMP

Median follow-up 36.7 months3-year OS: VMP: 69% MP: 54%, P=0.0008

VMP: 24.0 monthsMP: 16.6 months, P<0.000001

OS (ITT)

31% reduced risk of death with VMP

Median OS benefit: 13.3 months

5-year OS rates: 46.0% vs 34.4%

100

90

80

70

60

50

40

30

20

10

0

Pat

ient

s al

ive

(%)

0 6 12 18 24 30 36 42 48 54 60 66 72 78Time (months)

Number of patients at risk:338 301 262 240 216 196 168 153 133 112 61 24 3344 300 288 270 246 232 216 199 176 158 78 34 1

Group N Event Median HR (95% CI) P-value

MP 338 211 43.1

VMP 344 176 56.4 0.695 (0.567, 0.852) 0.0004

San Miguel et al. ASH 2011; abstract 476

Grade 3/4 Adverse Events

VMP (n=340) MP (n=337)Gr 3 Gr 4 Gr 3 Gr

4 Neutropenia, % 30 10 23 15

Thrombocytopenia, % 20 17 16 14

GI, % 19 1 5 <1

Peripheral Sensory Neuropathy, % 13 <1 0 0

Pneumonia, % 5 2 4 1

Herpes Zoster, % 3 0 2 0

Hematological SPM*, n(%) 3(1%) 3(1%)

Non-hematological SPM*, n(%) 16(5%) 10(3%)

San Miguel et al. ASH 2011; abstract 4761Howlader N, et al. SEER Cancer Statistics Review, 1975-2008.

http://seer.cancer.gov/csr/1975_2008/browse_csr.php?section=2&page=sect_02_table.07.html

Progress in the Treatment of Elderly Patients with MM

•Novel agents SHOULD be included: •Evidence based: bortezomib, lenalidomide > thalidomide•Generating promising data: lenalidomide, bortezomib, carfilzomib



• 8% if fully independent

• 14% if dependent in IADL

• 27% if dependent in ADL

• 40% if institutionalized

2-Year Mortality Rate for Persons Age 70 Years and Older

Reuben. Am J Med. 1992;93:663.

Comorbidity is a Key Factor in Survival

Charlson et al. J Chronic Dis. 1987;40:373.

Age-Comorbidity Score N

Actual 10-Year Survival (%)

0-1 369 97-99

2 136 87

3 109 79

4 42 47

5 29 34

Functional Assessment

UPFRONT Protocol

Induction: 21-day cyclesMaintenance: 35-day cycles

Cycles 1–4 Cycles 5–8

Vc: 1.6 mg/m2, days 1,8,15,22Rest period:days 23–35

VcDVc: 1.3 mg/m2, days 1,4,8,11D: 20 mg, days 1,2,4,5,8,9,11,12

VcTDVc: 1.3 mg/m2, days 1,4,8,11T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5,8,9,11,12

VcMPVc: 1.3 mg/m2, days 1,4,8,11M: 9 mg/m2, days 1,2,3,4 of every other cycle P: 60 mg/m2, days 1,2,3,4 of every other cycleR

AN

DO

MIZ

E 1

:1:1

Vc: 1.3 mg/m2, days 1,4,8,11D: 20 mg, days 1,2,4,5

Vc: 1.3 mg/m2, days 1,4,8,11T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5

Cycles 9–13

POSTER presentation ASH: 2013

VcD(N=100)

VcTD (N=100)

VcMP(N=100)

Median age, years (range) 73.5 (39–91) 73.0 (38–88) 72.0 (42–86)

≥75 years, %

48 40 34

≥80 years, %

20 17 13

Male, % 58 45 57

Race, %

White 78 73 72

Black 9 19 17

Other 11 8 10

Not reported 2 0 1

IgG / IgA / Light chain, % 59 / 28 / 13 58 / 28 / 14 63 / 21 / 14

KPS 50–60 / 70–80 / 90–100, % 9 / 42 / 48 9 / 38 / 53 13 / 47 / 40

ISS stage I / II / III, % 15 / 55 / 29 36 / 33 / 31 26 / 43 / 31

Charlson co-morbidity index 0 / 1 / ≥2, % 51 / 25 / 24 55 / 30 / 15 62 / 24 / 14Serum creatinine >1.5 x ULN, % 16 13 13

Median2-microglobulin, mg/L 4.5 3.4 3.7

Patient Demographics andBaseline Disease Characteristics

Median follow up was 13.4 months for the entire study population

Median PFS was 13.8, 18.4, and 17.3 months for the VcD, VcTD and VcMP arms, respectively

None of the pair-wise comparisons are statistically significant

PFS (ITT population N=502)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

VD: 168 144 123 95 79 68 50 34 25 20 17 15 9 7 2 – – –VTD: 167 134 117 84 71 59 45 32 23 17 13 12 6 4 – 2 – –VMP:167 145 125 102 81 69 57 39 32 21 16 11 6 3 1 – – –

Time (Months)

Pro

po

rtio

n o

f p

atie

nts VcTD (N=168, 29% PFS events)

VcD (N=167, 40% PFS events)

VcMP (N=167, 36% PFS events)

Pat

ient

s re

mai

ning

, n

Patient-reported QoL(mean global health status score by treatment arm)

In all three treatment arms, there was a trend for decreasing QoL during induction, followed by an improvement/stabilization in QoL during maintenance

There was a trend for poorer QoL in the VTD vs. VD and VMP armsUPFRONT QoL poster (Niesvizky et al., ASH 2011, abstract 1864)

58

56

54

52

50

48

46

44

42

40

Sco

re

Baseline Cycle 3 Day 1

Cycle 5 Day 1

Cycle 7 Day 1

Cycle 9 Day 1

Cycle 11 Day 1

Cycle 13 Day 1

Timepoint

VD VTD VMP

Induction Maintenance

Once-weekly Administration of Bortezomib as a Strategy to Improve Tolerability

Study detailsGrade ¾

GI toxicityGrade 3/4 peripheral

neuropathy

Discontinuation due to AE

VISTA: VMP1-3

Bortezomib twice-weekly

20% 14% 34%

(GIMEMA)4 Bortezomib once-weekly

- 5% 17%

(PETHEMA/GEM)5 Bortezomib once-weekly

7% 7% 12%†

†Discontinuations due to SAEs

1. San Miguel et al. NEJM 2008;359:9062. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix3. Mateos et al. J Clin Oncol 2010;28:2259-66

4. Palumbo et al. JCO 2010; 28:5101-095. Mateos et al. Lancet Oncol 2010;11:934-41

Study details CR+PR CR PFS 3 yrs-OS

VISTA: VMP1-3

Bortezomib twice-weekly 71% 30% TTP:24 m 68%

Modified VISTA4 (GIMEMA)Bortezomib once-weeklyVMPTVTVMP

90%81%

42%24%

37 m27 m

85%80%

Modified VISTA5 (PETHEMA)Bortezomib once-weeklyVMP vs VTPVT vs VP

80%23%42% 31 m 70%

Once-weekly Administration of Bortezomib as a Strategy to Maintain/Improve the Ffficacy

1. San Miguel et al. NEJM 2008;359:9062. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix3. Mateos et al. J Clin Oncol 2010;28:2259-66

4. Palumbo et al. J Clin Oncol 2010;28:5101-95. Mateos et al. Lancet Oncol 2010;11:934-41

Once-weekly Administration of Bortezomib as a Strategy to Improve Tolerability

Study details Planned bortezomib dose

Delivered bortezomib dose

VISTA: VMP1

Bortezomib twice-weekly 67.6 mg/m2 38.5 mg/m2

Modified VISTA2 Bortezomib once-weekly(GIMEMA)

46.8 mg/m2 39.4 mg/m2

Modified VISTA3 Bortezomib once-weekly(PETHEMA/GEM)

36.4 mg/m2 32.9 mg/m2

Mateos et al. IMW 2011: abstract 175

Bortezomib IV versus SC222 relapsed and/or refractory MM patients. Bz is given at conventional dose and scheme

Moreau et al. Lancet Oncology 2011; 12(5): 431-40Arnulf B et al. Haematologica 2012: Epub ahead of print

Bortezomib IV (n=73) Bortezomib SC (n=145)

Primary endpoint: response after 4/8cycles (single agent bortezomib or +/-dex))

ORR 42%/52% 42%/52%

CR 8%/12% 6%/10%

TTP 9·4 m 10·4 m

Bortezomib IV Bortezomib SC

All grades Grade ≥3 All grades Grade ≥3

Periph Neurop 53% 16% 38% 6%P=0·04 and 0·03

No diferences in pharmakokinetics studies



A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma

Jakubowiak, et al Blood, 2013

CR 42%>VGPR 62%

ECOG 00602641

ECOG 00602641

Palumbo0109319

Fun Neo San

Palumbo0109319

Fun Neo San

Celgene0109319Celgene0109319

SWOG0109319

SWOG0109319

Baz 617591 Baz 617591

OncoTx317811

OncoTx317811

UPFRONT507416

UPFRONT507416

Evolution507442

Evolution507442

Boccadoro1063179

Boccadoro1063179

Collaborators

Tomer Mark MDMorton Coleman, MDRoger Pearse, MDAdriana Rossi, MDDavid JayabalanKaren PekleArthur PerrySusan Matthew, PhD Scott Ely, MD/MPHSelina Chen-Kiang, PhDMonica Guzman, PhD

Linda TangenstamKathleen PogonowskiYasphal Agrawal, PhDPaul Christos

Stanley Goldsmith MD

Maureen Lane PhD

Paul Christos

Myelomacenter.org

Treatment of Transplant Ineligible/Elderly MM Patients

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