multiple myeloma treatment options for newly diagnosed the american perspective rafat abonour, m.d

Multiple Myeloma

Treatment Options for Newly Diagnosed

The American Perspective

Rafat Abonour, M.D.

Multiple Myeloma Facts

• Second most prevalent hematologic neoplasm

• Nearly 24,000 new cases diagnosed in the US per year and 130,000 worldwide

• Median age at diagnosis is 70 years

• Survival is increasing but cure has not been realized

• Based on SEER data the 5 survival of those diagnosed 1990-2005 was only 37.1%

BJH, 2000, 111, 1035-44

Multiple MyelomaThe First Recognized case

Sarah Newberry, 1844. Fractures of femurs and right humerus

Myeloma PathophysiologyMyeloma PathophysiologyMyeloma cells

Tumor-derived osteoclast activating factors

• Macrophage inflammatory protein 1

• Interleukin-3

Tumor-derived osteoblast inhibitory factorsDKK1, IL3, sFRP2, IL-7, TNFSclerostin

Bone

OsteoclastsOsteoblasts

(+) (–)(+)Stromal cells

– RANKL– Interleukin-6

Adapted from Roodman GD. N Engl J Med. 2004;350(16):1655-1664.

Activin A

Osteocytes

Scler

ostin

RANKL

Merphalan1957 Melphalan

1962

Thalidomide1999

Bortezomib2002

Lenalidomide2006

Prednisone 1957

ACTH 1950

Autologous transplantation1983

1950 1960 1970 1980 1990 2000

MM Therapy Over the Last 60 Years

Bisphosphonates1990-2000

Carfilzomib 2012

Pomalidomide2013

Kumar SK, et al. Blood. 2008;111:2516-2520.

OS Based on Time of Diagnosis

2006-2010 73% 56%

2001-2005 63% 31%

IMPACT OF NOVEL THERAPY 2012/2013

Median 7.3 years

5 YEAR SURVIVAL BY AGE

AGE≤ 65 YRS

AGE> 65 YRS

2012 ASH Abstract #3972 Kumar et al

Managing myeloma: the components

Supportive Care

Initial Therapy

Consolidation Maintenance

Treatment of Relapsed

disease

Transplant EligiblePatients

Transplant Ineligiblepatients

Consolidation/ Maintenance/ Continued therapy

Treatment sequence

Induction Consolidation

Front line treatment

Post consolidation

Maintenance

Rescue

Relapsed

OLD VADDEX

SCTNothing

PrednisoneThalidomide

Few options

NEW

Thal/Dex VD

Rev/DexCyBorD

VTDVRD

SCTVD/VRD

NothingThalidomide?Bortezomib?

Lenalidomide?

BortezomibLenalidomideThalidomideCarfilzomib

PomalidomideMonoclonal Ab (CD38)

ElotuzumabHDAC

Bendamustine

mSMART 2.0: Classification of Active MM

FISHc

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

GEP High risk

signature OS~~3 years

All others including: Trisomies t(11;14)e

t(6;14)

10 years

FISH t(4;14)d

Complex karyotype Metaphase

Deletion 13 or hypodiploidy

High PC S-phasef

5 years

High-Risk-20% Intermediate-Riska-20% Standard-Riska,b-60%

a Note that a subset of patients with these factors will be classified as high-risk by GEPb LDH >ULN and beta-2 M > 5.5 may indicate worse prognosis; cTrisomies may ameliorated Prognosis is worse when associated with high beta-2 M and anemiae t(11;14) may be associated with plasma cell leukemia; f Cut-offs vary

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v11 //last reviewed Dec 2013

0.0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150

Su

rviv

al p

rob

abil

ity

Su

rviv

al p

rob

abil

ity

MonthsMonths

P<0.001P<0.001

t(4;14)t(14;16)-17p13

t(4;14)t(14;16)-17p13

1313

All others includingt(11;14)All others includingt(11;14)

Poor 24.7 mosIntermediate 42.3 mosGood 51.0 mos

Poor 24.7 mosIntermediate 42.3 mosGood 51.0 mos

Fonseca et al Blood 101:4569, 2003

Molecular Prognostic ModelMolecular Prognostic Model

Induction Regimens

• Two new classes of drugs are being used in the management of multiple myeloma patients:• Proteasome inhibitors • Immune modulatory drugs.

• The choice of initial induction therapy can be influenced by the underlying medical conditions of the patients and their prognostic features.

What to Expect with Novel Combinations Prior to HD Therapy?

Author (n) Regimen CR/VGPR PFS OS

Cavo (236) VTD+2HD 38%/79% 68% (3 years) 86% (3 years)

Moreau (100) vTD+HD 30%/73%

Palumbo (102) PAD+2HD+C/M

66%/86% 69% (2 year) 86% (2 year)*

Rajkumar (90) R (D or d)+HD 92% (3 years)

Harousseau (223)

VD+HD 40%’ 68% 36 months 81% (3 years)

Richardson (27) RVD+ HD 29%/67% 75% (18 mon) 97% (18 mon)

N= number of subjects, Mon= monthVTD Bortezomib, thalidomide and dexamethasonevTD Modified bortezomib, thalidomide and dexamethasonePAD Bortezomibe, doxirubicin and dexamethasone * age 65-75RD or Rd Lenalidomide with high dose dexamethasone (D) or low dose (d)RVD Lenalidomide Bortezomib and Dexamethasone.HD high dose chemotherapy.

Survival & Complete Response

VISTA Trial MM-015 Trial FIRST TrialPETHEMA/GEM Trial VMPT vs VMP Trial

3-year Overall Survival Rates

Complete Response Rates

1:1

LenalidomideHigh-Dose

Dexamethasone(RD)

LenalidomideLow-Dose

Dexamethasone(Rd)

CR PRNewly

Diagnosed

Multiple MyelomaN = 445

1:1

SCT or Continue Off

Study

< PR ThalDex

CR PRSD

Lenalidomide: 25 mg daily, days 1-21 of a 28-day cycleHigh-Dose Dex: 40 mg, d1-4, 9-12, 17-20 (total 480 mg) Low-Dose Dex: 40 mg, d1, 8, 15, 22 (total 160 mg)

Primary EndpointResponse at 4 months

Primary EndpointResponse at 4 months

Rajkumar SV, et al. Lancet Oncology 2009

ECOG E4A03: Lenalidomide + Low- or High-Dose Dexamethasone

ECOG E4A03: Lenalidomide + Low- or High-Dose Dexamethasone

Response LenalidomideHigh-Dose Dex

N = 223

LenalidomideLow-Dose Dex

N = 222

P

≥ PR within 4 cycles 79% 68% 0.008

≥ VGPR within 4 cycles 42% 24% < 0.008

Toxicity

Any grade > 3 non-heme toxicity 53% 31% < 0.001

Early deaths (< 4 months) 5% 0.5% 0.003


Lenalidomide + Low- or High-Dose Dex ECOG E4A03: Overall Survival

LenalidomideHigh-Dose Dex

N = 223

LenalidomideLow-Dose Dex

N = 222

P

1-year OS 85% 95% 0.01

2-year OS 78% 88% 0.007

3-year OS 74% 75% NS


ECOG E4A03: Landmark Analysis

Median Follow Up: 36 Months

ECOG E4A03: Overall Survival

Continued Primary Therapy (Beyond 4 Cycles)

Rd RD

0 6 12 18 24 30 36

100

80

60

40

20

0P

atie

nts

Su

rviv

ing

(%

)

Time (months)P = NS

SCT After 4 Therapy Cycles

0 6 12 18 24 30 36

100

80

60

40

20

0

Pa

tient

s S

urv

ivin

g

(%)

Time (months)

3-yr OS: 79%P = NS

3-yr OS: 92%P = NS

Unplanned analysis, includes unbalanced arms

Stringent complete response (sCR) in patients with newly diagnosed multiple myeloma (NDMM) treated with carfilzomib (CFZ),

lenalidomide (LEN), and dexamethasone (DEX)

AJ Jakubowiak,1 K Griffith,2 D Dytfeld,3 DH Vesole,4 S Jagannath,5 T Anderson,2 B Nordgren,2 K Detweiler-Short,2 D Lebovic,2 K Stockerl-Goldstein,6 T Jobkar,2 S

Wear,7 A Al-Zoubi,2 A Ahmed,2 M Mietzel,2 D Couriel,2 M Kaminski,2 M Hussein,8 H Yeganegi,9 R Vij6

1University of Chicago, Chicago, IL; 2University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; 3Poznan University of Medical Sciences, Poznan, Poland; 4John Theurer Cancer

Center, Hackensack, NJ; 5Mount Sinai Medical Center, New York, NY; 6Washington University School of Medicine, St. Louis, MO; 7Multiple Myeloma Research Consortium, Norwalk, CT;

8Celgene, Inc, Summit, NJ; 9Onyx Pharmaceuticals, South San Francisco, CA

22

Stem cell collection

≥PR

CRd Cycles 9–24

CRdInduction

CRdMaintenance

CRd Cycles 1–4 CRd Cycles 5–8

ASCT

LEN Cycles 25+

Lenalidomide (off protocol)

Transplant-eligible

Transplant-eligible and --ineligible patients

• Assessments on D1 and 15 of C1 and D1 thereafter using modified IMWG Criteria with nCR• Cycles 1–8

• CFZ Days 1–2, 8–9, 15–16 at assigned doses1

• LEN 25 mg Days 1–21• DEX 40 mg weekly Cycles 1-4, 20 mg weekly Cycles 5–8

• Cycles 9–24• CFZ on Days 1–2 and 15–16 only• CFZ, LEN, DEX at last best tolerated doses• After Cycle 4, pts could undergo stem cell collection and then continue CRd with the option

to proceed to ASCT

Until disease progression or unacceptable toxicity

Treatment Schema

1. Jakubowiak AJ, et al. Blood. 2011;118: abstract 631.

Patient Characteristics

23

* 1 or more of the abnormalities listed; available for 51 of 53 patients†del 13 by metaphase only

Characteristics (N=53)

Median age, years (range) 59 (35–81)

≥65 years, n (%) 23 (43)

Male, n (%) 39 (74)

ISS stage II/III, n (%) 32 (60)

Durie-Salmon stage II/III, n (%) 46 (87)

Unfavorable cytogenetics*, n (%) 17/51 (33)

del 13†/hypodiploidyt(4;14)t(14;16)del 17p

10/505/490/487/48

(20)(10) (0)(15)

Responses

24

51%

Change from baseline

67%

81%

Pat

ien

ts (

%)

N= 53; median 12 cycles (range 1–25)

Initial Response Best Response

Responses at Different Time Points

25

20/22 patients (91%) with suspected CR had no evidence of MRD by multiparameter flow cytometry

0

25

50

75

100

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10 11 12

≥nCR sCR M-protein

M-p

rote

in le

vel

(% o

f b

as

eli

ne

)

Re

sp

on

se

(%

)

Cycle

Responses after Extended Treatment

26

6267

78

42 45

61

0

20

40

60

80

100 ≥nCR sCRR

es

po

ns

e (

%)

Overalln=53

Median 12 cycles (range 1–25)

8+ Cyclesn=36


4+ Cyclesn=49


Facon T, et al. Blood. 2013;122:abstract 2.

Arm BRd18

Arm CMPT

LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN 0.25mg/kg D1-4/42PREDNISONE 2mg/kg D1-4/42THALIDOMIDE 200mg D1-42/42

Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4

27

• Stratification: age, country and ISS stage

1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.

FIRST Trial: Study Design

LEN + Lo-DEX ContinuouslyLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

Arm AContinuous Rd

ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival

FIRST Trial: Overall Survival Interim Analysis 574 deaths (35% of ITT)


Pat

ien

ts (

%)

RdRd18MPT

535541547

488505484

457465448

433425418

403393375

338324312

224209205

121124106

434430

563

000

4-year OS

Rd (n= 535) 59.4%

Rd18 (n= 541) 55.7%

MPT (n= 547) 51.4%

Overall survival (months)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

Hazard ratio Rd vs. MPT: 0.78; P < 0.02 Rd vs. Rd18: 0.90; P = 0.3 Rd18 vs. MPT: 0.88; P = 0.2

28


Median PFS

Rd (n=535) 25.5 mos

Rd18 (n=541) 20.7 mos

MPT (n=547) 21.2 mos

Rd 535 400 319 265 218 168 105 55 19 2 0

Rd18 541 391 319 265 167 108 56 30 7 2 0

MPT 547 380 304 244 170 116 58 28 6 1 0

Hazard ratio Rd vs. MPT: 0.72; P < 0.001 Rd vs. Rd18: 0.70; P < 0.001 Rd18 vs. MPT: 1.03; P = 0.7

Time (months)

Pat

ien

ts (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

29

42% (Rd)

23% (Rd18) 23% (MPT)

FIRST Trial: Final Progression-free Survival

mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone.

San Miguel JCO. 2013 Feb 1;31(4):448-55.

Persistent OS benefit and no increased risk of 2nd malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated MM.

Survival from randomization

Reeder C.B. et al ASH 2013, #3192

Long-Term Survival With CyBorD Induction In Newly Diagnosed Multiple Myeloma (n=63)

The Overall, ≥ VGPR, and nCR/CR Rates for a Selection of Phase 2 and Phase 3 Trials

Stewart A K et al. Blood 2009;114:5436-5443 ©2009 by American Society of Hematology

Do we pick the therapy with the biggest green bar and call it a day?

So How Do We Choose?

1. Best CR rate?

2. Best PFS?

3. Best QOL?

4. Best OS?

5. Cost?

Doesn’t always translate to better outcomes, #2-5

Limited data

Limited data

Limited data

Bortezomib-Based Versus Nonbortezomib-Based Induction Treatment Before ASCT : .

Sonneveld. J Clin Oncol. 2013 Sep 10;31(26):3279-87.

Median TTP 37.5 months vs 31.3 months;

P< 0.0001

A Meta-Analysis of Phase III Randomized, Controlled Trials

Ov

era

ll s

urv

ival

Bortezomib-Based Versus Nonbortezomib-Based Induction Treatment Before ASCT :.

3-year OS rates were 80% and 75%, respectively.

Sonneveld. J Clin Oncol. 2013 Sep 10;31(26):3279-87.

A Meta-Analysis of Phase III Randomized, Controlled Trials

Dollar Cost of Regimens

1. VRD $23,000 (276K)

2. VTD $22,000 (264K)

3. PAD $14,400* (173K)

4. VD $13,800 (166K)

5. CyBorD (weekly) $ 9,200 (110K)

6. Rd $ 9,000 (108K)

7. TD $ 8,200 ( 98K)

per 28 daysper 28 days

*add $4000 if Doxil*add $4000 if Doxil

(per year)(per year)

How Deep a Response Required before ASCT?

MM06-04-12_6.ppt

Autologous Autologous TransplantTransplant

Diagnosis and Initial Diagnosis and Initial InductionInduction

Autologous Autologous TransplantTransplant

12 months from diagnosis to ASCT12 months from diagnosis to ASCT

Salvage CohortSalvage Cohort

No Salvage CohortNo Salvage Cohort

ASCTDiagnosis

Effect of Pre-transplant Salvage Therapy Prior to Autologous Transplant (ASCT) in Patients Not Responding to Initial Induction for MM

Salvage Salvage ChemotherapyChemotherapy

< PR to induction< PR to induction

Vij Blood 120(21) 2012, abstract 597

Outcomes with/without Pre-ASCT Salvage

(Source: Txz12_23 & _24) MM06-04-12_15.ppt

P = NS P = NS

Vij Blood 120(21) 2012, abstract 597

Median follow-up Salvage No Salvage Months 68 (110-180) 61 (9-181)

CONSOLIDATION

• Historically• 4 cycles of VAD (limited to 4 due to cardio

toxicity)• ASCT as consolidation• No further therapy later

• Now• Why limited to 4 cycles?• Why limited to pre transplant?

Phase 3: bortezomib consolidation versus no consolidation following ASCT

Mellqvist et al. IMW 2011

Induction + single or double ASCT (n=404)

Randomization (3 months post-ASCT) (n=392)

Bortezomib (n=149)

1.3 mg/m2

day 1, 4, 8, 11 for two 3-week cycles

then day 1, 8, 15 for four 4-week cycles

(total 20 injections over 21 weeks)

Observation (n=150)

Progression free survival

bortezomib

control

p=0.037

27 mo

20 mo

Mellqvist et al. IMW 2011

Phase 2: VRD induction, ASCT, VRD consolidation, lenalidomide maintenance (IFM 2008)

• Patients (n=31)

% After VRD induction

(3 cycles)

After ASCT After VRD consolidation

(2 cycles)

After Len maintenance

(12 months)

sCR 17 36 39 38

CR 6 6 9 10

VGPR 39 26 36 28

Roussel et al. ASH 2011 (Abstract 1872), poster presentation

• Improvement in responses

• Consolidation: upgraded response in 26%

• Len maintenance: no improvement in response rate

Findings Bortezomib-based treatment improves PFS (median 27

months vs 36 months) and OS (median 84 months vs not reached, p=0.05)

Bortezomib significantly improves long-term outcome of pts with renal failure (p<0.001)

Double ASCT improves PFS and OS in pts with ISS1

Bortezomib improves outcome in pts with intermediate/poor risk disease

No increased risk of SPM

Sonneveld et al._ASH 2013: Abstract 404, oral presentation

Bortezomib induction & maintenance improves OS:

Extended follow-up of HOVON-65/GMMG-HD4 Trial

Future Drug Targets in Myeloma

Anderson KC. J Clin Oncol 2012;30:445-52.

Future Drug Targets in MM

Cell Surface Targets

CytokinesBone Marrow

StromaAdhesion Molecules

CD38

CD40

CD138

FGFR3

CS1

BAFF-R

VEGF-R

IL-6

VEGF

IGF-1

SDF-1α

BAFF

APRIL

BSF-3

NF-κB

Smad

ERK

ICAM-1

VCAM-1

Fibronectin

LFA-1

MUC-1

VLA-4

Anderson KC. J Clin Oncol. 2012;30:445-452.

mSMART – Off-StudyTransplant Eligible

a Bortezomib containing regimens preferred in renal failure or if rapid response neededb If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixaforc Continue Rd for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year* Consider risks and benefits; consider limited duration 12-24 months

Standard Risk

Autologous stem cell transplant

4 cycles of Rda or CyBorD

Collect Stem Cellsb

Continue Rd;

c or

CyBorD for ~12 months

High Risk

4 cycles of VRd

Intermediate Risk

Autologous stem cell transplant

Bortezomib based therapy for minimum of 1 year

4 cycles of CyBorD

Autologous stem cell transplant, especially if

not in CR

V or VCd for minimum of 1 year

2 cycles of Rd consolidation; Then Len maintenance if not in VGPR and Len responsive*


mSMART – Off-StudyTransplant Ineligible

a Dex is usually discontinued after first yearb Bortezomib containing regimens preferred in renal failure or if rapid response needed*Clinical trials strongly recommended as the first option

Intermediate Risk Standard Risk*

MP + weekly Bortezomib or weekly CyBorD for

~12 months

Bortezomib based therapy for minimum of 1 year

High Risk

VRd* for ~12 months, Rda, b


Continue VRd as maintenance for minimum

of 1 year

Immune Based Therapy

• Monoclonal antibodies Daratumumab and Elotuzumab

• Vaccine based therapy using dendritic cells• Myeloma targeted therapy using CAR-T cell.

Patients own T cell engineered to attack myeloma specific antigen.

So What Are We Offering Our Patients Today?

• Unlimited number of combination regimens and sequences.

• Magical responses: Fast, Complete and sometimes Durable but are they the R-CHOP?

• Design-stupid: Achieving CR and Maintaining it never was the goal of clinical trials.

• Subset and Retrospective analysis led to speculative functional classification.

The New Paradigm

• Combination therapy with novel agents provide excellent disease control.

• Addition of high dose chemotherapy increase the number of patients with complete remission and very good partial response.

• Consolidation therapy and maintenance therapy improve progression free survival.

• Zoledronic acid appears to play important role regardless of the treatment delivered.

• Five year survival is approaching 81%.

multiple myeloma treatment options for newly diagnosed the american perspective rafat abonour, m.d

Documents

multiple myeloma factssecond

mayo clin

hd therapy

impact of novel therapy

kumar et almanaging

monthvtd bortezomib

years5 year survival

subset of patients