rafael fonseca md mayo clinic multiple myeloma 2012; update

Rafael Fonseca MDMayo Clinic

Multiple Myeloma 2012;Update

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Mayo Clinic College of MedicineMayo Clinic Comprehensive Cancer Center

Disclosures

• Consulting: AMGEN, Genzyme, BMS, Otsuka, Celgene, Medtronic, Lilly, Onyx.

• Millennium• Speakers Bureaus: None• Research: Cylene, Proteolix• Patent for FISH based prognostication in

MM

Clinical Features

• Calcium elevation• Renal disease• Anemia• Bone disease

• …and other constitutional

Smith. Br J Haematol. 2005;132:410.

Importance of progression events

4

Renal Metabolism of FLCs

0.1

1

10

100

1000

10000

Ligh

t cha

in c

once

ntra

tion

(mg/

L)

SPE

CZE IFE

Total k & l

Normal range in serum

FLC

UPE

Analytical sensitivity of laboratory methods for detection of FLCs

Katzmann, Clin Chem 2002; 48: 1437 - 1444

sFLCs published normal range

0.1

1

10

100

1000

10000

100000

0.1 1 10 100 1000 10000 100000

Serum Kappa FLC (mg/L)

Ser

um L

ambd

a F

LC (m

g/L)

Normal seraRenal impairment(non-MG)

Bradwell, Lancet 2003; 361: 489-491

sFLCs in LCMM and NSMM

Drayson Blood 2001; 97: 2900 – 2902

Normal seraKappa LCMMLambda LCMMNSMM

MTCG. J Clin Oncol 1998; 16:3832

Treatment of Myeloma

42% at 3 years

MP era 2008

93% at 3 years

Menon S. Cancer 112:1522-1528

Spanish Long Term

Blood 2011 blood-2011-01-332320 10

Transplant Outcomes

11Reeder et al, Leukemia 2009, 23:1337-41

Minimal Residual Disease

Ladetto M, et al. ASH 2009. Abstract 960.

PFS in PCR-negative patients

0 10 20 30 40 50 60 70 80 900

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

PCR POS

PCR NEG

P < .05

months

Obs

erve

d m

argi

nal m

edia

ns o

f ln

PCR

val

ues

Relapse (13 patients)

No relapse (25 patients)

DIA ASCT VTD-2 VTD-4 6 m 12 m 18 m 24 m 30 m

Obs

erve

d m

argi

nal m

edia

ns o

f ln

PCR

val

ues

Relapse (13 patients)

No relapse (25 patients)

Obs

erve

d m

argi

nal m

edia

ns o

f ln

PCR

val

ues

Relapse (13 patients)

No relapse (25 patients)

Relapse (13 patients)

No relapse (25 patients)

DIA ASCT VTD-2 VTD-4 6 m 12 m 18 m 24 m 30 mDIA ASCT VTD-2 VTD-4 6 m 12 m 18 m 24 m 30 m

Genomics and Precision Medicine

Submarine

REAL TIME REPORT GENERATED FOR PATIENT AND TREATING PHYSICIAN

N OF 1

• CCND1 2%• BRAF 4%• DIS3 (RPP44) 11%• FAM46C 13%• XBP1 4%• LRRK2 6%• IRF 6%• PRDM1 6%

• Known; ras (50%), NF-kB (37%), p53 (8%)

• Protein translation 42%• Histone modifying

enzymes (lead HOXA9) • Fibrin clot formation 16%

Nature 24 March 2011, 471:467

Study population stratified according

to cytogenetic abnormalities232

pts

no cytogenetic

abnormalities + del

(13q)

+ t(11;14)

188 pts(80%)

t(4;14) ± t(14;16)

+ del(17p)

44 pts(19%)

t(4;14)±del(13q

)

17 (7%)

del(17p)

±del(13q)

21(9%)

both

3 (1%)

t(14;16)

3 (1%)

Standard-risk High-risk

Overall survival according

to cytogenetic abnormalities

50454035302520151050

1.0

0.8

0.6

0.4

0.2

0.0

Prop

ortio

n of

pts

Time in months from 1st randomization

Standard risk: NR

High risk: 38m

HR: 2.3, 95% IC: 1.4-4.0

p=0.001

EFS and OS; t(4;14) VD (n = 106) vs VAD (n = 98)

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

EFS and OS; VD Treated t(4;14) (n = 106) vs not (n = 401)

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

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

No t(4;14) Bortezomib treated

t(4;14) Bortezomib treated

t(4;14) VAD treated

High Risk in Len Treated Patients

Lenalidomide maintenance on PFS of t(4;14)0.

000.

250.

500.

751.

00

0 6 12 18 24 30 36 42

Placebo Revlimid

p<.0001

IFM 2005-02 trial: general results for PFS

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42

Placebo Revlimid

p<.001

PFS for patients with del(13)

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42

Placebo Revlimid

p<.02

PFS for patients with del(17p) > 60%

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42

Placebo Revlimid

p<.04

PFS for patients wit t(4;14)

del13

del17p t(4;14)

Avet-Loiseau ASH 2010

Carfilzomib and PX-171-004

• Carfilzomib is a selective tetrapeptide epoxyketone proteasome inhibitor that displays potent and sustained proteasome inhibition.

• The high degree of selectivity of carfilzomib may account for its improved tolerability profile: – In early clinical studies, carfilzomib has not been associated with

dose-limiting peripheral neuropathy (PN).

• PX-171-004 is an ongoing multicenter, non-randomized, open-label, single-arm phase 2 trial of single-agent carfilzomib in patients with R/R MM who have received 1–3 prior lines of therapy.

K Stewart et al ASCO Abstract 8026

Study Design and Treatment

• Bortezomib-naïve patients (N=129) were enrolled in 2 sequential dose cohorts.

– In Cohort 1, patients received carfilzomib 20 mg/m2 IV on Days 1, 2, 8, 9, 15, and 16 every 28 days, for up to 12 cycles.

– In Cohort 2, patients received a stepped-up, dose-escalating regimen of carfilzomib 20 mg/m2 for Cycle 1 followed by carfilzomib 27 mg/m2 for all subsequent treatment cycles.

– Dexamethasone 4 mg was administered prior to carfilzomib in Cycle 1 only to ameliorate a potential “first dose” effect (including fever, chills, rigors, and dyspnea).

• Patients completing all 12 cycles were eligible to enroll in an extension study (PX-171-010).

K Stewart et al ASCO Abstract 8026

Significant Responses‡ in BTZ-naïve Patients

*Data cut-off date 9 February 2011†2 patients (3%) in Cohort 2 were excluded on the basis of missing baseline or post-baseline disease assessments.‡Responses confirmed by Independent Review Committee

Best response(N=127)

Cohort 1 20 mg/m2

(N=59)n (%)

Cohort 2†

20/27 mg/m2

(N=68)n (%)

CR 2 (3) 0 (0)VGPR 8 (14) 18 (26)PR 15 (25) 17 (25)MR 10 (17) 8 (12)SD 13 (22) 10 (15)PD 7 (12) 11 (16)NE 4 (7) 4 (6)

• Significant response rates were observed in both cohorts

ORR= 42% ORR= 51%

CBR= 63%CBR= 59%

K Stewart et al ASCO Abstract 8026

Substantial Duration of Response Observed for Cohorts 1 and 2*

*Data cut-off date 9 February 2011 K Stewart et al ASCO Abstract 8026

Similar Incidence and Severity of AEs Between Cohorts

• There were no discontinuations of treatment due to peripheral neuropathy.

• In no case were any toxicities (any grades) >2% higher in Cohort 2 than in Cohort 1; in general they were either similar or lower

• cumulative toxicities has been observed in patients continuing on extended carfilzomib treatment (PX-171-010).

K Stewart et al ASCO Abstract 8026

Pomalidomide in Len Treated PatientsPatient Characteristics

J Mikhael et al ASCO Abstract 8067

Response rate on Pomalidomide Despite Prior Treatment with Lenalidomide

J Mikhael et al ASCO Abstract 8067

MRC Myeloma IX—Analysis Schematic for ZOL vs CLO

Endpoints (ZOL vs CLO)Primary: PFS, OS, and ResponseSecondary: SREs (time to first SRE, SRE incidence) and SafetySREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions, or the appearance of new osteolytic bone lesions.

N = 1,960Patients with newly

diagnosed MM (stage I, II, III)

Clodronate (1,600 mg/d PO) + intensive or non-intensive chemotherapy

(n = 979)

Zoledronic acid (4 mga IV q 3-4 wk) + intensive or non-intensive chemotherapy

(n = 981)RANDOMISATION

Bisphosphonate treatment continued at least until disease progression

G Morgan et al ASCO Abstract 8010

MRC Myeloma IX—ZOL Significantly SREs vs CLO in the Overall Population

Abbreviations: CLO, clodronate; HR, hazard ratio; SRE, skeletal-related event; ZOL, zoledronic acid.

35.3%

27.0%

• ZOL reduced the risk of SREs by 26% vs CLO (HR = 0.74; P = .0004)

36 423024181260

0

10

20

30

40CLO

ZOL

Patie

nts

with

an

SRE,

%

Time from randomisation, months

138112

9774

201173

284256

390337

506465

663629

981979

ZOLCLO

Patients at risk, n

G Morgan et al ASCO Abstract 8010

ZOL Significantly OS vs CLO in Patients With Bone Disease at Baseline (n = 1,350)

5060708090

100

4030

Surv

ival

dis

trib

utio

n fu

nctio

n es

timat

eO

S, %

pat

ient

s

2010

0

0 1 2 3 4 5 6

668682

544534

447437

292271

165143

6453

30

Survival, years since initial randomisation

Clodronate (n = 682)Zoledronic acid (n = 668)

P = .0107HR: 0.82 (95% CI: 0.70, 0.96)

+ Censored

ZOLCLO

Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; ZOL, zoledronic acid. G Morgan et al ASCO Abstract 8010

Phase III IFM 2005-02: Lenalidomide as Consolidation/Maintenance Post-ASCT

First-lineASCT

< 65 years

Lenalidomide: 25 mg/d Days 1–21/month2 months

Primary end point: PFS

≤ 6 monthsNo PD

N = 614Lenalidomide: 10–15 mg/duntil relapse

Lenalidomide: 25 mg/d Days 1–21/month2 months

Placebo until relapse

Consolidation Maintenance

Attal et al, 2009.

Lenalidomide maintenance on PFS of t(4;14)0.

000.

250.

500.

751.

00

0 6 12 18 24 30 36 42

Placebo Revlimid

p<.0001

IFM 2005-02 trial: general results for PFS

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42

Placebo Revlimid

p<.001

PFS for patients with del(13)

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42

Placebo Revlimid

p<.02

PFS for patients with del(17p) > 60%

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42

Placebo Revlimid

p<.04

PFS for patients wit t(4;14)

del13

del17p t(4;14)

Avet-Loiseau ASH 2010

D-S Stage 1-3, < 70 years> 2 cycles of induction Attained SD or better 1 yr from start of therapy> 2 x 106 CD34 cells/kg

Placebo

Lenalidomide*10 mg/d with

↑↓ (5–15 mg)

RestagingDays 90–100

Registration

CALGB 100104 Schema

CRPRSD

Patient stratification based on diagnostic -2M level and prior thalidomide and lenalidomide use during Induction

Mel 200

ASCT

* provided by Celgene Corp, Summit, NJ

Randomization

ITT Analysis with a Median Follow-up from transplant of 18 months P < 0.0001

CALGB 100104, follow up to study un-blinding

Median TTP: 21.9 mo

Median TTP: 39.6 mo

Median follow-up of 28 monthsP = 0.018

CALGB 100104, follow up to 04/17/2011

23 deaths in the lenalidomide arm and 39 deaths in the placebo arm

1

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

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

Placebo

Placebo

Phase III Study Schema

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

Continuous LenalidomideTreatment

Lenalidomide(25 mg/day)

+/-Dexamethasone

Open-Label Extension Phase

N = 459, 82 centers in Europe, Australia, and Israel

Stratified by age (≤ 75 vs > 75 years) and stage (ISS I/II vs III)

10 mg/daydays 1-21

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

M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System.

1

Progression-Free Survival*All Patients

60% Reduced Risk of Progression

Time (months)

Patie

nts

(%)

HR 0.398 P < .0000001

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

Median follow-up 25 months

0 5 10 15 20 25 30 35 400

25

50

75

100

0 5 10 15 20 25 30 35 400

25

50

75

100

0 5 10 15 20 25 30 35 400

25

50

75

100

*Analysis based on data up to May 2010

HR 0.804P = .153

Other Notable Abstracts at ASH

J Mikhael et al ASCO Abstract 8067

• MLN9708, the oral proteasome inhibitor

• Marizomib (NPI-0052)• BT062 the antibody-drug conjugate• Phase 2 study of elotuzumab-

lenalidomide and low dose Dex• Vorinostat plus bortezomib as

Salvage therapy

Standard Risk MM SCT

16 weeks of weekly CyBORD with

supportive care

SC collection and SCT

Minimize gap between Rx end and SCT

Len maintenance(+/- Dex at start)

Start at day 100

High Risk MM SCT

16 weeks of weekly RVD with

supportive care

SC collection and SCT

Minimize gap between Rx end and SCT

Len maintenance(+/- Dex at start)

Start after CyBORD

16 weeks of CyBORD

consolidation

Bisphosphonate per Mayo; RNE responsibility

Bisphosphonate per Mayo; RNE responsibility

Sequencing of TreatmentsMaintenance approach

Biochemical relapse approach

Clinical relapse approach