Donna E. Reece, M.D.

Princess Margaret Hospital

Toronto, ON

23 October 2010

MYELOMA CANADA CONFERENCE

Relapsed and Relapsed/Refractory Multiple Myeloma

DefinitionsRelapsed disease—myeloma that progresses after a period of

remissionRelapsed/refractory disease—myeloma that progresses while on ≥

second-line therapy, or within 60 days of the last therapy

Criteria for progressive myeloma Increase in monoclonal protein by 25%New bone lesionElevated calcium levelNew plasmacytoma

Some patients can just be observed If the only sign of progression is a rise in monoclonal proteinNo other myeloma-related symptoms

Where We’ve Been Initial Therapy of Myeloma

Overall response rate 80% CR/nCR rate 20%

Median TTP 20-36 months

Overall response rate 40-50% CR/nCR 5%

Median TTP 12-15 months

ASCT

Patient Age

Oral melphalan (alkylator)and prednisone

>70 years<70 years

Novel Agents in Multiple Myeloma

Main Toxicities

Thalidomide

Bortezomib

Lenalidomide

Teratogenicity, peripheral neuropathy, constipation, sedation, rash, VTE

____________________________ Fatigue, GI toxicity, peripheral

neuropathy, decrease in platelets and neutrophils

____________________________ Myelosuppression, VTE

____________________________

Agent

VTE= venous thromboembolism

Activity of Novel Agents in Relapsed/Refractory Myeloma Patients

Agent CR/nCR PR Overall

Thalidomide1

Thalidomide +Dex2

< 5%

< 5%

28%

40-50%

30%

50%

Bortezomib3,4

Bortezomib + Dex5,6

5% / 5%

5% / 5-10%

20-25%

35-55%

30-40%

40-50%

Lenalidomide7

Lenalidomide + Dex8,9

6%

15-25%

18%

36-46%

25-40%

61%

1Glasmacher A, et al,Br J Haematol 132: 584-593,2005;2 Palumbo A, et al. Hematol J 2004; 5:31 8-320; 3Richardson PG, et al. N Engl J Med 352:2487-98, 2005; 4Richardson P, et al. Blood 110:3557-60, 2007; 5Jagannath S et al. Haematologica 91:929-32, 2006; 6Kropff MH, et al. Leuk Res 29:587-90, 2005; 7Richarson PG, et al. Blood 108; 3458-64, 2006; Weber DM, et al. N Engl J Med 357:2133-42, 2007; Dimopoulos M, et al. N Engl J Med 357:2123-32, 2007.

Considerations in the Management of Relapsed/Refractory Myeloma

Initial therapy (e.g., use of novel agents, prior ASCT)Initial treatment options are changing

Many patients are receiving novel agents as part of initial therapy

Duration of benefit of initial therapyDisease-related features

Biology of myeloma (e.g., cytogenetics)

Patient-related features (e.g. diabetes, peripheral neuropathy, renal failure)

Treatment-related features (toxicity profile, rapidity of response)

Availability of novel agent

After ASCT No prior ASCT(MP)

Time to Progression

2 years 2 years

Second ASCT

< 1 year 1 year

RepeatM + P

DexamethasoneCyclophosphamide + prednisone

Thalidomide +/- steroidsBortezomib

Lenaliomide + dexClinical trial

Reutilization of Initial Therapy Relapsed/Refractory Myeloma

Repeat oral alkylator therapy in elderly patientsMP if first remission ≥1 year1

Oral weekly cyclophosphamide (500mg) + alternate day prednisone (50-100 mg)—easier on the blood counts2

Repeat ASCT3

PMH policy: Consider if benefit of first ASCT ≥ 2 years4

NO data on MP—too hard on blood countsOral cyclophosphamide + prednisone can be considered5

PR rate 40%; MR rate 20%; stable disease 20%

Median PFS19 months

1Belch A, et al. Br J Cancer 57: 94-9, 1988; 352: 2487-98, 2005;2 Wilson K et al. Cancer Treat Rep 71:981-2,1987;3Abdelkefi A, et al. Blood 111:1805, 2008; 4Mikhael et al. Blood 2007;110:,abstract #110; 5Trieu Y, et al. Mayo Clin Proc 80:1578-82,2005

Second ASCT for Relapsed MyelomaPrincess Margaret Hospital (N=61)

Median age 56 (35-71) yearsMedian time to relapse after first ASCT 33 mos (10-86)Overall response rate 88% (8% CR)Median PFS from ASCT 15.8 mos, OS 4.2 yearsResults better if PFS after 1st transplant ≥2 years:

Mikhael et al. Blood 2007;110:abstract #110

Post 2nd ASCT Progression Free Survival

Grouped by =< or > 2 yrs PFS post 1st ASCT

PFS post ASCT2 (years)

6543210

Cu

m S

urv

iva

l

1.0

.8

.6

.4

.2

0.0

=< or > 2 yrs PFS

> 2yrs PFS

=< 2yrs PFS

Older Regimens Relapsed/Refractory Myeloma

Regimen Response rate Median TTP (range) (mos)

MP 57-80% NA

*Cy+ prednisone 36-40% NA (19 mos at PMH)

Dexamethasone 18-20% 4.7 (3.5-4.7)

VAD 20-40% 5.4 (4.9-8.0)

Thalidomide alone 28% 10 (6-14)

Thalidomide + steroids

50% 16 (8.2-30)

Thalidomide +chemotherapy

64% 12 (9-30)

*Cy=Cyclophosphamide

Glasmacher A, et al,Br J Haematol 132: 584-593,2005; von Lillienfeld-Toal M, et al. Eur J Haematol 2008; 81: 247-252; Reece et al. Leuk Lymphoma 2008; 49: 1471-1485.

Alkylator therapy

Dex-based

Thal-based

Thalidomide Combinations Relapsed/Refractory Myeloma

Many combination reportedCTD, 1,2 DVd-T,3 VTD4,5, Velcade + Doxil + thal6

Overview of resultsOverall response rates 60-75% (~20% CRs)TTP/PFS ~12 monthsRisk of blood clots increased

Only one comparative study (Offidani M, et al7)Case matched study of ThaDD vs thalidomide + dexOverall response rates 92% vs 63%CR/nCR rate 30% vs 10%Median PFS 21 vs 11 monthsMedian overall survival longer for the 3-drug combination

1D Roussou M, et . Leuk Lymphoma 2007; 48:754-758; 2Garcia Sanz R, et al. Leukemia 2004; 18: 856-863; 3Hussein MA, et al. Mayo Clin Proc 2006; 81:889-895; 4Zangari M, et al. Blood 2005;106: abstract #2552; 5Ciolli S, et al. Leuk Lymphoma 2006; 47:171-173; 6Chanan-Khan A, et al. Blood 2006; 108: abstract #3539; 7Offidani M, et al. Eur J Haematol 78: 297-302, 2007

Depth of Response in Multiple Myeloma

MR

PR

VGPRnCRCR

sCR

Treatment initiation

Progression

Time

Depth of response usually correlates with TTP

Phase III Trials in Relapsed/Refractory Multiple Myeloma

APEX1

Boretzomib versus dexamethsone

MMY-30012

Doxil + bortezomib versus bortezomib alone

MM090 and MM0103,4

Lenalidomide + dexamethasone versus dexamethasone alone

1Richardson PG, et al. N Engl J Med 2006 ;2 Orlowski RZ, et al. J Clin Oncol 2007; 25: 3892-901; 3 Weber DM, et al. N Engl J Med 2007; 357: 2133-42. 4Dimopoulos M, et al. N Engl J Med 2007; 357: 21.

Phase III Trial: Bortezomib + DOXIL® vs Bortezomib (MMY-3001)

Time to progression Overall survival

Orlowski RZ, et al. J Clin Oncol 2007;25:3892–3901PLD, pegylated liposomal doxorubicin

http://www.emea.europa.eu

Lenalidomide 25 mg/day, days 1-21Dex 40 mg/day, days 1-4, 9-12, 17-20*

Placebo on days 1-21Dex 40 mg, d 1-4, 9-12, 17-20*

Relapsed or refractory MM

>1 prior lines of tx

No dex resistance

Creatinine <2.5 mg/dL

LFTs 3 x normal

Lenalidomide + Dex vs Dex Alone for Relapsed/Refractory MM

Results of 2 Phase III Studies (MM-009, MM-010)

Treatment continued until disease progression

* Dex reduced to 40mg on day 1- 4 only after cycle 4 until PD

Weber M et al. Dimopoulos M et al. N Engl J Med, 2007

Lenalidomide + Dex vs Dex + Placebo in Relapsed MM

Time to progression (months)

0 10 20 300

25

50

75

100

Placebo/Dex

Len/Dex

Pat

ien

ts (

%)

5 15 25

100MM-009

0 5 10 15 20 250

25

50

75

Placebo/Dex

Len/Dex

Time to progression (months)

Pat

ien

ts (

%)

MM-010

Median time to progression (months)Median time to progression (months)

Len/DexLen/Dex Placebo/DexPlacebo/Dex P-value*P-value*

MM-009MM-009 11.111.1 4.74.7 <0.001<0.001

MM-010MM-010 11.311.3 4.74.7 <0.001<0.001

*`P-value from log-rank testWeber D, et al. NEJM 2007;357:2133Dimopoulos M, et al. NEJM 2007;357:2123

Subset Analysis of Phase III TrialsRelapsed/Refractory Myeloma

Number of Prior Regimens

Trial Rx Overall Response Rate (%)

Median TTP (months)

1 prior regimen

APEX BtzDex

45%26%

7.05.6

MM 009/010 Len/DexDex

69%22-30%

17.14.7-5.1

> 2 prior regimens

APEX BtzDex

34%13%

4.92.9

MM 009/010 Len/DexDex

57%18-21%

10.64.6-4.7

Richardson PG, et al. N Engl J Med 2005; 352: 2487-2498; Stadtmauer EA, et al. Eur J Haematol Mar 19 2009. [Epub ahead of print]

Subset Analysis of Phase III Trials Relapsed/Refractory Myeloma

Prior Thalidomide

Trial Rx ORR (%) Median TTP (months)

No prior thal

MM 009/010 Len/DexDex

65%27%

13.94.7

DOXIL-MMY-3001 Btz/PLDBtz

47%43%

9.86.3

Prior thal MM 009/010 Len/DexDex

54%14%

8.44.6

DOXIL-MMY-3001 Btz/PLDBtz

48%4.3%

9.06.8

Wang M, et al. Blood 2008 112; 4445-445; Sonneveld P, et al. Cancer 2008; 112: 1529-1537.

Bortezomib Combinations inRelapsed/Refractory Myeloma

Bortezomib is attractive agent to use in combination Predictable and reversible drop in platelets and neutrophils No cumulative myelosuppression No increased risk of blood clots Many 3- and 4-drug combinations reported

One Phase III trial shows superiority of combination Rx1

DOXIL- MMY- 3001: Bortezomib + DOXIL vs bortezomib alone Not much information on bortezomib + dex Many bortezomib combinations under investigation

Bortezomib + lenalidomide + dex2 Bortezomib + tipifarnib (MMRC)* Bortezomib + MoAb (HuLUC 63, anti-IL6) Bortezomib + histone deacetylase inhibitors (vorinostat*, panobinostat)* Bortezomib + mTor inhibitors Bortezomib + perifosine (Akt inhibitor)

* PMH trials1Orlowski RZ, et al. J Clin Oncol 2007;25:3892–3901; 2Richardson P, et al. Blood 2008;112:abstract #1742

“CYBOR-P”Weekly Bortezomib 1.5 mg/m2 + CY + P

Weekly bortezomib + weekly cyclophosphamide 300 mg/m2 + prednisone 100 mg q 2 days

N=13 Overall RR 85% (CR/nCR rate 54%) Only 2 progression events 1-year PFS 83% and OS 100%

76 cycles evaluable for toxicity Gr 4 ANC 1.3% Gr 4 pl 2.6% Gr 3 pl 1.3% Gr 1 PN in 7 patients (55%) Shingles in 4 patients

Reece D, et al. J Clin Oncol 2008; 10: 4778-4783

pfs:

0.00

0.25

0.50

0.75

1.00

pfsday

0 100 200 300 400 500

Legend: Product-Limit Estimate Curve Censored Observations

Progression-free survival

Lenalidomide Combinations in Relapsed/Refractory MM

AnthracyclinesDVd-R – PLD, vincristine, DEX, lenalidomideRAD – lenalidomide, adriamycin, DEX*

AlkylatorsRCD – lenalidomide, cyclophosphamide, DEX*CPR – cyclophosphamide, lenalidomide, prednisone*

Novel agentsLenalidomide, bortezomib (+/- DEX)* Lenalidomide, perifosine, DEX Lenalidomide, bevacizumab, DEXLenalidomide ,vorinostat, DEX*Lenalidomide, melphalan, prednisone, thalidomide (RMPT)*

*ASH abstracts 2008

“CPR”: Phase I-II Trial Dose Levels28-day Cycle (N=31)

Dose Level

N CY mg/m2

on Days 1,8,15

Lenalidomide (Revlimid)

mg per day

on Days 1-21

Prednisone mg

Q 2 days

Median #

cycles given

(range)

# on Rx

1 3 150 15 100 12

(12-34+)

1

2 3 300 25 100 10

(9-23)

0

3 26 300 25 100 17

(5-28+)

12

Reece, et al. IMW 2009, abstract; personal communications

DLT not identifiedOverall response rate is 94% (≥69%) at dose level 3

1-year PFS 78% and OS 93%

*All patients received ASA 81 mg

Lenalidomide, Bortezomib and Dex (Rev/Vel/Dex) in Relapsed/Refractory MM

Phase II Study (N=64)

Regimen Revlimid 15mg daily x 14 days Bortezomib 1.0 mg/m2 days 1,4,8,11 Responses (n=62) Dex 20 mg day on and after bortezomib

amended to 10mg Daily ASA; G-CSF permitted

Patients Relapsed 38(59%), refractory 26(41%) Prior ASCT 36% Prior btz 55%, len 8%, thal 77%, ASCT

Toxicities Most heme toxicity Gr 1-2 2 atrial fibrillation 2 VTE 1 death fungal pneumonia

Median TTP and PFS 12 months

CR/nCR PR Total

All 21% 47% 68%

Prior btz

17% 40% 57%

PriorIMiD

15% 40% 57%

Richardson PG, et al Blood 2008: 112: abstract 1742; Anderson K, et al. Proc ASCO 2009: abstract 8536.

Newer Regimens for Relapsed/Refractory Myeloma: Phase I-II Trials

Regimen # Cycles N Response rate (CR rate)

1-year PFS†

1-year Overall

Survival†

VMPT1 6 30 67% (17%) 61% 84%

CyBor-P2 8 37 85% (54%)* 56% 89%

VCD3 11 50 82% (16%) 50% ~75%

RVD4 8+ 33 68% (21%) 50% --

RAD5 6 69 76% (10%)* ~40% 88%

*At MTD

1 Palumbo A et al. Blood 2007; 109: 2767-272; 2 Reece D, et al. J Clin Oncol 2008. 229: 4777-4783; 3Kropff M, et al. Br J Haematol 2007; 138: 330-337; 4 Anderson K, et al. Proc ASCO 2009: abstract 8536.; 5Knop S, et al. Blood 2009 Jan 30 [Epub ahead of print]

Impact of Novel Agents on the Outcome in Relapsed/Refractory Disease (n=387)

Kumar et al. ASH 2007 (Abstract 3594)Time (months)

Su

rviv

al

00.0

20 40 60 80 100

0.2

0.4

0.6

0.8

1.0

P<0.001

Relapsed before 1998Relapsed 1998–1999Relapsed 2000–2001Relapsed 2002–2003Relapsed 2004–2005

Introduction of novel agents for relapsed myeloma have greatly improved survival

Important QuestionsManagement of Relapsed/Refractory Myeloma

What is the best therapy for recurrent myeloma in patients given novel agents at diagnosis?Can alkylating agents like MP or cyclophosphamide +

prednisone be used after MPT, VMP or lenalidomide + dex given as first line therapy?

How effective is repeating the same novel agent?How well does lenalidomide work after bortezomib and vice

versa?If lenalidomide is used as maintenance, can the dose be

increased and dex added at relapseShould novel agents be used in combination or

sequentially in relapsed/refractory myeloma?

What is the Optimal Strategy for Relapsed Myeloma?

Novel Agent Combination(e.g.,RVD, CyBorP) x 6-8 cycles

+/- maintenance

Len + Dex Bortezomib-based therapy

? Comparative Overall Survival ?

Bortezomib +/- steroids Len + Dex

ASCT in t(4;14) Myeloma

Study N # ASCT Median PFS (mos)

Chang/2004 16 1 9.9

Gertz/2005 26 1 8.2

Moreau/2007 100 2 21

• Translocation between heavy Ig gene locus and MMSET + FGFR3• Found in 15% of patients• Associated with IgA myeloma

Chang et al. Bone Marrow Transplant 2005;36:793; Gertz et al. Blood 2005;106:2837;Moreau et al. Leukemia 2007 2007;21:2024

Treatment of Progressive t(4;14) MM

Regimen N Response rate

Median TTP (mos)

Cyclophosphamide + prednisone/MP1

11 0 (63% SD) --

Thalidomide or dex1 17 41% 4.7

Bortezomib +/- steroids2

6 67% 10.5

Lenalidomide +

Dexamethasone3

28 77% 8.0

1Jaksic W, et al. J Clin Oncol 2003; 23:7069; 2Chang H, et al. Leuk Res 2007; 31:779-782; 3 Reece D, et al. Blood 2009; Mar 30 [Epub ahead of print].

The t(4;14) translocation 4 14

Dysregulated expression of FGFR3 and MMSET

Oncogenic transformation

DNA break in IgH4 14

DNA break in proximity of FGFR3 and MMSET

FGFR3 and MMSET under the control of the IgH enhancer

IgH

MMSET FGFR3

Chr. 14

Chr. 4

IgH

MMSET

FGFR3

IgH

der(14)

der(4)

Adapted from Grassot et al. Nucleic Acids Res. 2003 Jan 1; 31(1): 353-8.

CHIR258 IC50 in uMRTKFLT3 <0.001c-KIT 0.002CSFR1/c-fms 0.036FGFR1 0.008FGFR3 0.009VEGFR1/Flt1 0.01VEGFR2/Flk1 0.013VEGFR3/Flt4 0.008PDGFR 0.027PDGFR 0.21INSR 2EGFR1 2c-MET >3EphA2 4TIE2 4IGFR1 >10HER2 >20

CHIR258 is a Potent Inhibitor of Class III, IV & V Receptor Tyrosine Kinases

I II III IV V

IGFR1

CHIR258 IC50 < 210 nMCHIR258 IC50 >2 M

N

NN

N O

F N N

CHIR258 Inhibits Tumor Growth in a Xenograft Model of FGFR3 Myeloma

Placebo 60mg/kg 30mg/kg

Trudel S, 2004

R3Mab Antibody against FGFR3

Unique anti-FGFR3 monoclonal antibody (Genentech)

Advantage of selectivityAnti-tumor activity

mediated in part via ADCCPMH is lead site for phase

I-II trial in t(4;14) myeloma

(S. Trudel)

Qing J, el al. J Clin Invest 2009; 119: 1216-1229

ASCT in 17p Del

Author/Year N # ASCT

Median PFS

(mos)

Chang/2005 10 1 7.9

Gertz/2005 18 1 8.7

• Loss of p53 gene

• Found in 10% of patients at diagnosis and up to 30% at relapse

Chang et al. Bone Marrow Transplant 2005;36:793; Gertz et al. Blood 2005;106:2837

Treatment or Relapsed/Refractory Myeloma Patients with p53 Deletion (N=31)

Agent N ORR(%) Median PFS (mos)

Thalidomide 15 20% 5.0

Bortezomib 12 50% 5.6

Lenalidomide 11 60% 4.8

Alkylating agents 9 11% 5.1

Steroids 5 20% 1.9

Other 7 43% 6.3

Reece D, et al. Blood 2008; 112: abstract 1724

What is the optimal therapy in patients relapsing after more effective induction regimens?

Minimal data available for treatment of relapse after VMP, MPT or lenalidomide + dexamethasone in transplant ineligible patients

No data on second salvage transplants after novel agents integrated into induction therapy + ASCT

No data on the efficacy of ASCT deferred to the time of first relapse after first-line therapy with lenalidomide + dex or novel 3- and 4-drug regimens

Upcoming new drugs/combinations likely will be key to prolonging survivalDrugs under evaluation for “unmet medical need”

Pomalidomide + dex Bortezomib + HDAC inhibitors

Responses after Subsequent Therapy in VISTA Trial of VMP versus MP

Subsequent therapy*

VMP(N=129)

MPN=(194)

N (%) Response rate (CR) N (%) Response rate (CR)

Bortezomib-based(N=105)**

21(16%) 39% (6%) 84 (43%) 55% (10%)

Thalidomide-based(N=149)**

63 (46%) 48% (4%) 86 (44%) 55% (3%)

Lenalidomide-based(N=37)**

25 (16%) 56% (4%) 12 (6%) 55% (0)

San Miguel JF, et al. Blood 2008;112: abstract 650.

*Other agents were used as subsequent therapy, including dexamethasone; patients could receive multiple-agent regimens.** Single-agent use: 36% bortezomib, 37% thalidomide, 14% lenalidomide

Patients relapsing after VMP are not intrinsically more resistant than after using MP

Trial Candidate

After ASCT No prior ASCT

SecondASCT

Lenalidomide + dex +/-CYBortezomib +/- steroids +/- CY

Thalidomide +/- steroidsCyclophosphamide + prednisone

Bortezomib + dex + panobinostatBortezomib + Geminex (Mayo)

Bortezomib + Vorinistat (MMRC)Lenalidomide + carfilzomib + dex

Lenalidomide + dex + HuLuc MoAb(Pomalidomide +/- dex) [MMRC])

Akt inhibitor (GSK)TKI 258 (t[4;14])

Genentech MoAb (t[4;14])

no yes

Repeat M+P

≥ 2 year benefit≥ 1 year benefit

Treatment of Relpased/Refractory Multiple Myeloma-(1)

Many options/combinationsMay repeat initial therapy in selected patientsCombinations with novel agents produce high overall

and complete response rates—effect on PFS awaitedBortezomib and lenalidomide/dex can be effective in

patients with t(4;14)New targeted agents available in phase I-II trials

Most people eventually receive all of the effective drugs for different relapses

Treatment of Relapsed/Refractory Multiple Myeloma-(2)

Selection of therapy depends on many factorsTherapy can be optimized for patients with renal

impairment/failure Rapid anti-tumor responses observed with bortezomib

regimens Good safety profile for bortezomib and thalidomide Growing experience with lenalidomide

Therapy can be individualized for patients with peripheral neuropathy, decreased marrow reserve and steroid intolerance

Use of novel agents has improved survival after myeloma relapse