Update on Novel Combinations for Relapsed/Refractory Disease:

Approved Drugs

James R. Berenson, MDMedical & Scientific Director

Institute for Myeloma & Bone Cancer ResearchLos Angeles, CA

Treatment Choices

IMiDs Proteasome inhibitors

Chemotherapy

Steroids Clarithromycin

Clinical Trials

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Investigational Drugs

Novel Combinations

Thal

LenDex

Methylpred

Prednisone

Alkylating agents• Melphalan• Cyclophosphamide• Bendamustine

Anthracyclines• Doxorubicin• PLD

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Bortezomib Carfilzomib

Pom

Individualize your choice for the myeloma patient based on:

Co-morbid conditions

Disease characteristics

Work/ Lifestyle

Renal,Bone,Marrow,Subjective,Rate of ProgressionGenetics?

How active is the patient?Mobility?Is potential neuropathy an issue? (e.g.- surgeon, pianist)

Diabetes mellitus (steroids)Cardiac (Doxorubicin, PLD)Neuropathy(Thalidomide)

Prior Treatments

Responseand for how long?Side effects and tolerability

Principles of Treating Relapsed/Refractory Multiple Myeloma

• Be sure a patient has really progressed before changing therapy– REPEAT MYELOMA LABS!

• Try to use drugs patient has not seen before• HOWEVER,

– progression on one drug in combination does not mean that drug will not be effective w/ another agent

• e.g., pts progressing from bortezomib w/ melphalan often respond to bortezomib w/ PLD

• Even different drugs in the same class may be active so that– bortezomib+melphalan failures may respond to other alkylating agents-

cyclophosphamide or bendamustine– LEN failures may respond to THAL and vice versa

– pts progressing from a drug at one dose may respond to the same drug at a higher dose- e.g., LEN

– the same combination may be effective again if the patient has not seen the combination in a long time

• Initial approval in multiple myeloma based on phase II data• Only single agent to demonstrate a statistically significant survival

advantage (APEX)

Study Regimen Evaluable Patients (n)

OverallResponse*

Median OS(mos)

SUMMIT Bortezomib 1.3 mg/m2 202 27% 17

CREST Bortezomib1.0 mg/m2

1.3 mg/m254

30%38%

26.7Not yet reached

APEXBortezomib

Dex1.3 mg/m2

40 mg315312

43%18%

29.823.7

Single Agent Bortezomib Relapsed/Refractory Multiple Myeloma

*EBMT criteria

P = .0272

PHA

SE II

PHA

SE II

I

Efficacy and Safety of Bendamustine plus Bortezomib in R/RMM: A Phase 1/2 trial

Patients were assigned to one of 3 cohorts receiving doses of intravenous bendamustine at 50 mg/m2 (cohort 1), 70 mg/m2 (cohort 2), or 90 (cohort 3) mg/m2 in combination with a fixed dose of intravenous bortezomib (1.0 mg/m2) according to the schedule in Figure 1.

Berenson et al., Brit J Haematol, in press

No DLT was observed at any dose level.50 mg/m2 (n = 5)70 mg/m2 (n = 4)90 mg/m2 (n = 5)

The maximum dose of bendamustine (90 mg/m2) was well tolerated in combination with bortezomib 1.0 mg/m2 and was designated as the MTD

Overall response rate Overall 48% (1 CR, 2 VGPR, 9 PR, & 7 MR)At MTD (90 mg/m2) 52%Bortezomib-exposed (n=31) 42%Alkylator-exposed (n=28) 46%

Bendamustine & Bortezomib: Results

Berenson et al., Brit J Haematol, in press

Bendamustine (B) w/ Lenalidomide (L) and Dexamethasone (D): Phase 1/2 Trial

• R/R MM patients• N=29• Regimen (28-day cycles)

– B 75-100 mg/m2 d1 & 2– L 5-10 mg qd d1-21– Dex 40 mg PO weekly

• MTD: B 75/ L 10/ D 40• Results (only 25 considered evaluable for

response)– ORR (> PR): 52% w/ 24% VGPR– MR 24%– PFS: 6.1 mo

Lentzsch et al. Blood 2012

Bortezomib + PLD vs. Bortezomib in Previously Treated MM

1° Endpoint: TTP2° Endpoints: OS*, ORR

BORT 1.3 mg/m2 PLD 30 mg/m2

N=646

RANDOMI ZE

1 4 8 11Days

(n=324)

(n=322)

q 3 weeks up to 8 cycles

q 3 weeks up to 8 cycles

*Not enough events to determine statistical significance in overall survival.ORR=overall response rate; OS=overall survival; TTP=time to progression.

Doxorubicin HCl liposome injection Prescribing Information, Rev’d May 2007

Bortezomib ± PLD MMY-3001 Trial

• Response* B (n = 322)

B+D (n = 324) P value

CR + nCR 11% 13%PR 39% 40%

ORR 41% 44% 0.43• EfficacyDOR, months 7.0 10.2 0.0008

TTP, months 6.5 9.3 0.000004

An overall survival advantage was observed for the combination arm (P=0.0476)Survival rate (15 months) 65% 76% 0.03

*By EBMT criteria

Orlowski et al. J Clin Oncol 25:3892-901 (2007)

More Frequent Dosing with PLD Improves Anti-Myeloma Effect in a SCID-hu MM Model

1Twenty days post-implantation, mice received i.p. injection of PLD once weekly. Human IgG was measured weekly in the mouse serum by ELISA.

2Seventeen days post-implantation, mice received i.p. injection of PLD once daily for three consecutive days weekly. Human IgG was measured weekly in the mouse serum by ELISA.

0 10 20 30 400

100200300400500600700800900

10001100120013001400

VehicleDoxil (0.3 mg/kg)Doxil (1 mg/kg)Doxil (3 mg/kg)

Days Post ImplantationH

uman

IgG

Lev

els

(mg/

dL)

0 10 20 30 400

100

200

300

400

500

600VehicleDoxil (0.3 mg/kg)Doxil (1 mg/kg)Doxil (3 mg/kg)Doxil (10 mg/kg)

Days Post Implantation

Hum

an I

gG L

evel

s (m

g/dL

)

Weekly Dosing1 Daily Dosing2

Campbell et al. Br J Haematol 2006

Bortezomib + PLD + Dexamethasone for Patients with Previously Untreated Myeloma:

A Phase II Trial

Days 1 2 3 4 5 6 7 8 9 10 11 29

Cycle repeatsBortezomib: 1.0 mg/m2 IV PLD: 5 mg/m2 IV infusion

Dexamethasone 40 mg IV

Berenson et al. Brit J Haematol, 2011

Response Type Number of Patients (N = 35)

Complete Response (CR)(no serum M-protein)

7 (20%)

Very Good Partial Response (VGPR)(≥ 90% decrease in serum M-protein)

3 (8.6%)

Partial Response (PR)(50-74% decrease in serum M-protein)

15 (42.9%)

Minor Response (MR)(25-49% decrease in serum M-protein)

5 (14.3%)

Objective Response (CR+VGPR+PR+MR)

30 (85.8%)

Stable Disease (SD)(no serum M-protein)

3 (8.6%)

Disease Control (CR+VGPR +PR+MR+SD)

33 (94.4%)

Progressive Disease (PD)(>25% increase in serum M-protein)

2 (5.7%)

DVD: Response Rates

Berenson et al. Brit J Haematol, 2011

Adverse Event Comparison Between DVD (Current Study) and Standard Dosing (Jakubowiak et al., Blood 2009).

Comparison of Adverse Events w/ Modified DVD vs Conventional Dosing

Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up1

Richardson PG et al. ASH 2010, abstract #304915

–Endpoints: Primary: PFS; Secondary: ORR (≥MR), DOR, TTP, OS, safety –Patients: 64 pts with relapsed/refractory MM; median age 65 years (range 32–83); ISS stage I/II/III/unknown (%): 27/25/23/25; median 2 (range 1–3) prior therapies

–Study design: – Anticoagulation with aspirin ± warfarin or LMWH, and antiviral prophylaxis against

herpes zoster were required

Richardson PG et al. ASH 2010, abstract #3049 16

–Safety: • Median cycles received:

11 (range 1–48)• Median treatment duration: 7.9

months (range 0.4–36); 66% of pts completed ≥8 cycles with all three drugs

Best response,%CR/nCR 11/14PR/VGPR 36/3ORR (≥MR) 78

• Median duration of ≥MR: 8.3 months• Median duration of ≥PR: 8.4 months

Outcomes

Median, mos

1-yr, %

2-yr, %

TTP 9.5 37 16PFS 9.5 36 15OS 26 86 55

• Results: 62 pts evaluable for response

Gr ≥3 AE, % VRD (n=64)Neutropenia 30Thrombocytopenia 22Lymphopenia 11Leukopenia 9

Hyperglycemia 9

Hyponatremia 8

Hypophosphatemia 8

Fatigue 5Diarrhea 3Limb edema 3Pain in extremity 2

Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up

DVD-R (Bortezomib + PLD + Dexamethasone + Lenalidomide) for Patients with R/R MM:

A Phase II Trial

Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 29

Cycle repeatsBortezomib: 1.0 mg/m2 IV PLD: 4 mg/m2 IV infusion

Dexamethasone 40 mg IV

Berenson et al., Leukemia 2012

Len 10 mg po qd d1-14

DVD-R: Response RateN=39

Complete Response (CR)8* (21%)

(no serum M-protein)Very Good Partial Responses (VGPR)

4 (10%)(> 90% decrease in serum M-protein)Partial Response (PR)

7 (18%)(50-74% decrease in serum M-protein)Minor Response (MR)

14 (36%)(25-49% decrease in serum M-protein)Objective Response (CR+VGPR+PR+MR) 30 (85%)Stable Disease (SD)

4 (10%)(change in M-protein + 25%)Disease Control (CR+VGPR+PR+MR+SD) 37 (95%)Progressive Disease (PD)

2 (5%)(>25% increase in M-protein)

*Based on the modified Blade’ criteria

DVD-R Study: Adverse EventsGrade 3 adverse events included:

6 reversible neutropenia, 4 reversible anemia, 4 pneumonia, 1 dyspnea, 3 reversible thrombocytopenia, 1 reversible peripheral neuropathy, 1 mental confusion, 1 hypophosphatemia, 1 fall, 1 skin BCC, 1 allergic reaction to moxifloxacin, 1 dysphagia, 1 syncope, 1 respiratory distress.

Grade 4 adverse events included: 1 reversible thrombocytopenia & 1 anemia

No cases of stomatitis or hand-foot syndrome reported!

Treatment-emergent peripheral neuropathy (25%): Grade 1: n=8 (20%)Grade 2: n=1 (2.5%)Grade 3: n=1 (2.5%)

Retreatment w/ IMiDs for MM Patients

• Retrospective study in 140 pts treated firstline w/– THAL/DEX- 58%– LEN/DEX- 42%

• Retreatment w/ a regimen containing– THAL- 24%– LEN- 76%

• # of treatments before retreatment - median of 2 (range 1-6)

• 89% received IMiD w/ DEX• 113 considered evaluable

for response– 44% > PR– MR not reported

Madan et al. Blood 2011

LEN

LEN(n=48)

LEN

THAL (n=11)

THAL

LEN(n=58)

THAL

THAL (n=23)

> PR 54% 20% 48% 30%

PX-171-003-A0 (N=46)

PX-171-003-A1 (N=266)

Phase 2 Study Population

Dosing regimen, premedication, and hydration

were defined in 003-A0

Carfilzomib for Injection*

days 1,2,8,9,15,16(28-day cycles)

Maximum 12 cycles

Progressive disease required at study entryRelapsed from ≥2 prior lines of therapy

• Must include bortezomib• Must include thalidomide

or lenalidomideRefractory to last regimen

PX-171-003: Study Overview

Study expanded to registration trial

• Primary endpoint: Overall response rate– Assessed by an Independent Review Committee, using

International Myeloma Working Group criteria

*Cycle 1, 20 mg/m2

Cycle 2 and beyond, 27 mg/m2

Adapted from Siegel D, et al. ASCO 2011. Abstract 8027 (poster presentation).

PX-171-003-A1 (N=266): Disease characteristics

Median prior regimens (range) 5 (1-20)Median years since diagnosis (range) 5.35 (0.5-22.3)

Prior transplant 74.4%Refractory status to most recent therapyRefractory: Progression during most recent therapyRefractory: Progression within 60 days after completion of most recent therapyRefractory: ≤25% response to treatmentRelapsed: Progression after 60 days post treatment

74.4%14.3%

6.0%5.3%

Creatinine clearance <30 mL/min 2.3%Median serum b2-microglobulin (range) 4.3 (0.4-20.5)CytogeneticsNormal/FavorableUnfavorableUnknown

59.8%28.2%12.0%

PX-171-003-A1: Response

N=266Response rates*Overall response rate (ORR)Complete responseVery good partial responsePartial response

61 (22.9%)1 (0.4%)

13 (4.9%)47 (17.7%)

Median duration of response(95% CI)

7.8 months(5.6-9.2)

*As assessed by the Independent Response Review Committee

Carfilzomib in MM Patients Following 1-3 Prior Therapies

004, Phase II1:1Carfilzomib

Cohort 120 mg/m2

Relapsed / Refractory Multiple Myeloma

1-3 Prior TherapiesN = 165 Carfilzomib

Cohort 220 mg/m2→27 mg/m2

Bortezomib-treated

Bortezomib-naïve

Bortezomib-naïve

Bortezomib-naïve Bortezomib-treatedN 129 36Median age 65 years 63 yearsMedian # prior therapies

2 3

Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles

Stewart AK, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8026. Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813.

Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies

Bortezomib-Treated Cohort 1 (20 mg/m2 Carfilzomib)n = 34

ORR 21%CBR (> MR) 33%Median TTP 8.1 monthsMedian DOR (> PR) 11.5 months

Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813.

Bortezomib-naïve Cohort 1 (20 mg/m2)n = 59

Cohort 2 (20→27 mg/m2)n = 70

ORR 42% 52%CBR 59% 64%CR 3% 2%VGPR 14% 27%Median TTP 8.3 mo Not reachedMedian DOR 13.1 mo Not reachedMedian PFS 8.2 mo Not reached

Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed / Refractory MM

CarfilzomibLenalidomideLow-dose dex

MM: 1-3 Prior Therapies

N = 52

1o EndpointORR

2o EndpointDOR, TTP, OS, PFS, Safety

Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025.

CRdN = 51

Median age 63 yearsMedian # of prior therapies Prior bortezomib Prior lenalidomide Prior lenalidomide and bortezomib Prior thalidomide

285%73%50%44%

Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed/Refractory MM

Grade 3/4 Adverse Events CRdN = 51

Neutropenia 23%Thrombocytopenia 15%Anemia 15%Hypophosphatemia 13%Fatigue 12%

Response CRdN = 51

ORR 78% CR / nCR 24% VGPR 18% PR 37%

Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025.

ORR, overall response rate; CR, complete response; nCR, near complete response; VGPR, very good partial response; PR, partial response.

• Nontraditional intrapatient Phase I/II trial • Eligibility: Progressive disease while on

bortezomib or relapsed within 12 wks of the last dose of bortezomib in a combination regimen

• Carfilzomib replaces bortezomib in combination with:– Alkylating agent– Anthracycline– Glucocorticosteroid– IMiD

A Phase I/II Study of Carfilzomib as a Replacement for Bortezomib for Multiple Myeloma Patients Failing

Bortezomib-Containing Regimens

Study Design (cont’d)• Study treatment

– Carfilzomib• starting at 20 mg/m2 for the 1st cycle• increased to 27, 36 and 45 mg/m2 during cycles 2, 3 and

4, respectively if no DLT is observed– DLT considered > Grade 2

• administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle

– Cycle length, schedule(s) and dose(s) of other drugs identical to that of the previous bortezomib-containing regimen

• A patient must complete a minimum of a full cycle without DLT before continuing onto a subsequent cycle (cycles 1-4 only)

• Maximum # of cycles- 8

ResultsDemographicsEnrolled (N) 32Efficacy (N) 24Age (median) 67Sex (M:F) 21:11Prior RegimensNumber of prior regimens- median (range) 6 (1-18)Number of prior bortezomib-containing regimens- median (range) 2 (1-13)

Regimen Details

Cycle length

8 pts- 21-day 24 pts- 28-day

Cycles completed, median (range)

3 (range 0-12)

Follow-up median(range)

5.9 mo(0.4-14.4 mo)

Number of DLTs

8 (25%)

Regimen in addition to carfilzomib (N=32)Dexamethasone 9 (28%)Cyclophosphamide+ ascorbic acid 5 (16%)Cyclophosphamide+ascorbic acid+dexamethasone

1 (3%)

Melphalan 1 (3%)Bendamustine 3 (9%)Bendamustine+methylprednisolone 1 (3%)PLD 1 (3%)PLD+dexamethasone 5 (16%)Lenalidomide 2 (6%)Lenalidomide + dexamethasone 1 (3%)Lenalidomide + dexamethasone + PLD 1 (3%Thalidomide + dexamethasone 1 (3%)Thalidomide + lenalidomide + bendamustine + clarithromycin + methylprednisolone

1 (3%)

Best Response # of Patients %

PD 2 8%SD 4 17%MR 5 21%PR 7 29%VGPR 4 17%CR 2 8%Overall Response Rate (PR+VGPR+CR)

13 54%

Clinical Benefit Rate (MR+PR+VGPR+CR) 18 75%

Efficacy (N=24)

Summary• Intrapatient Phase I/II trial of MM patients

refractory to bortezomib combination therapy with and without IMiDs

• Treatment with same regimen w/ carfilzomib (CAR) replacing bortezomib

• CAR escalated from 20 to 27, 36, and 45 mg/m2 during cycles 1-4; maximum of 8 cycles

• MTD for one regimen (CY+CAR) reached at the maximum dose of CAR (45 mg/m2) with no DLT

• Well tolerated• Clinical benefit rate 75% including 8% CR, 17%

VGPR, 29% PR, & 21% MR– Responses observed with all drugs!

• Phase I/II, open-label, multi-center trial investigating weekly carfilzomib + dexamethasone in R/R MM patients

• Phase I: – 28-day cycle– Carfilzomib 45, 56 or 70 mg/m2 on days 1, 8 & 15– Dexamethasone IV at 40 mg days 1, 8, 15, & 22

• Phase II:– Carfilzomib at MTD on days 1, 8 & 15– Dexamethasone IV at 40 mg days 1, 8, 15, & 22

• Enrollment: second cohort (56 mg/m2) currently being treated!

A Phase I/II Trial of Weekly Carfilzomib in Combination With IV Dexamethasone for R/R

Multiple Myeloma

HDAC Inhibitor Vorinostat & Bortezomib for R/R MM: VANTAGE 088: Phase III Trial

Bortezomib + Placebo

Bortezomib + VorinostatMultiple Myeloma

1-3 Prior TherapiesN = 637

R

Bortezomib + Vorinostat

Bortezomib + Placebo

P

ORR 56% 41% < 0.0001CBR 71% 54% < 0.0001Median PFS 7.63 mo 6.83 mo < 0.01Median OS NR 28.1 mo 0.35

Dimopoulos MA, et al. ASH Annual Meeting Abstracts. 2011;118(21):811.

ORR, overall response rate; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival.

Vorinostat, Lenalidomide & Dexamethasone for R/R MM

1:1Vorinostat (300 or 400 mg, 1x daily)Lenalidomide (10, 20, 25 mg daily)Dexamethasone (40 mg weekly)

Relapsed / Refractory MMN = 28

ResponseVorinostat / Lenalidomide /

DexamethasoneN = 28

ORR 46% CR 7% > SD 86%

Siegel D, et al. Blood. 2009;114(22). Abstract 305. Vorhees PM, et al. Blood. 2009;114(22). Abstract 306.

Serious AE• Neutropenia, diarrhea, ↑ QTc, extrasystole, dehydration, ↑ troponin, fever

Grade 3 DVT in 2 patients No treatment-related deaths

Novel Combinations of Approved Drugs Greatly Expand the Therapeutic Options

for R/R Myeloma Patients!• Approved drugs

– Novel combinations– Modifications of dose and schedule

• Improve efficacy• Better tolerability

• Many new drugs in development– Similar targets

• Proteasome inhibitors- carfilzomib (FDA-approved!)• IMiDs- pomalidomide

– New classes of agents• HDAC inhibitors- vorinostat, panobinostat• Monoclonal antibodies

– Anti-CS-1- elotuzumab– Anti-CD40- dacetuzumab

• MTOR inhibitors- temsirolimus• PI3K inhibitors- perifosine