fri 9.00 sr colman dr galal multiple myeloma · brody t. clinical trials: study design, end points...

9/26/2016

1

Update on The Management of Relapsed and refractory Myeloma

Ahmed Galal MD, MSc, FRCPC

Avera Cancer Institute

Disclosures

Clinical Trial Support from: Celgene, BMS and Amgen

Consultant for: Celgene, Millennium, BMS, Amgen

Speaker for: Celgene, Millennium, BMS, Amgen, Gilead and Merck

Overview of Hematologic Malignancies

3

* Leukemias include acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and other leukemia.1. Surveillance, Epidemiology and End Results (SEER) Stat Fact Sheets. Available at: http://seer.cancer.gov. Accessed March 26, 2015. 2. Siegel RL et al. Ca Cancer J Clin. 2015;65:5-29.

9/26/2016

2

© 2013 Celgene Corporation

Epidemiology of MM in 2012*

• Prevalence

– More than 71,000 people in the US

• Incidence

– More than 21,000 people are diagnosed with MM each year in the US

• Annual age-adjusted incidence is 5.8 per 100,000

• Mortality

– Nearly 11,000 US MM patients die each year

– The overall 5-year relative survival rate for 2002-2008 was 41.1%

• Demographics

– Median age at diagnosis is 69 years

• Less than 3.8% of MM patients are younger than 45 years

– Incidence twice as high in African Americans as in whites

– More frequent in men than women

National Cancer Institute. Surveillance Epidemiology and End Results (SEER) stat fact sheets. http://seer.cancer.gov/statfacts/html /mulmy.html. Accessed October 2, 2012. 4

*Based on SEER data and estimates published in 2012.


FISH-Based Assays

1. Avet-Loiseau H, et al. Blood. 2007;109(8):3489-3495. 2. Dewald GW, et al. Blood. 2005;106(10):3553-3558. 3. Fonseca R, et al. Cancer Res. 2004;64(4):1546-1558. 4. Fonseca R, et al. Leukemia. 2009;23(12):2210-2221. 5. Ross FM, et al. Haematologica 2010;95(7):1221-1225. 6. Munshi NC. Hematology Am Soc Hematol Educ Program. 2008;298-305. 7. Rajkumar SV, et al. Mayo Clin Proc. 2006;81(5):693-703.

Prognosis may vary according to type of chromosomal abnormality1-7*

*Chromosomal abnormalities may be found in MGUS patients as well.5

Chromosomal abnormality(FISH based)

Incidence (%) Prognosis

Isolated del 13 48% No significance

t(14;20) 1.5% Poor

t(11;14) 7.8%-21% No significance

t(14;16) 1.9%-5% Poor

t(4;14) 6.5%-15% Poor

del 17p 11% Poor

del 13 with• del 17p• t(4;14)

8.6%11.9%

Poor

5


Trends in 10-Year Relative Survival of MM

Period estimates of 10-year relative survival of patients with MM by major age groups in defined calendar periods from 1984-1986 to 2002-2004

*Relative survival reflects survival of patients with cancer compared with survival of the general population.

Brenner H, et al. Blood. 2008;111(5):2521-2526.

Calendar period

1984-1986

1987-1989

1990-1992

1993-1995

1996-1998

1999-2001

2002-2004

10-y

ear

rela

tive

su

rviv

al

(%)*

0

5

10

1520

25

30

3540

45

50

15-49

50-59

60-69

70-79

80+

Age range

6

9/26/2016

3

Standard Risk

Intermediate Riskt(4;14)

High Risk

Survival (years)

1–2 years

3–4 years

0 101 2 3 4

6–9 months

Are we changing the clinical course of MM?Impact of novel agents

10 years

4-5 years

3 year


Tumor Burden in MM

MGUS, monoclonal gammopathy of undetermined significance.

M P

rote

in g

/dL

Time

10

5

2

Asymptomatic

MGUS orSmolderingMyeloma

Symptomatic

ActiveMyeloma

Relapse

RefractoryRelapse

Plateau Remission

Relapse

1. Adapted from Durie BG. International Myeloma Foundation. Concise Review of the Disease and Treatment Options: Multiple Myeloma Cancer of the Bone. 2011/2012 ed. http://www.myeloma.org. Accessed November 5, 2012. 2. Kumar SK, et al. Blood. 2008;111(5):2516-2520. 3. McGuire TR. Multiple myeloma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2008:2295-2307.8

MM cells

Bone Marrow Stromal Cells

PBMC

IL-6

TNF

IL-1

IL-2

IFN

CD8+ T Cells

Bone Marrow Vessels

ICAM-1

VEGF

bFGF

NK Cells

Role of Bone Marrow Microenvironment

Hideshima et al. Blood 96: 2943, 2000Davies et al. Blood 98: 210, 2001Gupta et al. Leukemia 15: 1950, 2001

Mitsiades et al. Blood 99: 4525, 2002Lentzsch et al Cancer Res 62: 2300, 2002

Osteoclast activating factorsOAFs increase expression of receptor activator of nuclear factor-kB ligand

9/26/2016

4

Signaling Cascades Mediate Growth, Anti-Apoptosis, and Migration in Myeloma

Reprinted with permission from Hideshima T, Anderson KC. Nat Rev Cancer. 2002;2:927

IL-6IGF1VEGFTNFIL-21

SDF-1

IL-6IL-21

IL-6IGF1VEGFTNF

SDF-1

Anti-apoptosis(drug resistance)

RAF MEK p42/44 MAPK Proliferation

MM cells

JAK STAT3

PI3K AKT (PKB)

Cell cycleFKHR KIP1

Cyclin D

BAD

NF-B

MigrationPKC

BCL-XLMCL1

BMSC

Caspase-9

Clinical Dilemma Myeloma clones are genetically heterogeneous at baseline

Additional genetic changes during evolution:

Serial acquisition as well as changes in earlier clones

Subclones have different:

Clonogenic potential Different levels of resistance

Factors Influencing Treatment Decision Response to prior therapy; tolerability of prior therapy

Patient-related factors such as age, cytogenetic profile, and clonal heterogeneity

Aggressiveness and prognostic features of individual patients

Number of relapses and refractory disease

9/26/2016

5

Definitions According to the International Myeloma Working Group

criteria: Progressive disease (PD) is defined by at least a 25% increase from

nadir in the serum paraprotein (absolute increase must be >0.5 g/dL) Urine paraprotein (absolute increase must be >200mg/24 hours) Difference between involved and uninvolved serum-free light-chain

(FLC) levels (with an abnormal FLC ratio and FLC difference >100 mg/L)

In patients who lack measurable paraprotein levels (oligo- or nonsecretory myeloma), an increase in bone marrow plasma cells (>10% increase)

New bone/soft tissue lesions increasing the size of existing lesions unexplained serum calcium >11.5 mg/dL

Analyzing Measures of PFS and OS

Measure of PFS/OS Across the Entirety of the Study Duration:

• Hazard ratio/relative risk reduction measures the magnitude of the difference between the two curves of a Kaplan-Meier plot1,2*

Measures of PFS/OS at a Specific Point in Time:

• Time point analyses estimate the presence or absence of sustained benefit at time points of interest (eg, 24 months)3

• Median duration is the time at which 50% of patients have either progressed or died4

Measures of PFS/OS

*A log-rank test is conducted to determine statistical significance between arms (represented by a P value ).5

1. Spruance SL et al. Antimicrob Agents Chemother. 2004;48:2787-2792. 2. Brody T. Clinical Trials: Study Design, End points and Biomarkers, Drug Safety, and FDA and ICH Guidelines. London: Academic Press, 2012:165-190. 3. Rich JT et al. Otolaryngol Head Neck Surg. 2010;143:331-336. 4. Friedman LM et al. Survival analysis. In: Friedman LM et al. Fundamentals of Clinical Trials, 4th ed. New York, NY: Springer;2010:1-18. 5. Bland JM,Altman DG. BMJ. 2004;328:1073.

• Endpoint measures that assess results across the entire duration of the trial and at particular time points of interest may facilitate improved understanding of immuno-oncology research1-4

14

Evaluating Clinical Endpoints in Hematologic Malignancies

• Assessment of multiple measures can provide a broad picture of the difference between the investigational arm and the control arm with respect to progression-free survival andoverall survival, as in the two hypothetical, randomized, controlled clinical trials described below

Kaplan-Meier curve intended for illustrative purposes only.* Calculated by log-rank test.OS, overall survival; PFS, progression-free survival.

15

P value* <0.05 P value* <0.05

Median duration

Median duration

9/26/2016

6


Evaluating Clinical Endpoints in Hematologic Malignancies (cont’d)

16



Time point analysis

Median duration

Time point analysis

Median duration

Evaluating Clinical Endpoints in Hematologic Malignancies (cont’d)

Time point analysis

Median duration

Hazard ratio/ relative risk reduction

Time point analysis

Median duration

Hazard ratio/ relative risk reduction

17




I-O Is an Evolving Cancer Treatment Modality in Hematology

• I-O is a fundamentally different approach to fighting cancer that harnesses the body’s own immune system1

18

Through I-O research, therapies are being investigated in an attempt to utilize the body's own immune system to fight cancer1-4

1. Murphy JF. Oncology. 2010;4:67-80. 2. Borghaei H et al. Eur J Pharmacol. 2009;625:41-54. 3. American Cancer Society: Detailed Guide for Non-Hodgkin Lymphoma. Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003126-pdf.pdf. Accessed September 25,2015. 4. Kirkwood JM et al. CA Cancer J Clin. 2012;62(5):309-335.

9/26/2016

7

Immunotherapies Can Be Classified as Either Passive or Active

• Immunotherapies are agents that work with the immune system and can be divided into two categories1:

19

Act on the tumor and indirectly engage immune cells to elicit an antitumor immune response1,2

Act directly on immune effector cells to elicit an antitumor

immune response1-3

Passive Immunotherapies Active Immunotherapies

1. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6-viii9. 2. Mellman I et al. Nature. 2011;480:480-489. 3. Rescigno M et al. BiochimBiophys Acta. 2007;1776:108-123.

• Natural Killer Cell–mediated cytotoxicity is a stepwise, targeted, and highly regulated process1

• Several activating receptors and inhibitory receptors are thought to be involved in regulating Natural Killer Cell activity, including CD137, SLAMF7, and KIR2,3

20

1. Mace EM et al. Immunol Cell Biol. 2014;92:245-255. 2. Long EO et al. Annu Rev Immunol. 2013;31:227–258. 3. Benson DM Jr et al. J Clin Oncol. 2012;30:2013-2015.

Natural Killer Cell–Mediated CytotoxicityActivating and Inhibitory Pathways Under Investigation

T-Cell–Mediated Cytotoxicity

• Activation of T-cell–mediated cytotoxicity is regulated by interactions involving receptors and ligands such as CD40L, CD137, CD28, and OX401,2

• T-cell activity may be negatively regulated by pathways including LAG-3, CTLA-4,B7-H3, and PD-11

• Tumors may enhance inhibitory pathways to block T-cell activation1,2

21

*Defined receptors are not yet known and precise mechanism of T-cell inhibition by B7-H3 is currently unknown.CTLA-4, cytotoxic T-Lymphocyte-Associated Protein 4; LAG-3, lymphocyte activation gene 3.1. Pardoll DM. Nat Rev Cancer. 2012;12:252-264. 2. Kirkwood JM et al. CA Cancer J Clin. 2012;62:309-335.

Activating and Inhibitory Pathways Under Investigation

9/26/2016

8

Based on preclinical studies,

Natural Killer Cells in the immune response to multiple myeloma

22

Natural Killer Cells are among the body’s first line of defense against cancer and may play an important role in the immune response to multiple myeloma2,3

Natural Killer Cells are initially capable of recognizing and eliminating myeloma cells while sparing normal cells4,5

As disease burden increases, however, Natural Killer Cells decrease in number and cytotoxic activity slows due to mechanisms of immune evasion and immunosuppression2

New immunomodulatory drugs

Proteasome pathway

Histone deacetylase inhibitors

Monoclonal antibodies

FDA Approved Newer Agents

9/26/2016

9

Carfilzomib in Relapsed/Refractory MM003-A1 Single-Arm Pivotal Study (N = 266)

• Progressive disease required (>2 lines of therapy)

• Median 5.4 years from diagnosis (range, 0.5-22.3)

• 99.6% prior bortezomib

• 80% refractory or intolerant to bortezomib and lenalidomide

Abbreviations: CBR, clinical benefit rate; DCR, disease control rate; ORR, overall response rate; PD, progressive disease; SD, stable disease.

Siegel DS, et al. Blood. 2012;120:2817-2825. Slide courtesy of Dr. Lonial.

• Well tolerated

• Very low rate of neuropathy

• G1/2 11.3%

• G3/4 1.1%

Responses not affected by prior treatment or cytogenetics

30

25

20

5

0

Pa

tie

nts

(%

)

15

10

35

CR*(n = 1)

VGPR(n = 13)

PR(n = 47)

MR(n = 34)

SD(n = 81)

PD(n = 69)

0.4%5.1%

18.3%

13.2%

31.5%

26.8%

DCR = 69%

CBR = 37%

ORR = 24%

Carfilzomib, Pomalidomide, and Low-Dose Dexamethasone

• Heavily pretreated patients (median 5 prior lines of therapy); 49% had high/intermediate risk cytogenetics at baseline

• Response rates

– ≥ very good partial response: 27%

– Overall response rate: 70%

– Clinical benefit rate: 83%

• Duration of response: median 17.7 months

• Progression-free survival (PFS): median 9.7 months

• Overall survival (OS): median >18 months

• Response rates, PFS, and OS were independent of fluorescence in situ hybridization/cytogenetic risk status

• Carfilzomib/pomalidomide/low-dose dexamethasone was well tolerated

– No unexpected toxicities

Shah J, et al. Blood. 2013;122:abstract 690.

Study Design—Carfilzomib, Cyclophosphamide, and Low-Dose Dexamethasone

• Phase II multicenter trial (10 centers)

• 28-day cycles

Bringhen S, et al Blood. 2013;122:abstract 685.

Carfilzomib/Cyclophosphamide/Low-Dose Dexamethasone Induction

(9 cycles)

Carfilzomib Maintenance

(Until Progression or Intolerance)

Cycle 1 Cycles 2–9 Maintenance

Carfilzomib20 mg/m2 IV (days 1,2)

36 mg/m2 (days 8,9,15,16)

Cyclophosphamide300 mg/m2

(days 1,8,15)

Dexamethasone40 mg

(days 1,8,15,22)

Carfilzomib36 mg/m2 IV

(days 1,2,8,9,15,16)

Cyclophosphamide300 mg/m2

(days 1,8,15)

Dexamethasone40 mg

(days 1,8,15,22)

Carfilzomib36 mg/m2 IV

(days 1, 2, 15, 16)

9/26/2016

10

CCd Study ResultsAnd Comparison with Other Regimens

Abbreviations: CCd carfilzomib/cyclophosphamide/dexamethasone; CR, complete response; nCR, near-complete response; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide/dexamethasone; sCR, stringent complete response; VGPR, very good partial response; VMP, bortezomib/melphalan/prednisone.

1. Bringhen S, et al Blood. 2013;122:abstract 685. 2. San Miguel JF, et al. N Engl J Med. 2008;359:906-917. 3. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

0%

20%

40%

60%

80%

100%

CCd

VMP

Rd

CCd1

VMP2

Rd3

9/26/2016

11

Abbreviations: HiDEX, high-dose dexamethasone; LoDEX, low-dose dexamethasone; PD, progressive disease; POM, pomalidomide.

San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

MM-003 Design—POM + LoDEX vs HiDEX

Patients were stratified by:

• Age (≤ 75 vs > 75 yrs)

• Number of prior treatments ( 2 vs ≥ 3)

• Disease population (refractory vs relapsed/refractory vs bortezomib intolerance)

* 20 mg > 75 yrs† Progression of disease was independently adjudicated in real time.

Randomization 2:1

PD† or unacceptable

toxicity

POM + LoDEX

POM: 4 mg/day (days 1–21)DEX: 40 mg* (days 1, 8, 15, 22)

HiDEX

DEX: 40 mg* (days 1–4, 9–12, 17–20)

• PFS

– POM + LoDEX: 4.0 months (95% CI 3.6–4.7)

– HiDEX: 1.9 months (95% CI 1.9–2.2)

– HR = 0.48 (95% CI 0.39–0.60), P <.0001

• OS

– POM + LoDEX: 12.7 months (95% CI 10.4–15.5)

– HiDEX: 8.1 months (95% CI 6.9–10.8)

– HR = 0.74 (95% CI 0.56–0.97), P = .0285

POM + LoDEX vs. HiDEX

Abbreviations: HiDEX, high-dose dexamethasone; HR, hazard ratio; LoDEX, low-dose dexamethasone; OS, overall survival; PFS, progression-free survival; POM, pomalidomide.

San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066.

3333

Pomalidomide-dex vs dex (phase III) Improved Overall Survival

n= 455 HR=0.53

9/26/2016

12

0.25 0.5

PFS Based on Cytogenetic Profile

• POM + LoDEX significantly improved PFS vs. HiDEX regardless of the presence of del17p or t(4;14)

Note: Data shown only for pts with available cytogenetics; totals will not sum.a Number of events/number of patients.Dimopoulos MA, et al. ASH 2013 [abstract 408].

ITT Population

del(17p)/t(4;14)

Standard-RiskCytogenetics

SubgroupPOM + LoDEXa HiDEXa HR (95% CI)

0.49 (0.40-0.61)

0.44 (0.28-0.68)

0.55 (0.40-0.75)

138/153

32/35

63/72

253/302

71/77

126/148

1

Favors POM + LoDEX

2

Favors HiDEX

MM-005 Study Design: POM + BORT + LoDEX

• Phase 1, multicenter, open-label, dose-escalation study; 3 + 3 design; 21-day cycles

– POM: days 1-14

– BORT: days 1, 4, 8, 11

– LoDEX: days 1-2, 4-5, 8-9, 11-12

• April 2013: study amended to allow SC BORT in 6 patients

*10 mg for patients age >75

Abbreviations: BORT, bortezomib; IV, intravenous; LoDEX, low-dose dexamethasone; MPD, maximum planned dose; MTD, maximum tolerated dose; OS, overall survival; POM, pomalidomide; RBC, red blood cell; SC, subcutaneous; SPM, second primary malignancy.

Richardson PG, et al. Blood. 2013;122:abstract 1969.

Cohort 1(n=3)

Cohort 2(n=3)

Cohort 3(n=3)

Cohort 4(n=3)

Cohort 5(n=3)

Expansioncohort(n=6)

POM:1 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*

POM:2 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*

POM:3 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*

POM:4 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*

POM:4 mg/day

BORT: 1.3 mg/m2 IV

LoDEX: 20 mg*

MTD/MPD

SC BORT(n=6)

POM:4 mg/day

BORT: 1.3 mg/m2 SC

LoDEX: 20 mg*

Pom + LoDEX + Bortezomib in Relapsed MM

* 8 of 9 patients were evaluable for response; one patient discontinued study treatment in cycle 2 due to treatment-unrelated metastatic pancreatic cancer.

Abbreviations: Exp, expansion; ORR, overall response rate.

Richardson PG, et al. Blood. 2013;122:abstract 1969.

Cohort ORR

Cohort 1 (n=3) 2 (67%)

Cohort 2 (n=3) 1 (33%)

Cohort 3 (n=3) 3 (100%)

Cohort 4 (n=3) 3 (100%)

Cohort 5 + Exp Cohort (n=9) 6 (67%)*

9/26/2016

13

Based on preclinical studies,

EMPLICITI™ (elotuzumab) directly activates the immune system6

37

ADCC=antibody-dependent cellular cytotoxicity; SLAMF7=signaling lymphocytic activation molecule family member 7.

EMPLICITI is an immunostimulatory antibody that specifically targets theSLAMF7 protein6

SLAMF7 is expressed on Natural Killer Cells (NKC) and myeloma cells6

SLAMF7 is also expressed on plasma cells and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage6

Please see Important Safety Information throughout the presentation and the full Prescribing Information available at this presentation.

A Phase 3, randomized, open-label study, evaluated the efficacy and safety of EMPLICITI™ (elotuzumab) in combination with Rd6

38

* Prior to EMPLICITI infusion, dexamethasone was administered as a divided dose: an oral dose of 28 mg and an intravenous dose of 8 mg. In the control group and on weeks without EMPLICITI, dexamethasone 40 mg was administered as a single oral dose. Each cycle was 28 days.6

Co-primary endpoints: Progression-free survival; Overall response rate6

Minimum follow-up of 24 months6


In combination with Rd relative to Rd alone in patients who had received 1 to 3 prior therapies,

EMPLICITI™ (elotuzumab) delivered a benefit in PFS that was maintained over time6,8

39

* p-value based on the log-rank test stratified by β2 microglobulins (<3.5 mg/L vs ≥3.5 mg/L), number of prior lines of therapy (1 vs 2 or 3), and prior immunomodulatory therapy (no vs prior thalidomide only vs other).6

CI=confidence interval; ERd=EMPLICITI + lenalidomide + dexamethasone; HR=hazard ratio; PFS=progression-free survival; Rd=lenalidomide + dexamethasone.


EMPLICITI + Rd delivered 19.4 months [95% CI, 16.6, 22.2] of median PFS vs 14.9 months [95% CI, 12.1, 17.2] with Rd alone6

At the time of this PFS analysis, there were fewer deaths in the ERd arm vs the Rd arm (94 [29%] vs 116 [36%])6

9/26/2016

14

ELOQUENT-2: Conclusions

Elotuzumab in combination with len/dex improved PFS and ORR– At 3-yr follow-up, pts receiving Elotuzumab had 27% reduction

in risk of progression or death vs len/dex alone– Pts in elotuzumab arm had median delay of 1 yr in time to next

treatment vs len/dex arm

Interim OS analysis shows trend in favor of Elotuzumab arm

Elotuzumab plus len/dex toxicity profile consistent with prior studies with minimal increase in toxicities vs len/dex alone

Dimopoulos MA, et al. ASH 2015. Abstract 28. Slide credit: clinicaloptions.com

TOURMALINE-MM1: Study Design

Randomized, double-blind, placebo-controlled phase III trial[1]

Primary endpoint: PFS by IRC per IMWG criteria[2]

Secondary endpoints (data not yet mature): OS, OS in del(17p) pts

1. Moreau P, et al. ASH 2015. Abstract 727. 2. Rajkumar SV, et al. Blood. 2011;117:4691-4695.

Ixazomib 4 mg PO D1,8,15 +Lenalidomide 25 mg* D1-21 +

Dexamethasone 40 mg D1,8,15,22(n = 360)

R/R MM pts with measurable disease; 1-3 prior treatments; CrCl ≥ 30 mL/min;

not refractory to PIs or lenalidomide

(N = 722)

Placebo D1,8,15 +Lenalidomide 25 mg* D1-21 +

Dexamethasone 40 mg D1,8,15,22(n = 362)

28-day cyclesuntil PD or

unacceptable toxicity

Stratified by prior therapy (1 vs 2-3), ISS stage (I-II vs III), and prior

PI exposure (yes vs no)

*10 mg for pts with CrCl ≤ 60 or ≤ 50 mL/min.

TOURMALINE-MM1: PFS

Moreau P, et al. ASH 2015. Abstract 727.

Addition of ixazomib to Rd resulted in 35% improvement in PFS vs Rd alone

PFS benefit with ixazomib seen in all prespecified subgroups, including cytogenetic high risk, PI and IMiD exposed

100

80

60

40

20

0

Log-rank P = .012HR (95% CI): 0.742 (0.587-0.939)Number of events: IRD 129; placebo-Rd 157

Median PFS:IRd: 20.6 mosPlacebo-Rd: 14.7 mos

0 2 4 6 8 10 12 14 16 18 20 22 24Time from randomization (mos)

Pro

bab

ilit

y o

f P

FS

(%

)

9/26/2016

15

TOURMALINE-MM1: Response

Moreau P, et al. ASH 2015. Abstract 727.

CharacteristicIxazomib + Rd

(n = 360)Placebo + Rd

(n = 362)P Value

ORR, % CR VGPR PR

78.311.736.466.7

71.56.6

32.364.9

.035

.019

Median time to response, mos 1.1 1.9

Median DoR, mos 20.5 15.0

Median TTP, mos 21.4 15.7 .007†

†HR: 0.712.

Addition of ixazomib to Rd improved clinical outcomes with fast/durable responses in R/R MM

– Significantly prolonged PFS vs placebo, including del(17p) pts

– Significantly improved TTP and response rates vs placebo

Ixazomib plus Rd has tolerable safety profile with limited additional toxicity over Rd alone

– Quality of life preserved vs placebo

Study investigators conclude that this all-oral triplet combination regimen could represent new standard of care for R/R MM pts[1]

– Ixazomib approved by FDA on November 20, 2015, for use in previously treated MM[2]

TOURMALINE-MM1: Conclusions

1. Moreau P, et al. ASH 2015. Abstract 727. 2. FDA.gov. Accessed December 8, 2015.

PHASE I/II STUDY OF DARATUMUMAB CD38 MONOCLONAL ANTIBODY IN RELAPSED/REFRACTORY MM

• Favorable safety profile as monotherapy

• In 15 of 32 (47%) showed benefit

– 4 patients achieving PR (13%)

– 6 patients achieving MR (19%)

– 5 patients achieving SD (16%)

• At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%)

• To be combined with lenalidomide dexamethasone

Plesner et al ASH 2012

9/26/2016

16

46

Daratumumab and lenalidomidedexamethasone in relapsed MM

The best change in response paraprotein evaluated according to IMWG 2011.

A: serum M-protein, B: urine-M-protein

Plesner et al ASH 2013

Development of Rationally Based Combination Therapies (HDAC and

Proteasome Inhibitors)

Hideshima T, et al. Clin Cancer Res. 2005;11:8530-8533. Catley L, et al. Blood. 2006;108:3441-3449. Anderson KC. J ClinOncol. 2012;30:445-452.

HDAC inhibitors

• Examples include vorinostat, panobinostat, and ricolinostat (ACY-1215)

• Block accessory pathway for protein degradation, which becomes activated when you block the proteasome using proteasome inhibitors

• Panobinostat + bortezomib (BTZ) + dexamethasone (PANORAMA2)1

– Phase II (N = 55)

– ≥2 previous therapies, including an immunomodulatory drug,BTZ-refractory

– Results

■ Objective response rate (ORR): 34.5% (near complete response [nCR]): 1.8%)

■ Progression-free survival (PFS): 5.4 months

• Panobinostat + BTZ + dexamethasone (PANORAMA1)2

– Phase III (N = 768)

– 1-3 previous therapies

– Results (vs placebo + BTZ + dexamethasone)

■ PFS: 12 vs 8.1 months (HR 0.63, P <.0001)

■ ORR: 61% vs 55% (nCR/CR: 28% vs 16%)

■ Duration of response: 13.1 vs 10.9 months

Clinical Data with Histone DeacetylasesPanobinostat

1. Richardson PG, et al. Blood. 2013;122:2331-2337. 2. Richardson PG, et al. J Clin Oncol. 2014;32(5s):abstract 8510.

9/26/2016

17

Promising Therapeutic Modalities Under Development

Kelley et al ASH 2013

Background: Targeting KSP with ARRY‐520 (Filanesib)

• Filanesib is a targeted Kinesin Spindle Protein (KSP) inhibitor

– KSP is a microtubule motor protein critical to the function of proliferating cells

• KSP inhibition induces aberrant mitotic arrest and rapid cell death

– Novel mechanism of action for MM

– Preferentially acts on MCL‐1 dependent cells including MM

– Not expected to be cross‐resistant with other drugs

51Lonial et al ASH 2013

9/26/2016

18

CAR-BCMA T Cells in Myeloma: Background

B-cell maturation antigen (BCMA): protein in TNF superfamily expressed by normal and malignant plasma cells and B cells[1]

Autologous T cells can be genetically modified to express chimeric antigen receptors (CARs) specific for malignancy-associated antigens

– BCMA a potential target for CAR T-cell therapy for MM

– BCMA expressed uniformly on malignant plasma cells from 60%-70% of patients with MM

Current study evaluated CAR-BCMA T cell infusion for treatment of advanced MM[2]

– Autologous T-cells were stimulated, transduced with CAR-BCMA retroviruses, and cultured for 9 days before infusion

1. Carpenter RO, et al. Clin Cancer Res. 2013;19:2048-2060.2. Ali SA, et al. ASH 2015. Abstract LBA-1.

CAR-BCMA T Cells in Myeloma: Study Design

First-in-human phase I trial

CAR-BCMA expression determined by flow cytometry

Pts with advanced R/R MM; ≥ 3 prior lines of therapy; normal organ function; clear, uniform BCMA expression on

myeloma cells(N = 12)

CAR-BCMA T cells*Single infusion

Cyclophosphamide 300 mg/m2

Fludarabine 30 mg/m2

QD for 3 days

*Dose escalation of CAR+ T cells/kg

0.3 x 106

1.0 x 106

3.0 x 106

9.0 x 106

Ali SA, et al. ASH 2015. Abstract LBA-1.

CAR-BCMA T Cells in Myeloma: Conclusions

First demonstration that CAR-T cells have activity in measurable MM

CAR-BCMA T cells eliminated plasma cells without causing direct organ damage

Responses included ongoing sCR in patient with significant burden of chemotherapy-resistant disease

Substantial but reversible toxicity comparable to that observed in previous CAR T cell studies

– Highest dose level of CAR-BCMA T cells to be reserved for patients with ≥ 50% bone marrow plasma cells

Authors conclude that CAR-BCMA T cells represent a promising novel therapy for MM

Ali SA, et al. ASH 2015. Abstract LBA-1.

9/26/2016

19

Treatment of Multiple Myeloma: Conclusions

• In newly diagnosed transplant candidates, three drug regimens incorporating immunomodulatory drugs and proteasome inhibitors before and after transplant can prolong PFS and OS.

• Lenalidomide dex until progression is standard of care for non transplant patients with newly diagnosed myeloma.

• Lenalidomide maintenance until progression prolongs PFS and OS, with an increased risk of secondary cancers in patients who have received MP or high dose therapy and ASCT.

TF5

Treatment of Multiple Myeloma: Conclusions

• Pomalidomide low dose dex is active in relapsed refractory MM, (including 17p deletion)

• Bortezomib or Carfilzomib and pomalidomide low dose dex increases response and is tolerated in relapsed refractory MM

• Novel agents including oral proteasome inhibitor ixazomib, monoclonal antibodies SAR650984 and daratumumab, KSP inhibitor filanesib, and HDAC6 inhibitor ricolinostat demonstrate promising activity in relapsed refractory MM

• Incorporation of novel therapies at all stages of disease is further improving patient outcome in MM

TF6

TF5 Dr Anderson and Dr Lonial: please provide overall conclusions for the slide set.Terrence Fagan, 1/3/2014

Slide 56

TF6 Dr Anderson and Dr Lonial: please provide overall conclusions for the slide set.Terrence Fagan, 1/3/2014

fri 9.00 sr colman dr galal multiple myeloma · brody t. clinical trials: study design, end points...

Documents