challenges and novel approaches to treating myeloma azmn roundtable march 2014
Download
Skip this Video
Download Presentation
Challenges and Novel Approaches to Treating Myeloma … AZMN Roundtable March 2014

Loading in 2 Seconds...

play fullscreen
1 / 27

Challenges and Novel Approaches to Treating Myeloma … AZMN Roundtable March 2014 - PowerPoint PPT Presentation


  • 179 Views
  • Uploaded on

Scottsdale, Arizona. Rochester, Minnesota. Jacksonville, Florida. Challenges and Novel Approaches to Treating Myeloma … AZMN Roundtable March 2014. Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona. Managing myeloma: the components. Initial Therapy. Consolidation.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' Challenges and Novel Approaches to Treating Myeloma … AZMN Roundtable March 2014' - dean


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
challenges and novel approaches to treating myeloma azmn roundtable march 2014

Scottsdale, Arizona

Rochester, Minnesota

Jacksonville, Florida

Challenges and Novel Approaches to Treating Myeloma…AZMN RoundtableMarch 2014

Joseph Mikhael, MD, MEd, FRCPC, FACP

Staff Hematologist, Mayo Clinic Arizona

managing myeloma the components
Managing myeloma: the components

Initial Therapy

Consolidation

Maintenance

Treatment of Relapsed disease

Transplant Eligible

Patients

Consolidation/ Maintenance/ Continued therapy

Transplant Ineligible

patients

Supportive Care

treatment sequence
Treatment sequence

SCT

VD/VRD

Thal/Dex

VD

Rev/Dex

CyBorD

VTD

VRD

Nothing

Thalidomide?

Bortezomib?

Lenalidomide?

Bortezomib

Lenalidomide

Thalidomide

Carfilzomib

Pomalidomide

Monoclonal Ab (CD38)

Elotuzumab

HDAC

Bendamustine

NEW

Maintenance

Front line treatment

Relapsed

Consolidation

Induction

Post consolidation

Rescue

SCT

VAD

DEX

Nothing

Prednisone

Thalidomide

Few options

OLD

slide4

IMPACT OF NOVEL THERAPY 2012/2013

Median 7.3 years

5 YEAR SURVIVAL BY AGE

AGE

≤ 65 YRS

AGE

> 65 YRS

2006-2010 73% 56%

2001-2005 63% 31%

2012 ASH Abstract #3972 Kumar et al

slide5

mSMART

Mayo Stratification for Myeloma And Risk-adapted Therapy

Newly Diagnosed Myeloma

Website: www.msmart.org

msmart 2 0 classification of active mm
mSMART 2.0: Classification of Active MM

FISH

Del 17p

t(14;16)

t(14;20)

GEP

High risk

signature

All others including:

Hyperdiploid

t(11;14)

t(6;14)

Standard-Risk 60%

High-Risk 20%

Intermediate-Risk 20%

  • FISH
    • t(4;14)*
  • Cytogenetic Deletion 13 or hypodiploidy
  • PCLI >3%

3 years 4-5 years 8-10 years

Mikhael et al Mayo Clinic Proceedings April 2013

slide7

mSMART – Off-Study

Transplant Eligible

High Risk

Intermediate Risk

Standard Risk

4 cycles of VRd

4 cycles of CyBorD

4 cycles of Rda or CyBorD

Collect Stem Cellsb

Autologous stem cell transplant, especially if not in CR

Autologous stem cell transplant

Autologous stem cell transplant

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

Continue

Rd;c or CyBorD for ~12 months

V or VCd for minimum of 1 year

Bortezomib based therapy for minimum of 1 year

aBortezomib containing regimens preferred in renal failure or if rapid response needed

b If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixafor

cContinue 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

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

slide8

mSMART – Off-Study

Transplant Ineligible

High Risk

Intermediate Risk

Standard Risk*

MP + weekly Bortezomib or weekly CyBorD for ~12 months

VRd* for ~12 months,

Rda, b

Bortezomib based therapy for minimum of 1 year

Continue VRd as maintenance for minimum of 1 year

a Dex is usually discontinued after first year

b Bortezomib containing regimens preferred in renal failure or if rapid response needed

*Clinical trials strongly recommended as the first option

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

first design lenalidomide and low dose dexamethasone rd rd18 vs mpt

Screening

LT Follow-Up

Active Treatment + PFS Follow-up Phase

PD or Unacceptable Toxicity

PD, OS and

Subsequent anti-MM Tx

LEN + Lo-DEX until Progressive Disease

LENALIDOMIDE 25mg D1-21/28

Lo-DEX 40mg D1,8,15 & 22/28

RANDOMIZATION 1:1:1

ARM A

Arm A

Rd

FIRST Design: Lenalidomide and Low-dose Dexamethasone (Rd/Rd18) vs. MPT

N = 535

n=535

LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28

Lo-DEX 40mg D1,8,15 & 22/28

Arm B

Rd18

n=541

MEL + PRED + THAL 12 Cycles1 (72 wks)

MELPHALAN 0.25mg/kg D1-4/42

PREDNISONE 2mg/kg D1-4/42

THALIDOMIDE 200mg D1-42/42

Arm C

MPT

n=547

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 100 mg D1-42/42, Melphalan2 0.2 mg/kg D1–4

n= 1,623 - 18 countries from North America, Asia-Pacific, and Europe represented from 246 Centers

  • Stratification: age, country and ISS stage

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

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

Facon T. et._ASH 2013: Abstract 2

first trial final pfs continuous rd the risk of pfs events pd or death by 28 vs mpt

100

80

60

40

20

0

FIRST Trial: Final PFSContinuous Rd  the risk of PFS events (PD or death) by 28% vs. MPT

Hazard ratio

Rd vs. MPT: 0.72; P = 0.00006

Rd vs. Rd18: 0.70; P = 0.00001

Rd18 vs. MPT: 1.03; P = 0.70349

Patients (%)

72 wks

6

12

18

24

30

36

42

48

54

60

0

Time (months)

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

Facon T. et._ASH 2013: Abstract 2

first trial overall survival interim analysis 574 deaths 35 of itt

100

80

60

40

20

0

6

12

18

24

30

36

42

48

54

60

0

Rd

Rd18

MPT

535

541

547

488

505

484

457

465

448

433

425

418

403

393

375

338

324

312

224

209

205

121

124

106

43

44

30

5

6

3

0

0

0

FIRST Trial: Overall Survival Interim Analysis574 deaths (35% of ITT)

Patients (%)

Hazard ratio

Rd vs. MPT: 0.78; P = 0.0168 ( 22% risk of death with Rd)

Rd vs. Rd18: 0.90; P = 0.307

Rd18 vs. MPT: 0.88; P = 0.184

The pre-specified boundary (p<0.0096) was not crossed for Rd_continuous vs MPT_18 months

Overall survival (months)

Facon T. et._ASH 2013: Abstract 2

first trial conclusions
FIRST Trial: Conclusions

Continuous Rd significantly extended PFS, with an OS benefit vs. MPT

PFS:

3 yr PFS: 42% continuous Rd vs 23% Rd18 and MPT

Planned interim OS: HR= 0.78 (P= 0.0168) but did NOT cross the pre-specified boundary (p<0.0096)

Safety profile with continuous Rd was manageable

Hematological and non-hematological AEs were as expected for Rd and MPT with more infections and cataract observed in the continuous Rd arm

Incidence of hematological SPM was lower with continuous Rd vs. MPT

Facon T. et._ASH 2013: Abstract 2

efficacy comparisons
Efficacy Comparisons

Facon et al. ASH 2013 (Abstract 2), plenary presentation

Palumbo et al. N Engl J Med 2012;366(19):1759-69

San Miguel et al. N Engl J Med 2008; 359: 906-917

San Miguel et al. J Clin Oncol 2013;31(4):448-55

Palumbo et al. ASH 2012 (Abstract 200), oral presentation

Mateos et al. Blood 2012; 120: 2581-2588

slide16

NEWER THERAPIES: ASH 2013

TOP 8

  • Anti-CD 38monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284)
  • MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983)
  • ARRY 520 (abstracts #285 and #1982)
  • ACY-1215 (abstracts #759 and #3190)
  • Selinexor (also known as KPT-330, abstract #279)
  • Anti-CD 138 monoclonal antibody (BT062, indatuximab ravatansine, abstract #758)
  • Panabinostat (abstract #1970)
  • Bendamustine (abstract #1971)
monoclonal antibodies in mm
Monoclonal antibodies in MM

Richardson et al. et al. IMW 2013 (Abstract P-214), poster presentation; Plesner et al. ASH 2013 (Abstract 1987), poster presentation; Martin et al. ASH 2013 (Abstract 284), oral presentation; http://www.clinicaltrials.gov/ct2/show/NCT00421525; http://www.clinicaltrials.gov/ct2/show/NCT00079716; http://www.clinicaltrials.gov/ct2/show/NCT00346255; http://www.clinicaltrials.gov/ct2/show/NCT01001442; Wong et al. ASH 2013 (Abstract 505), oral presentation; Hageman et al. Ann Pharmacother 2013;47:1069-74;

slide18

Thomas G. Martin III1, Stephen A. Strickland2, Martha Glenn3, Wei Zheng4, Nikki Daskalakis5and Joseph R. Mikhael6

1University of California San Francisco, San Francisco, CA

2Vanderbilt-Ingram Cancer Center, Nashville, TN

3University of Utah, Huntsman Cancer Institute, Salt Lake City, UT

4Sanofi Oncology, Cambridge, MA

5Sanofi US, Bridgewater, NJ

6Mayo Clinic in Arizona, Scottsdale, AZ

*NCT01084252 Trial Sponsored by Sanofi, Cambridge, MA

SAR650984, A CD38 Monoclonal Antibody in Patients with Selected CD38+ Hematological MalignanciesData From a Dose-Escalation Phase I Study (TED10893)*

sar650984 a humanized igg1 monoclonal antibody

1. Antibody-dependent

cellular cytotoxicity (ADCC) and phagocytosis (ADCP)

Antibody

Fc Receptor

Complement

SAR650984: A Humanized IgG1 Monoclonal Antibody

2. Complement-dependent cytotoxicity (CDC)

NK cell,

Macrophage

4. CD38 enzymatic activity inhibition

3. Direct apoptosis induction without crosslinking

NAD

cADPR

ADPR

sar650984 phase i dose escalation study
SAR650984: Phase I Dose Escalation Study

Primary Objective

  • Determine maximum tolerated dose (MTD)/maximum administered dose (MAD)

Secondary Objective

  • Characterize safety profile
  • Evaluate pharmacokinetic (PK) profile
  • Assess pharmacodynamics, immunogenicity, and preliminary disease response
sar650984 baseline characteristics
SAR650984: Baseline Characteristics
  • 39 treated patients
    • Median age = 65.0 (40 - 85)
  • Prior therapies of myeloma patients (n=34)
    • Median = 6 (2 – 14)
    • At doses≥ 0.3 mg/kg - all patients received prior lenalidomide and bortezomib
    • At doses ≥ 10 mg/kg - 69% of patient received carfilzomib and/or pomalidomide
sar650984 patients with infusion reactions patients treated at doses of 0 3 mg kg q2w or higher
SAR650984: Patients with Infusion ReactionsPatients treated at doses of 0.3 mg/kg Q2W or higher

Mandatory Prophylaxis in All Patients*

Symptoms of Infusion Reactions (N; max severity): Nausea (5; G 2); Pyrexia (4; G 1); Drug hypersensitivity, Chills (3; G 2); Headache (3; G 1); Vomiting , Hypoxia (2; G 2); Cytokine release syndrome, Dyspnea, Flushing, Nasal congestion, Bronchospasm, Tracheal stenosis, Laryngospasm (1; G 2); Influenza-like illness, Abdominal pain, Blurred vision, Lacrimation increased, Rhinorrhea, Cough, Restlessness (1; G 1)

7

No infusion reaction

Number of Patients

Grade 1

6

Grade 2

5

4

3

2

1

C1

C>11

C1

C>1

C1

C>1

C1

C>1

C = Cycle

C1

C>1

C1

C>1

C1

C>1

*methylprednisolone 100 mg IV, diphenhydramine 50 mg IV, ranitidine 50 mg IV, and acetaminophen 650-1000 mg po (or equivalents)

slide23

CR

PR

MR

SD

PD

NA

SAR650984: Time on Treatment by Best ResponseMyeloma Patients Treated at Doses of 1 mg/kg Q2W or higher

CR

*

PR

MR

SD

1 mg/kg Q2W

3 mg/kg Q2W

5 mg/kg Q2W

PD

10 mg/kg Q2W

10 mg/kg QW

20 mg/kg Q2W

NA

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

Week

* Off study since 23May2013 due to patient decision.

Ongoing

sar650984 phase 1 response summary1
SAR650984: Phase 1 Response Summary
  • Overall Response Rate (CR+PR)
    • Dosing cohorts ≥1mg/kg = 25% (2 CR, 4 PR of 24)
    • Dosing cohorts ≥ 10 mg/kg = 31% (2 CR, 2 PR of 13)
  • Clinical Benefit Rate (CR+PR+MR)
    • Dosing cohorts ≥ 1mg/kg = 33% (2 CR, 4 PR, 2 MR of 24)
    • Dosing cohorts ≥ 10 mg/kg = 38% (2 CR, 2 PR, 1 MR of 13)
  • Median Time to Initial Response (CR, PR, MR) = 6.1 weeks (3.4 – 12.3)
  • In 8 responders the median duration of response 5.0 months (0 - 15.4)
    • 6 patients still on treatment
  • Median duration of follow up is 6.5 months (1.9-16.3)
ad