New Therapies for Relapsed Myeloma

Abramson Cancer Center Update in Hematologic

Cancers

Dan Vogl, MD MSCE

Assistant Professor of Medicine

Hematology/Oncology Division

Abramson Cancer Center

January 22, 2016

Disclosures

Consulting:

• Celgene Corporation

• Onyx/Amgen

• Millennium/Takeda Pharmaceuticals

• Karyopharm

Research support:

• Millennium/Takeda Pharmaceuticals

• Acetylon

• GSK

• Constellation

• Calithera

Topics

Proteasome Inhibitors

• Carfilzomib

• Ixazomib

Histone Deacetylase Inhibitors

• Panobinostat

• Ricolinostat

Monoclonal antibodies

• Daratumumab

• Isatuximab

• Elotuzumab

Other drugs

• Ibrutinib, vemurafenib, filanesib, selinexor

Proteasome

Inhibitors carfilzomib, ixazomib

Carfilzomib: ASPIRE

Planned interim analysis of a randomized, open-label phase III trial

Pts with relapsed or

progressive MM,

1-3 prior treatments

with ≥ PR in

≥ 1 prior regimen,

ECOG PS 0-2, and

CrCl ≥ 50 mL/min

(N = 792)

Until PD or

unacceptable

toxicity

KRd Carfilzomib Days 1, 2, 8, 9, 15, 16/cycles 1-12,

Days 1, 2, 15, 16/cycles 13-18 Lenalidomide Days 1-21 +

Dexamethasone Days 1, 8, 15, 22 28-day cycle

(n = 396)

Rd Lenalidomide Days 1-21 +

Dexamethasone Days 1, 8, 15, 22 28-day cycle

(n = 396)

Stratified by β2-microglobulin, prior

bortezomib, and prior lenalidomide

Carfilzomib: 20 mg/m2 Days 1, 2 of cycle 1; 27 mg/m2 thereafter.

Lenalidomide: 25 mg.

Dexamethasone: 40 mg.

Stewart AK, et al. N Engl J Med. 2015;372:142-152.

Carfilzomib: ASPIRE

Stewart AK, et al. N Engl J Med. 2015;372:142-152.

Better responses

• CR 32 vs 9%

• ORR 87 vs 67%

Better PFS and (maybe) OS

Toxicity

• More diarrhea, cough, fever,

URI, hypokalemia, muscle

spasms, dyspnea,

hypertension

• No increase in heart failure

or renal failure

Carfilzomib: ENDEAVOR

Study design: Randomized, open-label, multicenter phase III trial

Dimopoulos MA, et al. ASCO 2015. Abstract 8509.

Relapsed MM with 1-3

previous lines of therapy; prior

V or K if response occurred

with no discontinuation due to

toxicity (N = 929)

Kd*

(n = 464)

Vd†

(n = 465)

Until PD or

unacceptable

toxicity Stratified by prior PI therapy,

prior lines of treatment, ISS

stage, and route of V

administration (IV vs SC)

*Carfilzomib: 20 mg/m2 IV on Days 1, 2 (cycle 1), then 56 mg/m2 on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle;

dexamethasone: 20 mg on Days 1, 2, 8, 9, 15, 16, 22, 23 of a 28-day cycle.

†Bortezomib: 1.3 mg/m2 IV or SC on Days 1, 4, 8, 11 of a 21-day cycle;

dexamethasone: 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 of a 21-day cycle

Carfilzomib: ENDEAVOR

Response better with carfilzomib

• ORR 77% vs 63% (p<0.0001)

• CR 13% vs 6% (p=0.001)

PFS better with carfilzomib

• HR 0.53, p<0.0001

• In patients with prior bortezomib

• In patients with no prior bortezomib

Toxicity:

• More anemia, dyspnea, fever, cough,

hypertension, muscle spasms, headache,

• Similar thrombocytopenia, diarrhea,

edema, fatigue, nausea

• Less constipation, neuropathy, dizziness

Carfilzomib: Weekly dosing CHAMPION-1

• Carfilzomib over 30 min 1, 8, 15 of 28, with dexamethasone 40 weekly

• Phase 1: 45, 56, 70, 88 mg/m2 (n=27)

• MTD 70 mg/m2 (n=104)

• 1-3 prior lines, carfilzomib-naïve, 52% Bz-refractory, 19% dual refractory

• ORR: 77% (63% Bz-refractory, 55% dual-refractory)

• Toxicity: fatigue (11% gr3), hypertension (8% gr3), nausea, diarrhea

wCCyD

• Newly diagnosed, transplant ineligible

• Weekly dosing on days 1, 8, 15 of 28

– Cyclophosphamide 300 mg/m2 PO

– Carfilzomib 70 mg/m2

– Dexamethasone 40 mg

• ORR 80%

• Toxicity: neutropenia (22% gr3/4), thrombocytopenia (7% gr3/4),

pulmonary edema (5%) Bringhen, ASH 2015, Abstract 1828..

Berenson, ASH 2015, abstract 373.

Oral boronate proteasome inhibitor

Toxicity: thrombocytopenia, neuropathy, nausea, diarrhea, rash

Single agent responses: ≥PR 27%

Moreau P, et al. ASH 2015. Abstract 727

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 cycles

until 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.

Ixazomib: TOURMALINE-MM1

Kumar SK, Blood 2014;124(7):1047-1055

Responses: better with ixazomib (ORR 78 vs 72%, CR 12 vs 7%)

PFS: better with ixazomib (HR 0.74, p=0.01)

Toxicity: More thrombocytopenia, diarrhea, nausea, vomiting,

neuropathy, rash

Ixazomib: TOURMALINE-MM1

Moreau P, et al. ASH 2015. Abstract 727

HDAC inhibitors panobinostat, ricolinostat

Panobinostat: PANORAMA1

Study design: Randomized, placebo-controlled, multicenter phase III trial

(n = 387)

Panobinostat 20 mg days 1, 3, 5, 8, 10, 12 of 21

Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11*

Dexamethasone 20 mg days 1, 2, 4, 5, 8, 9, 11, 12*

(n = 381)

Placebo days 1, 3, 5, 8, 10, 12 of 21

Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11*

Dexamethasone 20 mg days 1, 2, 4, 5, 8, 9, 11, 12*

Stratified by # of prior therapies and

prior bortezomib

*After cycle 8, bortezomib given on Days 1 and 8 of 21 and dexamethasone on days 1, 2, 8, and 9 of 21

San Miguel JF, et al. Lancet Oncol 2014;15(11)1195-1206.

Pts with measureable

R/R MM after 1-3 prior

treatments, excluding

primary refractory or

bortezomib-refractory

(N = 792)

21 day cycles

Panobinostat: PANORAMA1

Responses: CR 11% vs 6%

≥PR 61% vs 55%

Progression-free survival: 12 vs 8 months

(HR 0.63, p<0.0001)

Overall survival: 34 vs 30 months

(HR 0.97, p=0.26)

Toxicity: • Diarrhea: 68 vs 42%

(gr 3/4 25 vs 7%)

• Fatigue 57 vs 41%

(gr 3/4 24 vs 12%)

• Nausea 36 vs 21%

• Edema 29 vs 19%

• Fever 26 vs 15%

• Gr 3/4 thrombocytopenia 68 vs 31%

• Gr 3/4 neutropenia 35 vs 11%

Panobinostat with carfilzomib/dexamethasone

Phase I trial

• Panobinostat 15-20 mg TIW 3 of 4 weeks

• Carfilzomib 20/27-20/45 on days 1, 2, 8, 9, 15, and 16 of 28

• Dexamethasone 4 mg prior to each carfilzomib dose during cycle 1

MTD: panobinostat 20 mg, carfilzomib 20/36

Efficacy:

• All patients: ≥PR 46%, ≥ MR 58%, median PFS 11.4 months

• Bortezomib-refractory: ≥ PR 44%, ≥ MR 50%

Toxcity:

• Anemia (38% gr 3/4), thrombocytopenia (38% gr 3/4), neutropenia (19%

gr 3/4), diarrhea (50%, 8% gr 3/4), nausea (65%), anorexia (27%, 8% gr

3/4)

Kaufman JL, et al. ASH 2014. Abstract 32.

bortezomib/dex with ricolinostat (ACY-1215)

Ricolinostat is a selective inhibitor of HDAC6

Phase 1b study:

• Ricolinostat 40 mg qd – 160 mg bid on days 1-5 and 8-12 of 21

• Bortezomib 1.3 mg/m2 IV (cycle 1+) or SC (cycle 2+) on days 1, 4, 8, and 11

• Dexamethasone 20 mg PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12

Prior therapies:

• Median 5 lines

• 77% refractory to most recent therapy

• 88% prior lenalidomide

• 100% prior bortezomib, 63% bortezomib-refractory

Efficacy:

• All patients: ≥PR 30%, ≥MR 34%

• Bortezomib-refractory: ≥PR 14%, ≥MR 21%

Toxicity:

• Diarrhea (20 gr 1-2, 3 gr 3)

• Fatigue (13 gr 1-2, 3 gr 3)

• Thrombocytopenia (13 gr 3-4)

Vogl et al, ASH 2014, Abstract 759

Vogl et al, ASH 2015, Abstract 1827

Monoclonal

antibodies daratumumab, isatuximab, elotuzumab

Daratumumab

Human monoclonal antibody targeting CD38

Phase 2 dose: 16 mg/kg qwk x2m, q2 wks x4m, then q4 wks

Single agent activity: phase 1/2 study in rel/refr myeloma

• ORR 31%, VGPR 13%, 1 year PFS 46% Usmani et al, ASH 2015, Abstract 29

Combination with len/dex: phase I/II trial in rel/ref myeloma

• Phase 2 dose with len 25 mg on days 1-21 of 28 and dex 40 mg/wk

• median 2 prior lines, 3/45 patients len-refractory

• ORR 81%, 34% CR, 25% sCR

• Toxicity: Cytopenias (c/w lenalidomide), Infusion reactions (19/45)

• Updated ASH 2015 with similar results Plesner et al. ASH 2014. Abstract 84

Plesner et al. ASH 2015. Abstract 507

Daratumumab

Combination with pom/dex: phase I/II trial in rel/ref myeloma

• >= 2 prior lines of therapy, including len and Bz

• 98 patients, refractory to Bz (66%), Cz (30%), Len (89%), dual (67%)

• Phase 2 dose with pom 4 mg on days 1-21 of 28 and dex 40 mg/wk

• ORR 71% overall, 67% dual refractory

• Infusion reactions, cytopenias (60% gr 3/4 neutropenia), fatigue Chari, et al. ASH 2015. Abstract 508

Daratumumab: Infusion reactions

38% (1st infusion: 36%, 2nd: 2%, 3rd+: 3%)

Mostly grade 1-2

Grade 3: bronchospasm, dyspnea, chills/CRS, hypertension

Voorhees, ASH 2015, Abstract 1829.

INFUSION: 1 2 3+

Volume 1000 mL 500 mL 500 mL

Start 50 mL/h 50 mL/h 100 mL/h

• increase to 200 mL/h at 50 mL/h intervals

• with reaction: pause, restart at 50% of previous rate

Premedication

Methylprednisolone 100 mg (1st and 2nd) or 60 mg (3rd +)

Acetaminophen 650-1000 mg

Diphenhydramine 25-50 mg

Post-medication

Methylprednisolone 20 mg on days 2 and 3 of each infusion

Zoster prophylaxis

Infusion reaction prophylaxis

Monteleukast 10 mg qhs, days -1, 0, +1, +2 (x 4 weeks)

Methylprednisolone 100 mg IV

Acetaminophen 975 mg PO

Diphenhydramine 25 mg IV

PRN: famotidine 20 mg IV, lorazepam 1 mg IV

Dexamethasone 4 mg PO, days +1, +2

COPD/asthma: inhaled corticosteroid days 0, +1

Daratumumab: RBC transfusion

Binds CD38 on RBCs, agglutinates on indirect antibody testing (IAT)

Delays identification of RBC units

Patients can be transfused safely even with +IAT Chari et al. ASH 2015 Abstract 3571

Pre-treating RBCs with DTT eliminates problem

DTT also denatures Kell antigens, so Kell- RBC units must be

transfused Chapuy, et al. ASH 2015 Abstract #3567

DO:

• Send baseline type and screen

• Transfuse type-specific, least incompatible units OR

• Use DTT and transfuse Kell- units based on antibody testing

DO NOT:

• Let blood bank waste 10-15 hours identifying antibodies

• Transfer patients to Penn for transfusion

Isatuximab (SAR650984)

Humanized IgG1 mAb to CD38 receptor

Single agent activity:

• Optimized phase 2 dose: 20 mg/kg weekly x4, then q2 wks

• ORR 20-29% (depending on dose cohort)

Martin et al, ASH 2015, Abstract 509

Combination with len/dex:

• 3-10 mg/kg on days 1+15 of 28, with len 25 mg on 1-21 and dex 40 qwk

• Heavily refractory population: median 4 prior lines, 84% IMiD refractory

• 58% ≥PR, PFS median 6.2 months

• Toxicity: Cytopenias (c/w lenalidomide), Infusion reactions (15/31 pts) Martin TG, et al. ASH 2014. Abstract 83

.

Elotuzumab: ELOQUENT-2

Humanized IgG1 mAb targeting SLAMF7/CS1

Single agent response rate 0%

ORR 84% with elo/len/dex in len-naïve patients (Richardson, Blood 2014;124:302)

Study design: Randomized, open-label, multicenter phase III trial

Dimopoulos MA, et al. ASH 2015. Abstract 28.

Elotuzumab 10 mg/kg IV QW cycles 1, 2

then Q2W +

Lenalidomide 25 mg PO D1-21 +

Dexamethasone 40 mg PO QW

(n = 321)

Pts with R/R

MM and 1-3

prior

treatments

(N = 646)

Lenalidomide 25 mg PO D1-21 +

Dexamethasone 40 mg PO QW

(n = 325)

28-day cycles

Until PD or

unacceptable

toxicity

Elotuzumab: ELOQUENT-2

Lonial, NEJM 2015;373:621-631

Efficacy:

• Improved RR (79 vs 66%)

• 1y PFS 68 vs 57%

• consistent across

subgroups

Toxicity:

• more lymphopenia

• no more neutropenia

• increase in zoster but not other infections

• Possible increase in low-grade GI effects (diarrhea, constipation)

Elotuzumab: combination with Bz/dex

Randomized phase 2 trial

• 150 patients not refractory to proteasome inhibition

• Elotuzumab 10 mg/kg with bortezomib/dexamethasone vs Bz/dex

• PFS better with elo (HR 0.76, p=0.12)

• Toxicity

– More infections

– Infusion reactions (very few)

Palumbo, et al. ASH 2015, abstract 510.

Other drugs Ibrutinib, vemurafenib, selinexor, filanesib

ibrutinib

oral BTK inhibitor

Multi-dose phase 2 study

Toxicity:

• Infrequent cytopenias

• Diarrhea (~55%)

• Fatigue (~40%)

• Nausea (~25%)

• Dizziness (~30%)

• Muscle spasms (~20%)

• Arthralgias (~15%)

Phase 1 with carfilzomib/dex Chari, ASH 2015, Abstract 377

Vij R, et al. ASH 2014. Abstract 31. P

ts (

%)

420 mg/d

(n = 13)

560 mg/d

+ dex

(n = 18)

840 mg/d

(n = 18)

840 mg/d

+ dex

(n = 20)

50

40

30

20

10

0

PR MR SD ≥ 4 cycles

8%

8%

22%

6%

33%

25%

20%

5%

BRAF inhibition

Targetable BRAF mutations in 4-6% of myeloma

Case reports of responses to vemurafenib

• 960 mg twice daily

Vemurafenib

• myeloma cohort in phase 2 study

• 960 mg twice daily

• 8 patients: 5 refractory to Imid or proteasome inhibitor

• 1 VGPR, 4 SD, 3 patients still on study Raje et al. ASH 2015, Abstract 4263

Dabrafenib

+/- MEK inhibitor (trametinib, cobimetinib)

XPO1 inhibitor, Selective inhibitor of nuclear export (SINE),

Phase 1/2 study:

• 28 pts with refractory MM (median prior regimens: 6)

• selinexor at 30-60 mg/m2 twice weekly with or without dexamethasone

• Toxicity: Grade 1/2 nausea (70-82%), fatigue (40-86%), anorexia (36-

71%), and vomiting (10-57%)

• Response:

– selinexor 45 mg/m2 + dex 20 mg biw (n=10): ORR 60%

– selinexor 30 mg/m2 + dex <20 mg (n=7): ORR 14%, CBR of 86%

– selinexor (30-60 mg/m2), no dex (n=12): ORR 0%, SD 50% Chen, ASH 2014, abstract 4773

Combination studies with carfilzomib and bortezomib Jakubowiak, ASH 2015, Abstract 4223

Sullivan, ASH 2015, Abstract 3048

selinexor

Filanesib (ARRY-520)

kinesin spindle protein (KSP) inhibitor targeting a microtubule

motor protein critical to the function of proliferating cells

Single agent response rate 16%

Phase 1/2 trial with carfilzomib

• Up to 1.5 mg/m2 on days 1, 2, 15, 16

• carfilzomib up to 56 mg/m2

• G-CSF support weeks 1 and 3

• Phase 2 expansion

– carfilzomib naïve patients

– + carfilzomib 27 mg/m2 + dex 4

– ORR 44%

• Toxicity: cytopenias (18% gr 4 neutropenia), fatigue, diarrhea

SUMMARY (1): Combinations for early relapse

3 new combination therapies with Rd

• Elo-Rd, possible survival advantage

• KRd, possible survival advantage

• IRd

Other combinations for early relapse

• VRd

• Doublets (Vd, Rd, Kd, PomDex)

• Cyclophosphamide combinations (CyBorD, CyCarDex)

• Pomalidomide combinations (VelPomDex, CarPomDex)

SUMMARY (2): HDAC inhibition

Theoretic justification

• Combined targeting of protein degradation pathways

Biologic efficacy

• Improved response rate and PFS from panobinostat with Vel/dex

• Improved response rate and PFS from vorinostat with Vel/dex

• Responses in bortezomib-refractory patients from ricolinostat with

Vel/dex

Approved combination: panobinostat with IV bortezomib/dex

• Limited utility due to toxicity

Possible paths forward:

• Panobinostat with subcutaneous (+/- weekly) bortezomib

• Panobinostat with carfilzomib

• Ricolinostat with bortezomib/dexamethasone

• HDACi with lenalidomide or pomalidomide

SUMMARY (3): Daratumumab

Single agent efficacy

Early evidence for combinations with lenalidomide and

pomalidomide

Minimal toxicity

• Infusion reactions

• Interference with IAT for RBC transfusions

SUMMARY (4): Other agents

New targets

• Ibrutinib

• Vemurafenib (for patients with BRAF mutations)

• Selinexor

• Filanesib

Immunotherapy

• Pembrolizumab with lenalidomide or pomalidomide

• Antibody-drug conjugates

• CAR T cells

Trials at Penn

Myeloma, relapsed/refractory

• Randomized phase 2 study of carfilzomib 27 vs 56 mg/m2

• Phase 1/2 study of lenalidomide in patients with renal insufficiency

• Phase 2 study of daratumumab with backbone regimens

• Phase 2 study of subcutaneous daratumumab (coming soon)

• Phase 1/2 study of elotuzomab with anti-Kir or anti-CD137

• Phase 1 study of CPI-0610 (BET inhibitor)

• Phase 1/2 study GSK2857916 (anti-BCMA immunoconjugate)

• Phase 2 study of selinexor (SINE / XPO1 inhibitor)

• Phase 1 study of BCMA-directed CAR T cells

Penn’s Myeloma Program

Physician Investigators

Edward Stadtmauer

Dan Vogl

Brendan Weiss

Adam Cohen

Alfred Garfall

Hematologic Malignancies

David Porter

Jakub Svoboda

Noelle Frey

Selina Luger

Stephen Schuster

Sunita Nasta

Alison Loren

Donald Tsai

Alexander Perl

Rebecca Hirsh

James Mangan

Anthony Mato

Elizabeth Hexner

Daniel Landsberg

Nurse Practitioners

Patricia Mangan

Brenda Shelly

Colleen Erb

Mary Sanchez

Collaborating Researchers

Yulia Nefedova

Yair Argon

Ravi Amaravadi

Nicole Aqui

Michael Milone

Carl June

Bruce Levine

Research Staff

Diane Frazee

Rita Bhagat

Darneesha Smith

Jessica Savage

Maria Raguza-Lopez

Rebecca Cimildoro

Gayle Mallon

Dan Vernau

Gabrielle Gosciniak

Manasi Vinod

Cellular Therapy Staff

Karen Dengel

Naseem Kerr

Regina Ferthio

Tenesia Carey

Laurel Caffee

Lee Dengel