Future Strategies For Refractory Myeloma

Marc S. Raab

Multiple Myeloma

Clonal proliferation of malignant plasma cells.

• excess bone marrow plasma cells

• monoclonal protein

• osteolytic bone lesions

• renal disease

• genetically heterogeneous

• Still an incurable disease

• 2nd most frequent hematologic malignancy

• Germany: ~6000 new patients/year, 2% of all cancer deaths

Raab et al., Lancet, 2009

“Punched Out” Lesions

New challenges – refractory MM

refractory MM has the most urgent medical need

Current therapy: - Chemotherapy incl. stem cell transplantation

- Proteasome inhibitors (“PI“; Borte-/ Carfil-/ Ixazomib)

- Thalidomide-derivatives (“IMiD“; Lena-/ Pomalidomide)

Myeloma Overall Survival Newly diagnosed

Former therapy

PI + IMiD 60 mos

Relapsed / Refractory to PI + IMiD <9 mos

months

Kumar SK et al., 2008 & 2012

Novel and novel-novel

Immunomodulators

Thalidomide, Lenalidomide

Pomalidomide

Proteasome Inhibitors

Bortezomib

Carfilzomib

Ixazomib

Antibodies

Elotuzumab

Daratumumab

MOR202, SAR650894

Others

Panobinostat,

ABBV838, ACY-241, ABT199, ARRY520, CRM1, EDO-S101, PIM447, Ibrutinib, Afuresertib,

Trametinib, Dabrafenib

Blocking the aggresome pathway

HDAC-6 specific inhibition: ACY-1215

ACE-MM-102:

Combination of Ricolinostat with Pom/Dex • Over 80 refractory relapse patients in Phase 2, closing to accrual Nov 2015.

- As of August 3, 2015, 46 patients were safety evaluable and 36 were efficacy evaluable with median follow-up of 4 months

- ORR (≥PR) was 50%, regardless of refractory status to Len, Bort, or cytogeneic risk (t4;14 +/- del 17p)

- Pom/Dex historically had a 16% ORR at 4.2 mo in similar patient population

• Ricolinostat remains a tolerable and safe oral agent

- Common toxicities are predominantly low grade, including fatigue, diarrhea, neutropenia, anemia, thrombocytopenia and constipation

- No evidence of ricolinostat accumulation or drug-drug interaction with Pom

• PK of ricolinostat is similar to that observed in combination with Btz and Len.

ACY-241: Structure and Potency

Structurally similar to ACY 1215

Potency and selectivity similar to ACY 1215

Enhanced aqueous solubility allows tablet form

Similar single agent cytotoxicity

New chemical entity

Compound

HDAC1

(nM)

HDAC2

(nM)

HDAC3

(nM)

HDAC6

(nM) Solubility

ACY-1215 36 72 66 6 ~ 10 µg/mL

ACY-241 35 53 63 4.4 239 µg/mL

ACY-241 ACY-1215

HDAC-6 specific inhibition: ACY-241

ACY-241 / Pom / Dex

ACE-MM-200 Trial Outline: ACY-241/Pom/Dex

1a: ACY-241 monotherapy

1b: combination ACY-241 + Pom + Dex

* Continue dose escalation in 1a even if MTD reached in 1b

KPT inhibition - Selinexor

Novel small molecule

selective inhibitors of nuclear

export (SINE) compounds

that target CRM1 exportins:

Induce cell death, by the

forced nuclear retention of

tumor-suppressors,

transcriptional factors that are

otherwise inactive in these

cells due to aberrant CRM1

transport into the cytoplasm

Selinexor – single agent

Phase I/II study in hematologic malignancies

3+3 design

Broad Range of doses: 3 mg/m2 to 80 mg/m2

Varying regimens: 4- 8-10 does/cycle

Varying Histology: MM, WM, NHL, CLL

Selinexor - Adverse events

Selinexor single agent – limited activity

All 35 pts dosed: ORR (1/35) patients 3%, CBR (6/35) 17%

Selinexor and Dexamethasone

• Preclinical Data support synergy between steroids and Selinexor

Selinexor and Dexamethasone

Persistent G1/2 Nausea

Fatigue/Asthenia

Improved GI

20% Emesis/Diarrhea

Thrombocytopenia

Intent to Treat

Analysis: all 10 pts:

ORR 60%, CBR 80%

Selinexor and the future

• Trial in Quad refractory patients: Selinexor + Dex

• Single arm phase II for accelerated approval

• Combination Studies are ongoing/planned

• Bortezomib

• Pomalidomide

• Carfilzomib

• Lenalidomide

• Moffit: Selinexor + Pegylated Doxorubicin

Preclinical rationale to novel-novel combinations

BRDi + Selinexor

Melphalan?

ARRY-520, Filanesib

• Kinesin Spindle Protein

(KSP, eg5) is a

microtubule motor protein

required for mitosis and

separation of spindle pole

– KSP inhibition prevents

formation of bipolar spindle,

leading to cell death

(*Mol Cancer Ther. 2010 9: 2046-56)

ARRAY-520-212: Phase 2 Study Design

Cohort 1: ARRY-520 Single Agent

ARRY-520 1.5 mg/m2 q 2 weeks

2-stage, single-arm cohort (N=32)

Cohort 2: ARRY-520 + Dexamethasone Combination

ARRY-520 1.5 mg/m2 q 2 weeks

G-CSF

Dexamethasone 40 mg weekly

G-CSF

Dexamethasone 40 mg weekly

G-CSF

2 1 2 1

G-CSF

2 1 2 1

1st stage with 18 evaluable patients (21 treated)

of 2-stage, single-arm cohort (N=48)

ARRY-520-212: inclusion criteria

Cohort 1: Phase 2 ARRY-520 single agent

• ≥ 2 prior treatment regimens, including BTZ and an IMiD

• Disease should have progressed during or after last regimen

Cohort 2: Phase 2 ARRY-520 + Dexamethasone

• ≥ 2 prior treatment regimens

• Refractory (progression during or w/in 60 days) to last regimen

• ≥2 consecutive cycles of prior treatment that included Len and BTZ

– Refractory to Len, BTZ, and dex (40 mg per week)

• Patients intolerant to Len or BTZ not included

– Adequate prior alkylator therapy

ARRY-520-212: Prior therapies

ARRY-520 ARRY-520 + dex

N = 32 N = 55

Median Prior Regimens 6 8

Prior Proteasome Inhibitor 29 (91%) 55 (100%)

Prior BTZ 29 (91%) 55 (100%)

BTZ-refractory 17 (53%) 54 (98%)

Prior IMiD 32 (100%) 55 (100%)

Prior Len 31 (97%) 55 (100%)

Len-refractory 24 (75%) 55 (100%)

Prior Corticosteroid 32 (100%) 55 (100%)

Triple-Refractory (Len, BTZ, Dex)

13 (41%) 53 (96%)

Prior Alkylator 32 (100%) 55 (100%)

Prior Anthracycline 16 (50%) 38 (69%)

Prior Transplant 26 (81%) 49 (89%)

1-acid glycoprotein (AAG) is a potential selection

marker for filanesib

• Background

– 1-acid glycoprotein (AAG) is an acute-phase serum protein used to

diagnose and monitor inflammatory disorders

– AAG binds to ARRY-520

– Increasing [AAG] results in increased IC50 for ARRY-520 in vitro

– No correlation between [AAG] and common MM prognostic markers

• Hypothesis: Patients with elevated serum AAG may have

sub-therapeutic exposure due to lower available ARRY-520

– High pre-dose [AAG] correlates with lack of ORR and shorter time on

study for patients treated with ARRY-520

ARRY-520-212: AAG and response

ARRY-520 Single Agent ARRY-520 + dex

All Pts1 AAG-

High

AAG-

Low All Pts2

AAG-

High

AAG-

Low

n 32 6 21 55 15 36

ORR (≥ PR) 5 (16%) 0 (0%) 5 (24%) 8 (15%) 0 (0%) 7 (19%)

CBR (≥ MR) 6 (19%) 0 (0%) 6 (29%) 11 (20%) 0 (0%) 10 (28%)

Duration of

Response (months) 8.6 - 8.6 5.1 - 5.2

Time to Next

Treatment (Months) 3.7 2.6 5.3 3.4 2.0 5.1

OS (months) 19.0 4.5 23.3 10.5 2.9 10.8

ARRY-520-212: ongoing trials

1. Randomized Phase II study of Carfilzomib +/- Filanesib

• N=75

2. Single arm phase II Filanesib + dexamethasone registration enabling study

• Pts Prior Len + BZ and refractory to CFZ or Pom

3. Bortezomib- Filanesib Combination ongoing

4. Pomalidomide-Filanesib Combination

ABT-199, Venetoclax

BH3-only family member proteins include BIM, BAD, PUMA, and NOXA

Venetoclax Binds to and

Inhibits Overexpressed BCL-2

Venetoclax

BH3-only

BAK BCL-2 BCL-2

Mitochondria

An Increase in BCL-2

Expression Allows the

Cancer Cell to Survive

Mitochondria

Pro-apoptotic

Proteins

(BAX, BAK)

Anti-apoptotic

Proteins

(BCL-2)

2 1 Apoptosis is Initiated

Apoptosome

APAF-1

Cytochrome c

Active Caspase

Procaspase

Mitochondria

3

BAX

ABT-199 : background

• The anti-apoptotic protein BCL-2 is highly expressed in a

subset of myeloma cells and has been implicated in

mediating the survival of myeloma cells1

• Venetoclax is a potent, selective, orally bioavailable

small-molecule BCL-2 inhibitor2

• Venetoclax induces cell death in multiple myeloma cell

lines and primary samples in vitro

– Multiple myeloma cells harboring the t(11;14) chromosomal

translocation have a high level of BCL-2 and low level of MCL-1,

which increases sensitivity to single-agent venetoclax treatment

ABT-199: study design

Patients > 1 prior therapy were treated on a 21-day cycle

with daily venetoclax (3+3 design):

Patients received prophylaxis for tumor lysis syndrome and were monitored at first

dose and dose increases

Patients who progressed during treatment were permitted to add dexamethasone

ABT-199: patient disposition

Characteristics N = 29

Age, median [range] 66 [42–79]

Male gender, n (%) 16 (55)

White race, n (%) 24 (92)

ISS stage III, n (%)a 6 (22)

Cytogenetic abnormalities, n (%)a

t(11;14) 11 / 27 (41)

t(4;14) 2 / 26 (8)

del17p 4 / 26 (15)

del13q 14 / 26 (54)

Prior therapies

Median [range] lines of therapy 6 [1–13]

Stem cell transplant, n (%) 19 (66)

Bortezomib / Refractory, n (%)b 26 (90) / 15 (52)

Bortezomib and lenalidomide / Refractory, n (%)b 24 (83) / 10 (34)

Lenalidomide / Refractory, n (%)b 27 (93) / 12 (41)

Creatinine clearance 30–50 mL/min, n (%) 6 (21)

ABT-199: adverse events

Event, n (%) N=29

AEs, any grade 29 (100)

Common all-grade AEs (in ≥ 20% patients)

Diarrhea 12 (41)

Nausea 12 (41)

Fatigue 7 (24)

Asthenia 6 (21)

Neutropenia 6 (21)

Vomiting 6 (21)

AEs, grade 3 or 4 17 (59)

Common grade 3 or 4 AE (in ≥ 10% patients)

Thrombocytopenia 7 (24)

Neutropenia 4 (14)

Anemia 3 (10)

Event, n (%) N=29

Any serious AEa 10 (35)

Common SAEs (in ≥ 5% patients)

Cough 2 (7)

Malignant neoplasm progression 2 (7)

Pyrexia 2 (7) a1 SAE of upper abdominal pain was assessed as possibly related to venetoclax

• 2 patients had DLTs at 600 mg:

o Upper abdominal pain

o Nausea with abdominal pain

• MTD was not reached; RPTD of 1200 mg was

determined from safety and efficacy data in

each cohort

• No patients developed tumor lysis syndrome

ABT-199: response

Best Response, n (%) All Patients

n=29

t(11;14)

n=11

non-t(11;14)a

n=18

Overall Response 2 (7) 2 (18) 0

Complete response 2 (7) 2 (18) 0

Partial response 0 0 0

Minimal response 1(3) 1 (9) 0

Stable disease 15 (52) 3 (27) 12 (67)

Disease progression 11 (38) 5 (46) 6 (33)

Time on study 2.6 [0.4–11.8] 5.1 [0.7–11.8] 2.2 [0.4–10.0]

Time to progression 2.0 [1.2–4.0] 3.9 [1.2–6.0] 1.9 [1.2–4.0]

Duration of stable disease 2.6 [0.04-9.2] 3.5 [2.8–6.1] 1.3 [0.04–9.2]

Stable disease > 2 months, n (%)b 8/15 3/3 5/12

Median best percent change in M-protein

• Decrease of 15.6% in patients with t(11;14); increase of 10.6% in non-t(11;14)

ABT-199: summary

• Venetoclax monotherapy was well tolerated in heavily-pretreated R/R

multiple myeloma patients

• Preliminary efficacy data, including complete responses, are supportive

of single agent activity of venetoclax in this population, particularly in

t(11;14) patients

• Venetoclax exposure was dose proportional at almost all assessed dose

levels, based on limited pharmacokinetic data

• Recommended phase 2 dose was achieved; the study is currently

enrolling in the safety expansion cohort at 1200 mg

MEK inhibition in Multiple Myeloma:

early clinical data

MEK inhibition with partial responses in subsets of rMM

Heuck et al., Leukemia 2015

• Retrospective evaluation

• 58 refractory MM with RAS / BRAF mutations

• Median of 5 prior lines

• 22 pts received monotherapy

• 4/22 achieved PR

• Most significant AEs:

• Rash

• Diarrhea

• Cardiac toxicity (lower LV-function)

Cut down the tree or trim the branches?

Personalizing therapy based on rMM biology