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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