Transcript Pamidronate

Update on Novel Combinations
for Relapsed/Refractory Disease:
Approved Drugs
James R. Berenson, MD
Medical & Scientific Director
Institute for Myeloma & Bone Cancer Research
Los Angeles, CA
Treatment Choices
Anthracyclines
Thal
Pom
Carfilzomib
Bortezomib
+
IMiDs
+
Len
•Doxorubicin
•PLD
Proteasome
inhibitors
+
+
+
Chemotherapy
+
Dex
Methylpred
Steroids
+
Clarithromycin
Alkylating agents
•Melphalan
•Cyclophosphamide
•Bendamustine
Prednisone
Novel
Combinations
Clinical Trials
Investigational
Drugs
Individualize your choice for the
myeloma patient based on:
Response
and for
how long?
Side
effects
and
tolerability
Renal,
Bone,
Marrow,
Subjective,
Rate of
Progression
Genetics?
Prior
Treatments
Work/
Lifestyle
How active is the
patient?
Mobility?
Is potential
neuropathy an
issue?
(e.g.- surgeon,
pianist)
Diabetes
mellitus
Disease
Co-morbid
characteristics conditions
(steroids)
Cardiac
(Doxorubicin,
PLD)
Neuropathy
(Thalidomide)
Principles of Treating
Relapsed/Refractory Multiple Myeloma
• Be sure a patient has really progressed before changing
therapy
– REPEAT MYELOMA LABS!
• Try to use drugs patient has not seen before
• HOWEVER,
– progression on one drug in combination does not mean that
drug will not be effective w/ another agent
• e.g., pts progressing from bortezomib w/ melphalan often respond
to bortezomib w/ PLD
• Even different drugs in the same class may be active so that
– bortezomib+melphalan failures may respond to other alkylating
agents- cyclophosphamide or bendamustine
– LEN failures may respond to THAL and vice versa
– pts progressing from a drug at one dose may respond to the
same drug at a higher dose- e.g., LEN
– the same combination may be effective again if the patient has
not seen the combination in a long time
Single Agent Bortezomib
Relapsed/Refractory Multiple Myeloma
•
•
Initial approval in multiple myeloma based on phase II data
Only single agent to demonstrate a statistically significant survival
advantage (APEX)
PHASE III
PHASE II
Study
SUMMIT
CREST
APEX
*EBMT criteria
Regimen
Bortezomib
Bortezomib
Bortezomib
Dex
1.3 mg/m2
1.0 mg/m2
1.3 mg/m2
Evaluable
Patients (n)
Overall
Response*
Median OS
(mos)
202
27%
17
30%
26.7
38%
Not yet reached
54
1.3 mg/m2
315
43%
29.8
40 mg
312
18%
23.7
P = .0272
Efficacy and Safety of Bendamustine plus
Bortezomib in R/RMM: A Phase 1/2 trial
Patients were assigned to one of 3 cohorts receiving doses of intravenous
bendamustine at 50 mg/m2 (cohort 1), 70 mg/m2 (cohort 2), or 90 (cohort 3) mg/m2
in combination with a fixed dose of intravenous bortezomib (1.0 mg/m2) according to
the schedule in Figure 1.
Berenson et al., Brit J Haematol, in press
Bendamustine & Bortezomib: Results
 No DLT was observed at any dose level.
50 mg/m2 (n = 5)
70 mg/m2 (n = 4)
90 mg/m2 (n = 5)
 The maximum dose of bendamustine (90 mg/m2) was
well tolerated in combination with bortezomib 1.0 mg/m2
and was designated as the MTD
 Overall response rate
Overall 48% (1 CR, 2 VGPR, 9 PR, & 7 MR)
At MTD (90 mg/m2) 52%
Bortezomib-exposed (n=31) 42%
Alkylator-exposed (n=28) 46%
Berenson et al., Brit J Haematol, in press
Bendamustine (B) w/ Lenalidomide (L)
and Dexamethasone (D): Phase 1/2 Trial
• R/R MM patients
• N=29
• Regimen (28-day cycles)
– B 75-100 mg/m2 d1 & 2
– L 5-10 mg qd d1-21
– Dex 40 mg PO weekly
• MTD: B 75/ L 10/ D 40
• Results (only 25 considered evaluable for
response)
– ORR (> PR): 52% w/ 24% VGPR
– MR 24%
– PFS: 6.1 mo
Lentzsch et al. Blood 2012
Bortezomib + PLD vs. Bortezomib in
Previously Treated MM
1° Endpoint: TTP
2° Endpoints: OS*, ORR
N=646
R
A
N
D
O
M
I
Z
E
(n=322)
q 3 weeks
up to 8 cycles
Days
1
4
8
11
q 3 weeks
up to 8 cycles
(n=324)
BORT 1.3 mg/m2
PLD 30 mg/m2
*Not enough events to determine statistical significance in overall survival.
ORR=overall response rate; OS=overall survival; TTP=time to progression.
Doxorubicin HCl liposome injection Prescribing Information, Rev’d May 2007
Bortezomib ± PLD
MMY-3001 Trial
*By EBMT criteria
• Response*
CR + nCR
PR
ORR
• Efficacy
DOR, months
B
(n = 322)
11%
39%
41%
B+D
(n = 324)
13%
40%
44%
7.0
10.2
P value
0.43
0.0008
0.00000
TTP, months
6.5
9.3
4
An overall survival advantage was observed for the combination arm
(P=0.0476)
Survival rate (15
65%
76%
0.03
months)
Orlowski et al. J Clin Oncol 25:3892-901 (2007)
More Frequent Dosing with PLD Improves
Anti-Myeloma Effect in a SCID-hu MM Model
Daily Dosing2
Human IgG Levels (mg/dL)
Human IgG Levels (mg/dL)
Weekly Dosing1
600
Vehicle
Doxil (0.3 mg/kg)
Doxil (1 mg/kg)
Doxil (3 mg/kg)
Doxil (10 mg/kg)
500
400
300
200
100
0
0
10
20
30
40
1400
1300
1200
1100
1000
900
800
700
600
500
400
300
200
100
0
Vehicle
Doxil (0.3 mg/kg)
Doxil (1 mg/kg)
Doxil (3 mg/kg)
0
10
Days Post Implantation
1Twenty
days post-implantation, mice
received i.p. injection of PLD once weekly.
Human IgG was measured weekly in the
mouse serum by ELISA.
20
30
40
Days Post Implantation
2Seventeen
days post-implantation, mice
received i.p. injection of PLD once daily
for three consecutive days weekly.
Human IgG was measured weekly in the
mouse serum by ELISA.
Campbell et al. Br J Haematol 2006
Bortezomib + PLD + Dexamethasone for
Patients with Previously Untreated Myeloma:
A Phase II Trial
Dexamethasone 40 mg IV
Bortezomib: 1.0 mg/m2 IV
PLD: 5 mg/m2 IV infusion
Days 1 2 3 4 5 6 7 8 9 10 11
Cycle repeats
29
Berenson et al. Brit J Haematol, 2011
DVD: Response Rates
Response Type
Number of Patients
(N = 35)
Complete Response (CR)
7 (20%)
(no serum M-protein)
Very Good Partial Response (VGPR)
3 (8.6%)
(≥ 90% decrease in serum M-protein)
Partial Response (PR)
15 (42.9%)
(50-74% decrease in serum M-protein)
Minor Response (MR)
5 (14.3%)
(25-49% decrease in serum M-protein)
Objective Response (CR+VGPR+PR+MR)
Stable Disease (SD)
30 (85.8%)
3 (8.6%)
(no serum M-protein)
Disease Control (CR+VGPR +PR+MR+SD)
Progressive Disease (PD)
33 (94.4%)
2 (5.7%)
(>25% increase in serum M-protein)
Berenson et al. Brit J Haematol, 2011
Comparison of Adverse Events w/
Modified DVD vs Conventional Dosing
Adverse Event (all grades)
Anemia
Thrombocytopenia
Neutropenia
Peripheral neuropathy
Fatigue
PPE
Grade 1
Grade 2
Grade 3
Grade 4
Current
Study
(N=35)
Jakubowiak
et al., 2009
(N=40)
Current
Study
(N=35)
Jakubowiak
et al., 2009
(N=40)
Current
Study
(N=35)
Jakubowiak
et al., 2009
(N=40)
Current
Study
(N=35)
Jakubowiak
et al., 2009
(N=40)
0
2 (5.7%)
0
5 (14.3%)
10 (28.6%)
2 (5.7%)
38 (95%)
24 (60%)
0
28 (70%)
24 (60%)
19 (47.5%)
0
0
1 (2.9%)
5 (14.3%)
6 (17.1%)
0
13 (32.5%)
8 (20%)
16 (40%)
8 (20%)
11 (27.5%)
11 (27.5%)
0
0
2 (5.7%)
2 (5.7%)
0
0
1 (2.5%)
3 (7.5%)
4 (10%)
1 (2.5%)
5 (12.5%)
1 (2.5%)
0
0
0
0
0
0
0
1 (2.5%)
0
0
0
0
Adverse Event Comparison Between DVD (Current Study) and Standard Dosing
(Jakubowiak et al., Blood 2009).
Phase II Study of Bortezomib plus
Lenalidomide and Dex (VRD) in Rel/Ref MM:
Updated Results After >2 Years’ Follow-up1
–Endpoints: Primary: PFS; Secondary: ORR (≥MR), DOR, TTP, OS, safety
–Patients: 64 pts with relapsed/refractory MM; median age 65 years (range 32–83);
ISS stage I/II/III/unknown (%): 27/25/23/25; median 2 (range 1–3) prior therapies
–Study design:
– Anticoagulation with aspirin ± warfarin or LMWH, and antiviral prophylaxis against
herpes zoster were required
15
Richardson PG et al. ASH 2010, abstract #3049
Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD)
in Rel/Ref MM: Updated Results After >2 Years’ Follow-up
• Results: 62 pts evaluable for response
Best response,%
CR/nCR
PR/VGPR
ORR (≥MR)
11/14
36/3
78
Outcom
es
TTP
PFS
OS
Median,
mos
9.5
9.5
26
1-yr,
%
37
36
86
2-yr,
%
16
15
55
• Median duration of ≥MR: 8.3 months
Gr ≥3 AE, %
• Median duration of ≥PR: 8.4 months
Neutropenia
Thrombocytopenia
Lymphopenia
30
22
11
Leukopenia
9
Hyperglycemia
9
Hyponatremia
8
Hypophosphatemia
8
Fatigue
5
Diarrhea
Limb edema
3
3
Pain in extremity
2
–Safety:
• Median cycles received:
11 (range 1–48)
• Median treatment duration: 7.9
months (range 0.4–36); 66% of pts
completed ≥8 cycles with all three
drugs
Richardson PG et al. ASH 2010, abstract #3049
VRD (n=64)
16
DVD-R (Bortezomib + PLD + Dexamethasone +
Lenalidomide) for Patients with R/R MM:
A Phase II Trial
Dexamethasone 40 mg IV
Bortezomib: 1.0 mg/m2 IV
PLD: 4 mg/m2 IV infusion
Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Cycle repeats
29
Len 10 mg po qd d1-14
Berenson et al., Leukemia 2012
DVD-R: Response Rate
N=39
Complete Response (CR)
(no serum M-protein)
Very Good Partial Responses (VGPR)
(> 90% decrease in serum M-protein)
Partial Response (PR)
(50-74% decrease in serum M-protein)
Minor Response (MR)
(25-49% decrease in serum M-protein)
Objective Response (CR+VGPR+PR+MR)
Stable Disease (SD)
(change in M-protein + 25%)
Disease Control (CR+VGPR+PR+MR+SD)
Progressive Disease (PD)
(>25% increase in M-protein)
*Based on the modified Blade’ criteria
8* (21%)
4 (10%)
7 (18%)
14 (36%)
30 (85%)
4 (10%)
37 (95%)
2 (5%)
DVD-R Study: Adverse Events
Grade 3 adverse events included:
6 reversible neutropenia, 4 reversible anemia, 4 pneumonia,
1 dyspnea, 3 reversible thrombocytopenia,
1 reversible peripheral neuropathy, 1 mental confusion,
1 hypophosphatemia, 1 fall, 1 skin BCC, 1 allergic reaction to
moxifloxacin,
1 dysphagia, 1 syncope, 1 respiratory distress.
Grade 4 adverse events included:
1 reversible thrombocytopenia & 1 anemia
No cases of stomatitis or hand-foot syndrome reported!
Treatment-emergent peripheral neuropathy (25%):
Grade 1: n=8 (20%)
Grade 2: n=1 (2.5%)
Grade 3: n=1 (2.5%)
Retreatment w/ IMiDs for MM Patients
• Retrospective study in
140 pts treated firstline w/
– THAL/DEX- 58%
– LEN/DEX- 42%
LEN
• Retreatment w/ a regimen
containing
LEN
(n=48)
– THAL- 24%
– LEN- 76%
• # of treatments before
retreatment median of 2 (range 1-6)
• 89% received IMiD w/ DEX
• 113 considered evaluable
for response
> PR
54%
LEN
THAL
THAL
THAL
LEN
THAL
(n=11) (n=58) (n=23)
20%
48%
30%
– 44% > PR
– MR not reported
Madan et al. Blood 2011
PX-171-003: Study Overview
Phase 2 Study
Population
Study expanded to registration trial
PX-171-003-A0
(N=46)
Progressive disease required
at study entry
Relapsed from
≥2 prior lines of therapy
• Must include bortezomib
• Must include thalidomide
or lenalidomide
Dosing regimen,
premedication,
and hydration
were defined in
003-A0
Refractory to last regimen
PX-171-003-A1
(N=266)
Carfilzomib for
Injection*
days 1,2,8,9,15,16
(28-day cycles)
Maximum 12 cycles
*Cycle 1, 20 mg/m2
Cycle 2 and beyond, 27 mg/m2
• Primary endpoint: Overall response rate
– Assessed by an Independent Review Committee, using
International Myeloma Working Group criteria
Adapted from Siegel D, et al. ASCO 2011. Abstract 8027 (poster presentation).
PX-171-003-A1 (N=266):
Disease characteristics
Median prior regimens (range)
Median years since diagnosis (range)
Prior transplant
Refractory status to most recent therapy
Refractory: Progression during most recent
therapy
Refractory: Progression within 60 days after
completion of most recent therapy
Refractory: ≤25% response to treatment
Relapsed: Progression after 60 days post
treatment
Creatinine clearance <30 mL/min
Median serum b2-microglobulin (range)
Cytogenetics
Normal/Favorable
Unfavorable
Unknown
5 (1-20)
5.35 (0.5-22.3)
74.4%
74.4%
14.3%
6.0%
5.3%
2.3%
4.3 (0.4-20.5)
59.8%
28.2%
12.0%
PX-171-003-A1:
Response
N=266
Response rates*
Overall response rate (ORR)
Complete response
Very good partial response
Partial response
Median duration of response
(95% CI)
61 (22.9%)
1 (0.4%)
13 (4.9%)
47 (17.7%)
7.8 months
(5.6-9.2)
*As assessed by the Independent Response Review Committee
Carfilzomib in MM Patients
Following 1-3 Prior Therapies
004, Phase II
1:1Carfilzomib
Relapsed / Refractory
Multiple Myeloma
1-3 Prior Therapies
N = 165
Bortezomib-treated
Cohort 1
20 mg/m2
Bortezomib-naïve
Carfilzomib
Cohort 2
20 mg/m2→27 mg/m2
Bortezomib-naïve
Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles
N
Median age
Median # prior
therapies
Bortezomib-naïve
Bortezomib-treated
129
65 years
2
36
63 years
3
Stewart AK, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8026. Stewart K, et al. Hematologica. 2010;95(S2).
Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813.
Carfilzomib Monotherapy
MM Patients With 1-3 Prior Therapies
Bortezomib-Treated
Cohort 1 (20 mg/m2 Carfilzomib)
n = 34
21%
33%
8.1 months
11.5 months
ORR
CBR (> MR)
Median TTP
Median DOR (> PR)
Bortezomib-naïve Cohort 1 (20 mg/m2)
n = 59
ORR
42%
CBR
59%
CR
3%
VGPR
14%
Median TTP
8.3 mo
Median DOR
13.1 mo
Median PFS
8.2 mo
Cohort 2 (20→27 mg/m2)
n = 70
52%
64%
2%
27%
Not reached
Not reached
Not reached
Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts.
2011;118(21):813.
Carfilzomib / Lenalidomide / Dex (CRd)
in Relapsed / Refractory MM
MM: 1-3 Prior
Therapies
N = 52
Carfilzomib
Lenalidomide
Low-dose dex
1o Endpoint
ORR
2o Endpoint
DOR, TTP, OS, PFS, Safety
CRd
N = 51
Median age
Median # of prior therapies
Prior bortezomib
Prior lenalidomide
Prior lenalidomide and bortezomib
Prior thalidomide
Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025.
63 years
2
85%
73%
50%
44%
Carfilzomib / Lenalidomide / Dex (CRd)
in Relapsed/Refractory MM
Response
ORR
CR / nCR
VGPR
PR
Grade 3/4 Adverse Events
Neutropenia
Thrombocytopenia
Anemia
Hypophosphatemia
Fatigue
CRd
N = 51
78%
24%
18%
37%
CRd
N = 51
23%
15%
15%
13%
12%
ORR, overall response rate; CR, complete response; nCR, near complete response; VGPR, very good partial
response; PR, partial response.
Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025.
A Phase I/II Study of Carfilzomib as a Replacement
for Bortezomib for Multiple Myeloma Patients Failing
Bortezomib-Containing Regimens
• Nontraditional intrapatient Phase I/II trial
• Eligibility: Progressive disease while on
bortezomib or relapsed within 12 wks of
the last dose of bortezomib in a
combination regimen
• Carfilzomib replaces bortezomib in
combination with:
– Alkylating agent
– Anthracycline
– Glucocorticosteroid
– IMiD
Study Design (cont’d)
• Study treatment
– Carfilzomib
• starting at 20 mg/m2 for the 1st cycle
• increased to 27, 36 and 45 mg/m2 during cycles 2, 3 and
4, respectively if no DLT is observed
– DLT considered > Grade 2
• administered on days 1, 2, 8, 9, 15, and 16 of each 28-day
cycle
– Cycle length, schedule(s) and dose(s) of other
drugs identical to that of the previous
bortezomib-containing regimen
• A patient must complete a minimum of a full
cycle without DLT before continuing onto a
subsequent cycle (cycles 1-4 only)
• Maximum # of cycles- 8
Results
Demographics
Enrolled (N)
32
Efficacy (N)
24
Age (median)
67
Sex (M:F)
21:11
Prior Regimens
Number of prior
regimensmedian (range)
Number of prior
bortezomibcontaining
regimensmedian (range)
6 (1-18)
Regimen Details
Cycle
length
Cycles
completed,
median
(range)
Follow-up
median
(range)
Number of
DLTs
2 (1-13)
8 pts- 21-day
24 pts- 28-day
3
(range 0-12)
5.9 mo
(0.4-14.4 mo)
8 (25%)
Regimen in addition to carfilzomib (N=32)
Dexamethasone
9 (28%)
Cyclophosphamide+ ascorbic acid
5 (16%)
Cyclophosphamide+ascorbic
acid+dexamethasone
1 (3%)
Melphalan
1 (3%)
Bendamustine
3 (9%)
Bendamustine+methylprednisolone
1 (3%)
PLD
1 (3%)
PLD+dexamethasone
5 (16%)
Lenalidomide
2 (6%)
Lenalidomide + dexamethasone
1 (3%)
Lenalidomide + dexamethasone + PLD
1 (3%
Thalidomide + dexamethasone
1 (3%)
Thalidomide + lenalidomide + bendamustine +
clarithromycin + methylprednisolone
1 (3%)
Efficacy (N=24)
Best Response
# of Patients
%
PD
SD
MR
PR
2
4
5
7
8%
17%
21%
29%
VGPR
CR
Overall Response
Rate
(PR+VGPR+CR)
4
2
13
17%
8%
54%
18
75%
Clinical Benefit Rate
(MR+PR+VGPR+CR)
Summary
• Intrapatient Phase I/II trial of MM patients
refractory to bortezomib combination therapy
with and without IMiDs
• Treatment with same regimen w/ carfilzomib
(CAR) replacing bortezomib
• CAR escalated from 20 to 27, 36, and 45 mg/m2
during cycles 1-4; maximum of 8 cycles
• MTD for one regimen (CY+CAR) reached at the
maximum dose of CAR (45 mg/m2) with no DLT
• Well tolerated
• Clinical benefit rate 75% including 8% CR, 17%
VGPR, 29% PR, & 21% MR
– Responses observed with all drugs!
A Phase I/II Trial of Weekly Carfilzomib in
Combination With IV Dexamethasone for R/R
Multiple Myeloma
• Phase I/II, open-label, multi-center trial
investigating weekly carfilzomib + dexamethasone
in R/R MM patients
• Phase I:
– 28-day cycle
– Carfilzomib 45, 56 or 70 mg/m2 on days 1, 8 & 15
– Dexamethasone IV at 40 mg days 1, 8, 15, & 22
• Phase II:
– Carfilzomib at MTD on days 1, 8 & 15
– Dexamethasone IV at 40 mg days 1, 8, 15, & 22
• Enrollment: second cohort (56 mg/m2) currently
being treated!
HDAC Inhibitor Vorinostat & Bortezomib
for R/R MM: VANTAGE 088: Phase III Trial
Bortezomib +
Vorinostat
Multiple Myeloma
1-3 Prior Therapies
N = 637
R
Bortezomib +
Placebo
ORR
CBR
Median PFS
Median OS
Bortezomib +
Vorinostat
Bortezomib +
Placebo
P
56%
71%
7.63 mo
NR
41%
54%
6.83 mo
28.1 mo
< 0.0001
< 0.0001
< 0.01
0.35
ORR, overall response rate; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival.
Dimopoulos MA, et al. ASH Annual Meeting Abstracts. 2011;118(21):811.
Vorinostat, Lenalidomide &
Dexamethasone for R/R MM
Vorinostat1:1(300 or 400 mg, 1x daily)
Lenalidomide (10, 20, 25 mg daily)
Dexamethasone (40 mg weekly)
Relapsed / Refractory MM
N = 28
Response
Vorinostat / Lenalidomide /
Dexamethasone
N = 28
ORR
46%
CR
7%
> SD
86%

Serious AE
•


Neutropenia, diarrhea, ↑ QTc, extrasystole, dehydration, ↑ troponin, fever
Grade 3 DVT in 2 patients
No treatment-related deaths
Siegel D, et al. Blood. 2009;114(22). Abstract 305. Vorhees PM, et al. Blood. 2009;114(22). Abstract 306.
Novel Combinations of Approved Drugs
Greatly Expand the Therapeutic Options
for R/R Myeloma Patients!
• Approved drugs
– Novel combinations
– Modifications of dose and schedule
• Improve efficacy
• Better tolerability
• Many new drugs in development
– Similar targets
• Proteasome inhibitors- carfilzomib (FDA-approved!)
• IMiDs- pomalidomide
– New classes of agents
• HDAC inhibitors- vorinostat, panobinostat
• Monoclonal antibodies
– Anti-CS-1- elotuzumab
– Anti-CD40- dacetuzumab
• MTOR inhibitors- temsirolimus
• PI3K inhibitors- perifosine