Novel Agents and Regimens for
Relapsed and Refractory
Multiple Myeloma
Robert Z. Orlowski, M.D., Ph.D.
Director, Myeloma Section
Associate Professor of Lymphoma/Myeloma, and
Experimental Therapeutics; Division of Cancer Medicine
Faculty Disclosure
· Robert Z. Orlowski, MD, PhD, has
disclosed that he has received consulting
fees from Celgene, Cephalon, Janssen-
Cilag, Millennium, and Novartis.
Illustrative Case
· 49 yo M initially presented in 8/07 with a several-
month history of increasing back pain
· Plain radiography by primary physician showed three
thoracic vertebral compression fractures
· Additional studies revealed anemia (Hgb 9.5) and an
elevated total protein (11.2 g/dL; vs. albumin 3.3)
· Serum protein electrophoresis showed a 5.1 g/dL
IgG M-protein; BJP 235 mg of light chains; 2
microglobulin 5.6
· Bone marrow aspirate 56% plasma cells; CG with
del13, confirmed by FISH
Initial Therapy
· Underwent kyphoplasty and started bisphosphonates
· Received induction with four cycles of bortezomib,
lenalidomide, and dexamethasone (VRD), resulting
in a reduction of the M-protein to 1.1 g/dL; further
induction held due to grade 2 neuropathy
· Stem cells were harvested, and the patient received
high-dose melphalan (200 mg/m2), followed by
autologous stem cell rescue, resulting in a CR
· After a discussion of the risks and benefits, elected to
forgo maintenance therapy
Relapse
· Nine months after ASCT, immunofixation showed a
recurrent IgG M-protein
· Three months later, the patient developed worsening
fatigue and back pain, and radiography showed a
newly compressed vertebra
· Complete blood cell counting revealed new anemia
(Hgb 11.3), and also mild hypercalcemia (10.5),
despite continued bisphosphonate therapy
· Marrow aspiration showed 32% plasma cells, with
again del13 by CG and FISH, but no new
abnormalities *
You Would Recommend
1. Repeating VRD
2. Carfilzomib alone
3. Thalidomide-based regimen
4. Pomalidomide ± dexamethasone
5. Lenalidomide + dexamethasone + vorinostat
6. Carfilzomib with lenalidomide/dexamethasone
7. Lenalidomide + dexamethasone with elotuzumab
8. Bortezomib ± pegylated liposomal doxorubicin +
vorinostat
9. Cytotoxic chemotherapy combination, such as DT-
PACE or modified-CVAD
2010 Guidelines
· Repeat primary therapy (if relapse occurs at > 6
mos.)
· Bortezomib (cat. 1)
· Bortezomib/liposomal doxorubicin (1)
· Lenalidomide/dex (1)
· Bendamustine (2B)
· Bortezomib/dex
· Lenalidomide
· High-dose cyclophosphamide, or Cy-VAD
· Thalidomide, or thalidomide/dex
· Dex, or DCEP, or DT-PACE
NCCN Practice Guidelines. Multiple Myeloma. V.1.2011.
Bortezomib vs. Dex
78% improvement in median time to progression
1.0
Median TTP
All Pts
Post-1st relapse
0.9
Bortezomib
6.2 mos
7.0 mos
0.8
Dexamethasone
3.5 mos
5.6 mos
0.7
Patients
0.6
of
0.5
0.4
P = .0001
oportion
0.3
Pr
Bortezomib
0.2
0.1
Dexamethasone
0.0
0
30
60
90 120 150 180 210 240 270 300 330 360 390 420 450
Time (Days)
Richardson, PG et al. N. Engl. J. Med. 352:2487-2498, 2005.
Bortezomib/PLD vs. Bortezomib
00
PLD + Bortezomib
801
9.3 months
0
Progression-Free
Bortezomib
Patients
406
6.5 months
of
Percent
20
Statistical analysis:
HR (95% CI) 1.82 (1.41-2.35)
0
P = .000004
0
100
200
300
400
500
Time (Days)
Orlowski, RZ et al. J. Clin. Oncol. 25:3892-3901, 2007.
Bortezomib Combination Data
Regimen
Phase
n
CR + PR
CR + nCR
Reference
Bortezomib
3
333
43 %
16 %
Richardson PG, et al.
Blood 2007;110:3557-3560
+ Dex
3b
Mikhael JR, et al.
33 %
expanded
(after cycle 2 for PD or after cycle
638
51 %
access
Br J Haematol
(CR + VGPR )
4 for SD)
program
2009;144:169-175
+ Liposomal
3
324
52 %
17 %
Harousseau JL, et al. ASCO
doxorubicin
2007. Abstract 8002.
+ doxorubicin
Palumbo A, et al.
+ dexamethasone
2
64
67 %
25 %
Ann Oncol 2008;19:1160-
(PAD)
(CR + VGPR)
1165
+ intermediate-dose dex
Kropff M, et al.
+ cyclophosphamide
254
82 %
16 %
Br J Haematol
(VCD)
2007;138:330-337
+ melphalan
43 %
+ prednisone
1/2
30
67 %
Palumbo A, et al.
(includes
Blood 2007;109: 2767-2772
+ thalidomide (VMPT)
VGPR)
Lenalidomide/Dex vs. Dex
Survival benefit retained despite 47% cross-over
100
P = .015
80
(%)
Median 35 months
60
Len/Dex
40
Patients
(58% remain alive)
Placebo/Dex
Median 31 months
20
Overall Survival (Months)
0
0
10
20
30
40
50
Dimopoulos, MA et al. Leukemia 23:2147-2152, 2009.
Other Lenalidomide Combinations
Lenalidomide
Phase
n
CR + PR
CR + nCR
Reference
+ melphalan
Palumbo A,
+ prednisone
34 %
244
75 %
(VGPR +
Leukemia.
+ thalidomide
2010;24:1037-
CR)
1042.
(MPTR)
+ bortezomib
Anderson KC, et
+ dexamethasone
264
69%
26 %
al. ASCO 2009.
(VRD)
Abstract 8536.
87 %
+ cyclophosphamide
Reece DE, et al.
(including
NA
ASH 2008.
+ prednisone (RCP)
1/2
15
MR)
Abstract 1723.
Knop S, et al.
+ doxorubicin
15 %
Blood
+ dex (RAD)
1/2
69
73 %
(CR only)
2009;113:4137-
4143.
Upcoming Promising Approaches
· Novel single agents
Carfilzomib
Pomalidomide
· New combination regimens
Bortezomib + siltuximab /vorinostat /panobinostat /
tanespimycin /perifosine
Bortezomib/PLD + vorinostat
Carfilzomib + len/dex
Lenalidomide/dex + vorinostat /-CS-1/
thalidomide
2009 ASH Abstract 303
PX-171-004, An Ongoing Open-Label, Phase II Study
of Single-Agent Carfilzomib (CFZ) in Patients With
Relapsed or Refractory Myeloma (MM); Updated
Results From the Bortezomib-Treated Cohort
Siegel D, Wang L, Orlowski RZ, Kaufman JL, Stewart AK, Kukreti
V, Alsina M, Jakubowiak AJ, Jagannath S, McDonagh KT, Belch A,
Bahlis NJ, Shustik C, Le MH, Kunkel L, Bennett MK, Kauffman M,
Vij R, and The Multiple Myeloma Research Consortium (MMRC)
Prior Therapies & Refractory Status
Siegel D, et al. ASH 2009. Abstract 303.
Patient Characteristics
Vij R, et al. ASCO 2010. Abstract 8000.
Responses
Siegel D, et al. ASH 2009. Abstract 303.
Outcomes
Vij R, et al. ASCO 2010. Abstract 8000.
Time to Progression
Siegel D, et al. ASH 2009. Abstract 303.
Vij R, et al. ASCO 2010. Abstract 8000.
Adverse Events
Siegel D, et al. ASH 2009. Abstract 303.
Vij R, et al. ASCO 2010. Abstract 8000.
Neuropathy
Siegel D, et al. ASH 2009. Abstract 303.
Vij R, et al. ASCO 2010. Abstract 8000.
2009 ASH Abstract 301
A Phase 1/2 Multi-Center, Randomized, Open Label
Dose Escalation Study to Determine the Maximum
Tolerated Dose, Safety, and Efficacy of Pomalidomide
Alone or in Combination With Low-Dose
Dexamethasone in Patients With Relapsed and
Refractory Multiple Myeloma Who Have Received Prior
Treatment That Includes Lenalidomide and Bortezomib
Richardson R, Siegel D, Baz R, Kelley SL, Munshi NC, Sullivan D,
McBride L, Doss D, Larkins G, Jacques C, Donaldson A, and
Anderson KC
Study Design
Phase 1 (MTD)
Dose
Discontinue
2 mg
POM therapy
Progressive disease (PD)
Option to add
and follow-up
PD
(QD on days 1-21 of
for survival
3 mg
low-dose dex
or no response after
and
a 28-day cycle)
(40 mg/wk)
4 mg
completion of 4 cycles
subsequent
treatment
5 mg
Phase 2 (Open Label)
Arm A
PD
Discontinue
and follow-up
TION
POM (4 mg)
+ low-dose dex
for survival
and
subsequent
treatment
PD
Option to add
Arm B
low-dose dex
RANDOMIZA
POM (4 mg)
(40 mg/wk)
Richardson P, et al. ASH 2009. Abstract 301.
Safety Profile
POM Dose
2 mg
3 mg
4 mg
5 mg
Adverse event, n
(n = 6)
(n = 8)
(n = 8)
(n = 10)
Neutropeniaa
88
7
9
Thrombocytopeniaa
26
0
0
Anemiaa
27
2
0
VTE
1 (G2)
0
0
1 (G3)
Treatment-emergent SAEs
7
7
4
4
Deathsb
21
1
0
POM dose reduction
0
1
0
9
SAEs, severe adverse events; VTE, venous thromboembolism.
a. Grade 3/4; b. Includes deaths occurring at least 28d after last treatment (both due to rapid PD).
Richardson P, et al. ASH 2009. Abstract 301.
Best Responses
POM Dose
Best Responsea[1]
(± Dex)
2 mg (n = 6)
1 PR, 1 SD, 1 PD, 3 NE
3 mg (n = 8)
1 CR, 1 MR, 5 SD, 1 NE
4 mg (n = 8)
2 PR, 3 MR, 1 SD, 2 NE
5 mg (n = 10)
3 PR, 2 MR, 3 SD, 1 PD, 1 NE
CR, complete response; MR, minimal response; NE, not evaluable; PD, progressive disease;
PR, partial response; SD, stable disease. a. As measured using modified EBMT criteria[2,3] every 28d.
· 7/25 evaluable pts (28%) PR; 13/25 pts (52%) MR[4]
· 15 pts received dex in addition to POM for either lack of
response or PD; 8/15 pts (53%) improved response after dex
added, with durability of response also improved from 13.5 to
16.9 wks[1]
1. Richardson P, et al. ASH 2009. Abstract 301. 2. Bladé J, et al. Br J Haematol. 1998;102:1115-1123. 3.
Richardson PG, et al. N Engl J Med. 2003;348:2609-2617. 4. Anderson KC, et al. Leukemia. 2008;22:231-239.
2009 ASH Abstract 306
Vorinostat in Combination With Pegylated
Liposomal Doxorubicin and Bortezomib for Patients
With Relapsed/Refractory Multiple Myeloma:
Results of a Phase I Study
Voorhees PM , Gasparetto C, Richards KL, Garcia R, Strader JS,
Ferraro M, MacLean J, Winans D, Moore DT, Dodd A, Foster MC,
Gabriel DA, Shea TC, Serody J, van Deventer HW, Rizvi S,
Orlowski RZ, and Hurd DD
Study Design
· Multi-center phase I trial targeting relapsed
and/or refractory myeloma
Dose
Vorinostat*
Level
D 4-11
AEN1
Vorinostat
1
200 mg
Day 14
811
21
2
300 mg
21-day cycle
= PLD 30 mg/m2 D 4
3
400 mg
= Bortezomib 1.3 mg/m2 D 1, 4, 8, 11
* Vorinostat dosed 2 hours prior to PLD
Voorhees PM, et al. ASH 2009. Abstract 306.
Slide 31
AEN1
no corresponding dagger. ok?
Andrea Neal, 12/2/2010
Response Rate
· ORR 78% (7/8); 1 non-responder in cohort 1
Dose Level
Response
(# evaluable pts)
1 (N=3)
2 PRs, 1 PD
2 (N=3)
1 CR, 1 VGPR, 1 PR
3 (N=2)
2 VGPRs
Disease refractory to prior bortezomib-based therapy and VAD
2 VGPRs with unmeasurable disease by SFix and UFix awaiting bone marrow
confirmation of response depth
Voorhees PM, et al. ASH 2009. Abstract 306.
2008 ASH Abstract 867
Preliminary Results of CNTO 328 (Siltuximab), an
Anti-Interleukin-6 Monoclonal Antibody, in
Combination With Bortezomib in the Treatment of
Relapsed or Refractory Multiple Myeloma
Rossi J-F, Manges RF, Sutherland HJ, Jagannath S, Voorhees P,
Sonneveld P, Delforge M, Pegourie B, Alegre A, de la Rubia J,
La Police D, Bandekar R, Xie H, and Orlowski RZ
C0328T06 Study Design
R
A
INDUCTION: Bortezomib @ 1.3 mg/m2 on days
N
1, 4, 8, 11, 22, 25, 29, 32 every 42 days for up to 4
D
cycles
O
M
290 patients with
Maintenance phase after induction
I
relapsed and/or
Dexamethasone added at
Z
refractory myeloma
progression
A
T
INDUCTION: Bortezomib as above + CNTO 328
I
@ 6 mg/kg on days 1, 15, and 29 for up to 4 cycles
O
N
Primary endpoint: PFS
Secondary: OS, ORR, safety, PK, PD
Rossi JF, et al. ASH 2008. Abstract 867.
Responses
· Responses by EBMT criteria seen in 57%
CR or PR: 12 pts (3 with CR, 9 with PR)
· Median TTP: 8.7 months
Range 1.2-22.4
· Randomized comparison of bortezomib
versus CNTO 328 + bortezomib underway
Accrual completed
Rossi JF, et al. ASH 2008. Abstract 867.
2009 ASH Abstract 304
Phase Ib Multicenter Dose Escalation Study of
Carfilzomib Plus Lenalidomide and Low-Dose
Dexamethasone (CRd) in Relapsed and Refractory
Multiple Myeloma (MM)
Niesvizky R, Wang L, Orlowski RZ, Bensinger W, Alsina M,
Gabrail N, Gutierrez A, Kunkel L, Kauffman M and The Multiple
Myeloma Research Consortium (MMRC)8
Study Design
· Multi-center phase Ib study
· Patients with 1-3 prior lines of therapy and
relapsed multiple myeloma
· Cycles q 28 days
Niesvizky R, et al. ASH 2009. Abstract 304.
Prior Therapies
Niesvizky R, et al. ASH 2009. Abstract 304.
Adverse Events
· No DLTs or
grade 5
toxicities
through first 5
cohorts (N =
27)
· No fatigue
grade 3 or
thrombotic
events
Niesvizky R, et al. ASH 2009. Abstract 304.
Activity
· All responses seen at <MTD; 29/32 pts evaluable
· Cohort 6 will use carfilzomib at 27 mg/m2 in cycle 2
Niesvizky R, et al. ASH 2009. Abstract 304.
2009 ASH Abstract 305
Combined Vorinostat, Lenalidomide and
Dexamethasone Therapy in Patients With Relapsed or
Refractory Multiple Myeloma: A Phase I Study
Siegel D, Weber DM, Mitsiades CS, Dimopoulos MA, Harousseau
J-L, Rizvi S, Howe J, Reiser D, Byrne C, Anderson KC, and
Richardson P
Study Design
Multicenter, open-label, non-randomized, Phase I, dose-
escalation study
in patients with relapsed/refractory MM
Dose level
Dosing regimen
Vorinostat (mg qd)
Lenalidomide (mg qd)
Dexamethasone (mg qd)
7 days on, 7 days off
x 21 days
(Days 1-7 and Days 15-21)
(Days 1-21)
(Days 1, 8, 15, and 22)
in each 28-day cycle
in each 28-day cycle
in each 28-day cycle
1
300
10
40
2
400
10
40
3
400
15
40
4
400
20
40
5
400
25
40
Siegel D, et al. ASH 2009. Abstract 305.
Study Dosing
Richardson PG, et al. ASCO 2010. Abstract 8031.
Response in Evaluable Patients
Patients
n=11
(n=28;
%)
n=6
n=5
n=4
n=2
CR
PR
MR
SD
PD
Best overall single response rate (CR+PR): 46%
(13/28)
Siegel D, et al. ASH 2009. Abstract 305.
Response in Evaluable Patients
Patients
(n=30;
%)
Best overall single response rate (CR+PR): 53%
(16/30)
*Includes 2 CR + 2 VGPR.
Richardson PG, et al. ASCO 2010. Abstract 8031.
Response if Prior Lenalidomide
Non-refractory patients (n=6)
Refractory* patients (n=6)
Patients
(n=3)
(n=3)
(%)
(n=2)
(n=1)
(n=1)
(n=1) (n=1)
00
CR
PR
MR
SD
PD
Response rate (non-refractory; CR+PR): 50% (3/6)
Response rate (refractory; CR+PR): 17% (1/6)
Response rate (refractory; CR+PR+MR+SD): 50% (3/6)
*Lenalidomide refractory: no response to prior lenalidomide-containing regimens or progression on or 60
days of receiving lenalidomide-containing regimen, or relapsed, refractory, intolerant, and/or ineligible for
other therapies, including bortezomib.
Siegel D, et al. ASH 2009. Abstract 305.
Response if Prior Lenalidomide
Patients
(n=13;
%)
MR or better in nonrefractory patients: 57.1% (4/7)
MR or better in refractory* patients: 33.3% (2/6)
*Defined as no response on or progression within 60 days of receiving lenalidomide-containing
regimen, or relapsed, refractory, intolerant, and/or ineligible for other therapies, including bortezomib.
Richardson PG, et al. ASCO 2010. Abstract 8031.
2009 ASH Abstract 432
Phase 1/2 Study of Elotuzumab in Combination With
Lenalidomide and Low Dose Dexamethasone in
Relapsed or Refractory Multiple Myeloma:
Interim Results
Lonial S, Vij R, Harousseau J-L, Facon T, Kaufman J, Mazumder
A, Moreau P, Leleu X, Fry J, Singhal A, and Jagannath S
Lonial S, et al. ASCO 2010. Abstract 8020.
Response Rate
Total Patients
Patients w/o Prior
(%)
Lenalidomide
Total treated population (1 dose)
28
22
ORR (PR; IMWG criteria)
23 (82%)
21 (95%)
VGPR
5 (18%)
5 (23%)
PR
18 (64%)
16 (73%)
SD
4 (14%)
1 (4%)
PD
00
NE
1 (4%)
0
Lonial S, et al. ASH 2009. Abstract 432.
Response Rate: Phase Ib
Lonial S, et al. ASCO 2010. Abstract 8020.
Lenalidomide/Thalidomide/Dex
Lenalidomide Thalidomide
Dexamethasone
(Days 1-21)
(Days 1-28)
(c1, 2: Days 1-4, 9-12, 17-20; c3+: Days 1-4)
Dose level 1
15 mg
100 mg
40 mg
Dose level 2
25 mg
100 mg
40 mg
Dose level 3
25 mg
200 mg
40 mg
Cohort
Patients enrolled
DLT
1
30
2
6
Steroid-induced
3
9
1: G3 Rash; 1: G3 Hypertension
Shah, JJ et al. ASH 2010. Abstract 1948.
RTD : Efficacy
· Based on studies of the
mechanisms of resistance 100%
ORR
90%
CR or VGPR
92%
to lenalidomide
80%
CR or nCR
70%
· Phase I portion
60%
50%
completed
40%
38%
30%
· Predictable side effects
20%
10%
· Evidence of anti-
15%
0%
myeloma efficacy
Response Rates (%)
Shah, JJ et al. ASH 2010. Abstract 1948.
Targeting Kinesin Spindle Protein
· Inhibiting KSP stops myeloma cell
division, causing apoptosis
· Phase I ARRY520: well tolerated
No neuropathy signal
Cytopenias and GI effects
· In phase I, two patients with PRs,
several with MRs and SD
· Phase II portion started
Shah, JJ et al. ASH 2010. Abstract 1959.
Patient Outcome
· Started CRd
and achieved
Len/Thal/
Carfilzomib/Len/Dex
Dex
CR
Bortezomib/Len/
Dex
· Disease
progressed
on CRd after
ASCT
6 months
·Started RTD
Shah, JJ et al. Personal communication, 2010.
Novel Agents and Regimens for
Relapsed and Refractory
Multiple Myeloma: Summary
Robert Z. Orlowski, M.D., Ph.D.
Director, Myeloma Section
Associate Professor of Lymphoma/Myeloma, and
Experimental Therapeutics; Division of Cancer Medicine
Relapsed/Refractory Therapy
· RDex and VDox are the standards of care in
this setting
How well do they work with prior R and V?
· Novel single agents, such as carfilzomib
and pomalidomide
Combine well with other agents
· New combinations, such as with siltuximab,
elotuzumab, vorinostat
Other Options
· "Novel-er" agents on the way as well
ARRY520
· Add old agents that are new again to prior
active regimens
Cyclophosphamide
· Mix and match agents that had been used in
different combinations
If had RD, VD RVD
If had RD, TD RTD
Impact of Novel Agents at Relapse
1.0
Relapsed before 1998
Relapsed 19981999
0.8
Relapsed 20002001
Relapsed 20022003
Relapsed 20042005
0.6
0.4
Survival
0.2
P<0.001
0.0
0
20
40
60
80
100
Time From After ASCT Relapse (Months)
Kumar, S et al. Blood 111:2516-2520, 2008.