A Phase 1 Trial of Lenalidomide
(REVLIMID®) With Bortezomib
(VELCADE®) in Relapsed and Refractory
Multiple Myeloma
P.G. Richardson,1 R. Schlossman,1 N. Munshi,1 D. Avigan,2
S. Jagannath,3 M. Alsina,4 D. Doss,1 M. McKenney,1 K. Hande,1
M. Farrell,1 S. Gorelik,1 K. Colson,1 D. Warren,1 L. Lunde,1
R. Michelle,1 G. Cole,2 C. Mitsiades,1 T. Hideshima,1 T. Myers,5
R. Knight,6 and K. Anderson1
1Dana-Farber Cancer Institute, MA; 2Beth Israel Deaconess Medical Center, MA;
3St. Vincent's Cancer Center, NY; 4Moffitt Cancer Center, FL;
5Millennium Pharmaceuticals Inc., MA; 6Celgene Corporation, NJ
Author Disclosure Statement
Millennium Pharmaceuticals, Inc.
Research Support/P.I. Celgene, Inc.
Employee
N/A
Consultant
N/A
Major Stockholder
N/A
Speakers'
Millennium Pharmaceuticals, Inc.
Bureau/Advisory
Celgene, Inc.
Board
Presentation includes discussion of the following off-label use of a
drug: Lenalidomide in multiple myeloma
Bortezomib
Potent preclinical activity against multiple myeloma (MM) via
inhibition of NF-B, activation of caspases 3, 8, 91
Maximum tolerated dose (MTD) 1.3 mg/m2 twice wkly for 2 wks
followed by 1 wk of rest 2-4
Efficacious in phase 2 trials of relapsed and/or refractory MM:
SUMMIT,5 CREST6
Pivotal phase 3 randomized trial (APEX,7 n = 669)
­ Significant improvements in response rate (RR), time to
progression (TTP), survival compared with high-dose
dexamethasone (dex) in relapsed MM pts with 1­3 prior
therapies
In frontline trials in MM, RR 75%­95%, complete response
(CR)/near CR (nCR) 25%­31%8-10
1. Hideshima et al. Cancer Res. 2001.
6. Jagannath et al. Br J Haematol. 2004.
2. Orlowski et al. J Clin Oncol. 2002.
7. Richardson et al. N Engl J Med. 2005.
3. Aghajanian et al. Clin Cancer Res. 2002.
8. Harousseau et al. J Clin Oncol. 2005.
4. Papandreou et al. J Clin Oncol. 2004.
9. Jagannath et al. Br J Haematol. 2005.
5. Richardson et al. N Engl J Med. 2003.
10. Oakervee et al. Br J Haematol. 2005.
Lenalidomide
Potent preclinical activity against MM via caspase 8-dependent
apoptosis; T cell proliferation/stimulation, IL-2, IFN- production;
TNF & IL-1 inhibition1-4
Active, well tolerated in MM: responses with 50% M-protein
reduction in
­ 24%­40% of pts receiving lenalidomide ± dex, with relapsed and
relapsed/refractory MM, including prior thal and bortezomib5-7
2 pivotal phase 3 randomized trials with HD dex (MM-009, n=354,
010, n=351)
­ Significant improvement in RR (CR, PR),TTP vs HD dex alone in
relapsed MM pts with 1-3 prior therapies 8
In frontline with high dose dex, RR 91%, CR / nCR 38%9
1. Hideshima et al. Blood. 2000.
6. Zangari et al. Blood. 2003.
2. Davies et al. Blood. 2001.
7. Richardson et al. Blood. 2003.
3. Mitsiades et al. Blood. 2002.
8. Weber et al. Haematologica. 2005.
4. Lentzsch et al. Cancer Res. 2002.
9. Rajkumar et al. Blood. 2005.
5. Richardson et al. Blood. 2002.
Combination of Lenalidomide + Bortezomib
50
Pt Cells (bortezomib-resistant)
Lenalidomide
40
100
0 M
5 M
80
30
60
Growth, %
Cell Death, %
40
20
20
10
0
0
10
20
Bortezomib, nM
0

M
1M
1M
Len
Bz 3 n
Len
+ Bz 3 nM
Mitsiades et al. Blood. 2002.
Len = lenalidomide; Bz = bortezomib
Hideshima et al , unpublished data
Rationale
Lenalidomide sensitizes MM cells to bortezomib and
dex in preclinical studies1
Expected overlapping toxicities manageable
(primarily hematologic)2
In phase 1
­ MTD of lenalidomide 25 mg (PO daily, 28-day
cycle)2,3
­ MTD of bortezomib 1.3 mg/m2 (IV twice weekly,
21-day cycle)4-6
1.
Mitsiades et al. Blood. 2002.
2.
Richardson et al. Blood. 2002.
3.
Zangari et al. Blood. 2003.
4.
Orlowski et al. J Clin Oncol. 2002.
5.
Aghajanian et al. Clin Cancer Res. 2002.
6.
Papandreou et al. J Clin Oncol. 2004.
Objectives
Primary
­ Evaluate safety of combination in pts with
relapsed or relapsed/refractory MM
­ Identify MTD and recommended dose for phase 2
study
Secondary
­ Evaluate response
­ Assess PK
­ Explore pharmacogenomics/surrogate markers
Schema
Bortezomib, mg/m2
Lenalidomide, mg
5
10
15
20
1.0
Cohort 1
Cohort 3
Cohort 5
Cohort 7
1.3
Cohort 2
Cohort 4
Cohort 6
Cohort 8
· 8 cohorts of 3­6 pts, with additional 10 pts enrolled at the MTD
21-day cycle*
1 4 8 11
14 21
B
B
B
B
Lenalidomide daily
*For a maximum of 8 cycles; dex added (20 mg day of and day following bortezomib) for pts with
progressive disease (PD): extension phase for pts in response
Eligibility
Inclusion criteria
­ Relapsed or relapsed/refractory MM (at least
1 prior therapy)
­ Age 18 years
­ ECOG performance status 0­2
­ Prior thalidomide, lenalidomide, bortezomib
permitted
­ Women of childbearing potential: negative
pregnancy test
Eligibility
Exclusion criteria
­ Creatinine > 2 mg/dL
­ Concomitant corticosteroids, chemotherapy, or
radiation
­ Peripheral neuropathy (PN) grade 3 or grade 2
with pain
­ Platelets < 50,000 cells/mm3
­ ANC < 1,000 cells/mm3
­ Hgb < 8.0 g/dL
­ AST 2 × ULN
­ Intolerance to bortezomib or lenalidomide or
hypersensitivity to thalidomide
Evaluation
Response using EBMT criteria1 (after 2 cycles and
after every subsequent cycle)
Adverse events assessed using NCI CTC version 3.0
Dose-limiting toxicity (DLT)
­ Non-hematologic toxicity G 3
­ Thrombocytopenia with platelets < 10,000/mm3 on
more than 1 occasion despite transfusion support
­ Neutropenia occurring for more than 5 days
and/or resulting in neutropenic fever
MTD: dose level prior to that resulting in 2 DLTs
EBMT = European Group For Blood and Marrow Transplantation; NCI CTC = National Cancer Institute
Common Toxicity Criteria.
1. Bladé et al. Br J Haematol. 1998.
Results
Baseline Characteristics (N = 24)
Characteristic
Median age, y (range)
58 (37­79)
Male, %
54
Myeloma type, %
IgG
58
IgA
25
Durie-Salmon stage III, %
25
Disease status
Relapsed, n
10
Relapsed/refractory, n
14
Median no. of prior therapies (range)
4 (1­8)
Prior SCT, n (%)
16 (67)
Prior bortezomib, n (%)
12 (50)
Prior lenalidomide, n (%)
2 (8)
Prior thalidomide, n (%)
20 (83)
Disposition
Enrollment
N = 24
Evaluable for
21
response*
Cohort 1
3
Cohort 2
3
Cohort 3
4
Cohort 4
6
Cohort 5
5
Cohort 6
3
Cohort 7­8
0
*Confirmed at cycle 2 and at each subsequent cycle.
Adverse Events: Hematologic
Dose
Cohort
Bz (mg/m2)/
Cycle
Adverse Event
Len (mg)
1
1.0/5
3
G4 neutropenia* (ANC 420 in 1 pt)
2
1.3/5
2, 4
G3 thrombocytopenia (plats 32,000 in 2 pts)
3
1.0/10
1
G4 neutropenia* (ANC 300 in 1 pt)
G3 hyponatremia (Na 129 mmol/L in 1 pt)
4
1.3/10
1, 4
G4 thrombocytopenia (plats 19,000 in 1 pt)
G3 thrombocytopenia (plats 38,000 in 1 pt)
5
1.0/15
2, 6
G3 neutropenia (ANC 890 in 1 pt)
6
1.3/15
NA
NA
*Less than 5 days (not DLT). Determined to be drug related (DLT). NA = not available
Toxicity
No discontinuations
No significant PN or fatigue (> G3)
No thrombotic events
No DLT through first 3 cohorts
One DLT in cohort 4
­ G3 hyponatremia; G1 hyponatremia present at baseline
No DLT in cohort 5
One DLT in cohort 6
­ Delay in treatment 2ary to G2 HZV infection
MTD not yet reached, cohort 7 to open in January 06
Dose Reductions
Dose reductions in cohorts 2-5
­ 6 pts for bortezomib only (cycles 2-5)
­ 3 pts for both bortezomib (cycles 3-6) and lenalidomide (cycles 6-7)
Bortezomib dose reductions
· 1.3
1.0 mg/m2: thrombocytopenia (n = 1), neutropenia and
thrombocytopenia (n = 1), angioedema (n = 1), hyponatremia (n = 1)
· 1.3
1.0
0.7 mg/m2: hypotension (n = 1), fatigue (n = 1)
· 1.0
0.7 mg/m2 : thrombocytopenia (n = 3)
Lenalidomide dose reductions
· 15
10 mg: thrombocytopenia (n = 1)
· 10
5 mg: neutropenia (n = 1) and fatigue (n = 1)
Best Response (n=21)*
Bortezomib,
Response
# of
(n = 21)*
Cohort
Lenalidomide
Cycles
(mg/m2:mg)
CR
nCR
PR
MR
SD
PD
1
1.0
5
20­22
2
1
2
1.3
5
16­20
1
2
3
1.0
10
12­18
1
2
4
1.3
10
3­12
2
2
1
1
5
1.0
15
3­8
1
3
6
1.3
15
1­2
2
CR + nCR + PR + MR: 67%
CR=complete response, PR=partial response, MR = minor response; PD = progressive disease
* Evaluable patients, EBMT criteria
1 pt not evaluable
Dex added
Summary
Combination of lenalidomide and bortezomib well tolerated
­ One DLT in cohort 4, cohort 6
­ No DVT
­ No significant PN or fatigue
Active in heavily pretreated pts, including pts who received
either agent alone
­ 67% RR (CR + nCR + PR + MR)
­ Dex added in 3 pts ­ no added toxicity; PD in 1 pt, SD in
2 pts
Study ongoing to determine MTD
­ Additional 10 pts to be enrolled at MTD
Future Directions
Completion of PK, surrogate marker analysis
Phase 2 studies in relapsed and relapsed
refractory MM
Phase 2 study in newly diagnosed pts
"Steroid sparing" approach (lower dose dex)
Potential oral/IV regimens using lenalidomide
and bortezomib in combination with other
novel agents
Acknowledgments
Dana-Farber Cancer Institute
­ CRC nursing team
­ Research pharmacy
BIDMC, HCC
St. Vincent's Comprehensive Cancer Center
Moffitt Cancer Center
Millennium Pharmaceuticals, Inc.
Celgene Corporation
MMRF and IMF
The Patients and Their Families