Phase II study of pegylated liposomal
doxorubicin (PLD), low dose
dexamethasone (DEX) and lenalidomide
(LEN) in patients with newly diagnosed
(ND) multiple myeloma (MM).
Rachid Baz, Mohamad A. Hussein, Dan
Sullivan, Jyoti Raychaudhuri, Jose L.
Ochoa, Lisa Nardelli, Kara Kosakowski,
William Dalton and Melissa Alsina

Disclosures
Advisory Board:
Celgene Corporation
Research Support:
Celgene Corporation
Ortho Biotech

Background
LEN / low dose DEX is an active regimen for
patients with newly diagnosed MM.
ORR: 71%, VGPR+:40% as best responses
ORR: 70%, VGPR+:25% after 4 cycles
LEN / Low dose DEX was associated with
an improved 1 year survival compared to
LEN and High dose DEX
Rajkumar et al. Blood, 110(11), 2007, #74

Background
Phase I/II study of LEN, PLD and Dex in patients
with relapsed and refractory myeloma:
MTD of LEN 10 mg D1-21, PLD 40mg/m2 D1, and DEX
40 mg D1-4.
ORR: 75%, VGPR and better in 29% of patients.
Anticipated better tolerance of DdR in ND MM
than in relapsed / refractory setting
Less BM compromise
Baz R et al. Ann Oncol 2006

Treatment Plan
Planned full dose LEN in combination with
full dose PLD in the first 6 patients.
If well tolerated, proceed with phase II study
to evaluate the combination at standard
dose of LEN in combination with PLD and
DEX.

Endpoints
1. Primary endpoints

Overall response rate using International Myeloma
Working Group Response Definitions

Quality of response (% CR+VGPR) to induction Dd-R as
assessed using International Myeloma Working Group
Response Definitions per Appendix II
2. Secondary endpoints

Progression Free Survival to induction Dd-R followed by
maintenance therapy with lenalidomide and
dexamethasone

Overall Survival

Eligibility Criteria
1.
Previously untreated symptomatic multiple myeloma with
measurable paraprotein as per IMWG
2.
ECOG PS0-2, (PS 3 allowed if due to bone disease)
3.
Bilirubin < 3.0 and (ALT or AST) < 3 x ULN.
4.
Must have adequate bone marrow function:

Absolute neutrophil count > 1,000 cells/mm3 (1.0 x 10
9/L). Patients with
bone marrow >50% plasma cells are permitted to have a neutrophil
count of < 1,000 cells/mm3.

Platelets 50,000 cells/mm3. Patients with bone marrow >50% plasma
cells are permitted to have a Platelet count < 50, 000 cells/mm3
5.
Must have adequate renal function: Creatinine 2.5 mg/dL.
6.
Must have a 2-d echocardiogram indicating LVEF 50% within 42
days prior to first dose of study drug.
7.
Able to tolerate aspirin, LMWH or warfarin.

Treatment Plan
INDUCTION
MAINTENANCE:
PLD 40 mg/m2 IV D1
Len 25 mg PO D1-21
ND MM
Len 25 mg PO D1-21
Dex 40 mg PO Weekly
Dex 40 mg PO D1-4
Off study HDT
Repeat cycles every 28 days for 4-8
cycles
Aspirin 81 mg daily (LMWH or Warfarin if allergy / intolerant to ASA)
Fluoroquinolone and acyclovir prophylaxis recommended
G-CSF allowed at the discretion of the treating physician

Patient characteristics
Between 2/2008 and
Characteristic
N =29
8/2008, 31 patients
Age, median (range); years
64 (41-82)
were screened.
Gender, male
17 (58%)
Two patients were
IgG
16 (55%)
screen failures.
IgA
6 (21%)
Enrollment stopped
Light chain myeloma
6 (21%)
in 8/2008 for a
B2m, median (mg/L)
2.8 (1.5-9.5)
planned interim
analysis.
Bone Marrow Involvement (%), median
41
Cytogenetics, High risk
35%
ISS stage I, II, III
16 / 10 / 3
ECOG PS
8 / 18 / 3

Toxicity: Hematologic
No (%) of patients with worse grade toxicity
Grade 2
Grade 3
Grade 4
Grade 3 / 4
Neutropenia
1 (3%)
12 (41%)
6 (21%)
18 (62%)
Anemia
8 (27%)
6 (21%)
0
6 (21%)
Thrombocytopenia
5 (17%)
3 (10%)
1 (3%)
4 (13%)

Toxicity: Non hematologic
No (%) of patients with worse grade toxicity
Toxicity
GRADE 2
GRADE 3
GRADE 4
GRADE 3+4
Febrile neutropenia
0
2 (7%)
0
2 (7%)
Pneumonia
0
2 (7%)
1 (3%)
3 (10%)
Infections (other)
4 (13%)
4 (13%)
0
4 (13%)
Infections (all)
4 (13%)
8 (26%)
1 (3%)
9 (31%)
DVT/PE
0
1 (3%)
2 (7%)
3 (10%)
Fatigue
4 (13%)
9 (31%)
1 (3%)
10 (34%)
Fluid overload
3 (10%)
3 (10%)
0
3 (10%)
Anorexia
4 (13%)
1 (3%)
0
1 (3%)
PPE
2 (7%)
1 (3%)
0
1 (3%)
Hyperglycemia
1 (3%)
0
1 (3%)
1 (3%)
GI
7 (24%)
4 (13%)
0
4 (13%)
Neuropathy
1 (3%)
0
0
0

Responses: IMWG
Of the 29 treated patients, median 5 cycles:
1 was non evaluable
100%
90%
80%
PD
ORR: 71%
70%
SD
60%
PR
VGPR +: 50%
50%
VGPR
40%
30%
CR
20%
sCR
10%
0%
IMWG Response

Follow Up and Survival
No patient died during induction.
As of May 2009,
14 patients went off study to proceed with HDT
9 patients underwent HDT and 5 are in the process
of undergoing HDT
6 have went on maintenance lenalidomide and
dexamethasone therapy
7 have developed disease progression
2 were lost to follow up

Summary
The combination of Lenalidomide, PLD and
dexamethasone is an active combination with a
ORR of 71% and VGPR rate of 50% after 4 cycles
of therapy.
A high rate of severe fatigue (34%) and grade
neutropenia (62%) was noted.
The protocol was amended to reduce the dose of
PLD to 30 mg/m2 IV D1 in combination with
standard dose of lenalidomide (25 mg D1-21) and
low dose dexamethasone (40 mg D1-4).

Impact of PLD in combination with
LEN?
DdR
Rd
ORR after 4 cycles, %
71%
70%
VGPR and better after 4 cycles, %
50%
25%
Gr Neutropenia, %
62%
18%
Gr Fatigue, %
34%
14%
Gr All Infection, %
31%
14%
Too early to draw definitive conclusions regarding the role
of anthracyclines in combination with lenalidomide and
dexamethasone in newly diagnosed multiple myeloma.
Rajkumar et al. Blood, 110(11), 2007, #74

Acknowledgements
Co-Investigators:
Mohamad Hussein
Dan Sullivan
Jyoti Raychaudhuri
Jose L. Ochoa
William Dalton
Melissa Alsina
Research nurses and coordinators
Kara Kosakowski
Lisa Nardelli
Celgene Corporation and Ortho Biotech
The patients and their families