A PHASE 3, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY TO COMPARE THE EFFICACY AND SAFETY OF POMALIDOMIDE, BORTEZOMIB AND LOW-DOSE DEXAMETHASONE VERSUS BORTEZOMIB AND LOW-DOSE DEXAMETHASONE IN SUBJECTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA

Multiple myeloma (MM) is a rare and incurable progressive neoplastic disease
that accounts for 10% of all hematological malignancies. It was estimated in
2010 that 20,180 new cases and 10,650 deaths from the disease occurred in the
United States (US) (Jemal, 2010).
Significant progress has been made in the treatment of newly diagnosed MM with
different combinations of melphalan, prednisone, dexamethasone, doxorubicin,
thalidomide, lenalidomide and proteasome inhibitors (bortezomib) or autologous
stem cell transplant following high-dose chemotherapy in appropriate patients
(National Comprehensive Cancer Network [NCCN] Clinical Practice Guidelines in
Oncology for MM, 2012; Child, 2003; Fermand, 2005). In recent years, innovative
therapies such as proteasome inhibitors and immunomodulators have improved the
prognosis for previously treated MM subjects (Kumar, 2008). However, the
disease follows a relapsing course in the majority of patients, regardless of
treatment regimen or initial response to treatment. MM remains incurable using
conventional treatments, with median survival duration of approximately 5 years
(Richardson, 2007a). Therefore, there is a need for more effective therapeutic
options for the treatment of relapsed or refractory multiple myeloma.

Study Objectives
To compare the efficacy of POM + BTZ + LD-DEX with BTZ + LD-DEX in subjects
with relapsed or refractory MM
Secondary Objectives:
To evaluate the safety and additional efficacy of POM + BTZ + LD-DEX versus BTZ
+ LD-DEX in subjects with relapsed or refractory MM.
Exploratory Objectives:
• To explore the pharmacokinetics of pomalidomide and the relationship between
drug exposure and response (pharmacodynamic effects, safety and/or efficacy as
appropriate) in subjects with relapsed or refractory MM treated with
pomalidomide
• To evaluate the differences in pharmacoeconomics of POM + BTZ + LD-DEX versus
BTZ + LD-DEX in subjects with relapsed or refractory MM
• To evaluate the differences in clinical benefits of POM + BTZ + LD-DEX versus
BTZ + LD-DEX in subjects with relapsed or refractory MM
• To evaluate the differences in key efficacy variables of POM + BTZ + LD-DEX
versus BTZ + LD-DEX within defined subgroups
• To evaluate the differences in health-related quality of life of POM + BTZ +
LD-DEX versus BTZ + LD-DEX in subjects with relapsed or refractory MM
• To evaluate Minimal Residual Disease (MRD), genomic, molecular/mechanistic
and immune biomarkers and their correlation to clinical outcome measures for
only those subjects who give their consent (Optional)

This study is a multicenter, randomized, open-label, phase 3 study comparing
the efficacy and safety of POM + BTZ + LD-DEX (Treatment Arm A) versus BTZ +
LD-DEX (Treatment Arm B) in subjects with relapsed or refractory MM.

There are two different treatments that will be compared in this study.
The first study treatment (treatment A) will be a combination of pomalidomide,
bortezomib, and dexamethasone and the second (treatment B) a combination of
bortezomib and dexamethasone.
Subjects will receive the study treatment in cycles; each cycle will be 21 days
long. The first cycle will start when subjects take their first dose of study
treatment (Cycle 1 Day 1).
The study will last for 5 years.

1. POTENTIAL BENEFITS
This is a Phase 3, Multicenter, Randomized, Open-label Study to Compare the
Efficacy and Safety of Pomalidomide (POM), Bortezomib (BTZ) and Low-Dose
Dexamethasone (LD-DEX) (Treatment Arm A) versus Bortezomib and Low-Dose
Dexamethasone (Treatment Arm B) in Subjects with Relapsed or Refractory
Multiple Myeloma (MM).
The objectives for this study are as follows: To compare the efficacy of POM +
BTZ + LD-DEX with BTZ + LD-DEX in subjects with relapsed or refractory MM and
To evaluate the safety and additional efficacy of POM + BTZ + LD-DEX versus BTZ
+ LD-DEX in subjects with relapsed or refractory MM.
For Treatment Arm A (POM + BTZ + DEX), the dose was based on the results from
the CC-4047-MM-005 (MM-005) Phase 1 dose escalation MTD study in which
bortezomib was administered via IV infusion. In the MM-005 study, the maximum
planned dose (MPD), POM (4 mg) + IV BTZ (1.3 mg /m2) and DEX (20 mg subjects <=
75 years old/10 mg subjects > 75 years old) was reached without any DLTs.
Considering an early POM single agent MTD study (Richardson, 2013) as well as
the findings in MM-005, the MPD was determined to be the optimal dose for the
triple combination therapy. With the optimal dose determined, MM-007 was
initiated using the MPD dose for the combination of POM + BTZ + LD-DEX (with IV
BTZ).
During the conduct of the MM-005 study, subcutaneous (SQ) BTZ was approved as
an alternative administration method for BTZ (23 Jan 2013). The SQ BTZ was
reported to have a decreased incidence of neurotoxicity versus the IV BTZ
(Velcade® Prescribing Information, 2014). To explore the SQ route of BTZ
administration in combination with POM and DEX, the MM-005 protocol was amended
to add a cohort of 6 subjects at the MPD/optimal dose for the combination of
POM + BTZ + LD-DEX with BTZ administered via SQ injection. Based on the safety,
efficacy and PK data for this SQ BTZ cohort and general adoption in medical
practice of SQ BTZ as standard of care due to decreased neurotoxicity, BTZ
administration is now to be SQ for both arms in the MM-007 study (Treatment Arm
A and B). Subjects consented to the original MM-007 protocol can continue with
IV BTZ or switch to SQ BTZ at the discretion of the treating physician.
Subjects randomized into MM-007 under IV BTZ treatment will not be replaced.
Multiple myeloma (MM) is a rare and incurable progressive neoplastic disease
that accounts for 10% of all hematological malignancies. It was estimated in
2010 that 20,180 new cases and 10,650 deaths from the disease occurred in the
United States (US) (Jemal, 2010).
Significant progress has been made in the treatment of newly diagnosed MM with
different combinations of melphalan, prednisone, dexamethasone, doxorubicin,
thalidomide, lenalidomide and proteasome inhibitors (bortezomib) or autologous
stem cell transplant following high-dose chemotherapy in appropriate patients
(National Comprehensive Cancer Network [NCCN] Clinical Practice Guidelines in
Oncology for MM, 2012; Child, 2003; Fermand, 2005). In recent years, innovative
therapies such as proteasome inhibitors and immunomodulators have improved the
prognosis for previously treated MM subjects (Kumar, 2008). However, the
disease follows a relapsing course in the majority of patients, regardless of
treatment regimen or initial response to treatment. MM remains incurable using
conventional treatments, with median survival duration of approximately 5 years
(Richardson, 2007a). Therefore, there is a need for more effective therapeutic
options for the treatment of relapsed or refractory multiple myeloma.
The treatment options approved for use in relapsed and/or refractory MM
currently include: Lenalidomide in combination with dexamethasone for the
treatment of patients with MM who have received at least one prior therapy
(Bortezomib monotherapy for the treatment of patients with relapsed MM,
Pegylated liposomal doxorubicin (PLD) in combination with bortezomib for the
treatment of patients with MM who have not previously received bortezomib and
have received at least one prior therapy. Carfilzomib for the treatment of
multiple myeloma in patients who have received at least 2 prior therapies
including bortezomib and an immunomodulatory agent and have demonstrated
disease progression on or within 60 days of completion of the last therapy.
Pomalidomide for the treatment of multiple myeloma in patients who have
received at least 2 prior therapies including lenalidomide and bortezomib and
have demonstrated disease progression on or within 60 days of completion of the
last therapy. Other options that may be considered for salvage therapy in MM
patients include thalidomide alone or in combination with dexamethasone or
other agents, lenalidomide monotherapy, lenalidomide in combination with
bortezomib and dexamethasone, or lenalidomide or bortezomib in combination with
cyclophosphamide and dexamethasone (NCCN Clinical Practice Guidelines in
Oncology for Multiple Myeloma, 2012).
Bortezomib (Velcade®) was approved for the treatment of relapsed or refractory
MM based on the results of a Phase 3 trial (APEX Trial) comparing bortezomib to
high dose dexamethasone as salvage therapy. In an updated efficacy analysis of
the APEX trial, the response rate was 43% with bortezomib vs. 18% for
dexamethasone and the overall survival (OS) was 30 months with bortezomib vs.
23.7 months with dexamethasone (Richardson, 2007c).
The benefits of the adding dexamethasone to bortezomib therapy were shown in
the SUMMIT trial in which 202 relapsed or refractory MM subjects were enrolled
(Richardson, 2003). In this phase 2 study, patients received 1.3 mg/m2 of
bortezomib for up to eight cycles. In patients with a suboptimal response, oral
dexamethasone (20 mg daily, on the day of and the day after bortezomib
administration) was added to the regimen. Seventy-eight patients who had either
stable or progressive disease (PD) while receiving bortezomib alone
subsequently received dexamethasone in combination with bortezomib. Of these
76, a total of 74 patients could be evaluated for a response to this
combination, and 13 of these patients (18 percent) had a minimal or partial
response. In 6 of these 13 patients, the disease had previously been refractory
to corticosteroid therapy. Bortezomib in combination with dexamethasone is
therefore included in the NCCN clinical practice guidelines as a category 2A
recommendation for salvage therapy in MM patients (NCCN Clinical Practice
Guidelines in Oncology for MM, 2012).
The most recent approval of Doxil® (doxorubicin HCl) in combination with
bortezomib has led to more treatment options for relapsed or refractory MM. The
approval of this regimen was based on a Phase 3 study in 646 patients showing a
significant increase in median time to disease progression in Doxil plus
bortezomib arm compared to bortezomib monotherapy arm (9.3 vs. 6.5 months,
respectively). Starting from the 2010 NCCN clinical practice guidelines for
Multiple Myeloma, this combination was recommended as superior over bortezomib
monotherapy for relapsed / refractory MM. However, no data were submitted in
support of the conventional treatments, with median survival duration of
approximately 5 years (
Richardson, 2007a). Therefore, there is a need for more effective therapeutic
options for the treatment of relapsed or refractory multiple myeloma.
The treatment options approved for use in relapsed and/or refractory MM
currently include: Lenalidomide in combination with dexamethasone for the
treatment of patients with MM who have received at least one prior therapy
(Bortezomib monotherapy for the treatment of patients with relapsed MM,
Pegylated liposomal doxorubicin (PLD) in combination with bortezomib for the
treatment of patients with MM who have not previously received bortezomib and
have received at least one prior therapy. Carfilzomib for the treatment of
multiple myeloma in patients who have received at least 2 prior therapies
including bortezomib and an immunomodulatory agent and have demonstrated
disease progression on or within 60 days of completion of the last therapy.
Pomalidomide for the treatment of multiple myeloma in patients who have
received at least 2 prior therapies including lenalidomide and bortezomib and
have demonstrated disease progression on or within 60 days of completion of the
last therapy. Other options that may be considered for salvage therapy in MM
patients include thalidomide alone or in combination with dexamethasone or
other agents, lenalidomide monotherapy, lenalidomide in combination with
bortezomib and dexamethasone, or lenalidomide or bortezomib in combination with
cyclophosphamide and dexamethasone (NCCN Clinical Practice Guidelines in
Oncology for Multiple Myeloma, 2012).
Bortezomib (Velcade®) was approved for the treatment of relapsed or refractory
MM based on the results of a Phase 3 trial (APEX Trial) comparing bortezomib to
high dose dexamethasone as salvage therapy. In an updated efficacy analysis of
the APEX trial, the response rate was 43% with bortezomib vs. 18% for
dexamethasone and the overall survival (OS) was 30 months with bortezomib vs.
23.7 months with dexamethasone (Richardson, 2007c).
The benefits of the adding dexamethasone to bortezomib therapy were shown in
the SUMMIT trial in which 202 relapsed or refractory MM subjects were enrolled
(Richardson, 2003). In this phase 2 study, patients received 1.3 mg/m2 of
bortezomib for up to eight cycles. In patients with a suboptimal response, oral
dexamethasone (20 mg daily, on the day of and the day after bortezomib
administration) was added to the regimen. Seventy-eight patients who had either
stable or progressive disease (PD) while receiving bortezomib alone
subsequently received dexamethasone in combination with bortezomib. Of these
76, a total of 74 patients could be evaluated for a response to this
combination, and 13 of these patients (18 percent) had a minimal or partial
response. In 6 of these 13 patients, the disease had previously been refractory
to corticosteroid therapy. Bortezomib in combination with dexamethasone is
therefore included in the NCCN clinical practice guidelines as a category 2A
recommendation for salvage therapy in MM patients (NCCN Clinical Practice
Guidelines in Oncology for MM, 2012).
The most recent approval of Doxil® (doxorubicin HCl) in combination with
bortezomib has led to more treatment options for relapsed or refractory MM. The
approval of this regimen was based on a Phase 3 study in 646 patients showing a
significant increase in median time to disease progression in Doxil plus
bortezomib arm compared to bortezomib monotherapy arm (9.3 vs. 6.5 months,
respectively). Starting from the 2010 NCCN clinical practice guidelines for
Multiple Myeloma, this combination was recommended as superior over bortezomib
monotherapy for relapsed / refractory MM. However, no data were submitted in
support of the effectiveness of this combination treatment in patients who had
received bortezomib previously (Orlowski, 2007).
Pomalidomide, [4-amino-2-(2, 6-dioxopiperidin-3-yl) isoindoline-1], 3-dione, is
a novel drug in the class of immunomodulatory drugs (IMiDs®), which include
thalidomide and lenalidomide. IMiDs may affect the immune system in several
ways, such as inducing immune responses, enhancing activity of immune cells,
altering and modulating the induction of pro- and anti-inflammatory cytokines,
and inhibiting inflammation. Pomalidomide binds to its molecular target
cereblon, a protein that is part of an E3 ubiquitin ligase complex, which is
responsible for the polyubiquitination of substrate proteins, targeting them
for subcellular redistribution and destruction by the proteasome. IMiDs are
also anti-angiogenic. Although their precise mechanism of action is currently
under investigation, these agents offer promise for their anticancer and
anti-inflammatory activities. In addition to its anti-tumor, immunomodulatory
and anti-fibrotic properties, pomalidomide also affects the regulation of fetal
hemoglobin expression by erythroid precursors in healthy adults as well as
adults with sickle cell disease (SCD), making it a potential therapeutic agent
for the treatment of nonmalignant hematologic disorders such as SCD and β-
thalassemia. The pharmacologic properties of pomalidomide are of potential
therapeutic benefit in the treatment of hematologic neoplasms, such as multiple
myeloma (MM) and myelofibrosis (MF), non-oncologic hematologic disorders, such
as SCD, non-neoplastic non-hematologic disorders, such as systemic sclerosis
(SSC), as well as solid tumor neoplasms, such as soft tissue sarcoma and lung
cancer.
Pomalidomide was first approved for marketing in the US under the trade name
Pomalyst® on 08 Feb 2013, for the treatment of patients with MM who have
received at least two prior therapies including lenalidomide and bortezomib and
have demonstrated disease progression on or within 60 days of completion of the
last therapy. Pomalidomide was approved within the EU (Imnovid®, originally
Pomalidomide Celgene®) on 05 Aug 2013 in combination with dexamethasone for the
treatment of adult patients with relapsed and refractory multiple myeloma who
have received at least two prior treatment regimens, including both
lenalidomide and bortezomib, and have demonstrated disease progression on the
last therapy. Most recently, pomalidomide was approved in Canada (Pomalyst*) on
20 Jan 2014 in combination with dexamethasone for patients with MM for whom
both bortezomib and lenalidomide have failed and who have received at least two
prior treatment regimens and have demonstrated disease progression on the last
regimen.
Pomalidomide is formulated for oral administration in clinical studies as 0.5
mg, 1 mg, 2 mg, 3 mg, 4 mg and 5 mg gelatin capsules. In ongoing
Celgene-sponsored studies, pomalidomide has been administered in doses ranging
from 0.5 to 4 mg once daily generally on a cyclical regimen (eg, days 1-21 of a
28-day cycle) in hematology/oncology clinical studies.

2. POTENTIAL RISKS AND PRECAUTIONS
The safety profile of pomalidomide appears to have some similarity to that of
thalidomide and lenalidomide. However, with Pomalidomide*s human exposure to
date, true similarities and differences have not been fully elucidated,
therefore, due vigilance must be exercised in monitoring subjects for safety.
Individual subject care should be optimized, and every precaution undertaken to
ensure careful medical monitoring. To this end, it is expected that centers
participating in studies will be able to provide a high standard of clinical
care as well as conduct clinical research in accordance with Good Clinical
Practice (GCP).
As expected, based on the preclinical experience of pomalidomide, the common
adverse events associated with the use of pomalidomide were related to the
blood and lymphatic system, namely, neutropenia and thrombocytopenia. These AEs
can be dose limiting toxicities that should be managed through dose
adjustments, clinical and laboratory monitoring, and the use of hematopoietic
growth factors as required. Other adverse events observed with pomalidomide and
also associated with other immunomodulatory agents (ie, IMiDs compounds) have
included infection, fatigue, renal failure, neuropathy, venous thromboembolic
events, and constipation.
In the 9-month toxicity study in monkeys (Report CC-4047-TOX-006), pomalidomide
was administered at doses of 0.05, 0.1, and 1 mg/kg/day.
Pomalidomide-associated morbidity and early euthanasia (3/sex) were observed in
the 1 mg/kg/day group, and were attributed to immunomodulation/
immunosuppression (decreased peripheral lymphocytes, histologic lymphoid
depletion, and hypocellularity of bone marrow), effects associated with the
pharmacology of pomalidomide. These immunosuppressive effects were associated
with staphylococcal infection and chronic inflammation of the large intestine.
Villous atrophy of the small intestine and minimal and mild bile duct
proliferation were also present. In addition, findings consistent with AML were
observed in 1 of these females that was terminated early. Clinical observations
and clinical pathology and/or bone marrow alterations were also consistent with
immunosuppression. In the surviving animals, there were no treatment-related
changes in body weight, electrocardiography, blood pressure measurements,
ophthalmology, and urinalysis. Evaluation of recovery animals indicated that
all treatment related findings were reversible after 8 weeks of dosing
cessation, except for proliferation of intrahepatic bile ducts observed in 1
animal in the 1.0 mg/kg/day group.
The NOAEL was 0.1 mg/kg/day, corresponding to Day 272 pomalidomide AUC24hr of
227, and 211 ng•h/mL for male and female monkeys, respectively (approximately
0.5-fold exposure ratio relative to a 4 mg clinical dose).
Cardiovascular assessment (vital signs, electrocardiogram [ECG], respiration,
and heart rate) conducted in the 3 and 9 months monkey studies (Reports
CC-4047-TOX-002; CC-4047-TOX-006), indicated no test article-related
cardiovascular changes at doses up to 2 mg/kg/day for 3 months, and up to 1
mg/kg/day for 9 months (Cmax = 1249 and 653 ng/mL, both sexes combined, at 2
and 1 mg/kg/day respectively).
Second primary malignancies have also been reported, and to date, the incidence
rate appears to be below what would be expected in similar populations
independent of any treatment. As of 07 Feb 2014, 29 subjects have experienced a
total of 34 SPMs across all programs, including ongoing Celgene-sponsored
studies (Study CC-4047-MM-002 Phase 1 [2 subjects, including 1 subject with 2
SPMs); Study CC-4047-MM-002 Phase 2 [4 subjects]; Study CC-4047-MM-003/C [7
subjects, including 1 subjects with 5 SPMs]; Study CC-4047-MM-005 [2 subjects];
Study CC-4047-MM-010 [7 subjects], Study CC-4047-MF-002 [6 subjects], and Study
CC-4047-SCLC-002 [1 subject]).
Events of AML have also been reported, primarily from studies in subjects where
the natural course of the disease being treated, MPN-associated MF, includes a
risk of disease progression to AML (leukemic transformation or transformation
to blastic phase), and therefore were reported as disease progression and not
SPMs.
The important identified risks with pomalidomide continue to be those
previously identified, including teratogenicity, neutropenia, thromboembolic
events, and thrombocytopenia.
Tumor lysis syndrome (TLS) may occur in subjects treated with pomalidomide.
Subjects at risk for TLS are those with high tumor burden prior to treatment.
These subjects should be monitored closely and appropriate precautions taken.
Subjects with a prior history of serious allergic reactions associated with
thalidomide or lenalidomide were excluded from clinical studies, may be at
higher risk of hypersensitivity and should not receive pomalidomide.

3. ADDITIONAL PRECAUTIONS
No data are available on administration of pomalidomide to pediatric or
adolescent subjects (< 18 years of age).
No dosage adjustment is required for pomalidomide in the elderly. For subjects
>= 75 years of age, the starting dose of dexamethasone is 20 mg/day on Days 1,
8, 15 and 22 of each 28-day treatment cycle.
A study in subjects with renal impairment has not been conducted with
pomalidomide. Subjects with serum creatinine > 3.0 mg/dL were excluded from
study CC-4047-MM-002. Subjects with creatinine clearance < 45 mL/minute were
excluded from study CC-4047-MM-003.
A study in subjects with hepatic impairment has not been conducted with
pomalidomide. Subjects with serum bilirubin > 2.0 mg/dL were excluded from the
efficacy studies.
Pomalidomide tested negative for mutagenicity and genotoxicity, however, tests
to evaluate the carcinogenic potential of pomalidomide have not been performed..
Fertility and Early Embryonic Development
In a fertility and early embryonic development non-clinical study in rats,
pomalidomide treatment of males and females resulted in a decrease mean number
of viable embryos and an increase in postimplantation loss at dosages of 25
mg/kg/day or higher. These effects were not observed when treated males were
mated with untreated females. The NOAEL was < 25 mg/kg/day. Pomalidomide was
found to be teratogenic in both rats and rabbits when administered during the
period of major organogenesis. The NOAELs for developmental toxicity were < 25
mg/kg/day for rat and < 10 mg/kg/day for rabbit.
The effect of pomalidomide on human fertility and early embryonic development
is currently unknown, therefore proactive precautionary family planning options
and/or alternatives should be thoroughly discussed with female study subjects,
as appropriate.
Use in Pregnancy
Pomalidomide was found to be teratogenic in embryo-fetal development toxicity
studies in rats and rabbits. Pomalidomide crossed the placenta and was detected
in fetal blood following administration to pregnant rabbits.
A teratogenic effect of pomalidomide in humans cannot be ruled out. All
patients and investigators must follow the Global Pregnancy Prevention Program.
Use During Lactation
It is not known if pomalidomide is excreted in human milk. Pomalidomide was
detected in milk of lactating rats following administration to the mother.
Because of the potential for adverse reactions in nursing infants from
pomalidomide, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the
mother.
Effects on Ability To Drive Vehicles and Operate Machinery
No studies on effects of pomalidomide on the ability to drive or use machines
have been performed. Confusion, fatigue, depressed level of consciousness and
dizziness have been reported with the use of pomalidomide. Therefore, caution
is recommended when driving or operating machines in persons receiving
pomalidomide.
Interactions and Overdose
Pomalidomide is not anticipated to cause clinically relevant pharmacokinetic
drug-drug interactions due to enzyme inhibition or induction or transporter
inhibition when co-administered with substrates of these enzymes or
transporters. The potential for such drug-drug interactions, including the
potential impact of pomalidomide on exposure of oral contraceptives, has not
been evaluated clinically.
If strong inhibitors of CYP1A2 are co-administered with pomalidomide, subjects
should be closely monitored for the occurrrence of side effects.
Dexamethasone is a weak to moderate enzyme inducer and its effect on warfarin
is unknown. Close monitoring of warfarin concentration is advised during
treatment.
No drug/laboratory test Interactions interactions identified.
Pomalidomide can be administered without regard to food intake.
Doses of pomalidomide explored in clinical trials are between 0.5 and 4 mg/day,
pomalidomide doses as high as 50 mg as a single dose in healthy volunteers and
10 mg as once-daily multiple doses in MM patients have been studied without
reported serious AEs related to overdose. No specific information is available
on the treatment of overdose with pomalidomide, and it is currently unknown
whether pomalidomide or its metabolites are dialyzable.

4. CONCLUSIONS
Currently available information supports an acceptable investigational
benefit-risk balance for pomalidomide when used in accordance with the
precautions, risk mitigation/management, dosing and safety monitoring outlined
in the study protocol, and routine trial safety surveillance practices.