Understanding
Revlimid®
International Myeloma Foundation
12650 Riverside Drive, Suite 206
North Hol ywood, CA 91607 USA
Telephone:
800-452-CURE (2873)
(USA & Canada)
818-487-7455
Fax: 818-487-7454
TheIMF@myeloma.org
www.myeloma.org
Table of Contents
Introduction
5
What is Multiple Myeloma?
5
What are the Stages of Multiple Myeloma?
6
What is Revlimid® and
How Does it Work?
8
What are the Possible Side Effects
of Revlimid®?
15
Other Side Effects to be Aware
of When Revlimid® is Combined
with Dexamethasone
21
Will a Dose Reduction in Revlimid®
Change the Effectiveness of Treatment?
21
How is Revlimid® Given?
22
About the IMF
23
Glossary
26
©, International Myeloma Foundation, North Hollywood, California
Introduction
You have been given this booklet to learn
more about a new drug cal ed Revlimid®
(lenalidomide). After reading this booklet
you should know:
n What Revlimid® is
n How Revlimid® works
n The possible side ef ects of Revlimid®
n How Revlimid® is given
This booklet is meant to provide you with
general information only. It is not meant to
replace the advice of your doctor or nurse.
Your doctor or nurse can answer questions
related to your specific treatment plan. Al
words that appear in bold type are defined
in the glossary at the end of the booklet.
What is Multiple Myeloma?
Multiple myeloma (also known as myeloma
and as plasma cel neoplasm) is a malig-
nancy of the immunoglobulin-producing
plasma cel s found in the bone marrow. It
is a hematologic malignancy resembling
leukemia. However, the malignant plasma
cel s, or myeloma cel s, rarely enter the
blood stream as in a true leukemia. Instead,
the myeloma cel s accumulate in the bone
marrow, causing:
n Disruption of normal bone marrow func-
tion, most commonly giving rise to ane-
mia (a low level of red cel s in the
bloodstream), although reduction in
4
5
white blood cel and platelet counts
blood are normal or close to normal, and the
can also occur
amount of M protein is very low.
n Damage to bone surrounding accumu-
Stage II (intermediate cell mass): An
lated myeloma cel s
intermediate stage between stage I and I I
n Release
of an abnormal protein,
Stage III (high cell mass): More
monoclonal protein (M protein), into the
advanced disease. One or more of the
bloodstream
fol owing are present:
n Suppression of normal immune function,
n Anemia
observed as reduced levels of normal
n A high level of calcium in the blood
immunoglobulins and increased suscepti-
n More than 3 areas of advanced lytic bone
bility to infection
lesions
Myeloma cel s can also grow in the form
n A high level of M protein in the blood
of localized tumors or plasmacytomas.
or urine
Plasmacytomas may be single or multiple
and either medul ary (confined within bone
Multiple myeloma is a serious malignancy,
marrow and bone) or extramedul ary (out-
but it is treatable. Many patients experience
side of the bone). When there are multiple
a series of responses, relapses, and remis-
plasmacytomas inside or outside bone, this
sions. With new treatments, the average
condition is also cal ed multiple myeloma.
survival of 5 years for patients diagnosed
with multiple myeloma may be extended.
Confronted with a diagnosis of multiple
myeloma, it is important for your doctor to
Fol owing diagnosis, several options are
determine the stage of the disease. Disease
available for initial or frontline therapy.
staging wil help determine what parts of the
For patients who may be candidates for
body have been af ected and to what extent.
high-dose therapy with transplant, various
This wil al ow the doctor to decide the best
induction regimens can be considered,
treatment option.
including thalidomide with dexamethasone,
dexamethasone alone, or other dexametha-
The Stages of Multiple Myeloma
sone-containing combinations. The combina-
tion of the alkylating agent melphalan plus
Stage I (low cell mass): Early disease.
prednisone, a simple oral therapy, is an
The bone structure appears normal or close
option for patients not considering trans-
to normal on x-ray images; the number of
plant with intravenous high-dose melphalan.
red blood cel s and amount of calcium in the
At the time of relapse, newer agents are
6
7
cytokines
and/or
interleukins,
and
affect cel s of the immune system.
Immunomodulatory agents enhance the acti-
vation of specialized white blood cel s of the
immune system both the T-cel lymphocytes
and T cel s known as natural kil er cel s, or
NK-cel s which help kil cancer cel s.
Revlimid® is a vascular endothelial growth
factor inhibitor. It belongs to a group of
immunomodulatory agents with the ability
to inhibit new blood vessel development on
which cancer cel s depend. Revlimid® is
structural y related to thalidomide but has
been modified by researchers to take advan-
tage of the anticancer properties, and at the
same time substantial y reduce the likelihood
frequently required to achieve further
of nerve or neurologic toxic side ef ects
response. Revlimid® is an important new
(peripheral neuropathy). Revlimid® has direct
agent available for use in this setting.
and indirect ef ects on myeloma cel s, includ-
Velcade® (bortezomib) is also an important
ing the ability to induce programmed cel
new agent available for relapse in patients.
death of myeloma cel s, inhibit myeloma cel
growth, inhibit new blood vessel growth,
and reduce adhesion of myeloma cel s
What is Revlimid® and
to bone marrow stromal cel s. Moreover,
How Does it Work?
Revlimid® can act synergistical y with other
Revlimid® is an immunomodulatory agent.
antimyeloma agents and kil myeloma cel s
It is a drug that can modify or regulate the
that are resistant to conventional therapy.
functioning of the immune system. These
Clinical studies are investigating the ef ects
agents appear to have multiple actions,
of Revlimid® on newly diagnosed patients
including both anticancer and anti-inflam-
and on patients with relapsed and refractory
matory
activities.
Immunomodulatory
myeloma.
agents induce immune responses, enhance
Two pivotal Phase I I clinical trials of Revlimid®
the activity of immune cel s, and inhibit
and high-dose dexamethasone versus high-
inflammation. They are able to alter the
dose dexamethasone alone in patients with
levels of various growth factors, called
8
9
relapsed or refractory myeloma exceeded
28 days. Beginning at cycle 5, the dose
the prespecified interim ef icacy end point
intensity of dexamethasone was reduced to
for disease progression. Because of these
40 mg daily on days 14 only, every 28
data, the trials were unblinded many months
days. Patients resistant to dexamethasone
earlier than anticipated, and al patients not
were excluded. Patients were stratified with
on Revlimid® had the opportunity to add
respect to bone-marrow involvement, previ-
Revlimid® to their dexamethasone regimen
ous stem-cel transplant, and number of previ-
if needed.
ous regimens.
The identical North American and internation-
The trials included a primary end point
al trials enrol ed a total of 705 patients and
of time-to-disease progression, calculated
are being conducted in 97 sites in the United
as the time from randomization to the first
States, Europe, Israel, and Australia. Patients
documentation of progressive disease. The
were randomized to receive Revlimid® (25
definition of a complete response (CR) is the
mg/day) and high-dose dexamethasone or
disappearance of M protein in serum and
an identical y appearing placebo and high-
urine and less than 5% plasma cel s in the
dose dexamethasone.
bone marrow, confirmed at 2 separate time
points 6 weeks apart. The definition of a par-
Patients al received standard high-dose
tial response (PR) is at least a 50% reduction
dexamethasone at a dose of 40 mg daily
in the level of the serum M protein. Patients
on days 14, 912, and 1720 every 28
achieving a response or stable disease con-
days and were randomized to receive either
tinue on therapy.
Revlimid® 25 mg daily oral y on days 121
every 28 days, or placebo. One cycle was
The international study enrol ed 351 patients
from 50 clinical sites, and the North American
study enrol ed 354 patients from 47 clinical
sites. In both studies, the responses exceeded
the preestablished ef icacy stopping rule for
the primary end point: time-to-disease pro-
gression. Response data were available on
al 691 eligible patients of the 705 enrol ed
in the study.
Response rates achieved with the combination
were about 60%: more than double that seen
with dexamethasone alone. Together, these
data confirm a significant clinical benefit for
10
11
patients receiving Revlimid® plus dexametha-
sone. Data from these studies wil continue to
be col ected on an ongoing basis.
In both trials, patients treated with the com-
bination had an increase in side effects
compared with patients receiving dexameth-
asone alone. The side ef ects were gener-
al y manageable and included constipation,
neutropenia, diarrhea, thrombocytopenia,
rash, fatigue, and deep vein thrombosis
(blood clot).
New findings in support of low-dose
Dexamethasone
However, many oncologists are now pre-
scribing dexamethasone in a once-weekly
cycle, often at a dose lower than 40 mg.
Based upon recent ECOG trial data the
once-weekly dosing schedule is now more of
a 28-day cycle. Dexamethasone was given
a preferred approach. The ECOG trial evalu-
oral y at a dose of 40 mg daily on days
ated the Revlimid/dexamethasone (high- and
14, 912, 1720 of each cycle. The dose
low-dose) combinations in the frontline set-
of dexamethasone was reduced to 40 mg on
ting. The once per week schedule "low-dose"
days 14 of each cycle for patients continu-
proved to be more ef ective (bet er survival
ing therapy beyond 4 months. Patients also
at 1 year) and had significantly fewer side
received an aspirin once daily to decrease
ef ects. Results were presented at ASCO
the risk of a blood clot.
2007. Your doctor wil work with you to find
a dosing schedule that is wel tolerated and
Al patients were evaluated for response and
appropriate to treat your multiple myeloma.
toxicity. Of the 34 patients, 31 (91%) had an
objective response (a response confirmed by
Additional findings for Revlimid® and
a health-care provider), including 2 patients
newly-diagnosed Myeloma
(6%) who achieved a complete response
Revlimid® has been reported to be ef ective
(CR), 11 patients (32%) who achieved a
in newly-diagnosed multiple myeloma. In a
near complete response/very good partial
clinical trial, 34 patients received Revlimid®
response (nCR/VGPR), and 18 patients
at a dose of 25 mg daily on days 121 of
(53%) who achieved a partial response (PR).
12
13
Of the 3 patients not achieving an objective
travels to the lung) but recovered with
response, 2 met criteria for minor response,
therapy.Twolargecooperativegrouptrialsare
and one had stable disease. The median time
currently testing Revlimid®/dexamethasone
to response was 1 month. Adequate stem cel s
as initial therapy for multiple myeloma in the
(>3.0 mil ion stem cel s [CD34 cel s]/kg
United States.
body weight) were obtained in al patients
Revlimid® is also being tested for use as a
who proceeded to autologous stem cel
single agent. A multicenter, Phase I , open-
transplantation. The side effect profile
label study is ongoing to evaluate the ef ec-
was manageable, but there was a 47%
tiveness and safety of single-agent Revlimid®
incidence of grade 3 (out of 4 possible
administered at a dose of 30 mg once a
grades) or higher nonhematologic toxic-
day for 21 days every 28 days. The study
ity: most commonly fatigue (15%), muscle
enrol ed 222 patients, al of whom had
weakness (6%), anxiety (6%), pneumonitis
received at least 2 previous treatments for
(lung inflammation) (6%), and rash (6%).
myeloma. Preliminary results show that a PR
One patient died while participating in
or bet er occurred in 25% of patients and
the study; the death was considered unre-
stable disease or bet er in 71%. Time-to-
lated to therapy. One patient developed a
progression was a median of 22.4 weeks
pulmonary embolism (blood clot that
(range 1.866 weeks). The most common
treatment-related side ef ects included upper
respiratory tract infection, neutropenia, and
thrombocytopenia. Side ef ects have been
manageable with a very low incidence of
deep vein thrombosis (DVT) and minimal
treatment-caused neuropathy.
What are the Possible Side Effects
of Revlimid®?
Most of the side ef ects associated with
Revlimid® are manageable and predictable.
The most important side ef ects are described
here. Your doctor or nurse can provide more
information in greater detail about these and
other possible side ef ects.
14
15
In clinical trials conducted to date, Revlimid®
male patients are required to complete a
has a dif erent safety profile from thalido-
monthly phone survey. Clinicians must check
mide. Significant sleepiness, constipation,
pregnancy tests, limit prescriptions to a
or neuropathy common side ef ects seen
28-day mail supply, and report any pregnan-
with thalidomide therapy are much less
cies to the FDA.
frequent. Revlimid® does not appear likely to
Safety information about Revlimid® is derived
cause the type of severe birth defects noted
from clinical trials, and as many clinical trials
in the past with thalidomide, but nonetheless
are ongoing, no definitive conclusions can yet
is an analogue of thalidomide. Additional
be made. The events that have been observed
studies are ongoing to determine the risk
are listed below, from most frequent to
of birth defects. While these studies are
least frequent.
being conducted, a risk-management plan
cal ed RevAssist is designed to prevent expo-
· Constipation
sure during pregnancy. With RevAssist, only
· Neutropenia
registered pharmacists and clinicians can
· Diarrhea
prescribe and dispense Revlimid®. The plan
requires patients, including female patients of
· Thrombocytopenia
child-bearing potential, to undergo manda-
· Rash
tory pregnancy testing, and to give informed
· Fatigue
consent before taking Revlimid®. Female
· Deep-vein thrombosis (DVT)
patients of child-bearing potential and al
Recently, the FDA approved Revlimid® for
the treatment of patients with myelodsyplastic
syndromes, a disorder in which the bone
marrow does not function normal y, and a
suf icient number of normal blood cel s are
not produced. With this approval, Black Box
Warnings have been included to address
the prevention of exposure during preg-
nancy and the potential need to modify the
dose due to lowered blood counts and an
increased risk of blood clots.
Remember, speak with your doctor or nurse
if you notice any changes in your health.
16
17
Decreased Platelet Levels thrombocytopenia
Fatigue
Patients taking Revlimid® may experience a
Fatigue is commonly associated with Revlimid®
condition cal ed thrombocytopenia: a low-
therapy. Although fatigue is general y not
ered level of platelets in the blood. Platelets
severe, caution is advised if you are operating
help blood to clot; fewer platelets can lead to
machinery, including automobiles.
bruising, bleeding, and slower healing.
Prevention and Treatment of Fatigue
Prevention and Treatment of Decreased Platelet
Management of fatigue may include support-
Levels
ive care as determined by your physician.
You should inform your physician if you
experience excessive bruising or bleeding.
The ef ects of fatigue may be minimized by
Management may include platelet transfu-
maintaining:
sions at the discretion of your physician.
n A moderate level of activity
Decreased White Blood Cel Levels neutropenia
n A healthy diet and proper fluid intake
Patients taking Revlimid® may experience
n A consistent sleeping schedule with
a condition cal ed neutropenia: a lowered
enough rest
level of white cel s (neutrophils) in the blood.
n Regularly scheduled visits with your
Neutrophils help blood to fight infection;
doctor or health-care provider to
fewer neutrophils can lead to a "cold" with
discuss fatigue issues
fever, sore throat, and mouth sores.
Deep Vein Thrombosis
Prevention and Treatment of Decreased White
Deep vein thrombosis (DVT) is a serious condi-
Blood Cel Levels
tion and is potential y life threatening. DVT is a
You should inform your physician if you
experience fever, sore throat, or mouth sores.
Fever is the symptom that usual y indicates
infection in a person who has neutropenia. It
is an important sign that immediate medical
at ention is needed. The treatment of neu-
tropenia depends on its cause and severity.
Sometimes the bone marrow recovers by
itself without treatment. The neutropenia
accompanying viral infections (such as influ-
enza) may be transient and resolve after
the infection has cleared. Mild neutropenia
general y has no symptoms and may not
need treatment.
18
19
blood clot in a deep vein of the lower extremi-
Other Side Effects to be Aware of
ties (usual y occuring in the leg or thigh, and
When Revlimid® is Combined with
very occasional y in the neck or upper arm). A
blood clot from a DVT can break loose (emboli-
Dexamethasone
ze) and travel to the heart or lungs. An embolus
The major studies mentioned above, indicat-
is very dangerous. If you start taking Revlimid®
ing benefit of Revlimid® in the relapse set-
and experience warmth, swel ing, redness,
ting, used a combination of Revlimid® with
dif iculty breathing, and/or pain in an extrem-
dexamethasone. It is important to be aware
ity, notify your doctor as soon as possible.
that additional toxicities can occur with this
Prevention and Treatment of DVT
combination versus Revlimid® alone.
You are strongly advised to contact your physi-
Side ef ects that may occur with Revlimid®
cian if you experience swel ing and/or redness
plus dexamethasone include muscle weak-
and/or pain in a leg or thigh. Your doctor wil
ness, anxiety, agitation, cardiac arrhythmias,
diagnose your condition to determine whether
nausea, increased blood sugar, elevated
or not it is a DVT. Treatment of a DVT may
liver enzymes, and constipation and/or diar-
depend upon both its location and underlying
rhea. Ful details with regard to dexametha-
cause. Your doctor may prescribe a blood thin-
sone are discussed in a separate booklet.
ner to keep the clot from get ing larger.
Remember to discuss any changes in your
Rash
health with a doctor or nurse on your health-
Rash is a serious concern. Although it seldom
care team.
occurs, it is potential y dangerous, as a rash
may be mild initial y and then escalate in
Will a Dose Reduction in Revlimid®
severity. Drug rashes vary in severity from
Change the Effectiveness of
mild redness with tiny bumps over a smal
area to peeling of the entire skin. Rashes
Treatment?
may appear suddenly within minutes after a
It is important to communicate openly with
person takes a drug, or they may be delayed
your doctor or healthcare professional and
for hours or days.
keep regular appointments to maintain your
Prevention and Treatment of Rash
Revlimid® treatment schedule. Your doctor
You are strongly urged to notify your doctor if
may choose to modify your dose of Revlimid®
you experience any rash. Proper evaluation
as part of an overal plan to manage a par-
of a skin rash requires a visit to a doctor or
ticular side ef ect that you experience. The
other healthcare professional. If detected and
dose used in the Phase I I clinical studies is
managed appropriately, a rash is reversible.
25 mg per day. If you experience a severe
20
21
side ef ect, your doctor may modify your
About the IMF
dose in either amount or schedule to reduce
the severity of the side ef ect while maintain-
"One person can make a dif erence,
ing treatment.
Two can make a miracle."
How is Revlimid
Brian D. Novis
® Given?
IMF Founder
Revlimid® is given as capsules. The most
Myeloma is a lit le-known, complex, and
common dosing used in multiple myeloma is
often misdiagnosed bone marrow cancer
25 mg given oral y daily on days 121 and
that at acks and destroys bone. Myeloma
repeated every 28 days (days 2228 are
af ects approximately 75,000 to 100,000
rest days). Doses are then modified based
people in the United States, with more than
on side ef ects.
20,000 new cases diagnosed each year
according to recent data. While there is
IMF Hotline:
presently no known cure for myeloma, doc-
USA & Canada only: 800-452-CURE (2873)
tors have many approaches to help myeloma
patients live bet er and longer.
Elsewhere: 818-487-7455
IMF Web site: www.myeloma.org
The International Myeloma Foundation (IMF)
was founded in 1990 by Brian and Susie
Novis shortly after Brian's myeloma diagno-
sis at the age of 33. It was Brian's dream that
future patients would have easy access to
medical information and emotional support
throughout their bat le with myeloma. He
established the IMF with the 3 goals of treat-
ment, education, and research. He sought
to provide a broad spectrum of services for
patients, their families, friends, and health
care providers. Although Brian died 4 years
after his initial diagnosis, his dream didn't.
Today the IMF reaches out to an international
membership of more than 165,000. The IMF
was the first organization dedicated solely to
myeloma, and today it remains the largest.
22
23
The IMF provides programs and services to
MYELOMA TODAY NEWSLETTER
aid in the research, diagnosis, treatment,
Our quarterly newslet er is available free of
and management of myeloma. The IMF
charge by subscription.
ensures that no one must brave the myeloma
SUPPORT
bat le alone.
MYELOMA HOTLINE: 800-452-CURE (2873)
We care for patients today, while working
Toll-free throughout the United States and
toward tomorrow's cure.
Canada, the IMF Hotline is staf ed by trained
information specialists and is in frequent inter-
How Can the IMF Help You?
action with members of our Scientific Advisory
Board.
PATIENT EDUCATION
INFORMATION PACKAGE
SUPPORT GROUPS
Our free IMF InfoPack provides comprehensive
A worldwide network of more than 100 myelo-
information about myeloma, treatment options,
ma support groups hold regular meetings for
disease management, and IMF services. It
members of the myeloma community. The IMF
includes our acclaimed Patient Handbook.
conducts annual retreats for myeloma support
group leaders.
INTERNET ACCESS
Log on to www.myeloma.org for 24-hour
RESEARCH
access to information about myeloma, the IMF,
BANK ON A CURE ®
education, and support programs.
This DNA bank wil provide genetic data
ONLINE MYELOMA FORUM
research in new drug development.
Join the IMF Internet Discussion Group at
www.myeloma.org/listserve.html to share your
THE INTERNATIONAL STAGING SYSTEM (ISS)
thoughts and experiences.
This updated staging system for myeloma wil
enhance physicians' ability to select the most
MYELOMA MINUTE
appropriate treatment for each patient.
Subscribe to this free weekly email news-
let er for up-to-the-minute information about
RESEARCH GRANTS
myeloma.
Leading the world in col aborative research
and achieving extraordinary results, the IMF
PATIENT & FAMILY SEMINARS
Grant Program supports both junior and senior
Meet with leading experts in myeloma treat-
ment to learn more about recent advances in
researchers working on a broad spectrum of
therapy and research.
projects. The IMF has at racted many young
investigators into the field of myeloma, and
MYELOMA MATRIX
they have remained in the field and are actively
On our website and in print, this document is a
pursuing a cure for this disease.
comprehensive guide to drugs in development
for myeloma.
24
25
Glossary
Alkylating agent: An agent that prevents the growth and
Multiple myeloma: A cancer arising from the plasma cel s
division of new cancer cel s by inhibiting their ability to
in the bone marrow. The plasma cel s in patients with
replicate DNA.
multiple myeloma form abnormal antibodies, possibly
Anemia: A low level of red blood cel s in the blood-
damaging the bone, bone marrow and other organs.
stream.
Neutrophil: A white blood cel .
Antibody: A protein produced by some of the body's white
Neutropenia: A low level of white blood cel s in the
blood cel s that helps fight infection.
bloodstream.
Bone marrow: A soft spongy tissue found in most large
Peripheral neuropathy: Numbness, tingling, and/or pain in
bones that produces red and white blood cel s and
the hands, feet, legs, and/or arms.
platelets.
Plasma cell: A type of white blood cel that produces
Cell: The smal est unit of life. Mil ions of microscopic cel s
antibodies.
comprise each body organ.
Plasmacytoma: A tumor made up of cancerous plasma
Cytokine: A growth factor produced by T-cel s that stimu-
cel s.
lates the growth of T cel s and B cel s.
Platelet: An element in the blood that helps with clot ing,
Enzyme: A type of protein that causes chemical reactions
which in turn helps repair damaged blood vessels.
of other substances without undergoing change in the
Protein: A group of compounds that are the main compo-
process.
nents of a cel .
Febrile neutropenia: Presence of a low neutrophil count in
Red blood cell: A blood cel that carries oxygen from the
the blood that is associated with fever; may indicate the
lungs throughout the body.
presence of infection.
Side effect: An ef ect caused by the treatment with a drug.
Immunoglobulin: An antibody.
The term usual y refers to an unwanted ef ect, but some
Immunomodulatory agent: Drug that af ects, enhances, or
side ef ects may be beneficial.
suppresses the immune system.
Stromal cell: Structural cel s of the bone marrow that help
Interleukin: Various cytokines involved in the growth and
support and nourish the blood-producing cel s.
survival of myeloma cel s.
Thrombocytopenia: A low level of platelets in the blood.
Lymphocyte: A type of white blood cel , mainly B-cel s
These low levels can cause bruising or bleeding as wel
that produce immunoglobulins and T-cel s that produce
as delay in the injury healing process.
cytokines and interleukins. Also includes natural kil er cel s
Vascular endothelial growth factor (VEGF): A growth factor
(NK-cell). A type of lymphocyte with enzymes that can kil
that promotes the growth of new blood vessels (angio-
tumor cel s or microbial cel s.
genesis).
Lysis (lytic): Dissolution or destruction of cel s
White blood cell: A cel made by the bone marrow that
Monoclonal protein (M protein): An abnormal protein pro-
helps fight infection and/or disease.
duced by myeloma cel s that accumulate in and damages
bone and bone marrow. A high level of M protein indi-
cates that myeloma cel s are present in large numbers.
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