Managing Side Effects of
Novel Agents
Beth Faiman RN, MSN, APRN-BC, AOCN
Nurse Practitioner
Cleveland Clinic Cancer Institute
Cleveland, Ohio
Introduction to the International Myeloma
Foundation Nurse Leadership Board
The IMF has formed a Nurse Leadership Board which
is made up of 20 expert nurses from around the United
States. Through their affiliation with myeloma
treatment centers, they have been chosen to assist in
dispersing information to patients, families and health
care providers dealing with multiple myeloma.
The following information is intended to help you
better understand possible treatment options, side
effects to treatments and management of those side
effects. Please be sure to consult your provider if you
have any questions or concerns regarding your
diagnosis, symptoms or treatment plan.
1
Multiple Myeloma Is Like a Puzzle!
· Cancer of plasma cells
· Many factors to be considered in
diagnosis and management
· Help from other doctors,
healthcare professionals,
and YOU!
Pathophysiology
· Many organs and body
systems may be affected
Bone disease Weak bones can break
Infections from myeloma itself
Anemia makes you tired, short of breath
Kidney damage- from proteins, anemia
Neurologic effects Nerve damage,
neuropathy from drugs or the disease
What happens to the plasma cell?
· Abnormal, overproduction of 1
immunoglobulin; it makes a "clone" of itself
· Referred to as the "M" protein
(monoclonal), or "M spike," normal plasma
cell that turns malignant
· M protein is present in 80%90% of patients
· Excess amounts of abnormal proteins
interfere with humoral immunity
Diagnostic Tests What do we look for?
· Metabolic panel organ and
electrolyte function
· Kidneys (Creatinine) liver, bones, see if myeloma
active
· Albumin `gobbled up' by the myeloma and may
signal active disease -# goes down)- Normal 3.5-
5.0
· Beta-2 Microglobulin- shed from myeloma cell
and may go up if active disease
Complete Blood Count CBC
· CBC: look for infection, bone marrow function,
anemia
· Key numbers in the CBC may go low with active
disease as myeloma cells crowd out healthy
cells
WBC fight infection , high with steroids, low
with chemo or treatment
Hemoglobin (HgB) carry oxygen
over 10.0 mg/dL
Platelets (Plts) clot your blood
Complete Blood Count CBC
"Anemia" (low HgB)- can be from many things
· blood loss
· Not making red cells in your bone marrow
· iron or vitamin deficiency
· Myeloma may be preventing the making of
healthy red cells
Diagnostic Tests What do we look for?
· M proteins 90% will have measurable
proteins in the Serum and urine
· protein electrophoresis and immunofixation
tells you what kind of abnormal myeloma you
have (Ig G Kappa is most common)
· Quantitative immunoglobulins- These are the
`IgG, IgA or IgM' numbers, but M SPIKE is
most specific
Diagnostic Tests What do we look for?
· Urine 24 hour protein
· Bone survey
· Bone marrow biopsy
How Will Your Health Care Provider
Decide on Treatment?
· Treatment is individualized for each patient based
upon:
Physical exam and laboratory test results
Disease stage, symptoms and complications
at time of diagnosis
Whether the patient has been treated previously
for multiple myeloma
Age and general health
Lifestyle and quality of life
Information from current clinical trials
From International Myeloma Foundation. Multiple myeloma: patient handbook. 2006. IMF, North Hollywood, CA. www.myeloma.org
10
Goals of Treatment
· Stop disease from damaging organs
· Extend length of time without evidence of disease
· Prolong life expectancy
· Relieve pain and other symptoms
· Maintain normal levels of activity and a good
quality of life
11
Treatments Used for Multiple Myeloma
· Chemotherapy (Drug therapy)
Conventional therapy:
· Steroids (Dexamethasone, Prednisone)
· Alkylating Agents (Melphalan, Cyclophosphamide)
· Anthracyclines (Doxorubicin, Liposomal doxorubicin)
Novel Therapy:
· Bortezomib (Velcade)
· Thalidomide (Thalomid)
· Lenalidomide (Revlimid)
· Drugs are can be given alone or in combination
From International Myeloma Foundation. Multiple myeloma: Concise Review of the Disease and Treatment Options.
12
2006. IMF, North Hollywood, CA. www.myeloma.org
Treatment for Multiple Myeloma
(continued)
· Stem cell transplantation - use of very high dose
chemotherapy, requiring a stem cell rescue for bone
marrow recovery
· Radiation therapy - use of high-energy external beam
radiation to destroy cancer cells or stop them from
growing
· Treatments under clinical investigation
From International Myeloma Foundation. Multiple myeloma: Concise Review of the Disease and Treatment Options.
13
2006. IMF, North Hollywood, CA. www.myeloma.org
Updates for the Use of Novel
Agents for Treatment of Multiple
Myeloma
Thalidomide (Thalomid)
Lenalidomide (Revlimid)
Bortezomib (Velcade)
Novel Agents
What is Targeted Therapy
Normal
Cells
Cancer
Cells
·Drugs targeted at pathways, processes and physiology which are
uniquely disrupted in cancer cells:
Receptors
Genes
Angiogenesis
Tumor pH
·New agents improve outcomes either alone or combined with
chemotherapy and/or radiation
15
Novel Treatments for Multiple Myeloma -
Thalidomide and Lenalidomide
· These medications are called Immune-Modulating
therapies because they act to improve the
immune system
· Oral administration
· Strong evidence that these drugs kill cancer cells
in two ways
Improve body's immune system response to cancer
Block the blood supply to cancer cells, so that tumors
cannot grow
From Understanding Thalidomide. The International Myeloma Foundation, North Hollywood, CA. 2006
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Potential Side Effects - Thalomid
(thalidomide)
· Blood clots, particularly in combination with steroids or
chemotherapy
· Peripheral neuropathy numbness or tingling in your
hands or feet
· Sedation, fatigue
· Constipation
· Rash, usually on trunk, back, arms, legs
· Teratogenic - severe birth defects if taken during
pregnancy
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Potential Side Effects - Revlimid
(lenalidomide)
· Blood clots, particularly in combination with steroids or
chemotherapy
· Low blood counts
· Rash
· Itchy scalp
· Diarrhea
· Fatigue
· Muscle cramping
· Kidney: Dose must be reduced
18
Novel Treatments for Multiple Myeloma
Velcade (bortezomib)
· Bortezomib is the first drug in a class called Proteasome
Inhibitors which inhibit cancer cell growth
· Normal cells can recover from effects of proteasome
inhibitor, whereas myeloma cells are more likely to be
effected
· Administered by intravenous injection (IV) several days
during a month
· Indications
Approved for use in previously untreated patients (June, 2008)
Used to treat patients who have received at least 1 previous
therapy for multiple myeloma
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Potential Side Effects - Velcade
(bortezomib)
· Peripheral neuropathy numbness or tingling in your
hands or feet
· Low platelet counts
· Weakness and fatigue
· Loss of appetite, nausea, vomiting, diarrhea, or
constipation
· Joint pain, muscle cramps
· Shortness of breath, dizziness, blurred vision,
hypotension
· Increase risk of shingles Acyclovir
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Managing Side Effects of
Myeloma Treatment
Gastrointestinal
Myelosuppression
Thromboembolic
Peripheral Neuropathy
Steroids
Possible Side Effect of Treatment:
Gastrointestinal (GI)
GI side effects can happen individually or in
combination and commonly include:
· Nausea
· Vomiting
· Diarrhea
· Constipation
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Possible Gastrointestinal Side Effect of
Treatment - Managing Nausea/Vomiting
Things that may help - Nausea and Vomiting
· Concentrate on staying hydrated · Restrict fluids with meals
· Eat before getting too hungry
· Chew food thoroughly
· Eat bland food, cold or at room
· Suck on mints or hard candy;
temperature
popsicles or ice chips.
· Find fresh air when possible
· Try peppermint or ginger tea
· Use relaxation techniques
· Apply a cool compress to the
· Try hypnosis or acupuncture
forehead, neck, wrists
Medications to control nausea may be ordered by your health care
provider. Take as directed.
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Possible Gastrointestinal Side Effect of
Treatment - Managing Nausea and Vomiting
Things to avoid - Nausea and Vomiting
· Avoid strong odors
· Avoid favorite foods (they
· Do not lie flat after eating
may become associated with
· Avoid sweet, salty, fatty,
nausea or vomiting)
spicy, heavy foods
· Avoid citrus and tomatoes
· Do not exercise after eating
If nausea and vomiting continue, your health care provider
may add more anti-nausea medication and/or lower the
dose of treatment medication.
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Possible Gastrointestinal Side Effect
of Treatment - Managing Diarrhea
Medications that may cause diarrhea
· Laxatives
· Antibiotics
· Antacids with magnesium
· Antidepressants
· Prescription medications: check with your provider
Herbal supplements that may cause diarrhea
· Milk thistle
· Aloe
· Cayenne
· Saw palmetto
· Ginseng
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Possible Gastrointestinal Side Effect
of Treatment - Managing Diarrhea
Eating hints for diarrhea
· Increase fluid intake (water, Ricelyte ®, Pedialyte®, sports
drinks, diluted fruit juice, and broth)
· Avoid caffeinated, carbonated, or heavily sugared beverages
Take anti-diarrheal medication
· Imodium® or Lomotil® if recommended by a clinician
· Fiber binding agents Metamucil®, Citracil®
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Possible Gastrointestinal Side Effect
of Treatment - Managing Constipation
Eating hints for constipation
· Increase fluid intake
· Drink warm/hot beverage prior to normal timing for bowel
movement
· Eat foods high in fiber, for example....
Other techniques to manage constipation
· Ensure comfort, privacy, and convenience during bowel movement
· Increase physical activity
· Use stool softeners or laxatives or fiber binding agents
Metamucil®, Citracil®
Contact your provider if symptoms continue. Your
medications may need to be changed.
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Possible Side Effect of Treatment:
Myelosuppression (low blood counts)
· The healthy bone marrow cells include:
Red Blood Cells (RBC) transport oxygen
White Blood Cells (WBC) fight against infection
Platelets protect against bleeding and bruising
· These cells can be effected by active disease, myeloma
treatment, and other medications or medical conditions.
· Decreased function of the bone marrow is called
"Myelosuppression"
· Your health care provider will monitor blood counts
regularly during therapy
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Miceli, Colson, Gavino, Lilleby CJON Supplement, June, 2008. In press
Anemia (low red blood cells)
Commonly seen with myeloma. May also be a
result of decreased kidney function, myeloma
treatment or other medications.
Symptoms of anemia
Fatigue, low energy level
Unable to do regular activities
Shortness of breath or chest pain with activity
Pale appearance
Treatment
· Use of red blood cell supplements, with caution
· Possible red blood cell transfusion
· "Energy-sparing" activities
· Reduced dose of medications
29
Miceli, Colson, Gavino, Lilleby CJON Supplement, June, 2008. In press
Neutropenia (low white blood cells)
May be a result of myeloma disease, treatment or other
medications.
The greatest concern with this side effect is infection.
Symptoms to watch for
· Fever and shaking chills
· Dizziness or fainting
· Redness or swelling of skin or open wound
· Respiratory symptoms such as cough or sinus congestion
Precautions
· Thorough hand washing to reduce contact exposure
· Use of mask as instructed
· Avoid crowds and potential contagion
· Preventative antibiotic therapy as prescribed
30
Miceli, Colson, Gavino, Lilleby CJON Supplement, June, 2008. In press
Thrombocytopenia (low platelets)
May be a result of myeloma disease, treatment or other
medications.
Watch for symptoms that may include
· Frequent or large bruises
· Blood in urine or stool
· Spontaneous nosebleeds
· Small red or purple spots on the body (petechiae)
· Bleeding that does not stop with pressure
To reduce risk of bleeding these practices are recommended:
· Do not take aspirin, ibuprofen or naproxen unless instructed
· Avoid activities that can cause bruising or bleeding such as contact
sports and heavy lifting
· May need platelet transfusion at signs of bruising or bleeding or
before any necessary invasive procedure
31
Miceli, Colson, Gavino, Lilleby CJON Supplement, June, 2008. In press
Possible Side Effect of Treatment: Deep
Vein Thrombosis and Pulmonary Embolism
Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE)
develop by a blood clot partially or completely blocking a
blood vein or artery.
Risk factors for developing blood clots:
- Multiple myeloma
- Diabetes
- Recent surgery
- Immobility
- Obesity
-Smoking
- Family history of clots
- Current use of oral contraceptives or hormones
- Cardiac problems
- Varicose veins
- Some combination treatments such as steroids
with thalidomide or lenalidomide
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Possible Side Effect of Treatment: Deep
Vein Thrombosis and Pulmonary Embolism
Symptoms of DVT
Symptoms of PE
·Swollen, warm extremity
· Shortness of breath, difficult
·Dull ache, pain or tight feeling
or labored breathing
·Rapid heart rate
· New onset of chest or
shoulder blade/arm pain
·Abnormal redness of skin
· Anxiety
·Bluish color and cool skin
· Rapid heart rate
Report DVT and PE symptoms immediately
These events are considered a medical emergency
and require immediate care
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Managing Side Effects of Treatment: Deep
Vein Thrombosis and Pulmonary Embolism
Strategies to reduce risk of clots:
· Anti-embolism stockings (elastic stockings)
· Exercise regimen
· Low-dose aspirin
· Moving frequently when sitting long periods
· Travel precautions (Foot/leg exercises, walking, ASA if not
already on blood thinner)
When taking Thalidomide or Lenalidomide, medications
may be adjusted to reduce the risk of a a clot from
occurring:
· Lower drug doses
· Different dosing schedule
· Blood thinning with warfarin or heparin therapy
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Possible Side Effect of Treatment:
Peripheral Neuropathy
Peripheral Neuropathy develops by injury, inflammation,
or degeneration to the peripheral nerve fibers of one's
extremities
Symptoms of peripheral neuropathy include:
· Numbness
· Tingling
· Prickling sensations
· Sensitivity to touch
· Muscle weakness
· Burning Pain or Cold Sensation
**Report symptoms of peripheral neuropathy to
your health care provider early**
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What to Do in Case of Numbness or Pain
Due to Peripheral Neuropathy
If you experience numbness, tingling, freezing, throbbing or shooting
pain due to peripheral neuropathy, you might:
· Massage the affected area with cocoa butter regularly
· Take Glutamine, B-complex vitamins (B1, B6, B12) supplements
· Take folic acid supplements
· Take amino acid supplements
If these symptoms worsen you should call your health care provider,
who may recommend:
· To stop treatment or reduce the dose of Thalidomide, Lenalidomide, or
Bortezomib
· A pain medication like gabapentin or Lidoderm® patch
· Physical therapy
Proper management of PN will promote safety, increase
mobility, and prevent unnecessary pain and discomfort.
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Steroid Therapy
Steroids are a very important part of the treatment for
multiple myeloma. Dexamethasone and prednisone are
commonly used.
They have been used as a single drug or in
combination with other drugs for many years.
Steroids target the myeloma cells for programmed cell
death.
- A recent study found benefit in using lower doses of
steroids over the conventional higher doses. Using
lower doses represented better overall survival and
less side effects. (Rajkumar, et al, 2007)
37
Potential Side Effects - Steroids:
Increase in blood sugar levels this can cause or worsen
diabetes
Fatigue/Hyperactivity
Difficulty sleeping (Insomnia)
Flushing/Sweating
Irritability, mood swings, depression
Increased in risk of gastrointestinal complications including
stomach bloating, hiccups, heartburn, ulcers or gas.
Body image changes - Weight gain, hair thinning/loss, skin
rashes
Increase in blood pressure and water retention
Increased susceptibility to infections
Sexual dysfunction
Muscle weakness or muscle cramping
Blurred vision
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Managing Side Effects to Steroid Therapy
Things to consider while taking steroids:
Take with food
Over-the-counter or prescription medications are
recommended to prevent stomach discomfort
Steroid schedule (am vs. pm)
Medications to prevent shingles, thrush or other
infections may also be prescribed
Report signs and symptoms of infection (fever of more
than 100.5 ° F, shaking chills even without fever, dizziness,
shortness of breath, low blood pressure)
Do not stop or adjust steroid doses without
discussing it with your health care provider.
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LIVING WELL -Infections
· Watch people with colds and coughs
· WASH your hands
· Notify your healthcare provider if you feel sick
· FLU vaccine
· Pneumonia vaccine
· IVIG (Intravenous Immune Globulin)
LIVING WELL Bone Health
· Everyone has cells called `osteoclasts' that nibble away
and `osteoblasts' that build bone
· Cancer cells make chemicals that dissolve or `nibble
away at healthy bone
· These chemicals are found in higher levels in the body
when the myeloma is active, bone loss
· Kill the chemicals that dissolve bone by treating the
myeloma with steroids or `other
· Bisphosphonates "Aredia", "Zometa"
· Infection that leads to bone death
LIVING WELL - Exercise
· Prevents pneumonia and infections
· Prevents blood clots
· Makes you feel better
· If you are on steroids will strengthen your muscles and prevent
weakness!
· Weight gain caused by steroids
LIVING WELL Vitamin therapy
· Not many herbals or vitamins have been tried in patients with
myeloma
· "curcurmin" (tumeric)
· Vitamin B6- May protect nerve endings from damage caused by
myeloma or treatment
· Folate helps healthy red blood cells to form
LIVING WELL Vitamin therapy
· Green Tea with antioxidants may stimulate the immune system
in a positive way and allow you to fight the protein (MGUS or
Myeloma)
· If on bortezomib: Also avoid Vitamin C on the day or your
injection, green tea
· Always consult with your healthcare provider as to whether or not
these are safe for you!
Overview of Key ASH Treatment Updates
· Lenalidomide maintenance in newly diagnosed,
transplant ineligible patients
· Lenalidomide maintenance after ASCT
· Subcutaneous bortezomib
· Carfilzomib
· Pomalidomide
· Elotuzumab
· With lenalidomide
· With Bortezomib
Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Older Patients
with NDMM
· Study Objective:
·
In previous studies Lenalidomide was efficacious in relapsed/refractory MM
·
Compare safety and efficacy of MPR in NDMM patients
·
Giving lenalidomide to patients until relapse decreased their risk to progress
·
Does this translate to overall survival (living longer?)
46
Palumbo et al, Blood 114, Abstract 613, 2009
Lenalidomide after ASCT
· Study objectives:
Controlling the residual disease after highdose therapy
Lenalidomide 25 mg/day for 21 days/month for 2 months, THEN
· Lenalidomide, 1015 mg/day
· Patients remained in remission longer with lenalidomide after
transplant than those who did not take lenalidomide
· Cancer and Leukemia Group B (CALGB)
· 568 patients were given lenalidomide 10 mg a day until relapse
· Dose: Lenalidomide 10 mg/day, escalated to 15 mg/day after 3 months
and continued until disease progression
· Results: At 18 months patients were in remission an average of 42
months with lenalidomide versus placebo (22 months)
47
Attal et al,Abst #310 2010
Subcutaneous (SC) versus Intravenous Administration of
Bortezomib In Patients with Relapsed MM
· Patients with MM may have trouble with IVs
· 222 patients from 53 centers in 10 countries
participated in this study and randomized to SC (148)
or IV (74).
· The data highlight the efficacy of bortezomib
irrespective of its route of administration
· Remission 10.2 mos SC vs 8.0 mos IV arm
· 1yr OS 72.6% in the SC group and 76.7% IV.
· Less toxicity with SC
· Less peripheral neuropathy (PN) (38% SC vs. 53% IV),
· Less grade 3 and higher PN (6% SC vs. 16% IV), and
· Less gastrointestinal disorders (37% SC vs. 58%IV)
Moreau et al., 2010
Carfilzomib (CFZ) In Patients (pts) with Relapsed and Refractory
MM
· 266 pts were enrolled with MM for average 5.4 years
· 83% had progressed on or within 60 d of last therapy
and/or <25 % response to the regimen immediately before
study entry.
· Of these heavily pre-treated patients 24% went into
remission with a median duration of response 7.4 months
Incidence of PN <1%, side effects mostly hematologic
· Carfilzomib represents another promising agent with few
side effects
Siegel et al, 985, 2010
Pomalidomide (CC4047) Plus Low-Dose Dexamethasone as
Therapy for Relapsed Multiple Myeloma. IFM 2009-02
Results:
83
Arm A: Pomalidomide 4mg d 1-21
Patients
of 28d and
·Median DOR was 77 and
89 days in arm A & B
Dexamethasone 40 mg days 1, 8, 15
and 22
·57% and 61% patients
Randomized
remained progression free
·Myelosuppression most
Arm B: Pomalidomide 4mg d 1-28
common toxicity
of 28d and
·PN was not seen
Dexamethasone 40 mg days 1, 8, 15
and 22
·Pomalidomide is a
promising agent for patients
with RRMM
All patients received VTE prophyllaxis
Leleu et al., Abstract 859, 2010
Elotuzumab
· Elotuzumab In Combination with Lenalidomide and
Dexamethasone In Patients with RRMM: Interim Results of a
Phase 2 Study
Generally well tolerated with 84% response
· Elotuzumab In Combination with Bortezomib In Patients with
RRMM: Phase I
Generally well tolerated with 48% response
Richardson et al, Abstract 986, 2010
Jakubowiak et al., Abstract #3023, 2010
Summary
· Multiple myeloma is a very complex diagnosis
· Nurses are in the unique position to manage side
effects and encourage adherence to the selected
regimen
· Although incurable the overall survival has improved
dramatically in the last decade as a result of newer
agents, better supportive therapy
· NO gold standard treatment for MM exists but
clinical trials yield exciting results
· Emerging therapies will hopefully provide additional
options for our patients
Let me hear from you
Questions & Comments
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